Datasets:

vgoldberg

/

longform_article_summarization

like 9

we used data of a cohort of patients with incident lea , for which analyses on incidence have been published elsewhere ( 3 ) . in brief , these patients were derived from the gmnder ersatzkasse ( gek ) , a statutory health insurance company that insured 1.6 million people located in all regions of germany ( 1.9% of the german population ) . we included all people who were members of the gek for at least 1 year within the period 1 january 2004 to 31 december 2007 . diabetic patients were defined according to an established procedure ( 12 ) as subjects with at least one of the following characteristics : 1 ) diabetes diagnosis ( icd e10-e14 ) in at least three of four consecutive quarters , 2 ) at least two prescriptions of antidiabetic medication ( atc code a10 ) within 12 months , or 3 ) at least one prescription of an antidiabetic medication and one diabetes diagnosis or one measurement of blood glucose or hba1c within 12 months . we assessed all incident leas between 2005 and 2007 in patients with an amputation - free period of at least 1 year . lower limb amputations were classified according to a previous study ( 3 ) using specific operation procedure codes ( ops codes 5864. , 5865. , and 5869.0 ) of the hospital discharge documentation . the current study was restricted to major amputations ( any resection proximal to the midtarsal level , according to the 2007 international consensus of the diabetic foot ) . patients with minor amputations were further followed up until 31 december 2009 and were included if a major amputation occurred . a total of 454 patients with an incident major lea were studied , of whom 418 had their event between 2005 and 2007 . we further excluded all people coinsured as a dependent and members who left the gek for reasons other than death within the study period ( n = 10 ) . both criteria were applied to avoid informative censoring in the survival analysis ( e.g. , an insurance period ends because of death but this reason might not be documented in these cases ) . our final cohort , therefore , comprised 444 patients with a first major lea between 2005 and follow up to 2009 . treatment with cardiovascular drugs ( -blockers , ace inhibitors , sartans , statins , ezetimibe , fibrates , and clopidogrel ) and antidiabetic drugs ( insulin , oral antidiabetic agents ) was assessed . because it has been shown that the number of distinct medications prescribed in the previous year is a good predictor of mortality ( 14 ) furthermore , we assessed the following outpatient diagnoses : 1 ) hypertension ( icd-10 : i10-i15 ) , 2 ) chronic ischemic heart diseases ( icd-10 : i20-i21 , i25 ) , 3 ) cerebral ischemia / chronic stroke ( icd-10 : g45 , i60-i64 , i69 ) , and 4 ) renal failure ( icd-10 : n18-n19 ) coded according to a previous study using german claims data ( see supplementary ref . 5 ) . at least one of these diagnoses had to be recorded in a 1-year period ( including the quarter of the index date and the preceding three quarters ) . quarters had to be chosen because this is the basic time period for coding diagnoses in outpatient care in germany . target variable was the time from the first major lea up to death or the end of the study period ( 31 december 2009 ) , whichever came first . crude differences between diabetic and nondiabetic individuals were planned to be statistically compared using the log - rank test , if the proportional hazard assumption was not violated . but because survival curves of the diabetic and the nondiabetic group were crossing , proportional hazards could not be assumed , which was statistically tested using the test proposed by grambsch and therneau ( 15 ) . we then performed cox regression using discrete time intervals to model the time dependency of diabetes ( 16 ) and to evaluate predictors of death in multivariate analyses . as predictors , we included diabetes , interaction of diabetes with the discrete time intervals ( 30 and 60 days , 6 , 12 , 24 , 36 , and 60 months ) , and age ( as continuous variable ) . in a second model , the location of the amputation ( below or above knee ) and the number of prescribed medications , which were categorized into quartiles , were added as further independent variables . in a sensitivity analysis , we also included the above given outpatient diagnoses for hypertension , chronic ischemic heart diseases , cerebral ischemia / chronic stroke , and renal failure . all analyses were performed using r ( a language and environment for statistical computing , release 2.10.1 ; r foundation for statistical computing , http://www.r-project.org ) , and the results of the cox models were verified using the statistical analysis systems sas ( sas for windows xp professional , release 9.2 ts2m0 ; sas institute , cary , nc ) . we used data of a cohort of patients with incident lea , for which analyses on incidence have been published elsewhere ( 3 ) . in brief , these patients were derived from the gmnder ersatzkasse ( gek ) , a statutory health insurance company that insured 1.6 million people located in all regions of germany ( 1.9% of the german population ) . we included all people who were members of the gek for at least 1 year within the period 1 january 2004 to 31 december 2007 . diabetic patients were defined according to an established procedure ( 12 ) as subjects with at least one of the following characteristics : 1 ) diabetes diagnosis ( icd e10-e14 ) in at least three of four consecutive quarters , 2 ) at least two prescriptions of antidiabetic medication ( atc code a10 ) within 12 months , or 3 ) at least one prescription of an antidiabetic medication and one diabetes diagnosis or one measurement of blood glucose or hba1c within 12 months . we assessed all incident leas between 2005 and 2007 in patients with an amputation - free period of at least 1 year . lower limb amputations were classified according to a previous study ( 3 ) using specific operation procedure codes ( ops codes 5864. , 5865. , and 5869.0 ) of the hospital discharge documentation . the current study was restricted to major amputations ( any resection proximal to the midtarsal level , according to the 2007 international consensus of the diabetic foot ) . patients with minor amputations were further followed up until 31 december 2009 and were included if a major amputation occurred . a total of 454 patients with an incident major lea were studied , of whom 418 had their event between 2005 and 2007 . we further excluded all people coinsured as a dependent and members who left the gek for reasons other than death within the study period ( n = 10 ) . both criteria were applied to avoid informative censoring in the survival analysis ( e.g. , an insurance period ends because of death but this reason might not be documented in these cases ) . our final cohort , therefore , comprised 444 patients with a first major lea between 2005 and follow up to 2009 . treatment with cardiovascular drugs ( -blockers , ace inhibitors , sartans , statins , ezetimibe , fibrates , and clopidogrel ) and antidiabetic drugs ( insulin , oral antidiabetic agents ) was assessed . because it has been shown that the number of distinct medications prescribed in the previous year is a good predictor of mortality ( 14 ) furthermore , we assessed the following outpatient diagnoses : 1 ) hypertension ( icd-10 : i10-i15 ) , 2 ) chronic ischemic heart diseases ( icd-10 : i20-i21 , i25 ) , 3 ) cerebral ischemia / chronic stroke ( icd-10 : g45 , i60-i64 , i69 ) , and 4 ) renal failure ( icd-10 : n18-n19 ) coded according to a previous study using german claims data ( see supplementary ref . 5 ) . at least one of these diagnoses had to be recorded in a 1-year period ( including the quarter of the index date and the preceding three quarters ) . quarters had to be chosen because this is the basic time period for coding diagnoses in outpatient care in germany . target variable was the time from the first major lea up to death or the end of the study period ( 31 december 2009 ) , whichever came first . crude differences between diabetic and nondiabetic individuals were planned to be statistically compared using the log - rank test , if the proportional hazard assumption was not violated . but because survival curves of the diabetic and the nondiabetic group were crossing , proportional hazards could not be assumed , which was statistically tested using the test proposed by grambsch and therneau ( 15 ) . we then performed cox regression using discrete time intervals to model the time dependency of diabetes ( 16 ) and to evaluate predictors of death in multivariate analyses . as predictors , we included diabetes , interaction of diabetes with the discrete time intervals ( 30 and 60 days , 6 , 12 , 24 , 36 , and 60 months ) , and age ( as continuous variable ) . in a second model , the location of the amputation ( below or above knee ) and the number of prescribed medications , which were categorized into quartiles , were added as further independent variables . in a sensitivity analysis , we also included the above given outpatient diagnoses for hypertension , chronic ischemic heart diseases , cerebral ischemia / chronic stroke , and renal failure . all analyses were performed using r ( a language and environment for statistical computing , release 2.10.1 ; r foundation for statistical computing , http://www.r-project.org ) , and the results of the cox models were verified using the statistical analysis systems sas ( sas for windows xp professional , release 9.2 ts2m0 ; sas institute , cary , nc ) . thus we report the results for the whole population . of the 444 individuals with incident major amputation between 2005 and up to 2009 , 319 ( 71.8% ) were male , and mean age ( sd ) was 69.1 ( 11.7 ) years . of the individuals , 259 ( 58.3% ) of them had diabetes and 192 ( 43.2% ) of the leas were above the knee . diabetic patients were slightly older , more likely to be male , and had more prescribed medications compared with nondiabetic individuals . the proportion of amputations above the knee was lower in diabetic than in nondiabetic patients . diabetic patients were more likely to have a diagnosis of hypertension , chronic ischemic heart diseases , cerebral ischemia / chronic stroke , or renal failure . table 1 shows the description of the subjects with incident major amputation , stratified for diabetes . description of the study population : patients with first lea during 2005 to 2009 ( gek insurants , germany ) age at time of first major lea ; substances , in the year before first major lea ; -blockers , ace inhibitors , sartans , statins , ezetimibe , fibrates , and clopidogrel ; in the quarter of the first major lea and in the preceding 3 quarters ( e.g. , 1 year ) . overall , 245 individuals died within the study period of up to 5 years , 146 and 99 with and without diabetes , respectively . the mean observation time per patient ( sd ) was 1.9 ( 1.6 ) years . survival after first major lea ( gek insurants , germany , 20052009 ) figure 1 shows the kaplan - meier curves crossing each other after about 2 years in the whole population ( number of survivors under the curves in table 2 ) . the assumption of proportional hazards seemed to be violated : there was a significant time dependency of diabetes ( p = 0.003 ) . this means corresponding to the figure that the relative mortality risk as a result of diabetes was time dependent : in the first time after lea , diabetic individuals had better survival . but in the time course the diabetes risk increased yielding crossed survival curves after about 2 to 3 years . the relative mortality risk for diabetes , adjusted for sex and age , was as follows : baseline 030 days : 0.50 [ 95% ci 0.310.84 ] ; 3160 days : 0.60 [ 0.251.41 ] ; 61 days to 6 months : 0.75 [ 0.381.48 ] ; > 6 to 12 months : 1.27 [ 0.632.53 ] ; > 12 to 24 months : 1.65 [ 0.883.08 ] ; > 24 to 36 months : 2.02 [ 0.805.09 ] ; and > 36 to 60 months : 1.91 [ 0.705.21 ] . cumulative mortality after 1 month , 1 year , and 5 years , as derived from the kaplan - meier estimates , was 10 , 31 , and 68% in diabetic and 19 , 40 , and 59% in nondiabetic individuals , respectively . crude survival curves after first major lea ( gek insurants , germany , 20052009 ) . model 2 in table 3 shows the results when the lea location and the number of prescribed medications are included as further predictors . amputation above the knee ( 1.50 ; 1.161.94 ) , and quartile category 3 or 4 of number of prescribed medications ( 1.64 ; 1.122.40 and 1.76 ; 1.202.59 ) were both significantly associated with mortality . predictors for mortality after first major lea , cox regression ( gek insurants , germany , 20052009 ) the inclusion of hypertension , chronic ischemic heart diseases , cerebral ischemia / chronic stroke , and renal failure in a sensitivity analysis did not alter our findings ( data not shown ) . of the 444 individuals with incident major amputation between 2005 and up to 2009 , 319 ( 71.8% ) were male , and mean age ( sd ) was 69.1 ( 11.7 ) years . of the individuals , 259 ( 58.3% ) of them had diabetes and 192 ( 43.2% ) of the leas were above the knee . diabetic patients were slightly older , more likely to be male , and had more prescribed medications compared with nondiabetic individuals . the proportion of amputations above the knee was lower in diabetic than in nondiabetic patients . diabetic patients were more likely to have a diagnosis of hypertension , chronic ischemic heart diseases , cerebral ischemia / chronic stroke , or renal failure . table 1 shows the description of the subjects with incident major amputation , stratified for diabetes . description of the study population : patients with first lea during 2005 to 2009 ( gek insurants , germany ) age at time of first major lea ; substances , in the year before first major lea ; -blockers , ace inhibitors , sartans , statins , ezetimibe , fibrates , and clopidogrel ; in the quarter of the first major lea and in the preceding 3 quarters ( e.g. , 1 year ) . overall , 245 individuals died within the study period of up to 5 years , 146 and 99 with and without diabetes , respectively . the mean observation time per patient ( sd ) was 1.9 ( 1.6 ) years . survival after first major lea ( gek insurants , germany , 20052009 ) figure 1 shows the kaplan - meier curves crossing each other after about 2 years in the whole population ( number of survivors under the curves in table 2 ) . the assumption of proportional hazards seemed to be violated : there was a significant time dependency of diabetes ( p = 0.003 ) . this means corresponding to the figure that the relative mortality risk as a result of diabetes was time dependent : in the first time after lea , diabetic individuals had better survival . but in the time course the diabetes risk increased yielding crossed survival curves after about 2 to 3 years . the relative mortality risk for diabetes , adjusted for sex and age , was as follows : baseline 030 days : 0.50 [ 95% ci 0.310.84 ] ; 3160 days : 0.60 [ 0.251.41 ] ; 61 days to 6 months : 0.75 [ 0.381.48 ] ; > 6 to 12 months : 1.27 [ 0.632.53 ] ; > 12 to 24 months : 1.65 [ 0.883.08 ] ; > 24 to 36 months : 2.02 [ 0.805.09 ] ; and > 36 to 60 months : 1.91 [ 0.705.21 ] . cumulative mortality after 1 month , 1 year , and 5 years , as derived from the kaplan - meier estimates , was 10 , 31 , and 68% in diabetic and 19 , 40 , and 59% in nondiabetic individuals , respectively . crude survival curves after first major lea ( gek insurants , germany , 20052009 ) . model 2 in table 3 shows the results when the lea location and the number of prescribed medications are included as further predictors . amputation above the knee ( 1.50 ; 1.161.94 ) , and quartile category 3 or 4 of number of prescribed medications ( 1.64 ; 1.122.40 and 1.76 ; 1.202.59 ) were both significantly associated with mortality . predictors for mortality after first major lea , cox regression ( gek insurants , germany , 20052009 ) the inclusion of hypertension , chronic ischemic heart diseases , cerebral ischemia / chronic stroke , and renal failure in a sensitivity analysis did not alter our findings ( data not shown ) . in this population - based study we could analyze survival in patients with incident major amputation in germany up to 5 years ( 20052009 ) , with a focus on diabetes as a predictor . after 3 years follow - up , more than 50% of the patients in our cohort had died . interestingly , the influence of diabetes in our study was significantly time dependent : in the first time after incident lea , mortality was lower in diabetic than in nondiabetic individuals . there was an increasing trend of diabetes risk during observation time , and after about 2 to 3 years , diabetic individuals had a higher mortality than nondiabetic individuals . the number of prescribed medications , included as a proxy for comorbidity , and the amputation level were significantly associated with mortality ; however , they did not alter these estimates . looking for an explanation of our finding , one could argue that diabetic individuals have more comorbidities , as indicated by medications and outpatient diagnoses , but are , however , more closely monitored by several specialists because of their chronic disease , and if problems arise they are identified and treated early . in germany , nationwide disease management programs for diabetes have been implemented since 2003 . these programs defined contents and time frames for the treatment of diabetes and its complications , and they provided interfaces among the different levels of care . diabetic individuals were more likely to have an amputation below the knee eventually because of the more distally pronounced distribution pattern of peripheral arterial disease compared with nondiabetic patients ( 17,18 ) . in previously published series , patients with below - knee amputation had been reported to have significantly better survival outcomes than above - knee amputees ( 7,19,20 ) . when we stratified our analyses for amputation level , the time dependency of diabetes seemed to be only present for below - knee amputations , not for amputations above the knee ( data not shown ) . further analyses are warranted . in the above - mentioned disease management programs , networks of specialized physicians have been introduced in various german regions and are thought to be responsible for a recently observed decline in major amputation rates as well as reductions of the excess amputation risk because of diabetes in german diabetic populations ( 3,21 ) . one might argue that even those diabetic patients in whom major amputation can not be avoided might profit from improved treatment structures by achieving more distal major amputation levels , tighter glycemic control , and more aggressive cardiovascular risk management . such a concept has been proven to be effective by improving 5-year survival rates in diabetic foot ulcer patients recently ( 22 ) . in this context the observed larger number of prescribed medications in diabetic patients also might be a hint for more aggressive management of cardiovascular risk factors , not only a marker of comorbidity . other factors may play a role , like a lower proportion of smokers among diabetic individuals undergoing amputation compared with their nondiabetic counterparts ( see supplementary ref . in our data we have no information about detailed clinical or lifestyle variables , e.g. , smoking habits or glycemic control , and only limited information about history of coronary or cerebrovascular events , chronic heart failure , and renal function . the 1-year mortality of diabetic patients in our study ( 31% ) was comparable with the numbers from other studies ( 3134% ) ( 7,11,23 ) . the 5-year mortality in diabetic patients in our cohort showed conformity with those from the study of aulivola et al . ( 7 ) ( 68 and 69% , respectively ) but was lower than reported from other cohorts investigated in the 1990s reporting 8090% mortality after 5 years ( 5,10 ) . mortality reported from nondiabetic patients in other studies showed much more variability , probably because of more heterogenous patient cohorts ( 1-year : 2943% , 5-years : 4977% ) ( 5,7,8,10,11,23 ) . diabetes has been considered to be associated with an excess mortality in patients after lea , in particular in the perioperative period and during the first year ( 5,6 ) . some studies found contrasting results , with similar mortality in diabetic compared with nondiabetic patients ( 711,23 ; and supplementary refs . however , several studies were not population based but used data from specialized diabetes centers . an improved survival of diabetic patients 1 and 2 years after major amputation compared with nondiabetic patients and a loss of this difference during longer follow - up periods has been described also by pohjolainen and alaranta ( 10 ) . a few other studies found similar early death rates ( up to 3 years ) for diabetic and nondiabetic patients following major amputation with worsening of the prognosis for diabetic patients during further observation ( up to 10 years ) ( 79 ) . most other studies did not evaluate an interaction between diabetes and time ( 5,6,9,23 ) . thus study results remain conflicting , and further studies are warranted to confirm and explain our findings . first , in particular in the last years of observation , the case numbers are low , leading to a lack of power to detect statistically significant differences between patients with and without diabetes . second , we have only limited information about clinical variables and do not know patients lifestyles . however , we included the number of prescribed drugs as well as outpatient diagnoses of relevant comorbidities . we also had no information about the reason of amputation and thus could not exclude traumatic amputations . however , the proportion of amputations as a result of trauma can be considered to be low ( see supplementary ref . finally , the insurants of the gek are not representative for the german population with respect to age , sex , and socioeconomic position ( 24 ) , which might have an impact on morbidity and on the utilization of health care resources . however , the incidence of lea in our population was well in line with the incidence of lea in a study based on hospital records in a german region as was the proportion of patients with diabetes ( 21 ) . the main strength of our study is that we were able to analyze a large population - based dataset without selection with respect to diabetes complications and that diabetes status could directly be assessed at study entry . in conclusion , in our german population - based study , we found a high mortality in patients with a first major amputation . interestingly , the influence of diabetes was time dependent : in the first ~2 to 3 years after first lea , mortality was lower in diabetic than in nondiabetic individuals . only thereafter , diabetic patients had a higher mortality than nondiabetic patients . possible explanations may be differences in comorbidities , the access to specific treatment structures for diabetic patients , or smoking habits , as indicated by a higher proportion of above - knee amputations in nondiabetic patients . however , results remain conflicting , and further studies are warranted to confirm and explain the results . in this population - based study we could analyze survival in patients with incident major amputation in germany up to 5 years ( 20052009 ) , with a focus on diabetes as a predictor . after 3 years follow - up , more than 50% of the patients in our cohort had died . interestingly , the influence of diabetes in our study was significantly time dependent : in the first time after incident lea , mortality was lower in diabetic than in nondiabetic individuals . there was an increasing trend of diabetes risk during observation time , and after about 2 to 3 years , diabetic individuals had a higher mortality than nondiabetic individuals . the number of prescribed medications , included as a proxy for comorbidity , and the amputation level were significantly associated with mortality ; however , they did not alter these estimates . looking for an explanation of our finding , one could argue that diabetic individuals have more comorbidities , as indicated by medications and outpatient diagnoses , but are , however , more closely monitored by several specialists because of their chronic disease , and if problems arise they are identified and treated early . in germany , nationwide disease management programs for diabetes have been implemented since 2003 . these programs defined contents and time frames for the treatment of diabetes and its complications , and they provided interfaces among the different levels of care . diabetic individuals were more likely to have an amputation below the knee eventually because of the more distally pronounced distribution pattern of peripheral arterial disease compared with nondiabetic patients ( 17,18 ) . in previously published series , patients with below - knee amputation had been reported to have significantly better survival outcomes than above - knee amputees ( 7,19,20 ) . when we stratified our analyses for amputation level , the time dependency of diabetes seemed to be only present for below - knee amputations , not for amputations above the knee ( data not shown ) . further analyses are warranted . in the above - mentioned disease management programs , networks of specialized physicians have been introduced in various german regions and are thought to be responsible for a recently observed decline in major amputation rates as well as reductions of the excess amputation risk because of diabetes in german diabetic populations ( 3,21 ) . one might argue that even those diabetic patients in whom major amputation can not be avoided might profit from improved treatment structures by achieving more distal major amputation levels , tighter glycemic control , and more aggressive cardiovascular risk management . such a concept has been proven to be effective by improving 5-year survival rates in diabetic foot ulcer patients recently ( 22 ) . in this context the observed larger number of prescribed medications in diabetic patients also might be a hint for more aggressive management of cardiovascular risk factors , not only a marker of comorbidity . other factors may play a role , like a lower proportion of smokers among diabetic individuals undergoing amputation compared with their nondiabetic counterparts ( see supplementary ref . in our data we have no information about detailed clinical or lifestyle variables , e.g. , smoking habits or glycemic control , and only limited information about history of coronary or cerebrovascular events , chronic heart failure , and renal function . the 1-year mortality of diabetic patients in our study ( 31% ) was comparable with the numbers from other studies ( 3134% ) ( 7,11,23 ) . the 5-year mortality in diabetic patients in our cohort showed conformity with those from the study of aulivola et al . ( 7 ) ( 68 and 69% , respectively ) but was lower than reported from other cohorts investigated in the 1990s reporting 8090% mortality after 5 years ( 5,10 ) . mortality reported from nondiabetic patients in other studies showed much more variability , probably because of more heterogenous patient cohorts ( 1-year : 2943% , 5-years : 4977% ) ( 5,7,8,10,11,23 ) . diabetes has been considered to be associated with an excess mortality in patients after lea , in particular in the perioperative period and during the first year ( 5,6 ) . some studies found contrasting results , with similar mortality in diabetic compared with nondiabetic patients ( 711,23 ; and supplementary refs . however , several studies were not population based but used data from specialized diabetes centers . an improved survival of diabetic patients 1 and 2 years after major amputation compared with nondiabetic patients and a loss of this difference during longer follow - up periods has been described also by pohjolainen and alaranta ( 10 ) . a few other studies found similar early death rates ( up to 3 years ) for diabetic and nondiabetic patients following major amputation with worsening of the prognosis for diabetic patients during further observation ( up to 10 years ) ( 79 ) . most other studies did not evaluate an interaction between diabetes and time ( 5,6,9,23 ) . thus study results remain conflicting , and further studies are warranted to confirm and explain our findings . several limitations have to be considered . first , in particular in the last years of observation , the case numbers are low , leading to a lack of power to detect statistically significant differences between patients with and without diabetes . second , we have only limited information about clinical variables and do not know patients lifestyles . however , we included the number of prescribed drugs as well as outpatient diagnoses of relevant comorbidities . we also had no information about the reason of amputation and thus could not exclude traumatic amputations . however , the proportion of amputations as a result of trauma can be considered to be low ( see supplementary ref . . finally , the insurants of the gek are not representative for the german population with respect to age , sex , and socioeconomic position ( 24 ) , which might have an impact on morbidity and on the utilization of health care resources . however , the incidence of lea in our population was well in line with the incidence of lea in a study based on hospital records in a german region as was the proportion of patients with diabetes ( 21 ) . the main strength of our study is that we were able to analyze a large population - based dataset without selection with respect to diabetes complications and that diabetes status could directly be assessed at study entry . in conclusion , in our german population - based study , we found a high mortality in patients with a first major amputation . interestingly , the influence of diabetes was time dependent : in the first ~2 to 3 years after first lea , mortality was lower in diabetic than in nondiabetic individuals . only thereafter , diabetic patients had a higher mortality than nondiabetic patients . possible explanations may be differences in comorbidities , the access to specific treatment structures for diabetic patients , or smoking habits , as indicated by a higher proportion of above - knee amputations in nondiabetic patients . however , results remain conflicting , and further studies are warranted to confirm and explain the results .

objectiveto estimate the impact of diabetes on mortality in patients after first major lower extremity amputation ( lea).research design and methodsusing claims data of a nationwide statutory health insurance , we assessed all deaths in a cohort of all 444 patients with a first major lea since 2005 ( 71.8% male ; mean age 69.1 years ; 58.3% diabetic ; 43% with amputation above the knee ) up to 2009 . using cox regression , we estimated the time - dependent hazard ratios to compare patients with and without diabetes.resultsthe cumulative 5-year mortality was 68% in diabetic and 59% in nondiabetic individuals . in the first course , mortality was lower in diabetic compared with nondiabetic patients . later , the diabetes risk increased yielding crossed survival curves after 2 to 3 years ( time dependency of diabetes ; p = 0.003 ) . age- and sex - adjusted hazard ratios for diabetes were as follows : 030 days : 0.50 [ 95% ci 0.310.84 ] ; 3160 days : 0.60 [ 0.251.41 ] ; 61 days to 6 months : 0.75 [ 0.381.48 ] ; > 612 months : 1.27 [ 0.632.53 ] ; > 1224 months : 1.65 [ 0.883.08 ] ; > 2436 months : 2.02 [ 0.805.09 ] ; and > 3660 months : 1.91 [ 0.705.21 ] . the pattern was similar in both sexes . in the full model , significant risk factors for mortality were age ( 1.05 ; 1.031.06 ) , amputation above the knee ( 1.50 ; 1.161.94 ) , and quartile category 3 or 4 of the number of prescribed medications ( 1.64 ; 1.122.40 and 1.76 ; 1.202.59 ) . further adjustment for comorbidity did not alter the results.conclusionsin this population - based study , we found a time - dependent mortality risk of diabetes following first major lea , which may be in part a result of a healthier lifestyle in diabetic patients or the access to specific treatment structures in diabetic individuals .

a significant part of our understanding of nonperturbative phenomena in qcd , such as chiral symmetry breaking , confinement or the existence of nuclei , results from simulations of the qcd partition function on a euclidean space - time lattice ( see @xcite for reviews ) . in spite of its numerous successes , this approach has several disadvantages . one of them is the use of euclidean space - time which requires a highly nontrivial analytical continuation to minkowski space - time . one of the promising approaches that works directly in a hamiltonian framework is discrete light - cone qcd @xcite , but its results for 4-dimensional nonabelian gauge theories can not yet compete with lattice qcd . a second disadvantage of lattice qcd is that analytical understanding of most lattice data seems beyond reach . therefore , it is imperative to provide an analytical explanation of lattice observables whenever possible . one such observable is the euclidean dirac spectrum . we have proved @xcite our conjecture @xcite that the fluctuations of the smallest dirac eigenvalues are given by a chiral random matrix theory ( chrmt ) with the global symmetries of the qcd partition function . in this lecture we give a review of recent lattice simulations that support this assertion . a recent comprehensive review of chiral random in qcd was given in @xcite . of course , chrmt can not provide us with a @xmath0 description of the qcd dirac spectrum . what is the domain of validity of chrmt ? to answer this question we need to identify three different scales in the dirac spectrum . the first scale is the smallest nonzero eigenvalue , @xmath1 . its average position is given by the mean level spacing , @xmath2 , which is the inverse of the average spectral density near zero , @xmath3 , _ min = 1(0 ) = . because of the axial symmetry the nonzero eigenvalues of the euclidean dirac operator @xmath4 appear in pairs @xmath5 . the average spectral density is then defined by @xmath6 , and @xmath7 ( with @xmath8 the volume of space - time ) is identified as the chiral condensate , @xmath9 , through the banks - casher formula @xcite . a second scale in the dirac spectrum is the mass scale for which the compton wavelength of the corresponding goldstone boson is equal to the size of the box . this scale , also known as the thouless energy , is given by @xcite m_c = , [ thouless ] where @xmath10 is the linear size of the box . a third scale is the typical hadronic mass scale given by @xmath11 . because qcd has a mass gap , for volumes with @xmath12 , the qcd partition function in the phase of spontaneous broken chiral symmetry , reduces to that of a gas of goldstone bosons . for momenta and masses well below @xmath11 , this effective chiral partition function can be written down solely on the basis of the global symmetries of qcd . a further simplification arises for @xmath13 . in this domain the fluctuations of the constant fields are much larger than the fluctuations of the nonzero momentum modes and kinetic term of the chiral lagrangian can be ignored in the calculation of the mass dependence of the partition function @xcite . this is the domain of validity chiral random matrix theory . a formal proof of this statement @xcite requires the introduction of additional ghost quarks with spectral mass @xmath14 equal to the argument of the resolvent of the dirac operator . because @xmath14 is a free parameter , it can always be chosen such that @xmath15 , and the dirac spectrum in this domain is thus given by chiral random matrix theory . the chiral random matrix partition function with the global symmetries of the qcd partition function is defined by @xcite z^_(m ) = dw _ f= 1^n_f e^-4 w^w , [ ranpart ] where @xmath16 is a @xmath17 matrix with @xmath18 and @xmath19 . as is the case in qcd , we assume that the equivalent of the topological charge @xmath20 does not exceed @xmath21 , so that , to a good approximation , @xmath22 . then the parameter @xmath9 can be identified as the chiral condensate and @xmath23 as the dimensionless volume of space time ( our units are defined such that the density of the modes @xmath24 ) . the chiral ensembles are classified according to the dyson index @xmath25 . the matrix elements of @xmath16 are either real ( @xmath26 , chiral gaussian orthogonal ensemble ( chgoe ) ) , complex ( @xmath27 , chiral gaussian unitary ensemble ( chgue ) ) , or quaternion real ( @xmath28 , chiral gaussian symplectic ensemble ( chgse ) ) . for qcd with three or more colors and quarks in the fundamental representation the matrix elements of the dirac operator are complex and we have @xmath27 . the ensembles with @xmath29 and @xmath30 are relevant in the case of two colors or adjoint fermions . for staggered fermions , the value of the dyson index in these two cases is reversed . the reason for choosing a gaussian distribution of the matrix elements is its mathematically simplicity . it can be shown that the correlations of the eigenvalues on the scale of the average level spacing do not depend on the details of the probability distribution @xcite . we start this section by stressing that only spectral properties on the scale of the average level spacing can be described by random matrix theory . we thus unfold the spectrum by rescaling the eigenvalues according to the macroscopic average level spacing obtained by averaging over many consecutive levels inside a small but finite interval . below we always discuss the statistical properties of the unfolded eigenvalues , with average spectral density equal to unity . they have been analyzed in several different ways . first , by means of the microscopic spectral density defined by @xcite _ s(u ) = _ v 1v ( uv ) . [ rhosu ] for @xmath31 it is given by @xcite _ s(z ) = . [ micro2 ] the result for @xmath32 @xcite and @xmath30 @xcite is more complicated but can be expressed as an integral over bessel functions . the microscopic spectral density was first observed for dirac spectra of instanton liquid field configurations @xcite both for @xmath33 and @xmath34 . its first lattice studies , for quenched @xmath35 gauge theory with staggered fermions ( with dyson index @xmath32 ) , were performed in @xcite ( see fig . [ figmicro ] ) . the agreement between lattice qcd at random matrix theory is equally good for @xmath36 @xcite ( with dyson index @xmath37 ) , for qcd with adjoint fermions @xcite , which is in the class @xmath32 , and for strong coupling @xmath38 gauge theory @xcite ( also with dyson index @xmath37 ) . although most results have been obtained in the quenched limit , the agreement with chrmt for dynamical quark masses of order @xmath39 @xcite or massless quarks in the schwinger model @xcite is equally impressive . in fig . [ gernotfig ] we show the microscopic spectral density for dimensionless dynamical quark mass @xmath40 as given in the legend of the figure . a second way to study the dirac spectrum is by means of the valence quark mass dependence of the chiral condensate defined by ( z ) = 1v 1d+z . its analytical expression can be derived from the low - energy limit of the qcd partition function @xcite as well as from chrmt @xcite . for @xmath31 we find @xcite @xmath41\:,\ ] ] where @xmath42 and @xmath43 . in fig . [ valence ] we compare @xcite the analytical result ( full line ) with lattice data obtained by the columbia group @xcite . the point above which the lattice data depart from the the chrmt result agrees with our estimate of the thouless energy ( [ thouless ] ) . these results have been confirmed by independent simulations @xcite and have been extended to other symmetry classes @xcite . a third way to analyze the statistical properties of the dirac eigenvalues is by means of the distribution of the smallest eigenvalues . as an example , the analytical result for @xmath31 is given by @xcite , @xmath44 . the results for @xmath29 , @xmath30 , and nonzero quark masses , are more complicated @xcite . in fig . [ figmicro ] we show results @xcite for quenched @xmath35 lattice data . results for all three symmetry classes as well as nonzero topological charge @xcite are shown in fig . [ hellerfig ] . the latter results were obtained with the overlap dirac operator . dirac spectra of the schwinger model have also been analyzed at nonzero topological charge @xcite and complete agreement with chrmt was found @xcite . the continuum limit of the staggered dirac operators is approached very slowly , and on today s lattices the dirac spectra are described by analytical results for zero topological charge @xcite . recently , analytical results for the @xmath45th smallest eigenvalue @xcite gave a perfect description of the lattice data @xcite . a more subtle way to study the statistical properties of eigenvalues is by means of the two - point correlation function defined as ( , ) = _ k , l ( - _ k ) ( - _ l ) . the two - point correlation function for the quenched @xmath35 staggered dirac operator was compared with chrmt in @xcite . also for instanton liquid gauge field configuration one finds @xcite agreement with chrmt in its domain of validity . the volume dependence of the thouless energy was investigated both for instanton liquid configurations @xcite and lattice qcd simulations @xcite and good agreement with the theoretical predictions @xcite was found . a related quantity is the disconnected scalar susceptibility defined by @xmath46 lattice results @xcite ( see fig . [ chpt ] ) show a sharp transition point which can be identified as the thouless energy . below this energy the susceptibility follows the chrmt prediction ( dashed curve ) . a complete analytical description up to @xmath11 is obtained from chiral perturbation theory ( full curve ) @xcite which applies in the domain @xmath47 . similar agreement has been found for the scalar susceptibility of the @xmath38 staggered dirac operator @xcite . dirac spectra at finite temperature and nonzero chemical potential have been studied in much less detail . because of finite size effects comparisons with chrmt are difficult at the critical temperature . dirac spectra near @xmath48 were analyzed in detail in @xcite . because the chiral phase transition in chrmt has mean field critical exponents @xcite there is no reason to believe that the eigenvalue fluctuations follow the random matrix predictions @xcite at the critical point . however , beyond @xmath48 there is some evidence that the smallest eigenvalues show a fluctuation behavior as predicted by rmt @xcite . at nonzero chemical potential the dirac operator is nonhermitian and its eigenvalues are scattered in the complex plane . recent work @xcite shows that the global spectral properties are described by a chiral lagrangian @xcite or random matrix theory @xcite . the statistical analysis of the eigenvalue fluctuations is much more complicated in this case , but the first lattice results @xcite seem to confirm the theoretical expectations @xcite . up to now we only discussed the statistical properties of the dirac eigenvalues near @xmath49 . although physically less relevant , one can also analyze the statistics of the eigenvalues in the bulk of the spectrum . assuming that the statistical properties do not change along the spectrum we can average in two different ways : by averaging over independent gauge field configurations and by averaging over the spectrum . the advantage of spectral averaging is that it requires only one or a few independent gauge field configurations . the equality of the two averages is known as spectral ergodicity and was investigated in the context of qcd dirac spectra in @xcite . the thouless energy was only found in ensemble averaging . the enhanced eigenvalue fluctuations result from the `` collective '' motion of the eigenvalues in the evolution of the ensemble . in fig . [ bulk ] we show @xcite the spacing distribution @xmath50 of neighboring eigenvalues , the number variance @xmath51 and the @xmath52 statistic . the number variance is defined as the variance of the number of levels in an interval containing @xmath53 eigenvalues on average , and @xmath54 is obtained by integrating @xmath51 over a smoothening kernel . the question has been raised whether eigenvalue correlations in the bulk are different above and below @xmath48 , but no effects have been seen @xcite ( see also fig . [ trans ] ) . a transition toward poisson statistics only takes place at very small values of the coupling constant ( see fig . [ trans ] ) . finally , lattice results for qcd dirac operator in 3 dimensions @xcite have been compared with random matrix theory . in this case one finds agreement with the wigner - dyson ensembles @xcite , but we will not discuss this topic in this review . the generating function of the dirac spectrum is given by the qcd partition function with additional ghost quarks with a mass scale given by the region of the the dirac spectrum we are interested in . at low energies this partition function reduces to a gas of weakly interacting goldstone modes . in the domain where the kinetic term can be neglected it reduces to a chiral random matrix theory with the global symmetries of the qcd partition function . the predictions based on these arguments have been confirmed by numerous lattice qcd simulations . this does not mean that one can refrain from doing lattice simulations . the point is that universal behavior and the phenomenologically relevant nonuniversal properties are found in the same lattice simulations . the real progress is the understanding of the symbiosis of these two features of the strong interactions . 99 c. detar , _ quark - gluon plasma in numerical simulations of qcd _ , in _ quark gluon plasma 2 _ , r. hwa ed . , world scientific 1995 . m. creutz , hep - lat/0007032 . pauli and s. j. brodsky , phys . rev . * d32 * ( 1985 ) 1993 and 2001 . j. osborn , d. toublan and j. verbaarschot , nucl . phys . * b540 * ( 1999 ) 317 . damgaard , j.c . osborn , d. toublan , and j.j.m . verbaarschot , nucl . b 547 ( 1999 ) 305 . e.v . shuryak and j.j.m . verbaarschot , nucl . phys . a 560 ( 1993 ) 306 . verbaarschot , phys . lett . 72 ( 1994 ) 2531 . verbaarschot and t. wettig , ann . nucl . part . ( 2000 ) ( in press ) , hep - ph/0003017 . t. banks and a. casher , nucl . b169 ( 1980 ) 103 . j. gasser and h. leutwyler , phys . lett . 188b ( 1987 ) 477 . h. leutwyler and a.v . smilga , phys . d 46 ( 1992 ) 5607 . j.j.m . verbaarschot , phys . b 368 ( 1996 ) 137 . j.c . osborn and j.j.m . verbaarschot , phys . 81 ( 1998 ) 268 , nucl . b 525 ( 1998 ) 738 . e. brein , s. hikami , and a. zee , nucl . b 464 ( 1996 ) 411 . g. akemann , p.h . damgaard , u. magnea , and s. nishigaki , nucl . b 487 ( 1997 ) 721 . e. kanzieper and v. freilikher , phys . 78 ( 1997 ) 3806 ; phys . e 55 ( 1997 ) 3712 . jackson , m.k . sener , j.j.m . verbaarschot , nucl . b 479 ( 1996 ) 707 . t. guhr and t. wettig , j. math . * 37 * ( 1996 ) 6395 . jackson , m.k . sener and j.j.m . verbaarschot , phys . lett . * b 387 * ( 1996 ) 355 . e. kanzieper and v. freilikher , cond - mat/9809365 . j.j.m . verbaarschot and i. zahed , phys . * 70 * ( 1993 ) 3852 . verbaarschot , nucl . b 427 ( 1994 ) 534 . j.j.m . verbaarschot , nucl . phys . b 426 ( 1994 ) 559 . t. nagao and p.j . forrester , nucl . b 435 ( 1995 ) 401 . m.e . berbenni - bitsch , s. meyer , a. schfer , j.j.m . verbaarschot and t. wettig , phys . 80 ( 1998 ) 1146 . damgaard , u.m . heller , and a. krasnitz , phys . b 445 ( 1999 ) 366 . m. gckeler , h. hehl , p.e.l . rakow , a. schafer and t. wettig , phys . d59 ( 1999 ) 094503 . edwards , u.m . heller , and r. narayanan , phys . d 60 ( 1999 ) 077502 . b.a . berg , h. markum , r. pullirsch and t. wettig , hep - lat/0007009 ; b.a . berg , e. bittner , h. markum , r. pullirsch , m .- lombardo and t. wettig , hep - lat/0007008 . j. jurkiewicz , m.a . nowak , and i. zahed , nucl . b 478 ( 1996 ) 605 ; erratum b 513 ( 1998 ) 759 . berbenni - bitsch , s. meyer , and t. wettig , phys . d 58 ( 1998 ) 071502 . g. akemann and e. kanzieper , phys . rev . * 85 * ( 2000 ) 1174 . t. nagao and s.m . nishigaki , hep - th/0001137 ; hep - th/0003009 . f. farchioni , i. hip , c.b . lang , and m. wohlgenannt , nucl . b 549 ( 1999 ) 364 ; nucl . phys . suppl . 73 ( 1999 ) 939 . f. farchioni , i. hip , and c.b . lang , phys . b 471 ( 1999 ) 58 ; f. farchioni , i. hip and c.b . lang , hep - lat/9907011 ; f. farchioni , hep - lat/9902029 . s. chandrasekharan and n. christ , nucl . suppl . ) 47 ( 1996 ) 527 . damgaard , r.g . edwards , u.m . heller , and r. narayanan , phys . d61 ( 2000 ) 094503 ; p.h . damgaard , nucl . suppl . * 73 * , 602 ( 1999 ) ; p.h . damgaard , r.g . edwards , u.m . heller and r. narayanan , hep - lat/9909009 . p. hernandez , k. jansen and l. lellouch , phys . b469 ( 1999 ) 198 ; hep - lat/9909026 . forrester , nucl . phys . b * 402 * ( 1993 ) 709 . nishigaki , p.h . damgaard , and t. wettig , phys . d 58 ( 1998 ) 087704 . r.g . edwards , u.m . heller , j. kiskis , and r. narayanan , phys . 82 ( 1999 ) 4188 . m. schnabel and t. wettig , phys . d62 ( 2000 ) 034501 . hep - lat/9912057 . damgaard , u.m . heller , r. niclasen , and k. rummukainen , phys . rev . d 61 ( 2000 ) 014501 . damgaard and s.m . nishigaki , hep - th/0006111 . damgaard , u.m . heller , r. niclasen and k. rummukainen , hep - lat/0007041 . z . ma , t. guhr , and t. wettig , eur . j. a 2 ( 1998 ) 87 , 425 . a.m. garcia - garcia and j.j.m . verbaarschot , hep - th/0003159 , nucl . b ( 2000 ) ( in press ) . berbenni - bitsch , m. gockeler , t. guhr , a.d . jackson , j.z . ma , s. meyer , a. schfer , h.a . weidenmller , t. wettig and t. wilke , phys . lett . b438 ( 1998 ) 14 ; m.e . berbenni - bitsch , m. gockeler , s. meyer , a. schafer and t. wettig , nucl . * 73 * ( 1999 ) 605 . berbenni - bitsch , m. gckeler , h. hehl , s. meyer , p.e.l . rakow , a. schfer , and t. wettig , phys . b 466 ( 1999 ) 293 . p.h . damgaard and k. splittorff , phys . rev . * d62 * ( 2000 ) 054509 . d. toublan and j.j.m . verbaarschot , in preparation . f. farchioni , p. de forcrand , i. hip , c.b . lang , and k. splittorff , hep - lat/9912004 . damgaard , u.m . heller , r. niclasen and k. rummukainen , nucl . phys . * b583 * ( 2000 ) 347 . jackson and j.j.m . verbaarschot , phys . * d53 * ( 1996 ) 7223 . t. wettig , a. schafer and h.a . weidenmller , phys . * b367 * ( 1996 ) 28 . g. akemann , p.h . damgaard , u. magnea , and s.m . nishigaki , nucl . b 519 ( 1998 ) 682 . e. brzin and s. hikami , phys . e 57 ( 1998 ) 4140 . janik , m.a . nowak , g. papp , and i. zahed , phys . b 446 ( 1999 ) 9 . s. hands , i. montvay , s. morrison , m. oevers , l. scorzato and j. skullerud , hep - lat/0006018 . r. aloisio , a. galante , v. azcoiti , g. di carlo and a.f . grillo , hep - lat/0007018 . kogut , m.a . stephanov , d. toublan , j.j.m . verbaarschot and a. zhitnitsky , nucl . * b582 * ( 2000 ) 477 . d. toublan and j.j.m . verbaarschot , hep - th/0008086 . m. stephanov , phys . * 76 * ( 1996 ) 4472 . h. markum , r. pullirsch and t. wettig , phys . * 83 * ( 1999 ) 484 . y. fyodorov , b. khoruzhenko and h. sommers , phys . * 79 * ( 1997 ) 557 . y. fyodorov , b. khoruzhenko and h. sommers , phys . lett . * a 226 * ( 1997 ) 46 . yan v. fyodorov , mikhail titov and h .- j . sommers , phys . e. 58 ( 1998 ) 1195 . efetov , phys . 79 ( 1997 ) 491 ; phys . b 56 ( 1997 ) 9630 . a.v . kolesnikov and k.b . efetov , cond - mat/0001263 . halasz and j.j.m . verbaarschot , phys . 74 ( 1995 ) 3920 ; m.a . halasz , t. kalkreuter , and j.j.m . verbaarschot , nucl . b ( proc . suppl . ) 53 ( 1997 ) 266 . r. pullirsch , k. rabitsch , t. wettig , and h. markum , phys . b 427 ( 1998 ) 119 . b.a . berg , h. markum , and r. pullirsch , phys . d 59 ( 1999 ) 097504 . berg , h. markum , r. pullirsch and t. wettig , nucl . * 83 * ( 2000 ) 917 . . damgaard , u.m . heller , a. krasnitz and t. madsen , phys . * b440 * ( 1998 ) 129 .

in this lecture we review recent lattice qcd studies of the statistical properties of the eigenvalues of the qcd dirac operator . we find that the fluctuations of the smallest dirac eigenvalues are described by chiral random matrix theories with the global symmetries of the qcd partition function . deviations from chiral random matrix theory beyond the thouless energy can be understood analytically by means of partially quenched chiral perturbation theory .

the possibility of the states in which the dissipative electric current in a nonequilibrium electron system ( a system in which a majority of electrons have negative effective mass ) flows in the direction opposite to the electric field , i.e. , the usual ( or absolute ) conductivity of the system is negative , was discussed by kroemer in the late 50s @xcite . rather realistic mechanisms of such an absolute negative conductivity ( anc ) in two- and three - dimensional substantially nonequilibrium electron systems ( 2dess and 3dess ) in magnetic field were considered more than three decades ago @xcite . at the same time , the mechanism of anc in a 2des subjected to magnetic field and irradiated with microwaves associated with impurity scattering of 2d electrons accompanied by the absorption of microwave photons was proposed by one of us @xcite . it was shown that the dissipative conductivity is an oscillatory function of the ratio of the microwave frequency @xmath0 to the electron cyclotron frequency @xmath1 . at @xmath0 somewhat exceeding @xmath1 or a multiple of @xmath1 , the photon - assisted impurity scattering of 2d electrons with their transitions between the landau levels ( lls ) results in a contribution to the dissipative current flowing opposite to the electric field . at sufficiently strong microwave radiation , this scattering mechanism can dominate leading to anc when @xmath2 , where @xmath3 the transformation of the dissipative current vs electric field characteristic is schematically shown in fig.1 . without ( @xmath4 ) and with ( @xmath5 ) microwave irradiation.,width=264 ] and @xmath6 and ( b ) photon - assisted acoustic phonon scattering mechanisms ( only transitions for @xmath7 are shown).,width=302 ] the effect of vanishing electrical resistance ( in the hall bar configuration ) and of vanishing electrical conductance ( in the corbino configuration ) in a 2des in magnetic field irradiated with microwaves has recently been observed by mani _ et al . _ @xcite , zudov _ et al . _ @xcite , and yang _ et al . _ according to anderson and brinkman @xcite , andreev _ et al . _ @xcite , and volkov and co - workers @xcite suggested that this effect , i.e. , the appearance of zr - states ( and zc - states ) , is attributed to anc associated with photon - assisted impurity scattering of 2d electrons ( put forward in @xcite ) and an instability of homogeneous states in a conductive media with anc . the latter was noted by zakharov @xcite and discussed in early papers on anc in 2dess ( see , for example , @xcite ) . the structure of the electric - field distributions corresponding to zr- and zc - states arisen as a result of the instability is determined by the shape of the current - voltage characteristic ( in particular , by the value of @xmath8 ) and the features of the diffusion processes . recent experimental findings @xcite have stimulated a surge of experimental ( for example , @xcite ) and theoretical papers ( for example , @xcite ) . preliminary brief overviews can be found in @xcite . in particular , the results of early theoretical studies of anc caused by photon - assisted impurity scattering were generalized by the inclusions of the ll broadening and high microwave power effects @xcite . a quasi - classical model which is valid at large filling factors and sufficiently strong electric field ( or when a long - range disorder determines the dissipative current ) was developed by vavilov and aleiner @xcite . possible role of photon - assisted acoustic phonon scattering was discussed in @xcite . a theoretical model for zr- and zc - states should explain at least the following details observed experimentally : ( a ) the phase of the magnetic - field dependence of the resistance ( dissipative conductivity ) , i.e. , the positions of maxima and minima , ( b ) very slow dependence of the magnitude of the dissipative conductivity maxima and minima on the microwave power ( tending to saturation in the range of elevated powers ) , ( c ) steep decrease in the maxima and minima magnitude resulting in vanishing of anc and , hence , in vanishing zr- and zc - states with increasing temperature , and ( d ) relatively small magnitude of the minima and maxima in 2dess with moderate electron mobility that makes impossible the attainment of anc and its consequences . in this letter , we discuss a scenario for the appearance of zero - resistance ( zr ) as well as zero - conductance ( zc ) states in 2dess invoking the concept of anc associated with photon - assisted impurity scattering complicated by electron - electron interaction and photon - assisted acoustic phonon scattering . the proposed scenario provides plausible explanations of main experimental facts . the effect of anc in a 2des system in magnetic field under microwave irradiation is associated with the following @xcite . the dissipative electron transport in the direction parallel to the electric field and perpendicular to the magnetic field is due to hops of the electron larmor orbit centers caused by scattering processes . these hops result in a change in the electron potential energy @xmath9 . here @xmath10 is the dc electric force acting on an electron which is determined by the net in - plane dc electric field including both the applied and the hall components , and @xmath11 is the displacement of the electron orbit center . if the electron orbit center displaces in the direction of the electric force ( @xmath12 and @xmath13 ) , the electron potential energy decreases . in equilibrium , the electron orbit center hops in this direction are dominant , so the dissipative electron current flows in the direction of the net dc electric field . however , in some cases , the displacements of the electron orbit centers in the direction opposite to the electric force ( with @xmath14 and , hence , @xmath15 ) can prevail resulting in the dissipative current flowing opposite to the electric field . indeed , if an electron absorbs a photon and transfers to a higher ll , a portion of the absorbed energy @xmath16 ( @xmath17 is the planck constant ) goes to an increase of the electron kinetic energy , hence , the change in the electron potential energy is @xmath18 . if @xmath19 , so that @xmath20 ( see fig.2a ) , the potential energy of electrons increases with each act of their scattering . summarizing the results of previous calculations @xcite ( see also @xcite ) , the variation of the dissipative dc current under the effect of microwave radiation ( photocurrent ) can be presented as @xmath21 ^ 2}\ ] ] if @xmath22 , @xmath23\ ] ] when @xmath24 and @xmath25 , and @xmath26 when @xmath24 and @xmath27 ( smooth disorder ) . here @xmath28 the electron charge , @xmath29 is the ll broadening , @xmath30 is the magnetic length , @xmath31 is the spacing between 2des and the donor sheet , @xmath32 is the hall drift velocity , @xmath33 is the mcdonald function , and @xmath34 , where @xmath35 is the electron temperature . factor @xmath36 is due to the contribution of scattering processes with both absorption and emission of microwave photons . coefficients @xmath37 are determined by the matrix elements of photon - assisted interaction of electrons with impurities ( remote ones and those in 2des ) and surface roughness as well as by the amplitude of the ac microwave electric field @xmath38 and the electron distribution function . as follows from ( 1 ) - ( 3 ) , the microwave photocurrent reaches the maxima at @xmath39 and minima at @xmath40 with @xmath41 . according to ( 1 ) - ( 3 ) , the net dissipative current approximately coincides with its dark value at the resonances @xmath42 . at @xmath40 and sufficiently strong microwave radiation ( when @xmath43 ) , the net dissipative dc current @xmath44 becomes directed opposite to the electric field resulting in the instability . this pattern of the oscillatory behavior of the microwave photocurrent is in line with qualitative reasonings in the previous section . it is consistent with the experimental results @xcite . as shown , the photon - assisted acoustic phonon scattering processes ( see fig.2b ) also lead to an oscillatory dependence of the microwave photoconductivity . however , the phase of these oscillations is opposite to that in the case of photon - assisted impurity scattering @xcite . this can add complexity to the microwave photoconductivity oscillations and can even result in their suppression , particularly , at elevated temperatures ( see sec . the dependence of the factor @xmath37 microwave field is given by @xmath45 , where @xmath46 is the bessel function and @xmath47 is proportional to the amplitude of classical oscillations of the electron orbit center in the microwave field ( see , for example @xcite ) . the terms with @xmath48 correspond to the transitions with the absorption and emission of @xmath49 real microwave photons . thus , the magnitudes of the microwave photoconductivity maxima and minima @xmath50 and @xmath51 , where @xmath52 , are generally nonlinear functions of the microwave power @xmath53 . this is due to the effect of virtual photons absorption and emission on the electron scattering processes . at low microwave powers , @xmath54 and @xmath55 . however , when @xmath47 approaches @xmath56 , where @xmath56 corresponds to maximum value of @xmath46 , the magnitude of @xmath50 fairly slow increases with microwave power @xmath57 in line with experimental observations @xcite and others . this occurs at such powers that the amplitude of classical oscillations of the electron orbit center in the microwave field becomes of the order of @xmath30 . the pertinent characteristic power @xmath58 increases with @xmath0 approximately as @xmath59 @xcite . another consequence of the nonlinear mechanism in question is that at high microwave powers the magnitudes of maxima and minima corresponding to higher resonances ( @xmath60 with @xmath61 ) are not too small compared to those near the cyclotron resonance(@xmath62 ) . slowing down of the increase in @xmath50 and @xmath51 with increasing microwave power can be also associated with some heating of the 2des . as shown below , an increase in the electron temperature leads to broadening of the ll and , consequently , to smearing of the resonances . as seen from ( 1 ) , the microwave photoconductivity @xmath63 markedly decreases due to the processes with emission of microwave photons . this effect becomes essential when the electron temperature increases from @xmath64 to @xmath65 . the microwave photoconductivity maxima and minima also strongly depend on the ll broadening . the latter can be rather sensitive to the temperature . in particular , at moderate microwave powers @xmath57 , for the lorentzian shape of the lls , one obtains the following temperature dependence : @xmath66 here the dark conductivity and photoconductivity stem from the scattering processes involving inpurities , while the value @xmath63 depends on the sharpness of the resonances and , hence , on the net ll broadening . the net ll broadening is determined by the impurity ( and roughness ) scattering processes and by the electron - electron interaction . the ll broadening due to electron - electron interaction steeply increases with the electron temperature . taking into account that in the experimental situations the 2des fermi energy @xmath67 , one can use the following temperature dependence @xcite : @xmath68 , where @xmath69 is the effective rydberg . for @xmath70 ghz , the factor associated with the emission of microwave photons in ( 4 ) reduces approximately by half with the temperature increasing from 1 k to 3 - 4 k. setting @xmath71 mev , we find that @xmath72 . hence , according to ( 4 ) , in a 2des with high electron mobility ( in the absence of magnetic field ) in which @xmath29 is determined primarily by the electron - electron scattering so that @xmath73 , the span of the dissipative conductivity oscillations , i.e. , the values @xmath50 and @xmath51 can decrease by several orders of magnitude when the temperature increases by a few k. however , in 2dess with moderate electron mobility ( limited , say , by residual impurities and interface roughness ) in which @xmath74 , an increase in @xmath29 with increasing temperature and , hence , a decrease in @xmath50 and @xmath51 can be less pronounced as confirmed by experimental data . since photon - assisted acoustic phonon scattering provides the microwave photoconductivity maxima and minima at @xmath75 and @xmath76 , respectively , i.e. , approximately at the point where photon - assisted impurity scattering yields , on the contrary , the microwave photoconductivity minima and maxima , the former mechanism can interfere with the latter one modifying the oscillations and even effectively suppressing them this is possible if photon - assisted acoustic phonon scattering becomes essential with increasing temperature @xcite . a marked intensification of this mechanism occurs when @xmath77 , where @xmath78 is the speed of sound . in the experimental situations , @xmath79 k. although the oscillations of microwave photoconductivity as a function of the cyclotron frequency ( i.e. , the magnetic field ) were observed in 2dess with the electron mobility in rather wide range , sufficiently deep microwave photoconductivity minima which can result in anc were observed only in the samples with fairly high electron mobility . in the framework of the model under consideration , this can be explain as follows . the relative amplitude of the microwave photoconductivity oscillations is very sensitive to the ll broadening . in sufficiently perfect 2dess with weak scattering of electrons on residual impurities immediately in the 2des and on the interface roughness , the ll broadening is determined primarily by the electron - electron interaction . indeed , when the electron sheet concentration @xmath80 is about the sheet concentration of remote impurities @xmath81 , the ratio of quantities @xmath82 and @xmath83 can be estimated roughly as @xmath84 . the exponential factor in this formula is due a spatial separation of electrons and donors which gives rise to an exponential decrease in the matrix element of electron - impurity interaction . hence , at @xmath85 , one obtains @xmath86 . in the experiments with 2dess having high electron mobility , @xmath87 , so that the latter exponential factor is about of 0.06 . since the electron - electron scattering processes are effectively suppressed with decreasing temperature @xcite , the microwave maxima and , what is more important , minima are well pronounced and can surpass the dark conductivity at low temperatures and when the microwave radiation is strong enough . this leads to anc in some ranges of magnetic field when certain relations between @xmath0 and @xmath1 are met . in contrast , in the samples with moderate electron mobility , a significant contribution to the ll broadening is provided by residual impurities and interface roughness . this prevents the attainment of a sufficiently large ratio @xmath88 necessary for anc . we believe that main experimental facts on zr- and zc - states and related effects can be explained in the framework of the concept based on anc caused by photon - assisted impurity scattering of electrons and affected by electron - electron and photon - assisted acoustic phonon interactions . r.g.mani , j.h.smet , k.von klitzing , _ et al . _ , nature * 420 * , 646 ( 2002 ) . m.a.zudov , r.r.du , l.n.pfeiffer , and k.w.west , phys . lett . * 90 * , 046807 ( 2003 ) . c.l.yang , m.a.zudov , t.a.knuuttila , _ et al . _ , phys . * 91 * , 096803 ( 2003 ) . f.s.bergeret , b.huckestein , and a.f.volkov , phys . b * 67 * , 241303 ( 2003 ) . v.i.ryzhii , r.a.suris , and b.s.shchamkhalova , fiz . . poluprovodn . * 20 * , 2078 ( 1986 ) [ sov . phys .- semicond . * 20 * , 1299 ( 1986 ) ] . a. l. zakharov , zh . teor . fiz . * 38 * , 665 ( 1960 ) [ sov . phys . jetp * 11 * , 478 ( 1960 ) ] . s.i.dorozhkin , jetp lett . * 77 * ( 2003 ) 681 . s.a.studenikin , m.potemski , p.t.coleridge , _ et al . _ , solid state comm . * 129 * , 314 ( 2003 ) . r.g.mani , j.h.smet , k.von klitzing , _ et al . b * 69 * , 161306 ( 2004 ) r.l.willett , l.n.pfeiffer , and k.w.west , phys * 93 * , 026804 ( 2004 ) . a.c.durst , s.sachdev , n.read , and s.m.girvin , phys . rev . lett . * 91 * , 086803 ( 2003 ) . v.ryzhii and r.suris , j. phys . : cond . mat . * 15 * , 6855 ( 2003 ) . x.c.lei and s.y.liu , phys . rev . lett . * 91 * , 226805 ( 2003 ) m.g.vavilov and i.l.aleiner , phys . b * 69 * , 035303 ( 2004 ) . v.shikin , jetp lett . * 77 * , 236 ( 2003 ) v.ryzhii and v.vyurkov , phys . b * 68 * , 165406 ( 2003 ) . v.ryzhii , phys . b * 68 * , 193402 ( 2003 ) .

we present a model which provides a plausible explanation of the effect of zero - resistance and zero - conductance states in two - dimensional electron systems subjected to a magnetic field and irradiated with microwaves observed in a number of experiments and of the effect main features . the model is based on the concept of absolute negative conductivity associated with photon - assisted scattering of electrons on impurities . it is shown that the main features of the effect can be attributed to the interplay of different electron scattering mechanisms .

high - temperature superconductivity occurs in a state which is is frequently referred to as an ` rvb spin liquid ' . this state has no magnetic order , but strong short range antiferromagnetic correlations . undoubtedly the strong repulsion between electrons , which turns the system into a charge - transfer insulator at half - filling persists in the doped case , so that a description in terms of free - electron like slater - determinants is not really adequate . the problem then is , how to describe such a state theoretically . despite its frequently being referred to in the literature , the rvb spin liquid is a rather elusive concept . for example the precise nature of its ground state and low lying elementary excitations is not known to any degree of certainty . in the following we want to address this problem by studying a disordered state for the @xmath1 heisenberg antiferromagnet @xmath2 on an 2d square lattice . here @xmath3 denotes a spin 1/2 operator on site @xmath4 . one might expect that this is a kind of stepping stone also for the doped case , in that the elementary excitations of the undoped spin liquid persist to some degree also for finite doping . + perhaps the best - defined rvb spin liquid is the nearest neighbor rvb state@xcite - at least this wave function can be written down in compact form . we define the singlet generation operator on the bond @xmath5 @xmath6 where @xmath7@xmath8@xmath9 , are the constrained fermion operators , which do not allow the creation of a second electron on an already singly occupied site . introducing the operator @xmath10 where e.g. @xmath11 denotes the nearest neighbor of site @xmath4 in @xmath12-direction , the nearest neighbor rvb state on a 2d square lattice with @xmath13 sites can be written as @xmath14 where @xmath15 is a normalization factor . it corresponds to a superposition of all states which can be obtained by covering the plane compactly with nearest neighbor singlets , all with equal phase . covering the plane with singlets is equivalent to covering it with dimers , a well - known problem from statistical mechanics@xcite . we can therefore rewrite the state as @xmath16 where @xmath17 denotes a dimer covering of the lattice and @xmath18 the state obtained by putting singlets onto the dimers of @xmath17 . + in the following , we want to examine the problem of the possible elementary excitations of such a singlet background , and set up an effective hamiltonian governing their dynamics . the idea of ` expanding ' around a suitably chosen vacuum state is realized in simplest form in linear spin wave theory . the general line of thought here is quite analogous to linear spin wave theory , with the sole exception that the role of the vacuum ( which determines the symmetries of the ground state ) is played by the ` singlet soup ' ( [ rvb ] ) instead of the nel state . a similar approach has previously been applied to dimerized planar heisenberg - type models@xcite to spin ladders@xcite , to strongly coupled heisenberg planes@xcite , and to spin - peierls - like spin chains@xcite . an example where the fluctuations are fermionic rather than bosonic in nature is provided by the kondo lattice@xcite . the main difference as compared to the present work is that in all of these works a rather unique and simple dimer covering of the system is given by the topology or the form of the hamiltonian - the complications that arise from the use of a disordered ` singlet soup ' such as ( [ rvb ] ) then can be avoided . + while the technical complications arising from the use of a dimer basis are considerable , this approach also has some major advantages : in a site basis it is virtually impossible to even write down a disordered spin state , because one has to deal with the spin degeneracy on each single site . the calculation only becomes feasible if this site - degeneracy is lifted , for example by assuming strict nel order as in spin wave theory . on the other hand , the degeneracy is automatically taken care of in the dimer basis , because two interacting sites do have a unique ground state . a further considerable advantage of the dimer basis is , that it is easily enlarged by hole pairs on nearest neighbors , so as to describe a superconducting state . indeed , as will be seen below , the present description of the antiferromagnetic phase most naturally can be generalized to comprise also a superconducting phase , thereby providing a very simple microscopical picture for the so(5 ) rotations which smoothly connect antiferromagnetic and superconducting phase in zhang s theory@xcite of cuprate superconductors . the nearest neighbor - rvb state ( [ rvb1 ] ) has the symmetry properties expected for a homogeneous spin liquid : it is isotropic , translationally invariant , is an exact spin singlet and has no magnetic order . on the other hand , just as the nel state , it is not an eigenstate of @xmath19 . if we take one singlet configuration @xmath18 and act with the exchange term on a bond connecting two different singlets ( see figure [ fig1]a ) we can create a state which no longer can be represented as a superposition of only nearest neighbor singlets . such a state therefore represents a kind of fluctuation and as a first step we need to understand the character of these fluctuations . it might appear@xcite that the energetically most favorable fluctuation is the state shown in figure [ fig1]b : two nearest neighbor singlets are transformed into a configuration with only one nearest neighbor singlet and a second singlet connecting more distant sites . nominally the energy increases by only @xmath20 in this transition , because the only change is the loss of one nearest neighbor singlet . because singlet and triplet are degenerate for sites which are not connected by an exchange bond , we might as well consider the two spins connected by the ` long singlet ' as being unpaired ( see figure [ fig1]c ) . the transition from figure [ fig1 ] a@xmath21b could thus be viewed as pair creation of two unpaired spins . next , by acting with the exchange term on a bond which connects a dangling spin to another singlet ( see figure [ fig1]c ) , we can recouple the spins so as to form a new singlet and leave one of the formerly paired spins unpaired ( see figure [ fig1]d ) . this process corresponds to a propagation = 7.0 cm of the dangling spin . we would thus arrive at the conclusion that the fluctuations out of the nearest neighbor rvb state are unpaired spins , which carry a spin of @xmath22 and consequently must obey fermi statistics . clearly , these excitations should be identified with the ominous ` spinons ' . + further reasoning shows , however , that the line of thought leading to the introduction of the ` spinons ' misses a small but crucial detail . the first reason is that the state in figure [ fig1]b is not orthogonal to the vacuum , = 4.0 cm and thus can not represent a true fluctuation . more precisely , if we introduce ( see figures [ fig1 ] and [ fig2 ] ) ) @xmath23 ) that @xmath24@xmath8@xmath25 , in other words : after the ` transition ' figure [ fig1]a@xmath21b we remain in the original state , figure [ fig1]a , with a probability of @xmath26% . the problem of non - orthogonality is not restricted to the first step in figure [ fig1 ] : the states fig . [ fig1]c and [ fig1]d have an overlap of @xmath22 , and this generalizes to any two states which differ by one hopping process of a ` spinon ' . the non - orthogonality problem thus is omnipresent and severe . + let us therefore return to the first step , figure [ fig1 ] a@xmath21b , and consider how we can remedy the problem . the most natural way to proceed is to form the orthogonal complement @xmath27 so as to see ` what is really new ' in the state @xmath28 . a straightforward computation shows that after normalization to unity the orthogonal complement is @xmath29 here we have introduced the operators@xcite @xmath30 which create the three components of the _ triplet _ on the bond @xmath31 . we arrive at the conclusion that the true fluctuation out of the nearest neighbor singlet background is not the creation of two fermionic ` spinons ' , but rather the creation of two excited dimers , which carry a spin of @xmath32 and consequently should be modeled by bond - bosons@xcite . the further evolution of the created triplets then is quite obvious ( see figure [ fig3 ] ) ( but completely different from that of the ` spinons ' ) : by exchange along bonds connecting the triplets with neighboring singlets the triplets can de - excite while simultaneously the singlet turns into a triplet - this process , which is very much reminiscent of the propagation of a frenkel - type exciton corresponds to the propagation of the excited dimer . note that unlike the ` spinon ' states in figure [ fig1 ] , all different states in figure [ fig3 ] are mutually rigorously orthogonal . as a matter of fact there are problems with non - orthogonalities also for the triplet states - these are ` inherited ' from the original nearest neighbor rvb state . they will be discussed in detail below and be shown to be much less severe than those for the ` spinon ' states . their main effect is to replace the simple excited dimer by a more delocalized object , which resonates between different orientations within a limited spatial region . = 7.0 cm to be more precise , we now discuss the action of the heisenberg exchange on all possible configurations of nearest neighbor singlets and triplets . consider two _ nearest neighbor bonds _ @xmath31 and @xmath33 , and assume that they are connected by a single bond @xmath34 . denoting the heisenberg exchange along the latter bond by @xmath35 we have : @xmath36 these equations show that if we start out from states containing nearest neighbor singlets or triplets on the l.h.s . , the exchange term only produces states which again consist of nearest neighbor singlets or triplets on the r.h.s ( had the two bonds been connected by exchange along another bond , @xmath37 , @xmath38 or @xmath39 , we would have obtained the same equations with the sole difference that in some cases the prefactors change their sign ) . this proves rigorously that acting with an arbitrarily high power of the hamiltonian onto the nearest neighbor rvb state produces only states which can be built up from _ nearest neighbor _ singlets or triplets . + this ` theorem ' in fact holds true in a more general sense : on a single dimer @xmath40 , the @xmath41 states @xmath42 and @xmath43 do form a complete basis@xcite . thus , if we use a fixed dimer covering @xmath17 , the set of states obtained by placing singlets and triplets on the dimers of @xmath17 form a complete basis of the hilbert space . adding up such states obtained from _ all possible _ dimer coverings then clearly produces a highly overcomplete basis of the hilbert space , which therefore must automatically include states with singlets of arbitrary length . it follows that all states with longer - range singlets also can be represented as superpositions of states which are composed exclusively from nearest - neighbor singlets and triplets . these states are therefore redundant , and if we formulate a self - consistent theory in terms of nearest - neighbor singlets and triplets , we have automatically included these longer - ranged singlets . the fact that we are using a nearest - neighbor rvb state as the starting point for constructing our theory therefore means no loss of generality and in particular does by no means imply that we are considering only states with only very short - ranged antiferromagnetic correlations . in fact , it will be shown below that one can construct even states with infinite - range antiferromagnetic order by using exclusively nearest neighbor singlets and triplets . + the preceding considerations suggest that we should model the excitation spectrum of the nearest neighbor singlet vacuum by bosonic excitations , which approximately correspond to excited dimers . assuming that the bonds in the system have been labeled in some way , we denote the triplet operator on bond @xmath4 by @xmath44 . then , we introduce the following basis states @xmath45 where @xmath46 is a normalization factor . they describe a certain number ( @xmath40 ) of triplets which are ` immersed into the singlet soup ' . thereby the singlets fill the space in between the triplets compactly in all possible ways . all states which can be generated by pair creation and propagation of triplet bonds ( such as the ones shown in figure [ fig3 ] ) can be represented in this way . we next consider the triplets as boson - like elementary excitations of the singlet - background , in precisely the same way as misaligned spins are considered as bosonic excitations in a ` nel background ' in antiferromagnetic spin wave theory . re - interpreting the state @xmath47 where the @xmath48 represent boson operators , we may expect to describe the dynamics of these bosons by a hamiltonian of the form@xcite @xmath49 where we have grouped the three triplet components into a 3-vector @xmath50 so as to stress manifest rotation invariance . the first term in ( [ heff ] ) corresponds to the energy of formation of the triplets , the second term describes pair creation processes as in figure [ fig3]a @xmath21 [ fig3]b , and the third term accounts for the propagation of the triplets , see figure [ fig3]c @xmath21 [ fig3]d . the matrix elements @xmath51 and @xmath52 should be obtained by computing matrix elements of the heisenberg hamiltonian @xmath19 between the corresponding states ( [ basis ] ) . of course one thereby has to assume that for example the matrix element for a triplet jumping from bond @xmath40 to bond @xmath15 does not depend significantly on the positions of the other triplets - otherwise a description in terms of a single - particle like hamiltonian would not be feasible . as is the case in spin wave theory , the @xmath53-bosons have to obey a hard - core constraint , and in fact presence of one boson prohibits the presence of another boson not only on the same bond , but also on all bonds which share a site with the original one . + in the following , we will first study the problem of a single excited dimer in the singlet background , in other words we want to compute the ` bare ' boson dispersion @xmath54 in ( [ heff ] ) . as our basis states we consequently choose ( suppressing the @xmath12 @xmath55 or @xmath56 spin - index of the triplet ) : @xmath57 where @xmath58@xmath8@xmath59 denotes the direction of the bond in real space , and @xmath60 a normalization factor . in this state one triplet is put onto the bond @xmath61 and the remainder of the lattice is covered compactly by singlets in all possible ways . next , we introduce the fourier transforms @xmath62 in the hilbert space of bond - bosons , this state would be denoted by @xmath63 . the procedure to be followed then is like this : in a first step we compute the @xmath64 overlap matrix @xmath65@xmath8@xmath66 and diagonalize it . denoting the resulting eigenvectors and eigenvalues by @xmath67 and @xmath68 , the states @xmath69 form an orthonormal basis set and hence can serve as effective single particle orbitals with momentum @xmath70 . since the boson operators which correspond to the original triplets obey@xcite @xmath71 = n_{\alpha,\beta}$ ] , the operators @xmath72 obey the canonical commutation relations for boson operators : @xmath73=\delta_{\nu,\nu'}$ ] . they describe a triplet - like excitation which oscillates between @xmath12 and @xmath55-directed bonds within a certain spatial region whose extent is determined by the range of the real space overlap integrals @xmath74 . + next , we set up the @xmath64 hamilton matrix @xmath75@xmath8@xmath76 . diagonalizing @xmath77 , where @xmath78 denotes the expectation value of @xmath19 in the ` background ' state ( [ rvb1 ] ) , we obtain the desired dispersion relation of a single triplet boson . the pair creation matrix element is obtained in an analogous way . + this procedure in fact is neither new nor unconventional : a completely analogous construction is performed e.g. in the construction of the @xmath79 model@xcite , which describes the dynamics of the ( non - orthogonal ) zhang - rice singlets on the different plaquettes of the cuo@xmath80 plane . the only difference is that here we have two different nonorthogonal objects ( bosons on bonds in @xmath12 and @xmath55-direction ) per unit cell , whereas it was only a single zhang - rice singlet / unit cell in the case of the cuo@xmath80 plane . apart from that the construction is precisely the same . + in the next three sections we will calculate the dispersion relation , the pair creation matrix element , and discuss how these matrix elements depend on the density of triplets . readers which are not interested in these more technical parts are advised to proceed to section vi . to carry out our program we need to compute the real - space matrix elements @xmath81 and @xmath82 . in doing so the concept of a loop covering of the plane@xcite is of crucial importance . for two dimer coverings @xmath17 and @xmath83 the loop covering @xmath84 is obtained by drawing @xmath17 and @xmath83 ` on top of each other ' ( see for example figure 1 in ref . this produces a covering of the plane by closed loops @xmath85 , each of even length @xmath86 ( note that in the following we always measure the length of a loop @xmath87 ` in units of dimers ' ) . let us now consider each loop @xmath85 as an isolated 1d ring with @xmath86 sites . we assume that the sites along the ring are labeled such that the dimer covering @xmath17 corresponds to the state @xmath88 - the dimer covering @xmath83 then must correspond to @xmath89 . expanding the products we get @xmath90 different spin states from each covering , and there are precisely @xmath91 spin states which show up in both @xmath92 and @xmath28 namely the two possible nel states . we thus have @xmath93 . the same holds true for any other loop , whence , using @xmath94 , we find the scalar product of the two singlet distributions@xcite @xmath95 where @xmath96 is the total number of loops in the loop covering @xmath97 . + let us now assume that the singlets on the bond @xmath40 in @xmath18 and on the bond @xmath15 in @xmath98 have been replaced by a @xmath56-like triplet ( due to the explicit rotational invariance of the ` singlet soup ' the result for an @xmath12-like or @xmath55-like boson will be precisely the same - we are choosing the @xmath56-like component because the ambiguous states in this case are again the ones with nel order along the loop ) . then , a necessary condition for the scalar product to be different from zero is that there is a single loop @xmath99 in the resulting loop covering @xmath100 which passes through both bonds @xmath40 and @xmath15 . the reason is that the time - reversal parity of the triplet is negative whereas that of the singlet is positive . a necessary condition for a loop @xmath85 to give a nonvanishing overlap is that the total time - reversal parities ` along the loop ' are equal for both states @xmath18 and @xmath101 . this , however , is only possible if the triplets in @xmath18 and @xmath101 are within the same loop . each loop in @xmath100 therefore must contain either no triplet or both of them . + we can now split up the entire overlap integral @xmath102 into components which differ by the length and topology of the loop @xmath99 which passes through both triplets . the absolute numerical value of the overlap from this particular loop is identical to the case of pure singlet covering . the only change may be an extra minus sign , which originates because the singlets do have an orientation , whereas the triplets do not . we thus can rewrite the overlap as @xmath103 here @xmath104 is @xmath32 if the loop covering @xmath97 contains the loop @xmath85 and zero otherwise . we also note that @xmath105@xmath8@xmath32 , which fixes the normalization factor @xmath60 . with the exception of the @xmath106 all parts in ( [ over - real ] ) can be computed analytically . @xmath106 may be viewed as the norm of a nearest - neighbor rvb state which covers only the exterior of the loop @xmath85 , divided by the norm @xmath60 of the state which covers the exterior of a single bond . if we assume that the norm increases exponentially with the number of sites in the system , @xmath107 , with @xmath108 , one would estimate that @xmath109 . this suggests that @xmath106 is a quite rapidly decreasing function of @xmath87 . in the present work numerical values for @xmath106 were obtained by exact calculations on finite clusters ( see the appendix ) . the @xmath106 thereby indeed turned out to decay rapidly with @xmath87 , so only contributions with @xmath87@xmath110@xmath91 were kept in the present calculation . it should be noted that the computation of the @xmath106 is no fundamental obstacle to the present scheme : it may well be possible to obtain essentially exact values for these parameters by using monte - carlo techniques on large lattices . figure [ fig4 ] then shows the = 8.0 cm pairs of bonds @xmath111 and @xmath112 which can be connected by loops of length @xmath91 and @xmath113 as well as the corresponding signs @xmath114 . in this way we find the overlap matrix @xmath115 with @xmath116@xmath8@xmath32 and @xmath117 we proceed to a calculation of the matrix elements of the hamiltonian . we first recall that for the nearest neighbor rvb state the expectation value of @xmath19 between two dimer coverings @xmath18 and @xmath101 can be decomposed into contributions from each individual loop in the loop covering @xmath100@xcite : @xmath118 \;2^{p(a+b)-n } , \nonumber \\ e(u ) & = & \epsilon_s \ ; [ ( 2 -\delta_{l(u),1 } \ ; ) \;l(u ) + n_b(u)\;],\end{aligned}\ ] ] where @xmath119 is the number of nearest - neighbor bonds in @xmath85 which bridge the loop ( see figure [ fig5 ] ) , and @xmath120@xmath8@xmath121 the exchange energy / singlet . @xmath122 is the number of nearest - neighbor bonds that can be formed from the sites covered by @xmath85@xcite . this formula implies that there is no = 5.0 cm contribution from bonds connecting _ different loops_. the reason is that the exchange along a bond connecting different singlets can only lead to the pair creation of two triplets , see the first equation ( [ st ] ) . in order to maintain time reversal symmetry along each loop , it is then necessary that both triplets belong to the same loop - which is not possible if the bond in question connects different loops . + let us now again assume that the bond @xmath40 in @xmath18 and the bond @xmath15 in @xmath101 are occupied by a triplet , and consider the ` connected matrix element ' of @xmath19 between the two resulting states : @xmath123 . first , let us assume that we act with the exchange along a bond connecting @xmath40 and a neighboring bond @xmath124 ; the triplet can either propagate from @xmath40 to @xmath124 , or decay into two triplets on both @xmath40 and @xmath124 ( see the second equation ( [ st ] ) ) . neglecting the second possibility we obtain a nonvanishing contribution to the matrix element of @xmath19 only if there is a single loop @xmath125 which covers both , @xmath124 and @xmath15 . alternatively , if we act on a bond which connects @xmath15 and a neighboring bond @xmath126 , the triplet jumps from @xmath15 to @xmath126 and we get a nonvanishing contribution only if one single loop @xmath125 covers @xmath126 and @xmath40 . if , on the other hand , we act with the exchange along a bond which does not touch either of the triplet bonds @xmath40 or @xmath15 , both triplets will stay where they are and we get a nonvanishing matrix element only if both , @xmath40 and @xmath15 , are covered by a single loop @xmath125 . the same holds true if we act with the exchange along the bonds @xmath40 and @xmath15 themselves . + we first consider the case that @xmath40 and @xmath15 belong to two different loops , @xmath99 and @xmath127 . in the simplest case both ` loops ' consist only of a single bond , i.e. @xmath99 consists of the single bond @xmath40 and @xmath127 only of @xmath15 . since the two triplets belong to different loops , the overlap @xmath128 is zero . moreover , the matrix elements of the exchange along any bond which does not connect @xmath40 and @xmath15 vanishes - the calculation thus becomes very easy . the matrix element for the triplet hopping from @xmath40 to @xmath15 is @xmath129 , where the signs for different relative positions of the two bonds are shown in figure [ fig6 ] . to ` embed ' the hopping process = 3.0 cm into the singlet background , we need to renormalize this matrix element by @xmath130 which is again estimated from cluster calculations . the first contribution to the hamilton matrix then is : @xmath131 where the elements of the @xmath64 matrix @xmath132 are : @xmath133 to keep things simple we have moreover replaced the different @xmath134 by the average value @xmath135 . + next , we consider the case that one of the loops , e.g. @xmath127 , has a length @xmath136 . in other words , we a considering a process like the one shown in figure [ fig7 ] : the triplet jumps from bond @xmath40 to bond @xmath124 , and the triplet on @xmath124 = 4.0 cm overlaps with the triplet on bond @xmath15 along a loop ( in this case of length @xmath91 ) . there is also an analogous process , where the triplet jumps from @xmath15 to @xmath124 and @xmath124 and @xmath40 overlap by a loop . the respective matrix elements can be factorized into the matrix element for the hopping of the triplet times the overlap along the loop . this means that the matrix element can be written as @xmath137 where @xmath138;\ ] ] here @xmath139 and @xmath140 are the real - space versions of the matrices ( [ kin1 ] ) and ( [ gamma ] ) . fourier transformation gives @xmath141 where it has to be kept in mind that @xmath132 and @xmath142 are _ symmetric _ @xmath64 matrices . the ` embedding factor ' is @xmath143 where @xmath144 are like in figure [ fig7 ] . actually there are two inequivalent relative orientations of a single bond @xmath40 and an @xmath145 loop - the two respective values of @xmath146 do not differ strongly and for simplicity we use the average of the two values for the two configurations . processes involving even longer loops could be treated in an analogous way , but we neglect these . + we proceed to the second case , i.e. we assume that @xmath40 and @xmath15 are covered by a single loop @xmath99 . as was the case for the overlap integrals , the matrix elements then can be split up into contributions differing by the loop @xmath99 which covers both triplet bonds . once this loop is fixed , we can divide all bonds in the plane into three distinct classes . first , bonds belonging to any loop other than @xmath99 are not affected at all by the presence of the triplets and give the same contribution as in the pure singlet state . this becomes @xmath147 2^{p(a+b)-1 } \delta_{a+b , u_0}. \label{bulk1}\end{aligned}\ ] ] this is an energy of order of the system size @xmath148 ; in the end it must be canceled , up to terms of order @xmath149 , by a corresponding contribution in @xmath150 . this cancellation is the analogue of the familiar linked - cluster theorem of many - body physics . + second , we consider those bonds in @xmath99 which are not bridging bonds . they will be covered by either a singlet or a triplet in either @xmath17 or @xmath83 , whence these bonds together give the contribution @xmath151 \nonumber \\ & \;&\;\;\;\;\;\;\;\ ; 2^{1-l(u_0 ) } ( -1)^{\sigma(u_0 ) } \chi(u_0).\end{aligned}\ ] ] this is a ` connected ' contribution of order @xmath149 . + this leaves us with the bridging bonds ( see figure [ fig5 ] ) , which may give a nontrivial contribution . however , since the bridging bonds occur only for @xmath152 we neglect their contribution altogether . + the subtracted contribution , @xmath150 , may be rewritten as @xmath153 where we have used the expanded form ( [ over - real ] ) of @xmath154 . this is again an energy of order @xmath148 , which cancels the bulk term ( [ bulk1 ] ) up to terms of order @xmath149 . after some reshuffling ( using @xmath155@xmath8@xmath148 ) we can rewrite the contribution to the matrix element as @xmath156 with @xmath157\ ; \chi(u ) , % \nonumber \\ \epsilon_j(u ) & = & j\;(1 -\delta_{l(u_0),1 } \;)\ ; 2^{1-l(u ) } ( -1)^{\sigma(u ) } \chi(u ) \nonumber \\ \epsilon_{0}(u ) & = & \frac { ( -1)^{\sigma(u)}}{n_1 } \sum_{a , b } [ \;\sum_{u\in a+b}\bar{e}(u)\ ; ] 2^{p(a+b)-n } \delta_{a+b , u } , \nonumber \\ \bar{e}(u ) & = & e(u ) - l(u ) \frac{e_0}{n}. \label{mats}\end{aligned}\ ] ] the first term on the rhs of ( [ hmat ] ) is the ` bare ' on - site energy of the triplet . it is always proportional to the overlap integral , so upon switching to the effective bosons this term becomes a @xmath70-independent constant shift . the quantity @xmath158 may be thought of as describing a ` loss of resonance energy ' . it is the difference of the two contributions ( [ bulk1 ] ) and ( [ bulk2 ] ) and occurs because the loop @xmath99 is fixed , whence the area covered by this loop is not available for resonating between different singlet coverings . for example we have @xmath159 i.e. this quantity is an additive renormalization of the energy of formation for a single triplet due to its being ` embedded into the singlet soup ' . numerical evaluation in a cluster shows that this additive correction is quite large - for one triplet in a pure singlet background we find @xmath160 . while this is surprising at first sight it should be noted that a similar large value ( @xmath161 ) was previously found in spin ladders@xcite . a fixed triplet obviously leads to a quite substantial loss of resonance energy . the numerical values of @xmath158 and @xmath78 were again obtained by cluster calculations ( appendix ) . introducing @xmath162@xmath8@xmath163 we can write down the third part of the hamilton matrix : @xmath164 we can now add up the three contributions , ( [ eps1 ] ) , ( [ eps2 ] ) , and ( [ eps3 ] ) to obtain the total ` connected ' hamilton matrix @xmath165 . this is still expressed in terms of the non - orthogonal orbitals @xmath166 . what remains to be done therefore is to transform the hamilton matrix to the orthogonal orbitals ( [ ortho ] ) . to that end we take matrix elements of the form @xmath167 . introducing the @xmath64 transformation matrix @xmath168 the transformed hamiltonian then can be expressed as @xmath169 in this section we proceed to a discussion of the pair creation amplitude @xmath170 in equation ( [ heff ] ) . as discussed in section ii , by starting from an arbitrary singlet covering of the plane and acting with the hamiltonian along a bond connecting two different singlets , we _ only _ create a state where both singlets are replaced by triplets , see the first of eqs . ( [ st ] ) . the situation where the two singlets in question are ` parallel ' to each other , i.e. that the @xmath41 sites belonging to the @xmath91 singlets form a square with edge @xmath32 , requires special attention . as discussed above we have the identity @xmath171 i.e. the state with two parallel triplets can be expressed as a linear combination of the two perpendicular combinations of parallel singlet states . in other words : this state is already exhausted by the singlet background , and consequently must be omitted from our reduced hilbert space . the triplets thus have to obey the additional constraint of never being parallel to each other - one implication is that we must set the respective pair creation matrix element to zero . + to compute the numerical value of the matrix element , let us consider the action of @xmath19 on the rvb state ( [ rvb ] ) . we have @xmath172 the first term on the rhs originates from processes where the hamiltonian has ` hit ' a bond covered by a singlet , the second one originates from processes where the exchange has acted along bonds connecting two singlets on bonds @xmath40 and @xmath15 ( the prime on the sum indicates that only pairs of bonds connected by a bond are summed over ) . the modulus of the respective matrix element is @xmath173 ( see equation ( [ st ] ) ) and there is an extra sign which depends on the relative orientation of the bonds @xmath40 and @xmath15 . the dependence of this sign on the orientation is shown in figure [ fig8 ] . also , we have approximated the normalization factor which is included in the definition of @xmath174 by @xmath175 the factor of @xmath176 remains from the definition of ( [ rvb ] ) . to obtain the pair creation matrix element we now form the overlap between ( [ hrvb ] ) and the state @xmath177 . = 8.0 cm defining the @xmath64 matrix @xmath178 and bearing in mind that @xmath179 , we find for the pair creation matrix : @xmath180 this completes the derivation of the single - particle terms of the triplet hamiltonian . before we proceed , let us briefly return to the problem of non - orthogonality . strictly speaking , the state with two triplets is not orthogonal to the singlet background either . the reason is that if one draws a loop passing through both triplets , the time reversal parities of the two triplets cancel , and the state has a nonvanishing overlap with a state where the loop is covered only by singlets ( see figure [ fig9 ] ) . = 4.0 cm however , this overlap is rather small : in the case shown in figure ( [ fig9 ] ) it is for example @xmath181 , and obviously this is the most unfavorable case . for other relative orientations of the two triplets the overlap can be only achieved by a loop of length @xmath182 , whence these overlaps are @xmath183 . the non - orthogonalities thus are much more benign that those for the spinon - states , whence neglecting them altogether ( as we will do henceforth ) is probably quite justified . in the preceding sections we have computed the various overlap integrals and matrix elements for triplet propagation , pair creation and interaction . in all of these cases the matrix element could be factorized into a contribution from a ` local ' transition between different singlet / triplet coverings along a single or two neighboring loops , and a factor which describes the embedding of these active loops into the singlet background . thereby we have always given expressions for these ` embedding factors ' which are valid in the limit of vanishing triplet concentration , i.e. we have computed them as they would be for a pure singlet covering of the system . clearly , this is inappropriate for the real system , where quantum fluctuations have admixed a finite density of triplet bosons . in the following we want to discuss how we have to modify our theory to take the effect of a finite triplet concentration into account . it should be stressed from the very beginning that this is quite obviously a very complex problem and we will be forced to apply some relatively crude approximations . + if we want to derive single - particle like matrix elements for finite triplet concentration we should consider overlap integrals or matrix elements of @xmath19 of the type @xmath184 triplets stay unchanged , and only a single one ( which without loss of generality can be taken to be the first one ) changes its position ( but maintains its spin ) . in other words , we should calculate the embedding factors for singlet coverings containing a certain number of ` inert ' triplets . thereby we actually have to make the major _ assumption _ that the matrix element does not depend significantly on the positions of these inert triplets - otherwise , the very idea of a single particle - like propagation of the triplets would be invalid . one might then expect that approximate values can be obtained by distributing the @xmath40 inert triplets in all possible ways ( we call the number of possible distributions d(m ) ) over the system , and taking the average of the respective matrix elements computed for all d(m ) possible distributions . in this way , the embedding factors acquire a dependence on the density of triplets . + the numerical calculation in a finite cluster then proceeds as follows : we choose @xmath40 bonds @xmath185 , which obey the various constraints on the relative positions of triplets , and evaluate the ground state norm and energy according to @xmath186\;2^{p(a+b)-n}\prod_{\nu=1}^{m } \delta_{a+b , i_\nu}. \label{hugo}\end{aligned}\ ] ] the calculation of the various embedding factors then proceeds in an entirely analogous fashion i.e. in ( [ over - real ] ) , ( [ etadef ] ) , and ( [ mats ] ) we replace @xmath187 in this way we obtain all embedding factors for fixed distribution of inert triplets , and the value for triplet concentration @xmath188 is obtained by averaging over all allowed distributions of the bonds @xmath185 . in practice this calculation requires quite a substantial numerical effort so this was performed only for the @xmath189 cluster . = 4.0 cm one might expect , however , that the finite size effects are in fact smaller for the more relevant higher triplet concentrations : the main effect of the fixed triplets obviously is to reduce the importance of long loops . since the bonds occupied by the static triplets must be identical in the bra and ket state , loops of length @xmath190 which pass through these bonds are impossible . when the density of triplets gets appreciable , the probability to find enough space for forming longer loops becomes smaller and smaller . since longer loops may cause problems in the small clusters , a suppression of these may therefore even reduce finite - size effects . moreover , the suppression of longer loops is actually beneficial for our entire approach : it tends to eliminate the problems with the nonorthogonalities in the singlet soup and makes the truncation of the length @xmath191 a better approximation . + as an illustration figure [ fig10 ] shows the dependence of @xmath192 , i.e. the additive renormalization of the energy of formation of a triplet ( see ( [ renorm ] ) , evaluated in the @xmath189 cluster . the concentration dependence is as expected : for low triplet concentration @xmath192 is large because an added triplets blocks many long loops along which resonance could have occurred . as the triplet concentration gets higher , these longer loops a blocked anyway , so adding a further triplet does not increase the energy too much any more . in the high - density limit the additive renormalization approaches zero , as expected . the figure shows , however , that the concentration dependence is quite significant , i.e. this effect should not be neglected . + in addition to reducing the importance of longer loops , for a finite density of triplets we have to take care of the excluded volume constraint which the bond bosons have to obey . placing a triplet on one given bond @xmath40 blocks a total of @xmath193 other bonds , on which no more triplets can be placed ( see figure [ fig11 ] ) . = 4.0 cm of these , @xmath194 bonds are blocked because they share a site with @xmath40 , the remaining @xmath91 are blocked because they are ` parallel ' to @xmath40 and the state with two parallel triplets is actually a linear combination of singlets ( see ( [ combo ] ) ) . in order to take care of this _ blocking effect _ , we resort to a gutzwiller - type approximation . it has been shown by ogawa _ et al._@xcite that the essence of the gutzwiller approximation is the neglect of the difference in phase between states where the particles in question are distributed in different ways over the lattice . with this approximation , any real space distribution of @xmath40 bosons contributes the same number ( which without loss of generality can be taken to be @xmath32 ) to the norm of any state with @xmath40 bosons . the total norm of any such state then becomes simply the number of possible ways to distribute @xmath40 bosons over the plane , i.e. @xmath195 . in the present case , the situation is somewhat more complicated , because we still have to take into account the fact that due to the loop problem the norm of a state with @xmath40 fixed triplets is not @xmath32 ( unlike the case if the triplets were just ordinary bosons ) . we thus approximate the normalization factor of any state with @xmath40 triplets by @xmath196 where @xmath197 is the value obtained by averaging ( [ hugo ] ) over all allowed triplet configurations @xmath185 . clearly , this replacement will lead to a renormalization of the various embedding factors . to evaluate these , we usually have to consider a certain area @xmath198 , covered by one or two loops , in which the actual overlap , hopping or pair creation process takes place . we then determine ( again by simulation on the @xmath189 cluster ) the number of ways to distribute @xmath40 triplets over the exterior of the area @xmath198 . thereby we request that putting a triplet anywhere within @xmath198 always gives an allowed configuration of @xmath199 triplets . we call the number of allowed triplet configurations @xmath200 . defining the various areas @xmath201 as = 4.0 cm in figure [ fig12 ] , we then have to renormalize the various parameters as follows : @xmath202 for the pair creation amplitude we replace @xmath203 to summarize this section , figure [ fig10 ] shows the values of the different parameters as estimated by the procedure outlined above , for all possible triplet concentrations in the @xmath189 cluster . let us stress again that the approximations leading to the parameters in figure [ fig10 ] are probably rather crude - one may expect , however that we get roughly correct orders of magnitude and that the ratios of the different parameters come out approximately correct . let us first briefly summarize the discussion so far : we have shown that the elementary excitations of the singlet soup correspond to excited dimers , which must be modeled by bond - bosons . combining the matrix elements computed in the two preceding sections we obtain a hamiltonian of the form @xmath204 thereby the matrix elements @xmath205 and @xmath54 are functions of the triplet density . for given triplet density @xmath206 these parameters can be computed and the hamiltonian , which after the gutzwiller - type renormalization of the matrix elements we take to be a free - boson hamiltonian , is solved by bogoliubov transformation . combining the two different @xmath53-operators into a 2-vector @xmath207 the ansatz reads @xmath208 where the real @xmath209 matrices @xmath85 and @xmath210 have to fulfill @xmath211 the inverse transformation of ( [ bogo ] ) is therefore @xmath212 the hamiltonian can be transformed to free particle form : @xmath213,\end{aligned}\ ] ] provided the transformation matrices obey @xmath214 here we have introduced the @xmath64 matrix @xmath215 . the triplet density is @xmath216 , \label{den}\ ] ] where @xmath217 is the bose function . the requirement @xmath218 then provides a self - consistency condition for the density . + numerical evaluation shows that there is a minimum triplet concentration @xmath219 . for @xmath220 , the parameters are such that in a certain area around @xmath221 the eigenvalue problem ( [ eigenvalue ] ) does not have real eigenvalues . for @xmath219 the minimum of the triplet dispersion , which occurs at @xmath0 is precisely zero . with the coarse mesh of concentrations possible in the @xmath222-site cluster , we find @xmath223 . we therefore linearize all matrix elements @xmath12 , i.e. @xmath224 , using the values at @xmath225 and @xmath226 to determine @xmath227 and @xmath228 . this gives @xmath229 . + with increasing temperature , the self - consistent value of @xmath230 increases slowly , approaching @xmath219 for @xmath231 . figure [ fig13 ] shows the dispersion relation for the respective self - consistently determined triplet density at different temperatures . since we have two degrees of freedom / site ( the triplet in @xmath12 and @xmath55 direction ) we obtain two bands . while one of these bands is practically dispersionless , the dispersive one resembles results obtained for other spin = 5.0 cm liquids , such as the two - leg ladder@xcite or the bi - layer heisenberg antiferromagnet@xcite : the dispersion starts at relatively high energy at @xmath232 , takes a shallow maximum near the antiferromagnetic zone boundary and , as stated above , takes a more or less pronounced minimum at @xmath233 . for low temperatures the bandwidth is @xmath234 , which is quite close to the value for antiferromagnetic spin waves . the case of zero temperature requires special attention : it is obvious from figure [ fig13 ] that the gap at @xmath235 approaches zero for @xmath236 . assuming that the gap vanishes at zero temperature , we may then assume that this momentum becomes macroscopically occupied by a triplet density @xmath237 . to determine this condensed fraction we note that the limiting density @xmath238 is defined such that the gap at @xmath235 is exactly zero with the parameters calculated for this density . then , for @xmath239 we evaluate the density @xmath240 of uncondensed triplets ( i.e. we exclude @xmath241 from the sum in ( [ den ] ) ) and finally determine the condensate density from @xmath242 this is entirely analogous to the treatment of hirsch and tang@xcite of the condensation of schwinger - bosons in the mean - field theory of arovas and auerbach@xcite . as will be seen in a moment , just as for the schwinger bosons the condensation of the triplets corresponds to antiferromagnetic ordering . the ground state energy then is @xmath243\ ] ] where @xmath244 is the energy of the singlet background for triplet density @xmath230 . this is calculated from ( [ hugo ] ) . we obtain a value of @xmath245/bond , which is quite close to the true ground state energy of the 2d heisenberg antiferromagnet@xcite . an interesting figure is the lowering of the energy as compared to the original rvb - vacuum ( [ rvb ] ) . in the @xmath189 cluster ( which has been used to compute all matrix elements ) the expectation value of the pure nearest - neighbor rvb state is @xmath246/bond@xcite , so that the admixture of the triplets lowers the energy only by a tiny @xmath247/bond . in view of the strong approximations we were forced to make this result probably has little quantitative significance - it shows quite clearly , however , that the energy of the rvb - vacuum is lowered only by a very small energy by the triplet fluctuations . this is what must come out because in the thermodynamic limit the energy of the rvb state is @xmath248/bond@xcite , compared to the exact ground state energy of approximately @xmath249/bond@xcite . + we proceed to a discussion of the spin correlation function . since the bond - bosons are actually objects which extend over more than one unit - cell , they have something like a structure factor which depends on the type of operator by which they are probed . let us consider a single bond , @xmath31 , and introduce even and odd combinations of spin operators on this bond : @xmath250 due to their opposite parity under exchange of @xmath4 and @xmath251 these two operators have an entirely different effect on the @xmath41 possible spin states of the bond : @xmath252 annihilates the singlet and @xmath253 but converts @xmath254 and @xmath255 , whence @xmath252@xmath8@xmath256 . @xmath257 on the other hand converts the singlet into @xmath253 and vice versa , but annihilates both @xmath258 and @xmath252 , whence @xmath252@xmath8@xmath259 . if we still restrict ourselves to only a single bond @xmath15 we have to ` translate ' @xmath260 , \label{corr1}\end{aligned}\ ] ] where @xmath261 is the unit vector along the bond @xmath15 and @xmath262 denotes its center of gravity . let us next discuss how these matrix elements are modified due to the embedding into the singlet background . we act with the operator @xmath263 on some given state . the first term simply changes the @xmath56-spin and momentum of a triplet . it does not affect the number of triplets , so we need no further renormalizations . for the second term , let us start out from a state with one triplet , @xmath264 , and assume that the triplet is annihilated , i.e. converted into a singlet . this leaves us with the state @xmath265 the matrix element with the pure rvb state then is @xmath266 because it is easy to see that a state with one fixed singlet has an overlap of @xmath267 with the rvb state . if we want to extrapolate this to finite triplet density we again have to use the values of @xmath15 and @xmath60 computed with @xmath40 fixed triplets , and renormalize the matrix element by @xmath268 we thus find @xmath269.\end{aligned}\ ] ] by using the inverse transformation ( [ bogo_inv ] ) this can now be converted to the eigenvectors @xmath270 . the dynamical spin correlation function of the spin liquid thus consists of two components : first , there is a two - particle continuum , which dominates for momenta around @xmath271 . second , there is a single - particle like contribution , which dominates the cross section for momentum transfers near @xmath0 , and hence should be identified with the excitations seen in neutron scattering around this momentum . the situation is the same for ladders , where the single - particle spectrum is observable in the channel with momentum transfer perpendicular to the ladder , @xmath272 , and the two - particle continuum for @xmath273@xcite . + next , we discuss the relationship between condensation of triplets and antiferromagnetic ordering . the operator of staggered magnetization ( which is a _ vector _ ) can be written as @xmath274 here we have used the fact that for the high - symmetry momentum @xmath235 the overlap and hamilton matrix are trivially diagonalized by the symmetric and antisymmetric combinations of the bonds in @xmath12 and @xmath55-direction , @xmath275 . then , introducing the 3d unit vector @xmath276 , we can construct the coherent state @xmath277 this state corresponds to a condensate of the @xmath278 bosons , whose density is given by @xmath279 . the staggered magnetization per site is @xmath280 inserting the value for the condensate density @xmath237 obtained from ( [ conden ] ) we obtain the value @xmath281 . most current estimates for the 2d heisenberg antiferromagnet are around @xmath282@xcite . + as mentioned above , the identification of antiferromagnetic ordering and condensation of some kind of effective bosons is quite reminiscent of the treatment of hirsch and tang@xcite in the framework of schwinger - boson mean - field theory@xcite . in the present theory the direction of the staggered magnetization is given by the unit vector @xmath276 , which can be chosen arbitrarily . condensation of the triplet bosons determines the total density of triplets , but not their distribution over the three spin species . the ` ground state ' thus is actually an entire manifold of states which can be transformed into one another via so(3 ) rotations of the vector @xmath276 . one might thus conjecture the existence of low - energy states where the direction of @xmath276 changes slowly in real space . these states , which corresponds to a slow fluctuation of the antiferromagnetic order parameter may be describable in terms of a nonlinear @xmath283-model - we defer a detailed discussion of this issue to a separate paper . + to conclude this section , we discuss the relationship with zhang s so(5 ) symmetric theory of cuprate superconductivity@xcite . the preceding discussion has shown that an antiferromagnetic state can be viewed as a spin liquid where the triplet - like bond bosons have condensed into the state which has momentum @xmath0 and @xmath284-like symmetry under point group operations . the antiferromagnetic order parameter , a real 3-vector , then is the vector of condensation amplitudes of the three bond - boson species . this interpretation of the antiferromagnetic state in fact is a key ingredient for a microscopic interpretation of zhang s so(5 ) theory of cuprate superconductor . namely the @xmath285-operator , which acts as the ` ladder operator in charge direction ' in zhang s representation of the so(5 ) angular momentum algebra@xcite , precisely converts an @xmath284-like combination of bond triplets with momentum @xmath0 into a nearest neighbor @xmath286-wave hole pair . this can be seen by writing the @xmath285-operator in real space : @xmath287.\end{aligned}\ ] ] introducing a further bond boson @xmath288 , which stands for the hole pair , this could be written as @xmath289 where the momentum @xmath290 . acting with @xmath291 onto an undoped state with the triplet condensate densities @xmath292 will therefore convert this state into a condensate of @xmath286-like nearest neighbor hole - pairs with momentum @xmath271 . viewed in this way , the connection between the antiferromagnetic and the superconducting state appears quite natural . the only drawback would be that the hole pairs are strictly nearest - neighbor pairs , i.e. the present version of the @xmath285-operator neglects charge fluctuations . in summary , we have discussed the excitation spectrum of a completely disordered and homogeneous spin system . thereby we used an approach which might be viewed as a generalization of spin wave theory : whereas spin wave theory describes fluctuations around a nel ordered ` vacuum ' , we have instead used the nearest neighbor rvb state as basis for self - consistently constructing the excitation spectrum . this general idea of treating a completely disordered state is probably more widely applicable , for example to treat the ` orbital liquids ' proposed recently@xcite for manganates . + as a first key result , we then found that the elementary excitations of the singlet soup - like vacuum are not fermionic ` spinons ' , but rather bosonic excitations @xmath293 , which can be viewed as excited dimers propagating through the system while constantly resonating between @xmath12 and @xmath55 direction of the dimer . following a similar procedure as in the zhang - rice derivation of the t - j model , we could write down a hamiltonian for these bosonic excitations . the hamiltonian contains an energy of formation for the triplets , a term describing their propagation and a term describing pair creation and annihilation . all quantities in the derivation are quite well - defined , and can in principle be obtained by numerical techniques . in the present work we have actually attempted an ` ab initio calculation ' of the various parameters in the effective hamiltonian - a promising alternative to this somewhat clumsy approach might be a semi - empirical approach , where the parameters in the hamiltonian are adjusted to match e.g. experimental data . + the obtained ground state is an exact spin singlet , translationally invariant and isotropic - in short , it has precisely the symmetry properties expected for a spin liquid . the elementary excitations is a triplet mode , which reaches its lowest energy at @xmath235@xmath8@xmath0 . such a triplet mode is the most natural generalization of an antiferromagnetic spin - wave to the spin - liquid state . condensation of these bond bosons into the state with momentum @xmath0 then corresponds to antiferromagnetic ordering of the system . the breaking of rotational symmetry in spin space is due to fixing ( different ) condensation amplitudes for the three components of the triplet mode . the latter correspond to the three possible components of the antiferromagnetic order parameter . + in the present work we have chosen the completely isotropic nearest neighbor rvb - state as the starting point for constructing the triplet - hamiltonian . this is appropriate for an truly isotropic system , which probably is realized at finite doping and/or sufficiently high temperature . using a translationally invariant state , however , is not mandatory . for example by redefining the operator @xmath294 as @xmath295 with @xmath296 we can obviously generate a ` singlet soup ' with a preference for singlet orientation in @xmath12-direction . it is tempting to speculate that this may be appropriate for orthorhombic la@xmath297sr@xmath298cuo@xmath299 , where at @xmath300 columnar order is known to exist . analogous calculation as above , but with a finite @xmath301 may thus be appropriate to discuss the excitation spectrum of this material . + finally we note that the present scenario for the excitation spectrum of the spin - liquid provides a corner stone for a microscopic interpretation of zhang s so(5 ) symmetric theory of cuprate superconductors@xcite . as discussed above , an antiferromagnetic state may be thought of as being generated by condensing triplet - like spin excitations of the rvb spin - liquid into the state with momentum @xmath0 . the antiferromagnetic order parameter corresponds to the vector of condensation amplitudes of the three triplet species . then , so(5 ) symmetry states that such a triplet - excitation with momentum @xmath0 is ` dynamically equivalent ' to a @xmath302 hole pair@xcite . in fact the @xmath285-operator@xcite , which plays the role of a ladder operator for ` rotations in charge - direction ' in the so(5 ) theory@xcite , precisely replaces a bond - triplet with momentum @xmath0 by a hole pair with momentum @xmath271 . the fact that the @xmath285-operator is an approximate eigenoperator of the hamiltonian , @xmath303=\omega_0 \pi$ ] , then implies that the triplet and the hole pair are dynamically indistinguishable and differ only by their energy of formation . the @xmath285-operator thus would convert a condensate of triplets into a condensate of hole pairs , and , by the dynamical equivalence of these two objects , thus converts the antiferromagnetic ground state at half - filling into a superconducting state at finite - doping one . the somewhat ` toy - model - type ' discussion of ref.@xcite thus may very well be transferable almost literally to the fully planar t - j model . + in the present work we have restricted ourselves to a pure spin system . one my expect , however , that all considerations go through also for the doped system , with the sole difference that we get additional renormalizations of the matrix elements in the effective hamiltonian due to the fact that the doped holes reduce the volume available for pair generation and propagation of triplets . moreover , we will need terms which describe the coupling of the triplet branch to the mobile holes . in the simpler case of hole motion in a spin ladder this program has in fact already been carried out@xcite , leading to quite satisfactory agreement with numerical results . for the planar case we defer this to future work . + i would like to thank w. hanke , o. p. sushkov and shou - cheng zhang for instructive discussions and helpful comments . in this appendix we discuss the numerical work needed to obtain the values of @xmath106 , @xmath158 and the @xmath135 . to that end all possible dimer coverings of an @xmath304 cluster with periodic boundary conditions are generated on the computer the sums in ( [ over - real ] ) are evaluated numerically . restrictions on computer memory and cpu time do not allow to use @xmath305 , so that in practice only @xmath306 are possible . tu study the size dependence , we consider the quantities @xmath307 ; these give the ratio of the norm of an rvb state covering the exterior of a loop of length @xmath308 to the norm of an rvb state covering the entire cluster . similarly , we define @xmath309 , which gives the gain or loss in energy due to a fixed loop of length @xmath308 . the values for the different @xmath310 and @xmath311 are given in table [ tab1 ] and actually show already a quite remarkable independence of systems size . moreover , the expectation value of the energy / bond , @xmath312 , is @xmath313 for @xmath314 , @xmath315 for @xmath316 ; the estimate for @xmath317 is @xmath318@xcite . all in all the data suggest that already the @xmath189 cluster gives reasonably accurate estimates for the different parameters . + moreover , the data show that the @xmath319 and @xmath320 decrease quite rapidly with @xmath308 . truncation of the series after @xmath145 thus seems to be quite a reasonable approximation as well . s. kivelson , d. rokhsar , and j. p. sethna , phys . rev . b * 35 * , 865 ( 1987 ) . b. sutherland , phys . b * 37 * , 3786 ( 1988 ) . m. kohmoto , phys . b * 37 * , 3812 ( 1988 ) . e. fradkin , _ field theories of condensed matter systems _ , addison - wesley publishing company , 1991 . kasteleyn , physica * 27 * ( 1961 ) 1209 . s. sachdev and r. n. bhatt , phys . b * 41 * , 9323 ( 1990 ) . r. r. p. singh , m. p. gelfand , and d. a. huse , phys . * 61 * , 2484 ( 1988 ) . s. gopalan , t. m. rice , and m. sigrist , phys . b * 49 * , 8901 ( 1994 ) . r. eder , phys . b * 57 * , 12823 ( 1998 ) . a. v. chubukov and d. k. morr , phys . rev . b * 52 * , 3521 ( 1995 ) . v. n. kotov , o. sushkov , zheng weihong , and j. oitmaa , phys . lett . * 80 * , 5790 ( 1998 ) . han - ting wang , jue - lian shen , and zhao - bin su , phys . b. * 56 * , 14435 , ( 1997 ) . w. brenig , phys . b. * 56 * , 14441 , ( 1997 ) . r. eder , o. stoica , and g. a. sawatzky , phys . b. * 55 * , 6109 , ( 1997 ) ; r. eder , o. rogojanu , and g. a. sawatzky , phys . b. * 58 * , 7599 , ( 1998 ) . zhang , science * 275 * , 1089 ( 1997 ) . s. liang , b. doucot , and p. w. anderson , phys . lett . * 61 * , 365 ( 1988 ) . a. v. chubukov , jetp lett . * 49 * , 129 ( 1989 ) . it should be noted that by defining the states @xmath322 one could also construct a basis of ` spinon ' states and re - interpreting @xmath323 where the @xmath324 now correspond to spin-1/2 fermions one might be tempted to try and derive a _ fermionic _ hamiltonian for the ` spinons ' : @xmath325 readers uncomfortable with the triplet excitation picture put forward in this work are invited to try their hands on this calculation - the present author trusts that this experience will convince anybody that the triplets are the one and only sensible way of discussing the excitation spectrum of the spin liquid . g. stollhoff and p. fulde , j. chem . phys . * 73 * , 4548 ( 1980 ) . f. c. zhang and t. m. rice , phys . b * 37 * , 3759 ( 1988 ) . t. ogawa , k. kanda , and t. matsubara , progr . . phys . * 53 * , 614 ( 1975 ) ; see also d. vollhardt , rev . phys . * 56 * 99 ( 1984 ) . j. e. hirsch and s. tang , phys . b * 39 * , 2850 ( 1989 ) . d. p. arovas and a. auerbach , phys . b * 38 * , 316 ( 1988 ) . e. manouskais , rev . phys . * 63 * , 1 ( 1991 ) . r. eder , a. dorneich , m. g. zacher , w. hanke , and shou - cheng zhang , preprint cond - mat/9805120 . l. f. feiner , a. m. oles , and j. zaanen , phys . lett . * 78 * , 2799 ( 1997 ) . o. p. sushkov , preprint cond - mat/9808302 .

we discuss the excitation spectrum of a disordered , isotropic and translationally invariant spin state in the 2d heisenberg antiferromagnet . the starting point is the nearest - neighbor rvb state which plays the role of the vacuum of the theory , in a similar sense as the nel state is the vacuum for antiferromagnetic spin wave theory . we discuss the elementary excitations of this state and show that these are not fermionic spin-1/2 ` spinons ' but spin-1 excited dimers which must be modeled by bond bosons . we derive an effective hamiltonian describing the excited dimers which is formally analogous to spin wave theory . condensation of the bond - bosons at zero temperature into the state with momentum @xmath0 is shown to be equivalent to antiferromagnetic ordering . the latter is a key ingredient for a microscopic interpretation of zhang s so(5 ) theory of cuprate superconductivity . 2

SECTION 1. SHORT TITLE. This Act may be cited as the ``Life Sciences Jobs and Investment Act of 2010''. SEC. 2. INCREASED CREDIT FOR INITIAL LIFE SCIENCES RESEARCH. (a) In General.--Subsection (h) of section 41 of the Internal Revenue Code of 1986 is amended by redesignating subsection (h) as subsection (i) and inserting after subsection (g) the following new subsection: ``(h) Special Rules for Increased Initial Life Sciences Research.-- ``(1) In general.--In the case of qualified initial life sciences research expenses for any taxable year with respect to which the taxpayer elects the application of this subsection-- ``(A) Increased credit.--Subsection (a) shall be applied by substituting `40 percent' for `20 percent'. ``(B) Amounts paid for qualified life sciences research to certain research incubators, eligible small businesses, universities, and federal laboratories.-- Subsection (b)(3)(A) shall be applied by substituting `100 percent' for `65 percent', in the case of amounts paid or incurred to a qualified research incubator, or to persons described in subclause (I), (II), or (III) of subsection (b)(3)(D)(i), for qualified life sciences research. ``(C) Alternative simplified credit in case of initial qualified life science research.-- ``(i) Subsection (c)(5)(A) shall be applied by substituting `28 percent' for `14 percent', and ``(ii) subsection (c)(5)(B) shall be applied by substituting `12 percent' for `6 percent'. ``(2) Definitions.--For purposes of this subsection-- ``(A) Qualified initial life sciences research expenses.--The term `qualified initial life sciences research expenses' means so much of the amounts taken into account under subsection (a) as are attributable to qualified life sciences research and do not exceed $150,000,000. ``(B) Qualified life sciences research.--The term `qualified life sciences research' means any qualified research with respect to the branch of knowledge or study of biology, biochemistry, biophysics, bioengineering, microbiology, genetics, or physiology (in each case as such knowledge or study relates to human beings), except that the term does not include sociology or psychology. ``(C) Qualified research incubator.--The term `qualified research incubator' means any entity created by and operated under State law exclusively to conduct qualified life sciences research on behalf of the taxpayer and 1 or more unrelated taxpayers. ``(3) Coordination with 965A.--This subsection shall not apply with respect to any taxpayer for any taxable year for which an election is in effect under section 965A (relating to limited deduction for life sciences jobs and investment in United States). ``(4) Election.--Any election under this subsection shall be made in such manner as may be prescribed by the Secretary, and shall be made with respect to a taxable year not later than the due date (including extensions of time) for filing the taxpayer's return for such taxable year. ``(5) Termination.--This subsection shall not apply to any taxable year beginning after December 31, 2015.''. (b) Effective Date.--The amendments made by this section shall apply to taxable years beginning after the date of the enactment of this Act. SEC. 3. INCENTIVES TO INVEST IN LIFE SCIENCES JOBS, RESEARCH, AND FACILITIES. (a) In General.--Subpart F of part III of subchapter N of chapter 1 of the Internal Revenue Code of 1986 (relating to controlled foreign corporations) is amended by adding at the end the following new section: ``SEC. 965A. LIMITED DEDUCTION FOR LIFE SCIENCES JOBS AND INVESTMENT IN UNITED STATES. ``(a) Deduction.-- ``(1) In general.--In the case of a corporation which is a United States shareholder and for which the election under this section is in effect for the taxable year, there shall be allowed as a deduction an amount equal to 100 percent of the cash dividends which are received during such taxable year by such shareholder from controlled foreign corporations. ``(2) Dividends paid indirectly from controlled foreign corporations.--If, within the taxable year for which the election under this section is in effect, a United States shareholder receives a cash distribution from a controlled foreign corporation which is excluded from gross income under section 959(a), such distribution shall be treated for purposes of this section as a cash dividend to the extent of any amount included in income by such United States shareholder under section 951(a)(1)(A), including as a result of any cash dividend during such taxable year to-- ``(A) such controlled foreign corporation from another controlled foreign corporation that is in a chain of ownership described in section 958(a), or ``(B) any other controlled foreign corporation in such chain of ownership from another controlled foreign corporation in such chain of ownership, but only to the extent of cash distributions described in section 959(b) which are made during such taxable year to the controlled foreign corporation from which such United States shareholder received such distribution. ``(b) Limitations.-- ``(1) In general.--The amount of dividends taken into account under subsection (a) shall not exceed the lesser of-- ``(A) $150,000,000, or ``(B) the amount shown on the applicable financial statement as earnings permanently reinvested outside the United States. The amounts described in subparagraph (B) shall be treated as being zero if there is no such statement or such statement fails to show a specific amount of such earnings. ``(2) Requirement to invest in life sciences.--Subsection (a) shall not apply to any dividend received by a United States shareholder unless the amount of the dividend is invested solely in the United States and solely for the purpose of-- ``(A) the new hiring of additional scientists, researchers, and comparable personnel engaged in qualified life sciences research, ``(B) payments to universities, qualified research incubators, and other qualified organizations which are used by such organizations to conduct qualified life sciences research, or ``(C) the building or leasing of new facilities to be used in the conduct of qualified life sciences research. ``(3) Prohibited uses.--Subsection (a) shall not apply to any dividend any amount of which is used by the taxpayer to pay remuneration for services of any covered employee (as defined in section 162(m)(3)), to pay dividends to the shareholders of the taxpayer, or to pay interest or principal on any debt security of the taxpayer. ``(4) No reserve.--Subsection (a) shall not apply to any dividend if the taxpayer's compliance with this section is uncertain and requires a provision or reserve on the taxpayer's applicable financial statements. ``(5) Separate account.--Subsection (a) shall not apply to any dividend unless the amount of the dividend is held in a separate account, trust, or other arrangement that segregates the amount from other funds of the taxpayer until the amount is used solely for the purposes described in paragraph (2). ``(c) Substantiation of Compliance.-- ``(1) In general.--The taxpayer must substantiate its compliance with subsection (b) with written documents and such other credible evidence as the Secretary may reasonably require, and shall bear the burden of proof with respect to such substantiation. ``(2) Certification.--The chief executive officer and the independent director serving as head of the audit committee of the taxpayer, or comparable corporate officials, shall attest in writing to the taxpayer's compliance with each of the requirements of subsection (b). ``(d) Definitions and Special Rules.--For purposes of this section-- ``(1) Qualified life sciences research; qualified research incubator.--The terms `qualified life sciences research' and `qualified research incubator' shall have the respective meanings given such terms by section 41(d). ``(2) The term `qualified organization' means any organization described in subparagraph (A), (B), or (C) of section 41(e)(6). ``(3) The term `applicable financial statement' and `dividend' shall have the respective meanings given such terms by section 965(c). ``(4) Rules similar to the rules of paragraph (3) of section 965(b) shall apply for purposes of this section, except that such paragraph shall be applied by substituting `December 31, 2009' for `October 3, 2004'. ``(5) Rules similar to the rules of paragraphs (4) and (5) of section 965(c) shall apply for purposes of this section, except that such paragraph (5) shall be applied-- ``(A) by substituting `$150,000,000' for `$500,000,000', and ``(B) without regard to the reference to subparagraph (C) of section 965(b)(1). ``(e) Denial of Foreign Tax Credit.-- ``(1) No credit shall be allowed under section 901 for any taxes paid or accrued (or treated as paid or accrued) with respect to any dividend with respect to which an election is in effect under this section and which is included in income under section 951(a)(1)(A). ``(2) No deduction shall be allowed under this chapter for any tax for which credit is not allowable by reason of paragraph (1). ``(f) Election.--Any election under this section shall be made in such manner as may be prescribed by the Secretary, and shall be made with respect to a taxable year not later than the due date (including extensions of time) for filing the taxpayer's return for such taxable year. ``(g) Termination.--This section shall not apply to any taxable year beginning after December 31, 2015.''. (b) Clerical Amendment.--The table of sections for subpart F of part III of subchapter N of chapter 1 of such Code is amended by adding at the end the following new section: ``Sec. 965A. Limited deduction for life sciences jobs and investment in United States.''. (c) Effective Date.--The amendments made by this section shall apply to taxable years beginning after the date of enactment.

Life Sciences Jobs and Investment Act of 2010 - Amends the Internal Revenue Code to allow: (1) an increased research tax credit for qualified initial life sciences research expenses; and (2) certain corporations a tax deduction for investments in the United States to hire scientists and researchers engaged in life science research and to fund life science research at universities, qualified research incubators, and other qualified organizations. Terminates such tax incentives after 2015. Defines "qualified initial life sciences research expenses" as amounts, up to $150 million, attributable to the study of biology, biochemistry, biophysics, bioengineering, microbiology, genetics, or physiology, but excluding sociology or psychology.

a complete theory of stochastic processes was formulated by a.n . kolmogorov in 1933 @xcite . it included the characterization of stochastic processes in terms of finite - dimensional distribution functions @xcite . since the early xxth century , it had been clear that the theory of stochastic processes has important applications in electronics and communications , for the basic understanding of devices such as vacuum tubes and , later , solid state diodes and transistors as well as for the behavior of cable and wireless communication systems . in particular , it turned out that noise can be described in terms by equations like the following one @xmath0 where @xmath1 is the current produced by an electron reaching the anode of a vacuum tube at time @xmath2 , the @xmath3-th electron arrives at a random time @xmath4 and the series ( [ shotnoise ] ) is supposed to converge . s.o . rice gave an account of the early developments in a bell labs monograph published in 1944 @xcite . rice considers the example of the so - called random telegraph noise ( rtn ) or random telegraph signal ( rts ) , a stationary dichotomous noise where a current or a voltage randomly flips between two levels @xmath5 as shown in fig . 1 and flip events follow a poisson process . an early treatment of random telegraph signals can be found in kenrick s paper of 1929 @xcite . according to rice , kenrick was one of the first authors to use correlogram methods to compute the power spectrum of a signal @xmath6 . this was done by first obtaining the autocorrelation function @xmath7 ) ( x(t+\delta t ) - \mathbb{e } [ x(t+\delta t)])],\ ] ] where @xmath8 $ ] denotes the expected value of the random variable @xmath9 . based on results by wiener , khintchin and cramr , it is possible to show that , for a stationary signal when @xmath10 only depends on the lag @xmath11 , the power spectrum is the fourier transform of the autocorrelation function @xcite : @xmath12 for rts with @xmath13 and unitary average waiting time ( a.k.a . duration ) , one gets @xmath14 a results which will be derived below for positive @xmath11 , leading to a lorentzian power spectrum @xmath15 even if very simple , rts has interesting applications in different fields . a complete survey of the literature on rts and its applications is beyond the scope of the present paper . however , it is interesting to remark that rts has been used to explain 1/@xmath16 noise in electronic devices . indeed , a. mc whorter showed that an appropriate superposition of lorentzian spectra for rtss of different average duration gives 1/@xmath16 noise @xcite . more recently , p. allegrini _ et al . _ studied non - poisson dichotomous noise @xcite . their paper is particularly relevant here , as a particular case of non - poisson dichotomous noise is studied below in some detail , namely a generalized rts where waiting times between consecutive level changes follow a mittag - leffler distribution . this particular process never reaches a stationary state in finite time and , for this reason , standard spectral methods fail to properly represent its properties . our paper is organized as follows . in section ii , devoted to theory , the stationary case is briefly reviewed . then some tools are introduced taken from renewal theory . these methods lead to a general formula for the autocovariance function of a generalized rts . this is given at the beginning of section iii where the formula is then specialized to the case of mittag - leffler dichotomous noise . a comparison between analytical results and monte carlo simulations concludes this section . section iv contains a summary of results as well as some directions for future work . graphical representation of a rts.,width=15 ] the _ random telegraph signal _ is a simple _ compound renewal process_. a random variable @xmath6 can assume two opposite values , say @xmath17 , it starts with value , say , @xmath18 for @xmath19 and it suddenly changes value assuming the opposite one at time instants @xmath20 with the differences @xmath21 independently and exponentially distributed with common intensity @xmath22 . the probability density function of these differences is @xmath23 . if @xmath24 denotes the number of switches up to time @xmath2 , the probability @xmath25 of having @xmath26 jumps up to time @xmath2 is given by the poisson distribution : @xmath27 . the random telegraph signal is a time - homogeneous stochastic process , therefore the autocovariance function : @xmath28\ ] ] does not depend on @xmath2 , but only on the lag @xmath11 . a way to generalize exponential waiting times and the poisson process is provided by _ renewal theory_. a _ renewal process _ is a particular instance of one - dimensional _ point process_. renewal events occur at consecutive times @xmath29 and the differences @xmath21 are independent and identically distributed random variables . they are called _ durations _ or _ waiting times_. the _ counting process _ @xmath24 related to a renewal process is the positive integer giving the number of renewals up to time @xmath2 . @xmath30 denotes the probability of observing @xmath31 . renewal theory is discussed in great detail in the book by feller @xcite and in two monographs , one by cox and the other by cox and isham @xcite . an account for physicists also exists @xcite . the probability distribution @xmath30 can be related to the probability density , @xmath32 , of waiting times . it is sufficient to observe that @xmath33 , the instant of the @xmath26-th renewal event is also a random walk ( in this case the sum of i.i.d . positive random variables ) : @xmath34 and the probability of having @xmath26 jumps up to time @xmath2 coincides with the probability of @xmath35 ( @xmath26 jumps up to @xmath33 and no jumps from @xmath33 to @xmath2 ) : @xmath36 ( t)\,,\ ] ] where @xmath37 represents the convolution operator , @xmath38 is the @xmath26-fold convolution of the density @xmath32 and @xmath39 is the complementary cumulative distribution function ( a.k.a . survival function ) . a continuous time random walk ( ctrw ) with exponentially - distributed waiting times and poisson - distributed counting process is markovian , moreover it has stationary and independent increments and , therefore , belongs to the class of lvy processes @xcite . the exponential distribution is the only continuous memoryless distribution . in this case , the counting probability distribution @xmath40 of observing @xmath26 jumps from a generic instant @xmath2 to instant @xmath41 coincides with @xmath42 , that is the probability of observing @xmath26 jumps from @xmath43 to @xmath11 . in the general case , this is not true and @xmath40 explicitly depends on @xmath2 @xcite . in order to obtain @xmath40 , one needs to know the distribution of the _ forward recurrence time _ a.k.a _ residual life - time _ @xmath44 , the time interval between @xmath2 and the next renewal event . if @xmath45 denotes the probability density function of the residual life - time , one has @xmath46 ( \delta t ; t ) = \int_{0}^{\delta t } g(y;t ) p(n-1,\delta t - y)\,dy\,,\ ] ] because the probability of @xmath26 jumps occurring from instant @xmath2 to instant @xmath47 is given by the probability of @xmath48 and @xmath49 . the probability density function of the residual life - time @xmath45 can be written in terms of the _ renewal density _ @xmath50 . the renewal density is the time derivative of the average number of counts up to time @xmath2 , the so - called _ renewal function _ , @xmath51 , that is the average value of the random variable @xmath24 : @xmath52 $ ] , and @xmath53 . the renewal density is a measure of the activity of the renewal process . for the poisson process and exponentially distributed waiting times @xmath50 is a constant and coincides with the inverse of the average waiting time or the average number of events per time unit , in other words , @xmath54 . it can be shown that @xcite @xmath55 and that the density @xmath45 is given by @xcite @xmath56 f. mainardi and r. gorenflo , together with one of the authors of the present paper have studied the renewal process of mittag - leffler type @xcite . it is characterized by the following survival function @xmath57 where @xmath58 is the one - parameter mittag - leffler function @xmath59 where @xmath60 is euler gamma function . the mittag - leffler function is a legitimate survival function for @xmath61 , @xmath62 , @xmath63 and coincides with the exponential for @xmath64 . the mittag - leffler survival function interpolates between a stretched exponential for small values of @xmath65 and a power law for large values of @xmath65 . in particular , for @xmath66 one has : @xmath67 and for @xmath68 @xmath69 let us now consider a generalized random telegraph signal with durations that do not necessarily follow the exponential distribution . as the signal has zero mean , the autocovariance function @xmath70 $ ] coincides with the autocorrelation function . throughout this paper , autocovariance functions will not be normalized . the generalized rts is not a time - homogeneous ( stationary ) random process and the autocovariance function does depend on the initial time of evaluation . in particular , one gets @xmath71= a^2 \sum_{n=0}^{\infty } ( -1)^n p(n,\delta t ; t).\ ] ] equation ( [ autocorrns ] ) is a consequence of the fact that , in the time interval between @xmath2 and @xmath47 , with probability @xmath40 , there can be an arbitrary , but finite , integer number @xmath26 of renewal events where the process of amplitude @xmath72 changes sign . as @xmath40 is available from equations ( [ distribution2 ] ) , ( [ renewalequation ] ) and ( [ lifetimedistribution ] ) , in principle , one can compute the _ time dependent _ autocovariance from the knowledge of the distribution of waiting times . however , the use of convolutions is painful and some analytical progress is possible by means of the method of laplace transforms . given a sufficiently well - behaved ( generalized ) function @xmath73 with non - negative support , the laplace transform is given by @xmath74 ( a generalized function is a distribution in the sense of sobolev and schwartz @xcite ) . here , the method of the double laplace transform described by cox turns out to be very useful @xcite . let us denote by @xmath75 the variable of the laplace transform with respect to @xmath11 or @xmath44 and by @xmath76 the variable of the laplace transform with respect to @xmath2 . then @xmath77 , the double laplace transform of the residual life - time density @xmath45 in ( [ lifetimedistribution ] ) , is given by @xmath78 now , one gets from equation ( [ distribution2 ] ) that @xmath79^{n-1 } \tilde{\psi } ( s ) = \frac{(\tilde{\psi } ( s ) - \tilde{\psi } ( u))(1+\tilde{h } ( u))}{u - s } [ \tilde{\psi}(s)]^{n-1 } \tilde{\psi } ( s).\ ] ] the double inversion of the laplace transforms in equation ( [ doublelaplacedistribution ] ) may be as a formidable task as the direct calculation of convolutions . however , equation ( [ doublelaplacedistribution ] ) can be used to investigate the asymptotic behaviour of @xmath80 for small and large values of @xmath2 by means of tauberian - like theorems @xcite . if the average waiting time @xmath81 $ ] is finite , then for @xmath82 , as a consequence of the _ renewal theorem _ , one has that @xmath83 and the renewal process behaves as a poisson process @xcite . this is not the case for the renewal process of mittag - leffler type where @xmath84 ( and @xmath85 ) . in other words , all the rtss following a renewal process with @xmath86<\infty$ ] reach a _ stationary state _ after an initial non - stationary transient ; in this stationary state , the autocovariance does no longer depend on @xmath2 . the rts of mittag - leffler type never reaches such a state . let us consider the case @xmath43 . equation ( [ autocorrns ] ) simplifies to @xmath87 using the laplace transform of the mittag - leffler survival function ( [ ml ] ) @xmath88 and of the corresponding density function @xmath89 @xcite , one gets : @xmath90 this laplace transform can be inverted to yield @xmath91 for @xmath92 this formula reduces to @xmath93 indeed , equation ( [ autocorrrts ] ) can be directly derived for a rts with intensity @xmath94 . in this case , @xmath95 , therefore from equation ( [ autocorrml0 ] ) one gets @xmath96 thus , equation ( [ autocorrml0an ] ) coincides with the autocovariance function for the usual rts when @xmath64 . the essential ingredient for monte carlo simulation of a rts of mittag - leffler type is the generation of mittag - leffler deviates . an efficient transformation method has been thoroughly discussed in @xcite based on the theory of geometric stable distributions @xcite . mittag - leffler distributed random numbers can be obtained using the following formula @xcite : @xmath97 where @xmath76 and @xmath98 are real random numbers uniformly distributed in @xmath99 . for @xmath92 ( [ rachev ] ) gives exponentially distributed waiting times with @xmath100 . once a method for generating mittag - leffler deviates is available , the monte carlo simulation of an uncoupled ctrws is straightforward . it is sufficient to generate a sequence of @xmath101 independent and identically distributed waiting times @xmath102 until their sum is greater than @xmath2 . then the last waiting time can be discarded and @xmath103 alternate signs are generated . a monte carlo realisation starts , say , at @xmath104 , then at time @xmath105 the process flips to the new value @xmath106 and stays there for @xmath107 with @xmath108 , and so on . in fig . 2 , monte carlo estimates of the autocovariance function @xmath109 are compared to formula ( [ autocorrml0an ] ) for several values of @xmath110 and @xmath111 . the estimates have been produced using an _ ensemble _ average estimator . for each of 10000 values of @xmath11 , @xmath112 values of the product @xmath113 have been produced . the sampling frequency is assumed to be 1/1000 , so that the total length of the signal is 10 arbitrary units ( seconds ) . a direct eye inspection shows that the agreement between simulations and theory is excellent . 3 shows the effect of non - stationarity . the autocovariance functions @xmath114 are compared for @xmath115 , @xmath111 and several values of @xmath2 . for @xmath43 , the theoretical line is plotted . the dependence of the autocovariance function on the choice of @xmath2 points to the fact that standard spectral methods routinely used in signal analysis would fail in this case . ( color online ) monte carlo estimates of the autocovariance function @xmath109 ( red irregular lines ) compared to the exact result in equation ( [ autocorrml0an ] ) ( blue smooth lines ) for several values of @xmath110 and @xmath111 . time is in arbitrary units called seconds . the autocovariance functions are not normalized . ] ( color online ) non - normalized autocovariance functions @xmath114 for @xmath115 , @xmath111 and several values of @xmath2 . time is measured in arbitrary units called seconds . ] the main result of this paper is given in equation ( [ autocorrns ] ) for the autocovariance function of a generalized rts , the double laplace transform of the probability distribution @xmath80 is given in ( [ doublelaplacedistribution ] ) ; these results are further specialized to a rts of mittag - leffler type in equation ( [ autocorrml0an ] ) . the derivation of such equations is based on renewal theory . the analytical result in equation ( [ autocorrns ] ) is then successfully compared to monte carlo simulations . an important feature of a rts of mittag - leffler type is that the renewal density @xmath50 of the mittag - leffler renewal process vanishes for @xmath82 for @xmath116 . therefore , the hypoteses of the renewal theorem are not satisfied and the stationary regime is never reached . therefore , contrary to other renewal processes , such as the weibull process , that , after a transient , become stationary , the renewal process of mittag - leffler type is non - stationary also if it is observed far from its beginning . in particular , standard spectral methods fail to describe the features of the rts of mittag - leffler type . these considerations may be useful when studying the origin of 1/@xmath16 noise , a problem not addressed here but which will be the subject of a future paper . indeed , the renewal process of mittag - leffler type can be described as an infinite mixture of exponential distributions , for instance , one has for the survival function @xmath117 where @xmath118 therefore , based on the ideas developed in @xcite , one already expects to have a power spectrum following a power law . using the fact that @xmath119 = \int_{-\infty}^{+\infty } e_{\beta } \left ( -2 |v|^{\beta } \right ) \exp(i \omega v ) dv,\ ] ] one gets @xmath120,\ ] ] and the power spectrum for @xmath43 can be evaluated from equation ( [ autocorrml0lt ] ) . it turns out that @xmath121 = a^2 \frac{4 \omega^{\beta -1 } \sin ( \beta \pi/2)}{4 + 4 \omega^{\beta } \cos ( \beta \pi/2 ) + \omega^{2 \beta}}\ ] ] once again , it must be stressed that , due to non - stationarity , the power spectrum depends on @xmath2 and not only on the lag @xmath11 . e. scalas , r. gorenflo , f mainardi , phys . e , * 69 * , 011107 , ( 2004 ) . f. mainardi , r. gorenflo and e. scalas , vietnam journal of mathematics , * 32 * si , 53 , ( 2004 ) . f. mainardi , r. gorenflo , a. vivoli , fractional calculus and applied analysis , * 8 * , 7 , ( 2005 ) . s. kotz , t. j. kozubowski , and k. podgorski , _ the laplace distribution and generalizations : a revisit with applications to communications , economics , engineering , and finance _ , ( birkhuser , boston , 2001 ) .

a general method is presented to explicitly compute autocovariance functions for non - poisson dichotomous noise based on renewal theory . the method is specialized to a random telegraph signal of mittag - leffler type . analytical predictions are compared to monte carlo simulations . non - poisson dichotomous noise is non - stationary and standard spectral methods fail to describe it properly as they assume stationarity .

ngc4388 ( @xmath2 ) is a nearly edge - on ( @xmath3 ) spiral galaxy hosting a seyfert 2 nucleus ( phillips & malin 1982 ; filippenko & sargent 1985 ) , located near the core of the virgo cluster . the recession velocity measured for this galaxy ( 2540 ) is much higher than the cluster mean velocity ( 1100 ) . this suggests that the galaxy is moving away from us through the intracluster medium ( icm ) at a supersonic speed , and an interaction between the galaxy and icm has been suspected , particularly in the context of ram - pressure stripping of the interstellar medium ( chamaraux et al 1980 ; giovanelli & haynes 1983 ; kenney & young 1986 ; petitjean & durret 1993 ; veilleux et al 1999 ) . radio images show a compact double central source and a plume extending to the north ( stone , wilson & ward 1988 ; hummel & saikia 1991 ; falcke , wilson & simpson 1998 ) . no broad emission component was found in optical spectropolarimetric observations of the nucleus ( kay 1994 ) . however , the somewhat controversial detection of off - nuclear broad h@xmath1 emission by shields & filippenko ( 1988 ) led to the idea of an obscured seyfert 1 nucleus in ngc4388 . unambiguous confirmation of the hypothesis came from hard x - ray observations by which a strongly absorbed ( @xmath4 ) x - ray source has been detected ( hanson et al 1990 ; iwasawa et al 1997 ; forster , leighly & kay 1999 ; bassani et al 1999 ) . the presence of extended optical emission - line nebulae in ngc4388 has been known for a few decades ( ford et al 1971 ; sandage 1978 ; colina et al 1987 ; pogge 1988 ; corbin , baldwin & wilson 1988 ; veilleux et al 1999 ; yoshida et al 2001 ) . besides the low excitation optical emission extending along the galaxy disk , which probably traces active star forming regions , the high excitation extended emission above the galactic plane has been of great interest in connection with its kinematics and ionization mechanism . until recently , the extraplanar ionized gas was known to extend up to 4 kpc from the nucleus , but the wide - field images obtained from the subaru suprimecam show optical filaments extending up to 35 kpc to the north - east ( yoshida et al 2001 ) . studies of the excitation conditions in this extraplanar nebula suggest that it is likely to be photoionized by the central active nucleus , although some contribution by shock excitation has been claimed recently ( ciroi et al 2003 ) . the required ionizing luminosity is estimated to be of the order of @xmath5(colina 1992 ; kinney et al 1991 ; yoshida et al 2001 ) . the soft x - ray emission of ngc4388 was first shown to be extended from a rosat hri observation ( matt et al 1994 ) . however , the details of the extended x - ray emission and its origin have been unclear . in this paper , we present an imaging observation with the chandra x - ray observatory ( weisskopf et al 2000 ) , which reveals the detailed morphology of the extended x - ray nebula and spectral variations across the nebula , as well as the active nucleus seen in hard x - rays . the distance of the galaxy is assumed to be 16.7 mpc throughout this paper . the angular scale is then @xmath6 pc arcsec@xmath7 ( or 12 arcsec corresponding to 1 kpc ) . ngc4388 was observed with the chandra acis detectors on 2001 june 8 . the nucleus of the galaxy was positioned on the acis - s3 detector . the focal plane temperature for this observation was @xmath8c . the data reduction was carried out using the ciao 2.2 package and calibration files in caldb version 2.10 . the data at the position of the nucleus of ngc4388 are affected by photon pile - up ( the estimated pile - up fraction is about 10 per cent ) . the detector background of acis - s3 during this observation was relatively stable . the analysis for the emission at small radii was performed using the data of the full exposure of 20 ks . however , for extended emission found at larger radii , we filtered the event file using the 2.57 kev light curve from a source - free region on the s3 chip . data taken in periods when the background counts deviate by more than 20 per cent from the mean value have been discarded , which results in an exposure time of 14 ks for analysis . the spectral analysis was performed using xspec version 11 . the time dependent degradation of the acis sensitivity at low energies have been corrected with acisabs by chartas & getman . the total background - corrected observed fluxes are estimated to be @xmath9 in the 0.52 kev band , and @xmath10 in the 27 kev band . the composite x - ray image of the central part of ngc4388 , produced from the three energy bands , 0.31 kev , 13 kev and 47 kev , is shown in fig . the active nucleus is located at the position of the hard x - ray peak indicated in blue . the soft x - ray emission shows complex morphology . particularly bright is a conical feature to the south . these soft x - ray features are discussed in detail in the following section . the active nucleus of ngc4388 is very faint below 4 kev in the chandra image and not visible below 1 kev , due to obscuration probably associated with gas in the edge - on stellar disk . strong emission is seen at energies above 4 kev . its spectral shape is consistent with a strongly absorbed source ( fig . the spectrum presented in fig . 2 was taken from within 1.5 arcsec radius of the hard x - ray peak . it can be broadly described as having a heavily absorbed power - law above 3 kev with fe k line features at 6.4 and near 7 kev and a flat component at low energies . as mentioned in section 2 , the nucleus is so bright that the data were affected by moderate photon pile - up ( estimated to be @xmath11 per cent ) . the main consequences of the photon pile - up are a hardening of the spectrum and a reduction in the detected flux . we correct for these effects using the pile - up model of davis ( 2001 ) . the absorption column density is found to be @xmath12(hereafter quoted errors are for a 90 per cent confidence range for one parameter of interest , unless stated otherwise ) , when the photon index of the power - law continuum is assumed to be 1.8 and a simple absorbed power - law is fitted to the 47.8 kev data . a deep fe k photoelectric absorption edge seen above 7.1 kev is consistent with the large absorption column density . a strong fe k@xmath1 line is found at an energy of @xmath13 kev ( hereafter quoted line energies are corrected for the galaxy redshift ) with an equivalent width of @xmath14 ev . the line flux is @xmath15 . this line is unresolved and the 90 per cent upper limit of the line width is fwhm @xmath16 . there is also an excess peak at @xmath17 kev with @xmath18 ev , and a less significant peak at @xmath19 kev with @xmath20 ev ( 90 per cent confidence detection ) . the estimated line fluxes for these lines are @xmath21 and @xmath22 , respectively . given the low pile - up fraction , these weak emission features ( at least the statistically robust one at 7 kev ) are unlikely to be artifacts of pile - up . a similar feature was detected at @xmath23 kev in the asca sis spectrum . fe k@xmath24 emission is predicted to be three times weaker than the observed value . it could be blended with fexxvi k@xmath25 at 6.97 kev from a highly ionized medium . a similar k@xmath1 line from hydrogen - like iron has been detected in the xmm - newton spectrum of the seyfert 2 galaxy mrk463 ( sanders et al 2003 in prep . ) . the presence of such a highly ionized fe line is consistent with the high ionization gas ( log @xmath26 ) hypothesized in the following section . extrapolating the absorbed power - law leaves a faint excess below 4 kev . the spectrum is nearly flat @xmath27 in the 0.52 kev band . this component is probably scattered light of the hidden active nucleus . as the soft x - ray image shows , the nucleus is very faint below 1 kev , suggesting further obscuration to the scattering region , in addition to the primary obscuration of the central source occuring probably at much smaller radii . the observed fluxes ( corrected for pile - up ) in the 0.52 kev and 27 kev bands are @xmath28 and @xmath29 , respectively . the estimated absorption - corrected 210 kev luminosity , excluding the iron line luminosity , is @xmath30 . this value is lower than the two previous asca observations in 1993 and 1995 ( iwasawa et al 1997 ; forster et al 1999 ) by a factor of 23 . the obscuration of the nuclear region affects the measurements of the position of the optical nucleus of this galaxy . the northern blob of the central double radio source has been considered to be the active nucleus , since it has a flat spectrum ( carral , turner & ho 1990 ) . the best registration of the radio and optical images obtained so far is the one by falcke et al ( 1998 , see the paper for detailed discussion ) for the vla and hst data . the positions of the hst red peak and the northern blob in the vla 3.5 cm map are in agreement to within 0.45 arcsec . our 47 kev image shows a strong point - like source with a faint envelope . in this energy band , the nucleus is largely free of obscuration and its position should coincide with the active nucleus . we have applied the latest aspect correction using the alignment files released in 2002 may by the chandra science center . with this aspect correction , the expected absolute positional accuracy is smaller than 0.6 arcsec . our 47 kev peak is located at r.a . = @xmath31 , dec . = @xmath32 ( j2000 ) , which is @xmath33 arcsec ne of the vla radio nucleus . given the uncertainties , the optical , radio and the x - ray positions are all in agreement . the soft x - ray emission is spatially extended and shows interesting morphology . the 0.31 kev image of the central @xmath34 , or @xmath35 kpc is shown , along with the x - ray colour map ( 0.71 kev / 0.40.7 kev ) in fig . some regions of interest are investigated separately below . basic data for these regions are summarized in table 1 . the soft x - ray ( 0.31 kev ) image shows a well - defined conical extension to the south ( fig . 1 , fig . 3a ) , resembling the [ oiii]@xmath36 ionization cone ( pogge 1988 ; falcke et al 1998 ; veilleux et al 1999 ; yoshida et al 2001 ) . the western side of the soft x - ray cone , in particular , has a sharp , straight boundary at @xmath37 . its apex is , however , slightly north of the hard x - ray peak . with the apex of the cone slightly displaced from the nuclear position ( 0.5 arcsec to the east , 2.5 arcsec to the north ) when extrapolated with the rims of the cone , the opening angle of the x - ray cone is measured to be @xmath38 . the surface brightness of the soft x - ray emission drops at the centre due to strong absorption , whilst at radii from the nucleus larger than 2 arcsec , where the brightness peaks , its profile shows an exponential decline ( @xmath39 $ ] , where @xmath40 is the radial distance from the hard x - ray nucleus in arcsec ) . an alternative description is with a king profile with a core radius of 5.7 arcsec ( or 460 pc ) and a slope index of @xmath41 . in either case , the soft x - ray emission reaches the background level at radii of 2025 arcsec ( 1.62 kpc ) , and there appears to be no further emission at larger radii to the south ( in contrast to the northerly direction ; see the following section ) . the acis - s spectrum of the southern cone is shown in fig . the spectral data were taken from a conical region in the radial range of 1.519 arcsec from the nucleus . the spectrum is dominated by soft x - ray emission below 3 kev . although the steep rise of the soft x - ray spectrum down to 0.5 kev can be approximated by a power - law form with photon index of @xmath42 , the most likely explanation for the soft x - ray emission is a blend of strong emission lines . modelling by thermal emission spectra ( from collisionally ionized plasma , e.g. , mekal , kaastra 1992 ) is not favoured on the following grounds . if the observed x - ray emission is due to collisionally ionized plasma , a likely origin is a galactic outflow driven by a nuclear starburst . circumstantial evidence against this hypothesis is that , although star formation is taking place in the spiral arms of the stellar disk ( pogge 1988 ) , there is no strong evidence for a compact nuclear starburst in ngc4388 . to drive a well - collimated outflow , as seen in the southern cone , a compact starburst region needs to be thermalized to form a high pressure core ( e.g. , chevalier & clegg 1985 ) , which does not appear to be the case in ngc4388 . spectral analysis does not support the thermal emission hypothesis either . a single temperature model fails to explain the strong ovii emission lines at 0.56 kev , even with non - solar abundance ratio . strong ovii is emitted from @xmath43 kev gas if it is collisionally ionized . since this low temperature gas does not emit much above 0.7 kev , a higher temperature gas is required to explain the data . a two - temperature model in which one component has a fixed temperature of @xmath44 kev and the other has a fitted temperature of @xmath45 kev gives a reasonable fit to the data up to 1.5 kev with @xmath46 for 39 degrees of freedom . this fit , however , underestimates the mg emission feature at 1.3 kev by a factor of 2 , and the si feature at 1.8 kev by a factor of 4 , on extrapolation . this modelling also has two significant problems : 1 ) the metallicity , which is assumed to be identical between the two components , is very low , @xmath47 solar . this is not consistent with the gas which should have been enriched by supernovae through a starburst ; 2 ) large internal absorption of @xmath48 is required . with the galactic dust - to - gas ratio , this implies visual extinction of @xmath49 mag . unlike the northern extension ( see section 4.2 ) , the southern cone is located well outside the obscuration and such a large extinction is unlikely to be present ( even the nuclear optical spectrum taken from inner radii shows a smaller reddening @xmath50 , petitjean & durret 1993 ) . we therefore explore the possibility of photoionized plasma , as postulated for the optical ionization cone . in terms of quality of the fit to the data , the photoionization model described below gives a better fit to the data in the same energy range ( 0.41.5 kev ) with @xmath51 for 40 degrees of freedom . high resolution x - ray spectra of photoionized gas in seyfert 2 galaxies obtained from grating spectrometers show many emission features from a broad range of ionization in the soft x - ray band ( e.g. , see kinkhabwala et al 2002 ; brinkman et al 2002 for xmm - newton rgs and chandra letgs data , respectively , of ngc1068 ; sako et al 2000 for mrk 3 ) . these emission lines are heavily blended together and mostly difficult to resolve at the spectral resolution of the ccd . this heavy line blending also makes an estimate of the underlying continuum difficult in a ccd spectrum , if it is present at all . therefore , we will not perform a detailed analysis here as one would accomplish with a high resolution grating spectrum , but instead only describe some key features characterizing the observed spectrum and present a possible model , which should be treated as a guide only . a few of the strongest emission - line peaks can be recognized in the data at 0.56 , 0.86 , 1.33 , 1.77 and 2.33 kev , for which the typical error in the line centroids is 0.04 kev and the significance of the detection is larger than 90 per cent confidence level . these correspond to the ovii triplet , a blend of various fe l emission , oviii radiative recombination continuum ( rrc ) and neix ( 0.92 kev ) , and low ionization ( iv viii ; for the ionization parameter inferred below ) lines of mg , si and s , respectively . these are all low ionization features , and the 0.40.9 kev data and the three discrete emission - lines above 1 kev are explained well with emission from optically thin gas with log @xmath52 ( here , we compare with model spectra generated by xstar version 2.1 by t. kallman , see kallman & bautista 2001 , for optically thin gas , illuminated by a power - law continuum between 13.6 ev and 50 kev with a photon - index of 1.8 . the ionization parameter is defined as @xmath53 erg cm s@xmath7 , where @xmath54 is the 11000 ryd luminosity , @xmath55 is the density and @xmath56 is the distance from the ionizing source . xstar calculates physical conditions for a spherical gas shell by solving radiative transfer . the quoted value for @xmath57 is for the inner edge of the shell . therefore the calculated spectra include emission from a range of @xmath57 lower than the quoted value from outer radii ) . this fit requires no significant excess absorption by cold gas above the galactic value ( @xmath58 , dickey & lockman 1990 ) . the only significant residual below 0.9 kev is an excess at 0.65 kev , which could be oviii ly@xmath1 , indicating the presence of higher ionization gas . the 0.93 kev data unexplained by the above @xmath59 emission , apart from the mg , si and s emission lines , may be emission and scattered continua from highly ionized , low density gas , as suggested by the excess oviii at 0.65 kev . unfortunately , there is no other significant detection of spectral signatures , which could be used to constrain the ionization parameter . if fexxv at 6.7 kev , possibly present in the hard x - ray spectrum ( see section 5.1 ) , is real and originates from the same medium as the oviii emission , then the ionization parameter @xmath60 would be a few thousands . for example , the spectrum from high ionization gas with @xmath61 , when combined with the low ionization ( log @xmath62 ) spectrum , can provide a reasonable fit to the 0.43 kev data ( see fig . this high ionization spectrum has broader radiative recombination continua due to high temperature of the gas ( @xmath63 k ) , as well as high ionization lines , which could fill the continuum between the emission lines of low ionization spectrum . a possible alternative which would play the same role is the soft x - ray excess component of the reflection spectrum , which is seen in the hard x - ray band ( see e.g. , ross , fabian & young 2000 for a computed reflection spectrum from mildly ionized matter ) . further investigation is , however , beyond the capability of the present ccd spectrum . in summary , low ionization ( log @xmath52 ) photoionized gas appears to be a plausible explanation for prominent soft x - ray spectral features ; another component , which could be highly ionized ( log @xmath64 ) gas , is required , although its origin is not clear . it should , however , be noted that this two - component photoionization model is only an approximation required to describe the spectrum at the ccd resolution with limited signal - to - noise ratio , from which only a few strong emission features can be recognized . emission features from photoionized gas with a broad range of ionization parameter are likely to be present and would be detected in a high resolution spectrum . there are significant spectral changes within the southern cone ( see fig . spectra from radial ranges of 1.57 arcsec ( 0.10.6 kpc ) and 719 arcsec ( 0.61.5 kpc ) are compared ( cf . the [ oiii]/h@xmath65 maximum occurs at 3 arcsec from the nucleus , falcke et al 1998 ; veilleux et al 1999 ) . at the low energy end , the spectrum from the larger radii is slightly softer than that from the inner part . the spectral softening at larger radii can be explained by a slight increase in ionization parameter for the low ionization gas , or a decrease in absorption , or both . in the second case , with a constant ionization parameter of log @xmath62 , a marginal excess absorption ( @xmath66 ) above the galactic value is found for the inner part while no excess absorption is required for the outer part . in contrast to the southern extension , the inner part on the north side of the nucleus ( within @xmath67 arcsec , or 1.2 kpc ) is faint in the soft x - ray ( 0.31 kev ) band . however , the appearance of the image changes dramatically in the higher energies . in the 12 kev band , the northern and southern extensions show comparable brightness , apart from at very inner radii ( fig . 5 ) . this is also demonstrated by radial profiles in the two energy bands ( fig . this change in appearance of the x - ray image can be understood as a result of obscuration toward the northern extension ( and the nucleus ) . the soft x - ray spectrum taken from the radial range of 311 arcsec ( 0.20.9 kpc ) to the north of the nucleus is shown as `` n plume '' in fig . 4 . in comparison with the southern cone spectrum , the soft x - ray excess below 0.9 kev is much less pronounced , and the low ionization emission lines from mg and si in the 12 kev range are stronger relative to the emission complex at lower energies . the data can be modelled by the same combination of low and high ionization gases as used for the southern cone spectrum ( see section 4.1 ) but with a larger absorption column density of = @xmath68(the model is shown in solid histogram together with the data in fig . 4 ) . combining with the radial surface brightness profiles in fig . 6 , it can be argued that , in the absence of absorption , the nebulae to the north and south would share similar brightnesses and possibly ionization conditions . ngc4388 is viewed nearly edge - on , with the near side of the stellar disk being tilted upward by @xmath69 ( see fig . 5 of veilleux et al 1999 ) . this enables us to have a clear view of the sw cone . on the other hand , the tilted near side of the disk blocks our line of sight towards the northern extension , suppressing low energy x - ray emission through photoelectric absorption . probably we see the northern extended x - ray emission through the stellar disk for which the inferred column density appears to be reasonable . there are a few morphological and spectral features to note on the northern extension : the 12 kev image ( fig . 5 ) shows that a relatively narrow bright filament emanates from the nucleus at @xmath70 before bending northwards at @xmath71 arcsec from the nucleus , past which point the filament opens up , similar to the radio plume imaged with the vla ( falcke et al 1998 ) . besides the bright southern cone and the northern extension at small radii , lower surface brightness soft x - ray emission is seen in the radial range of 14 kpc from the nucleus . the extension is to the east along the stellar disk , to the west with a bent morphology , and to the north - east , as shown in fig . 3a . although there is possible evidence for spectral variations across the low surface brightness emission ( fig . 3b ) , limited statistics due to the short exposure of our observation prevent us from dividing the low surface brightness emission into multiple regions and analysing their spectra separately . the soft x - ray spectrum integrated over this region is shown in fig . 4 as `` lsb '' . although , as cautioned above , the photoionization model should be taken as only a guide , the spectrum favours a higher ionization parameter of log @xmath72 for the low ionization gas than that for the southern cone . a large absorption of @xmath73 is required . it should also be noted that the emission extended along the stellar disk might be different in origin . as the optical h@xmath1 image and the excitation map ( corbin et al 1988 ; veilleux et al 1999 ; yoshida et al 2001 ) show , this region is the site of intense star formation in the spiral arms , and the soft x - ray emission could originate in thermal hot gas with a temperature of a few million k. the spectrum there lacks the strong ovii feature at 0.55 kev , but the quality of the present data can not provide a clear answer to the question of whether the gas is collisionally- or photo - ionized . to the north - east , the soft x - ray image shows three shell - like structures , aligned parallel to each other with an approximate separation of 10 arcsec , or 0.8 kpc ( fig . they are located in the radial range of 1440 arcsec ( 1.13.2 kpc ) from the nucleus at pa@xmath74 , and coincide with the location of the [ oiii ] north - east complex ( e.g. , veilleux et al 1999 ) . the colour map ( fig . 3b ) shows that the three - shell region has a harder spectrum than the surroundings . in fact , the shell structure is clearer in the 0.71 kev image than in the 0.40.7 kev image . the large - scale image in the 0.32.5 kev band is shown in fig . the original image was produced from the entire acis - s3 chip with 5 arcsec binning . in this energy band , the virgo cluster emission is significant . the background obtained from a source - free region on the same detector was assumed to be constant over the field . after subtracting the background , the image has been adaptively binned so that each pixel has a signal - to - noise ratio larger than 2.5 . very low surface brightness emission extends to the north - east beyond the region shown in fig . 3 . there is a low sensitivity belt on the detector due to the ccd node boundary , which extends in @xmath75 at around 1.8 arcmin ( @xmath76 kpc ) from the nucleus . including this sensitivity gap , extended emission with significance above @xmath77 reaches 3.3 arcmin ( @xmath78 kpc ) from the nucleus . it coincides with the region where emission - line filaments are seen in both the h@xmath1 and [ oiii ] images taken by the subaru suprime - cam ( yoshida et al 2001 ) . the radial surface brightness profile of the 0.32.5 kev emission to the north - east ( in the p.a . range between @xmath79 and @xmath80 ) can be fit well with a power - law ( @xmath81 ; @xmath40 in kpc ) with @xmath82 . a fainter excess is seen further out at pa@xmath83 , 4 arcmin ( 20 kpc ) away from the nucleus , where there is a bright complex of h@xmath1 knots , which is a part of the subaru 35-kpc - long filament ( yoshida et al 2001 ) . however , the significance of this x - ray excess is just above @xmath84 . the spectrum taken from the region between 4 kpc and 9 kpc in radius is shown in fig . 4 ( as `` ne vlsb '' ) . no significant emission is detected above 2 kev . two prominent emission lines from low ionization mg and si at 1.3 and 1.8 kev , respectively , are seen in the 1 2 kev range . the inferred ionization parameter is found to be slightly low at log @xmath85 with galactic absorption . [ cols="<,^,^,^,^ " , ] the 47 kev emission is highly concentrated around the nucleus ( approximately 90 per cent of the total 47 kev flux comes from the central 2 arcsec in radius ) but marginally resolved . the surface brightness distribution of the hard x - ray emission is found to be skewed slightly to the north at low brightness levels ( see also the following subsection on the fe k@xmath1 emission ) . although the asymmetry suggests that the extension is real , since the point spread function ( psf ) of the chandra optics ( hrma ) has a broad low - level wing at high energies , we have examined the radial distribution of the hard x - ray emission . fig 9 shows radial surface brightness profiles in the 47 kev band , taken from northern and southern regions divided at p.a . of 80@xmath86 and 255@xmath86 to compare with the psf ( nb . the northern region overlaps the southern cone slightly at its inner western edge ) . we note that the photon pile - up at the nucleus results in a slightly diluted core . the innermost bins of the two observed profiles have been increased by 10 per cent as an approximate correction for pile - up . a psf was simulated at the monochromatic energy of 6.4 kev for the same position on the detector as that of the hard x - ray nucleus , using the standard psf library in ciao . the total hard x - ray spectrum peaks at the fe k@xmath1 band ( 6.16.6 kev ) , which carries @xmath87 per cent of the observed 47 kev counts . because the off - axis angle of the source is small ( 0.65 arcmin ) and 6.4 kev is close to the higher end of the bandpass , the simulated psf can be regarded as a conservative estimate of the psf for the 47 kev emission . while the radial profile for the southern half is consistent with the psf , the northern half shows significant excess emission above the psf but reaches the background level at around 30 arcsec ( @xmath88 kpc ) . the origin of the extended hard x - ray emission is probably some form of reflection of the hidden active nucleus , as suggested by the hard spectrum ( fig . this appears to be true , at least , for the spectrum of the low surface brightness emission region which shows a strong fe k line at @xmath89 kev with @xmath90 kev . a similar picture is consistent with the noisy spectrum of the inner northern plume , which barely shows evidence for an fe k line with @xmath91 ev . this cold reflection could contribute to low ionization lines at lower energies ( e.g. , 24 kev band ) , depending on the ionization state and obscuration to the reflecting medium . the reflecting medium could be molecular clouds distributed in the stellar disk ( recall the sgr b2 clouds near our galactic centre , which is located 100 pc away from the sgr a@xmath92 , e.g. , koyama et al 1996 ) . if ram - pressure stripping of the gas in the host galaxy is taking place ( e.g. , petitjean & durret 1993 ; cayatte et al 1994 ; veilleux et al 1999 ) and the stripped gas forms sufficient column density to the central source , it would also work as an x - ray reflector , albeit ram - pressure stripping is not expected to be effcient near the centre of a galaxy . much of the hard x - ray tail in the southern cone spectrum could be accounted for by the faint wing of the psf for the nuclear source , although a faint extension is present at the inner part of the western edge of the cone , on inspecting the 47 kev image . the hard x - ray spectrum lacks a strong fe k emission line ( fig . the 90 per cent upper limit on the ew of a narrow line at 6.4 kev is still consistent with the spectral shape of the nuclear source ( section 3.1 ) . a higher energy line , e.g. , at 6.7 kev , appears to be more favoured by the data ( in this case , the ew could be around 800 ev ) , although the significance of the line is sensitive to the assumed underlying continuum . this line may arise from the high ionization gas ( log @xmath26 ) in agreement with the soft x - ray emission ( section 4.1 ) . the fe k@xmath1 emitting region is spatially resolved in the chandra image . a narrow - band ( 6.26.5 kev ) image centred on cold iron k@xmath25 emission is shown in fig . while much of the line emission arises from the nuclear region , the image of the low surface - brightness emission shows ridges extending to the north - east and north - west . a faint extension appears to be present to the north up to 30 arcsec ( 2.5 kpc ) . the reality of this extended line emission is supported by the hard x - ray emission with an asymmetric extension examined in the previous subsection ( fig . 9 ) and the spectrum of the low surface brightness region ( lsb in fig . 10 ) which shows a strong fe k@xmath1 line with ew much larger than that of the nuclear spectrum . the energy of the line centroid ( @xmath93 kev ) of the lsb spectrum implies that the line emission originates in low ionization gas . the extension of the line emission is in rough agreement with the photoionized gas traced by soft x - ray emission , although any detailed correlation between the two emission components is unclear due to the low signal to noise ratio of the fe k@xmath1 emission data . the 6.4 kev fe k@xmath1 line is a reliable indicator of cold gas , and could trace the history of nuclear activity by mapping the iron line emission ( fabian 1977 ) . the extension of the line emission implies that the central source was turned on at least ten thousands years ago . more details could be obtained from a deeper observation . the soft x - ray image shows clear bi - conical extended emission , bearing a strong resemblance to the optical [ oiii ] ionization cone . the faintness of the northern cone is probably due to the effect of shadowing by the stellar disk on the near side ( see section 4.2 ) . the spatial correlation between the soft x - ray and optical line emission , which was not found in the much lower signal - to - noise image taken by the rosat hri ( matt et al 1994 ) , suggests a common mechanism working for the creation of the extended nebula . as discussed in section 4.1 , the extended x - ray emission in ngc4388 is unlikely to be thermal ( collisionally ionized ) emission from a shock - heated medium , as previously thought ( however , netzer , turner & george 1998 explained the asca spectrum with a photoionization model ) . convincing evidence for photoionized gas that is responsible for the soft x - ray emission in other seyfert 2 galaxies has been obtained from high resolution spectroscopy with the xmm - newton rgs and the chandra letg ( kinkhabwala et al 2002 ; brinkman et al 2002 ; ogle et al 2000 ; sako et al 2000 ; see also young , wilson & shopbell 2001 ) . this also seems to be the case for the x - ray nebula around ngc4388 . the strong ovii emission , together with the other low energy x - ray emission features , found in the spectrum of the southern cone suggests that photoionized gas with a low ionization parameter ( log @xmath94 ) dominates the bright soft x - ray emission . with the inferred low ionization , the same gas could explain the optical [ oiii ] luminosity , since photoionization codes predict the luminosity ratio of [ oiii]@xmath36 to ovii ( 0.55 kev ) to be @xmath95 for the ionizing spectrum we assumed ( this value is from xstar ) . given the rough power - law approximation to the shape of the ionizing spectrum for the photoionization calculation and various uncertainties , including the aperture difference and varying absorption / extinction across the region , which complicate any direct comparison , the observed line flux ratio ( @xmath96 for [ oiii ] measured with a @xmath97 aperture by falcke et al ( 1998 ) ; @xmath98 for ovii measured only from the southern cone ) is in a rough agreement with the prediction . recall that the @xmath57 quoted above is for the inner edge of a photoionized gas shell in the calculation of xstar ( see section 4.1 ) , and the ionization parameter varies across the gas : ovii peaks near the inner edge while oiii peaks at outer radii where @xmath60 is lower but the radial emissivity of the two have a significant overlap . in the southern cone , a comparison between the spectra of the inner and outer parts suggests the ionization parameter is approximately constant with radius ( section 4.1 ) . this implies that the radial density profile follows @xmath99 . since the temperature ( a few @xmath100 k here ) should hold for gas with the same ionization parameter , the pressure profile is also proportional to the inverse square of the radius , which is consistent with gas expanding at constant velocity , ejected matter from the active nucleus , for instance . if the x - ray nebula around ngc4388 is indeed photoionized gas , as we demonstrated , its size of over 10 kpc is larger than other photoionized nebulae known around nearby seyfert galaxies . high resolution x - ray spectroscopy is desirable to confirm the photoionization nature . the large extent of the x - ray emission would make a chandra grating observation difficlt . an observation with the xmm - newton rgs may still be possible , given the broader psf of the xmm - newton telescopes . note , however , such a grating observation will lose information on the spatial variation of gas properties , as we see in the chandra data . large scale x - ray nebulae with the size up to a few tens kpc , which are often associated with h@xmath1 emission ( e.g. , heckman et al 1996 ; lira et al 2002 ) , are usually attributed to thermal emission heated by starburst - driven winds ( e.g. , lehnert , heckman & weaver 1999 ; gallagher et al 2002 ; done et al 2003 ) . however , at least in the presence of an active nucleus , the possibility of photoionized gas as a source of an extended x - ray nebula should be considered , especially when there is a correlation with high ionization optical emission gas such as [ oiii]@xmath36 , as seen in ngc4388 . while the radial extent of the southern cone is limited , the question arises why the extension of the gas to the north is so much larger in both optical line and x - rays . various possibilities for the origin of this gas have been proposed : ram - pressure stripping of the interstellar medium ( petitjean & durret 1993 ; veilleux et al 1999 ) , debris of a small accreted galaxy ( yoshida et al 2001 ) , and a starburst - driven superwind ( e.g. , corbin et al 1988 ) . the last possibility is not favoured because the x - ray spectrum is not thermal ( see also veilleux et al 1999 ; vollmer & huchtmeier 2003 ) . the extended cold iron k emission rather favours a photoionization model . the narrow filaments of a few tens of kpc length , imaged by subaru , are certainly suggestive of the merger debris hypothesis . they are reminiscent of the tidal tails often observed in a major merger system , e.g. , in hi . of course , the unusual environment particular to ngc4388 , residing in the cluster core and moving at high velocity in it , may play an important role in causing the long one - sided matter distribution . the radial surface - brightness profile of the soft x - ray emission suggests that the density profile to the north side of the galaxy is significantly flatter than that to the south . if the ionized gas in the northern extension is excited through photoionization by the active nucleus , then its luminosity is controlled by the amount of matter available for photoionization . if the ionization parameters obtained from the photoionization models of the various regions are used as a guide , the very low surface brightness region at large radii ( 49 kpc or ne vlsb ; section 4.4 ) appears to have a lower ionization parameter than the inner north plume ( within 1 kpc ; section 4.2 ) . the decrease in the ionization parameter indicates that the density profile is flatter than @xmath99 . under a matter - bounded condition , the emissivity depends on the photoionization rate which is proportional to density . the observed power - law form of the soft x - ray surface - brightness profile ( @xmath101 , section 4.4 ) implies that the density profile to the north of the galaxy may have a similar form , if projection effects are not important , i.e. , it has a shallow depth , for example , of a sheet - like structure , as expected for a narrow streak of stripped gas , or the debris / tidal tail of a galaxy merger . the apparent high ionization condition found at intermediate radii ( lsb ; section 4.3 ) is not explained by the above scenario . this could result from a different ionization condition , i.e. , a different distribution function of ionization parameters , in the north - east `` three - shell '' region . although the x - ray spectrum of that region alone is too noisy to be conclusive , the x - ray colour map ( fig . 3b ) indicates that the shell region shows a harder spectrum than the surrounding area . the aligned shell - like structure resembles that in the optical ionization bi - cone of the seyfert 2 galaxy ngc5252 ( e.g. , tadhunter & tsvetanov 1989 ; acosta - pulido et al 1996 ) . it is also reminiscent of the x - ray bow structure found in the x - ray nebula around the vela pulsar ( pavlov et al 2001 ) . these structures may be due to a density discontinuity created by shock ( the shells in ngc5252 may be pre - existing hi rings ) . the harder spectrum of the shell region could be related to the shock - heated media , although increased absorption is an alternative explanation . the radio images show that radio - emitting plasma extends to the north at large radii whereas the axes of the ionization bi - cone and bright radio emission lie along the ne - sw direction . veilleux et al ( 1999 ) attributed this misalignment to buoyancy or refractive bending ( note that the ne extraplanar ionized gas is moving towards us and the axis of the ionization cone is not perpendicular to the stellar disk ) . as we noted in section 4.2 , the major axis of the 13 kev ( green colour in fig . 1 ) or 12 kev ( fig . 5 ) emission , which is likely to trace the path of the nuclear radiation at inner radii ( within 1 kpc ) , lies in the ne - sw direction . its southern extension also match the well - defined edge of the western side of the southern soft x - ray / oiii cone . the fact that the eastern edge of the southern cone is more blurred suggests that some buoyancy effect might bring the ionised gas southwards , while the true axis of the nuclear radiation which escapes from the nuclear obscuring torus is indicated by the 13 kev elongation . in this case , although the apparent opening angle of the southern cone is about @xmath102 , the nuclear ionizing radiation could be more collimated . on the north side , both the 12 kev x - ray emitting gas and radio plasma point towards the ne at small radii and bend towards the north at @xmath71 arcsec from the nucleus . ngc4388 is often believed to be interacting strongly with the virgo icm at supersonic speeds . a mach cone formed on the far - side of the galaxy with an opening angle of @xmath103 has been proposed by veilleux et al ( 1999 ) . some temperature rise in the bow - shocked region around the interaction point is expected above the surrounding icm , which should have a temperature of @xmath104 kev . unfortunately , we were unable to find such a bow - shocked region , mainly due to the presence of the extended ionized gas . the lack of evidence for strong interaction with the icm leaves room for the hypothesis that ngc4388 could be more distant than the virgo cluster and lies closer to at its hubble distance for @xmath105 . finally , with regard to the unification scheme of the two types of seyfert galaxies , if the nucleus of ngc4388 were viewed from a direction near the axis of the ionization cone , the central x - ray source would be seen through the low ionization gas ( and possibly very high ionization gas ) . the column density of the low ionization gas could be of the order of @xmath106 , depending on the filling factor . although the detailed x - ray grating spectra of bright seyfert 1 galaxies , such as ngc3783 ( kaspi et al 2002 ) , do not show clear evidence for such low ionization gas , it might be seen in other mildly - absorbed seyfert nuclei . xstar is maintained by tim kallman and his collaborators at goddard space flight center . acf and ki thank royal society and pparc , respectively , for support . this research was supported in part by nasa through grants nag 81027 and nag 81755 to the university of maryland . acosta - pulido j.a . , vila - vilar b. , prez - fournon i. , wilson a.s . , tsvetanov z.i . , 1996 , apj , 464 , 177 bassani l. , dadina m. , maiolino r. , salvati m. , risaliti g. , della ceca r. , matt g. , zamorani g. , 1999 , apjs , 121 , 473 brinkman a.c . , kaastra j.s . , van der meer r.l.j . , kinkhabwala a. , behar e. , kahn s.m . , pearels f.b.s . , sako m. , 2002 , a & a , 396 , 761 carral p , turner j.l . ho p.t.p . , 1990 , apj , 362 , 434 cayatte v. , kotanyi c. , balkowski c. , kotanyi c. , 1990 , aj , 100 , 604 chamaraux p. balkowski c. , grard e. , 1980 , a&a , 83 , 5 ciroi s. , contini m. , rafanelli p. , richter g.m . , 2003 , a & a , in press ( astro - ph/03011110v1 ) colina l. , fricke k.j . , kollatschny w. , perryman m.a.c . , 1987 , a&a , 186 , 39 colina l. , 1992 , apj , 386 , 59 corbin m.r . , baldwin j.a . , wilson a.s . , 1988 , apj , 334 , 584 davis j.e . , 2001 , apj , 562 , 575 dickey j.m . , lockman f.j . , 1990 , araa , 28 , 215 done c. , madejski g.m . , ycki p. , greenhill l.j . , 2003 , apj , in press fabian a.c . , 1977 , nat , 269 , 672 falcke h. , wilson a.s . , simpson c. , 1998 , apj , 502 , 199 filippenko a.v . , sargent w.l.w . , 1985 , apj , s , 57 , 503 ford w.k . , rubin v.c . , roberts m.s . , 1971 , aj , 76 , 22 forster k. , leighly k.m . , kay l.e . , 1999 , apj , 523 , 521 galagher s.c . , brandt w.n . , chartas g. , garmire g.p . , sambruna r.m . , 2002 , apj , 569 , 655 giovanelli r. , haynes m.p . , 1983 , aj , 88 , 881 hanson c.g . , skinner g.k . , eyles c.j . , wilmore a.p . , 1990 , mnras , 242 , 262 heckman t.m . , dahlem m. , eales s.a . , fabbiano g. , weaver k.a . , 1996 , apj , 457 , 616 hummel e. , saikia d.j . , 1991 , a & a , 249 , 43 iwasawa k. , fabian a.c . , ueno s. , awaki h. , fukazawa y. , matsushita k. , makishima k. , 1997 , mnras , 285 , 683 kaastra j.s . , 1992 , an x - ray spectral code for optically thin plasmas , internal sron - leiden report , updated version 2.0 kallman t. , bautista m. , 2001 , apjs , 133 , 221 kaspi s. et al , 2002 , apj , 574 , 643 kay l.e . , 1994 , apj , 430 , 196 kenney j.d . , young , j.s . , 1986 , apj , 301 , l13 kinkhabwala a. et al , 2002 , apj , 575 , 732 kinney a.l . , antonucci r.r.j . , ward m.j . , wilson a.s . , whittle m. , apj , 377 , 100 koyama k. , maeda y. , sonobe t. , takeshima t. , tanaka y. , yamauchi s. , 1996 , pasj , 48 , 249 lehnert m.d . , heckman t.m . , weaver k.a . , 1999 , apj , 523 , 575 lira p. , ward m.j . , zezas a.m murray s.s . , 2002 , mnras , 333 , 709 matt g. , piro l. , antonelli l.a . , fink h.h . , meur e.j.,a . , perola g.c . , 1994 , a&a , 292 , l13 netzer h. , turner t.j . , george i.m . , 1998 , apj , 504 , 680 ogle p.m. , marshall h.l . , , canizares c.r . , 2000 , apj , 545 , l81 pavlov g.g . , zavlin v.e . , sanwal d. , burwitz v. , garmire g.p . , 2001 , apj , 552 , 129 petitjean p. , durret f. , 1993 , a&a , 277 , 365 phillips m.m . , malin d.f . , 1982 , mnras , 199 , 905 pogge r.w . , 1988 , apj , 332 , 702 ross r.r . , fabian a.c . , young a.j . , 1999 , mnras , 306 , 461 sandage a. , 1978 , aj , 83 , 904 shields j.c . , filippenko a.v . , 1988 , apj , 332 , l55 stone j.l . , wilson a.s . , ward m.j . , 1988 , apj , 330 , 105 sako m. , kahn s.m . , paerels f. , liedahl d.a . , 2000 , apj , 543 , l115 tadhunter c. , tsvetanov z. , 1989 , nat , 341 , 422 veilleux s. , bland - hawthorn j. , cecil g. , tully r.b . , miller s.t . , 1999 , apj , 520 , 111 vollmer b , huchtmeier w. , 2003 , a&a , in press ( astro - ph/0304136 ) weisskopf m.c . , tananbaum h.d . , van speybroeck l.p . , odell s.l . , 2000 , proc spie , 4012 , 2 young a.j . , wilson a.s . , shopbell p.l . , 2001 , apj , 556 , 6 yoshida m. , et al , 2001 , apj , 567 , 118 detector - efficiency corrected versions of spectral data shown in fig . 2 , fig . 4 and fig . 10 are presented below . the count rate spetra have been divided by the effective area . the correction is independent of the fitted model but some uncertainty may have been introduced due to the detector resolution and data binning . the time - dependent efficiency degradation in the low energy range specific to the acis - s3 detector , which was taken into account by acisabs in the spectral analysis , has also been included .

we report on x - ray emission from the seyfert 2 galaxy ngc4388 observed with the chandra x - ray observatory . a hard x - ray peak is found at the position of the active nucleus suggested by optical and radio observations . extended soft x - ray emission correlates well with the ionization cone found in optical line emission . a large soft x - ray extension is found up to 16 kpc ( and possibly 30 kpc ) to the north of the galaxy . photoionized gas with low ionization parameters ( log @xmath0 0.4 ) appears to be the likely explanation of this emission . the same ionized gas clouds could be responsible for the optical [ oiii ] emission . fe k@xmath1 line emission from cold material is found to be extended by a few kpc . galaxies : individual : ngc4388 galaxies : ism x - rays : galaxies

the little - parks critical - temperature oscillations , with magnetic flux , of a large - radius thin - walled hollow cylindrical superconductor display a period @xmath0 @xcite . this oscillation period reflects the binding of electrons into cooper pairs @xcite . recent experiments by liu et al . @xcite have probed the regime in which the diameter of the hollow cylinder is comparable to zero - temperature coherence of the superconductor . their results confirmed the prediction by de gennes @xcite of the destruction of superconductivity in small rings for a certain regime of the external flux . liu et al . raised the interesting and fundamental issues of what would happen if the circumference of the structure were to be smaller than the superconducting coherence length , as well as whether or not the ginzburg - landau approach would be valid in this regime . these issues make a microscopic treatment desirable . on the other hand , the single - electron aharonov - bohm oscillations in the resistance or persistent current in a clean metallic ring have period @xmath1 @xcite . this leads to a related fundamental issue : as the radius of the ring becomes smaller , how would the single - particle @xmath1 period manifest itself in a little - parks type of experiment ? furthermore , does disorder affect the oscillation of critical temperature and the character of the transition between superconducting and normal states ? and if so , how ? these questions are not only of theoretical interest , but are also likely to be addressed experimentally , in view of recent progress in fabrication and experiments on small superconducting rings @xcite . recent work by czajka et al . @xcite , involing the exact diagonalization of the hubbard model for small numbers of sites and the numerical solution of the bogoliubov - de gennes ( bdg ) equation , shows that impurities can play an important role if they are located such that pinned density waves are in phase with one another : charge - density - wave ( cdw ) order would then be enhanced and superconducting order reduced . they also found that the mean - field results obtained via the bdg equations are consistent with the exact diagonalization results , even in the small systems they studied . very recently , a numerical study by loder et al . @xcite and analytical work by juricic et al . @xcite and by barash @xcite on clean @xmath2-wave superconducting loops has shown @xmath1-period oscillations in the supercurrent . ginzburg - landau ( gl ) theory is valid near the superconducting transition , as it is an expansion in powers of the superconducting order parameter . therefore it may not be applicable at sufficiently low temperatures . moreover , the gl approach can not give a complete account of multi - connected geometries of small size , as it is a description of the center - of - mass wavefunction of the cooper pairs . for small rings , in addition to propagating around the circumference together , electrons in cooper pairs can split apart and rejoin , and this process is not included in the gl description . in this paper , we study the oscillations of the critical temperature of @xmath3-wave superconducting rings theoretically , via consideration of the microscopic bcs theory of superconductivity @xcite , analyzed using gorkov s approach @xcite . our central purpose is to address the issues raised by liu et al . @xcite and mentioned above . our focus is on the correction to the oscillations that is due to finiteness of the radius of the superconducting structure . we consider both the clean and dirty regimes , and in the latter regime we shall ignore any tendency towards cdw ordering by assuming that the significant configurations of the impurities are sufficiently random that any pinned density waves are not in phase with one another . we shall see the emergence of an @xmath1 oscillation in the critical temperature , as the radius becomes smaller , and we shall also see that the transition to the normal state can be either discontinuous or continuous in the clean limit but is always continuous in the dirty limit . the origin of the @xmath0 oscillations lies in the fact that a cooper pair carries charge @xmath4 , which when circumnavigating the ring acquires a phase @xmath5 , where @xmath6 is the magnetic flux , linking the ring . the period in flux is thus @xmath0 ( with @xmath7 conveniently set to unity @xcite ) . the emergence of @xmath1 oscillations for small rings is due to the additional process in which electrons in a cooper pair can , from time to time ( so to speak ) , separate , propagate separately , and rejoin , the two trajectories having a nonzero winding number relative to one another . this process , which can only occur for ring sizes comparable to or smaller than the cooper - pair size , induces an oscillation with period @xmath1 . the organization of this paper is as follows . in sec . [ sec : clean ] we discuss the critical - temperature oscillations in the clean limit and in sec . [ sec : disordered ] we include the effect of disorder and discuss the dirty limit . we make some concluding remarks in sec . [ sec : conclude ] . in appendix [ app : gorkov ] we derive the effective one - dimensional gorkov equations by averaging over the cross - section ( or thickness ) of the ring . in appendix [ app : detail ] we provide supplementary details of the calculations that lead to the results in the main text . in appendix [ app : heuristic ] we provide two heuristic arguments for the emergence of the @xmath1 period : ( 1 ) by examining cooper s problem on a ring , and ( 2 ) by using an instanton approach . these two arguments lead to the physical picture described above , and complement the gorkov green - function approach adopted in the main text . we consider a ring ( to be more precise , a torus ) of radius @xmath8 ( and thickness @xmath2 , namely , the diameter in the cross - section , which is smaller than both @xmath8 and the cooper - pair size @xmath9 ) with a magnetic flux density @xmath10 threading the ring parallel to the ring axis ; see fig . [ fig : ring ] . we can describe this field by the vector potential @xmath11 . on the ring itself ( the circumference of which is @xmath12 ) , the vector potential @xmath13 is given by @xmath14 , where @xmath15 is the azimuthal unit vector and @xmath6 is the total flux enclosed by the ring , i.e. , @xmath16 . the normal and anomalous green functions obey the gorkov equations @xcite [ eqn : gorkov ] @xmath17g(\vec{r},\vec{r}';\omega_n)+\delta(\vec{r})f^\dagger(\vec{r},\vec{r}';\omega_n)= \hbar\delta(\vec{r}-\vec{r } ' ) , \\ & & [ -i\hbar\omega_n-\frac{1}{2m}(i\hbar\nabla-\frac{e \vec{a}}{c})^2+\mu]f^\dagger(\vec{r},\vec{r}';\omega_n)-\delta^*(\vec{r})g(\vec{r},\vec{r}';\omega_n)= 0,\end{aligned}\ ] ] where @xmath18 is the electron mass , @xmath19 is the electron charge , @xmath20 and @xmath21 are three - dimensional coordinates in the ring , and the order parameter @xmath22 is defined self - consistently via @xmath23 in which @xmath24 are matsubara frequencies , @xmath25 , @xmath26 is the temperature , and @xmath27 is the bcs pairing strength . we now invoke the narrowness of the ring to justify dropping all dependence on @xmath20 and @xmath21 except that associated with the one - dimensional coordinates along the ring , @xmath28 and @xmath29 . owing to the physical periodicity of the ring , all functions of @xmath28 and @xmath29 are periodic with period @xmath30 ( and the vector potential is a constant along the circumference of the ring ) . the gorkov equations then become one dimensional @xcite : [ eqn : gorkov1d ] @xmath31g(x , x';\omega_n)+\delta({x})f^\dagger(x , x';\omega_n)= \hbar\delta(x - x ' ) , \\ & & \big[-i\hbar\omega_n-\frac{1}{2m}\big(i\hbar\partial_x-\frac{e \phi}{c l}\big)^2+\mu\big]f^\dagger(x , x';\omega_n)-\delta^*(x)g(x , x';\omega_n)= 0.\end{aligned}\ ] ] we can expand @xmath32 and @xmath33 in fourier series , as follows : [ eqn : gnf ] @xmath34 where @xmath35 and @xmath36 are integers labeling single - particle states . due to the translational ( to be more precise , rotational ) invariance of the system , we assume that @xmath37 has no dependence on @xmath28 . this sets constraints on the nonzero fourier components for @xmath32 : @xmath38 . furthermore , we assume that @xmath39 , and hence @xmath40 . this sets constraints on the nonzero fourier components for @xmath41 : @xmath42 . the meaning of this is that the pairing occurs between the single - particle states @xmath35 and @xmath43 @xcite ; see fig . [ fig : pairing ] . the gorkov equations can be expressed in terms of the fourier components of @xmath32 and @xmath41 as follows : @xmath44g_{n_1+m ,- n_1-m}+ \delta_0\ , f^\dagger_{n_1,-n_1-m}= \hbar , \\ & & \big[-i\hbar\omega_n-\frac{\hbar^2}{2mr^2}\big(n_1+\phi\big)^2+\mu\big]f^\dagger_{n_1,-n_1-m}-\delta^*_0\,\ , g_{n_1+m ,- n_1-m}= 0,\end{aligned}\ ] ] where @xmath45 . in the following we shall set @xmath46 , @xmath47 , and @xmath48 , for the sake of convenience . but we shall refer to the single - particle flux quantum @xmath49 as @xmath1 @xcite . these equations can be solved explicitly , yielding @xmath50\big[-i\omega_n-\myomega(n_1\!+\!\phi)^2+\mu\big]+|\delta_0|^2 } , \\ \!\!\!\!\!\!\!\!\!f^\dagger_{n_1,-n_1-m}&= & \frac{\delta^*_0}{\big[i\omega_n-\myomega(n_1\!+\!m\!-\!\phi)^2+\mu\big]\big[-i\omega_n-\myomega(n_1\!+\!\phi)^2+\mu\big]+|\delta_0|^2},\end{aligned}\ ] ] where , for the sake of convenience , we have introduced @xmath51 ( noting that we have set @xmath46 in @xmath52 ) . the self - consistency equation ( [ eqn : selfconsistency0 ] ) then becomes @xmath53 we mainly discuss the case in which the chemical potential @xmath54 is kept fixed , e.g. by contact with a particle reservoir , or else we assume that the variation of @xmath54 with temperature and flux is sufficiently weak to be negligible near the superconducting transition . to solve for @xmath55 we set @xmath56 in the self - consistency equation , thus obtaining @xmath57[-i\omega_n-\myomega(n_1\!+\!\phi)^2+\mu]}.\ ] ] it is important to note the underlying assumption that the transition from superconducting to normal is associated with a vanishing order parameter , and hence is a continuous transition . the consistency of this assumption needs to be checked once we obtain the solution . we shall see , below , that for sufficiently small radii the assumption is not valid and the transition is actually associated with non - vanishing order parameter , and hence is discontinuous . next , we make use of the root of the poisson summation formula ( i.e. the dirac comb and its fourier series ) , @xmath58 , to turn the summation over @xmath35 in eq . ( [ eqn : tc ] ) into one over the conjugate variable @xmath59 : @xmath60[-i\omega_n-\myomega(n_1\!+\!\phi)^2+\mu]}\cr = & & \sum_{k \in z } \int_{-\inf}^{\inf } dx \,\,\frac{e^{i2\pi x k}}{[i\omega_n-\myomega(x\!+\!m\!-\!\phi)^2+\mu][-i\omega_n-\myomega(x\!+\!\phi)^2+\mu]}\,\,\,.\end{aligned}\ ] ] instead of placing a cutoff on the energy , we follow gorkov @xcite and place the cutoff ( which , in practice , is the debye frequency @xmath61 ) on the matsubara frequency . for sufficiently large @xmath8 we can ignore the correction terms associated with finite radius ( i.e. @xmath62 ) , and thus we obtain an equation relating the critical temperature at nonzero flux to that at zero flux . in the limits that the debye frequency is much smaller than the chemical potential ( i.e. @xmath63 ) , and that the chemical potential is much larger than the level spacing ( i.e. @xmath64 ) , we obtain ( see appendix [ app : cleanlarge ] for the derivation ) @xmath65 where @xmath66 is the critical temperature at zero flux for the same radius , @xmath67 [ with @xmath68 being chosen to minimize @xmath69 , i.e. the kinetic energy in the ginzburg - landau picture ] , and @xmath70 is the digamma function , @xmath71 where @xmath72 is the euler constant @xcite . the zero - flux , zero - temperature order parameter @xmath73 is related to the corresponding critical temperature @xmath74 in the weak - coupling limit by @xmath75 , where @xmath76 . we call the length @xmath77 the cooper - pair size ( where @xmath78 is the fermi velocity ) , so as to distinguish it from the zero - temperature ginzburg - landau coherence length @xmath79 . there are two further relevant energy scales : the chemical potential @xmath54 , and the single - particle energy - level spacing @xmath80 . the ratio @xmath81 can be estimated as @xmath82 which is set by on the ratio of the ring radius to the cooper - pair size . this motivates us to define a measure @xmath83 of the ratio of the radius to the cooper - pair size , via @xmath84 then , defining @xmath85 , we can re - write the equation for the critical temperature as @xmath86 an equation of this form was studied by sarma @xcite and by maki and tsuneto @xcite , both in the context of the effect of a magnetic exchange field on superconductivity . the correspondence is that the role of the exchange field normalized to the zero - temperature gap ( i.e. @xmath87 ) is , in the present setting , played by the combination of the normalized inverse ring radius and the flux ( i.e. @xmath88 ) . in refs . @xcite it was found that for large enough exchange field ( here , small enough ring radius ) eq . ( [ eqn : tcclean2 ] ) has multiple solutions and that , moreover , the correct interpretation is that the transition between the normal and superconducting states becomes discontinuous ( beyond certain value of the exchange field ) . by contrast , for small enough exchange field ( here , large enough ring radius ) the transition is continuous . by borrowing the results of refs . @xcite , as summarized in fig . [ fig : sfphase ] , we have that the threshold at which the transition changes character between continuous and discontinuous occurs at @xmath89 ( i.e. point b in fig . [ fig : sfphase ] ) . furthermore , one has that for extremely small rings , such that @xmath90 ( i.e. point d ) , the system never becomes superconducting @xcite . of course , these estimates would need to be modified if the finiteness of the radius were to be taken into account , but we expect that the qualitative separation into discontinuous- and continuous - transition regimes would still hold . for large - radius rings ( i.e. @xmath91 ) , we can expand the second digamma function in eq . ( [ eqn : tcclean2 ] ) to second order and the logarithm to first order , thus obtaining @xmath92 hence , we see that the fractional reduction in the critical temperature due to the flux is given by @xmath93 the integer @xmath68 must to be chosen such that @xmath69 is minimum , so as to obtain the most stable solution ; hence , we recover the standard little - parks oscillation result , for which the period is @xmath0 . equation ( [ eqn : expand ] ) can be re - expressed as @xmath94 the l.h.s . can be much smaller than unity if @xmath8 is much smaller than @xmath9 , but the value of the r.h.s . can range from @xmath95 to @xmath96 , depending on the value of external flux . this means that there can exist a range of fluxes for which no solution of @xmath97 exists . this reflects the fact that superconductivity is destroyed over certain ranges of flux @xcite . to make connection with the result by de gennes @xcite , let us multiply eq . ( [ eqn : min ] ) by @xmath98 and take the cosine of both sides . we recover the de gennes result for the transition temperature ( for the case in which the length of the side arm in ref . @xcite is set to zero ) @xmath99 where @xmath100 is the temperature - dependent ginzburg - landau coherence length in the clean limit . we note that , however , the ginzburg - landau approach is , strictly speaking , valid only near @xmath101 . furthermore , the existence of discontinuous transitions is beyond the reach of the ginzburg - landau approach . [ sec : clean_finite ] what is the correction to @xmath102 that arises from the finiteness of the radius ? by taking into account this correction we arrive at the following equation obeyed by the critical temperature ( see appendix [ app : cleanfinite ] for the derivation ) : @xmath103\right\},\end{aligned}\ ] ] where we recall that @xmath104 , @xmath105 is the bcs constant @xmath106 , we have defined @xmath107 , which is related to the number of cooper pairs , and the function @xmath108 is defined via the hypergeometric function @xmath109 @xcite : @xmath110 in figs . [ fig:1 ] and [ fig : multiple ] we show the flux dependence of the critical temperature for two particular ring radii . for the larger radius case , the value of @xmath97 at @xmath111 is essentially the same as that at @xmath112 and @xmath95 ; for the smaller radius case and for @xmath113 ( i.e. all the pair states are occupied at and below fermi level ) , the amplitude at @xmath111 is reduced , relative to that at @xmath112 and @xmath95 . thus , as the radius becomes small we clearly see the emergence of the single - particle flux quantum period @xmath1 . also worth noticing is the occurrence of a second solution ( with lower value ) for the critical temperature at sufficiently small radii , shown in fig . [ fig : multiple ] . compared to the higher @xmath114 solutions , for which our approximation of the @xmath114 equation ( [ eqn : tcclean ] ) , by keeping only the first two correction terms yields rather precise values , the evaluation of @xmath114 at these lower values of temperatures requires more terms ( e.g. four or more ) to be included in order to maintain the same accuracy . for the case of large rings ( i.e. @xmath91 ) , to determine the leading corrections it is adequate to retain only the @xmath115 term and to set the correction @xmath116 to zero , when compared to values of order unity , in the second @xmath108 function . thus , we arrive at the formula @xmath117.\end{aligned}\ ] ] the change in the reduced critical temperature @xmath118 is then approximately given by @xmath119 where we have used the fact that @xmath120 . again , the integer @xmath68 is to be chosen to minimize @xmath69 . we see that , in addition to the parabolic dependence on @xmath121 , there is a sinusoidal correction of period @xmath1 . this is the emergence of the single - particle flux dependence . we also note that this correction is not universal , in that it depends sensitively on the value of @xmath54 [ and , moreover , the form of @xmath122 results from the simple quadratic single - particle spectrum ] . it can happen that the correction due to the finiteness of the radius actually increases the critical temperature , i.e. when @xmath123 . as we have argued using the results of sarma @xcite and maki and tsuneto @xcite , the occurrence of multiple solutions in eq . ( [ eqn : tcclean2 ] ) for @xmath124 , for certain ranges of @xmath125 , leads to a change from a continuous to a discontinuous superconducting - to - normal phase transition . even with the corrections to @xmath102 due to the finite - radius effect , as the radius of the ring decreases ( to a value comparable to the coherence length ) , we observe that eq . ( [ eqn : tcclean ] ) still possesses multiple solutions for @xmath124 for certain ranges of @xmath125 ; see fig . [ fig : multiple ] . this implies that somewhere in these ranges ( of @xmath125 ) there exists a change from continuous ( at larger radius ) to discontinuous ( at smaller radius ) superconducting - to - normal transition . this is shown schematically in fig . [ fig : schematic ] . if the radius is sufficiently large , the transition is always continuous . if the radius is sufficiently small , the the curve representing the discontinuous transition in one `` dome '' can intersect with that of the nearby dome ( above the `` void '' region where no solution for @xmath126 of eq . ( [ eqn : tcclean ] ) exists ) . if this void region is large , the curve of the discontinuous transition can go to @xmath127 at certain value of @xmath121 without intersecting that from the nearby dome . however , calculations of @xmath55 alone can not determine the precise location of the change from continuous to discontinuous ; considerations of free energies are necessary to settle this issue . how does disorder , in the form of potential scattering from fixed impurities , alter the physical picture that we have obtained so far ? does it affect the critical temperature ? does it change the order of the superconducting - to - normal transition ? we now address these issues , assuming that the configuration of the impurities is sufficiently random that the tendency towards cdw formation is not enhanced . for the most part , we shall consider impurities that produce scalar potential scattering ; _ mutatis mutandis _ , the effects of exchange and spin - orbit scattering can be straightforwardly included . to begin with , we include potential scattering via the @xmath128 term in the gorkov equations @xcite , which now read ( here we restore the constants @xmath129 and @xmath7 ) @xmath130g(x , x';\omega_n)+\delta({x})f^\dagger(x , x';\omega_n)= \hbar\delta(x - x ' ) , \\ & & \!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\big[-i\hbar\omega_n-\frac{1}{2m}\big(i\hbar\partial_x-\frac{e \phi}{c l}\big)^2-v(x)+\mu\big]f^\dagger(x , x';\omega_n)-\delta^*(x)g(x , x';\omega_n)= 0,\end{aligned}\ ] ] where @xmath128 represents the potential from static impurities , i.e. , @xmath131 and @xmath132 indicates the spatial location of @xmath133 impurity . following gorkov @xcite , we introduce a green function @xmath134 that satisfies @xmath135g^0(x , x';\omega_n)= \hbar\delta(x - x').\ ] ] we can then express @xmath41 exactly in terms of @xmath136 and @xmath137 as @xmath138 because we are only concerned with solving for @xmath126 , near the transition , it is sufficient to keep g to zeroth order in @xmath22 and replace @xmath32 in eq . ( [ eqn : fd ] ) by @xmath137 ; thus we have @xmath139 we now consider the self - consistency equation ( [ eqn : selfconsistency0 ] ) , and average over the quenched disorder associated with the locations of the impurities : @xmath140 where @xmath141 indicates disorder averaging . we note that , as explained by gorkov @xcite , the green function @xmath137 oscillates on a much smaller length scale than @xmath136 and , hence , the disorder average of @xmath136 can be factorized . for convenience , we use @xmath142 to denote the disorder average of @xmath137 , i.e. , @xmath143 , the translational invariance of which is restored , viz . , @xmath144 to calculate the disorder average of the product of two green functions , we introduce the kernel @xmath145 @xcite , defined via @xmath146 if we retain only the ladder diagrams ( i.e. ignoring the crossed diagrams @xcite ) , we arrive at the result @xmath147,\ ] ] where we have simplified the notation by dropping the subscript @xmath148 on @xmath149 and moving @xmath149 from an argument to a subscript , and @xmath150 is the impurity concentration . assuming that the order parameter retains the form @xmath151 , the self - consistency equation can be reduced to @xmath152 we leave the detailed calculation of the kernel to appendix [ app : dirtylimit ] and simply quote here the resulting equation ( [ app : eqn : finite_dirty ] ) for the critical temperature in the disordered regime , i.e. @xmath153 : @xmath154,\end{aligned}\ ] ] where @xmath155 is the elastic mean free path , @xmath156 is the elastic scattering time , we recall that @xmath157 , and @xmath158 \big/\big(1+\frac{2\gamma l_e\xi_0 x_m^2}{t r^2}\big).\ ] ] we remark that the argument in the second digamma function in eq . ( [ eqn : finite_dirty ] ) is real , in contrast with the clean case , for which it is complex ; see eq . ( [ eqn : tcbulk ] ) . a consequence of this is that there is no longer a doublet of solutions for @xmath126 . moreover , the resulting single solution is consistent with the assumption that the order parameter becomes vanishingly small as the temperature approaches its critical value from the superconducting side . therefore , the transition to the superconducting state is continuous . to explore the consequences of eq . ( [ eqn : finite_dirty ] ) , we first examine the large - radius ( i.e. bulk ) limit , and show that we recover the de gennes results for the case of rings . we then proceed to compare how the finiteness of the radius affects the oscillations of @xmath124 . ignoring correction due to the finiteness of the radius , we obtain the following equation for @xmath126 of the bulk superconductor , i.e. , @xmath159 as we should . this is in agreement with the results of de gennes @xcite for rings and those obtained by lopatin et al . @xcite for hollow cylinders . to see that the de gennes results are recovered , we note that the critical value of @xmath160 , beyond which no superconducting solution for any @xmath161 exists , is given by @xmath162 @xcite . for a fixed radius , this defines the critical flux @xmath163 , which defines the boundary between normal and superconducting states . we then determine that the critical flux @xmath164 satisfies @xmath165 which gives the critical flux for a given radius , or vice versa , via @xmath166 when the flux dependence of the critical temperature is weak , as in the large - radius limit , @xmath167 is close to unity and @xmath168 , so one can expand the logarithm in @xmath169 and the second digamma function around @xmath96 in eq . ( [ eqn : bulk_dirty ] ) to obtain @xmath170 as we did for eq . ( [ eqn : dgclean ] ) in the clean limit , we can express this equation as @xmath171 where @xmath172 is the temperature - dependent ginzburg - landau coherence length in the dirty limit . thus , we recover the de gennes results @xcite , but via a microscopic calculation . we note that , strictly speaking , the ginzburg - landau approach is only valid near @xmath101 ( see also discussion at the end of sec . [ sec : largeradiusclean ] ) . strictly speaking , the de gennes results ( [ eqn : deg ] ) are only valid in the large - radius limit , as is clearly seen from our microscopic derivation . in the regime in which the radius of the ring is comparable to the zero - temperature coherence length or the cooper - pair size , we should take into account the effect of finite radius and use eq . ( [ eqn : finite_dirty ] ) instead of eq . ( [ eqn : bulk_dirty ] ) . in addition to the lengthscale defined by the cooper - pair size @xmath9 , the behavior of @xmath126 also depends on another length scale , viz . , the mean - free path @xmath173 . the correction terms ( i.e. the terms in the summation ) in eq . ( [ eqn : finite_dirty ] ) decay exponentially with @xmath174 , so that the series converges rather rapidly , even for @xmath175 or slightly smaller . in fig . [ fig : dirty ] we contrast the predictions of @xmath126 in the large - radius limit , eq . ( [ eqn : bulk_dirty ] ) , to those that include the finiteness corrections , eq . ( [ eqn : finite_dirty ] ) , for a small radius ( @xmath176 ) . figure [ fig : dirty ] also shows that the @xmath124 oscillation has a component of period @xmath1 , in addition to the usual little - parks component of period @xmath0 . in fig . [ fig : phasedirty ] we plot the critical temperature vs. radius for various flux values . we see that the deviation from the bulk result is mroe significant near @xmath177 , whereas the bulk result shows almost no deviation in the range @xmath178 . the deviation of the critical temperature of small - radius rings from that of large - radius rings is , however , not universal , as it depends on both the magnitude and sign of @xmath179 . we have seen that when the sign of @xmath180 is positive , the corrections from the finiteness of the radius can cause a reduction in the critical temperature near the flux value @xmath111 , compared to the bulk case . this corresponds to the case in which , at zero flux , all the electrons are paired up . however , when the sign of the cosine is negative , the critical temperature at @xmath111 can actually exceed its value at zero flux ; this corresponds to the case in which , at @xmath111 , all electrons are paired up , thus the system is more stable there than at @xmath181 . if the cosine term should happen to vanish accidentally , the oscillation at period @xmath1 would disappear . when the radius is not small the change in @xmath124 , relative to @xmath182 , is small , and we therefore need only retain terms in eq . ( [ eqn : finite_dirty ] ) to order @xmath115 and also may replace @xmath97 on the r.h.s . by 1 , as we did to obtain eq . ( [ eqn : tcdirtyapprox1 ] ) . thus we obtain @xmath183 hence , an oscillation of period @xmath1 is clearly seen to emerge , and whether the critical temperature reduces or increases ( e.g. at @xmath111 ) , compared to the bulk little - parks value , is seen to depend on the sign of the cosine term . for the case where all electrons are paired up at zero flux , the critical temperature is lower at @xmath111 than at @xmath181 . we have considered the oscillations in the critical temperature of a superconducting ring of finite radius in the presence of a threading magnetic flux . we have found that , as the radius of the ring is ( parametrically ) reduced , an oscillation in the critical temperature of period of @xmath1 emerges , in addition to the usual little - parks dependence ( the period of which is @xmath0 ) . our results provide corrections , due to the finiteness of the ring radius , to the results that de gennes obtained for a flux - threaded ring @xcite . we have argued that in the clean limit there is a superconductor - normal transition , as the ring radius becomes sufficiently small at nonzero flux , and that the transition can be either continuous or discontinuous , depending on the radius and/or flux . in the disordered regime , we have argued that the transition is rendered continuous , which results in a quantum critical point tuned by flux and radius . one may wonder how the system behaves as it goes from clean to dirty limit . at which point does the existence of multiple solutions in the critical temperature disappear ? by analyzing eq . ( [ eqn : arbitrarydisorder ] ) , we obtain that , ignoring the finiteness corrections , double solutions disappear when the disorder is such that @xmath184 . one question we should also address is the thickness @xmath2 of the ring cross - section . it causes an orbital pair - breaking effect . for the purpose of estimating this we can use the result from a wire with same thickness in a field perpendicular to the wire axis ( for the calculation , see , e.g. ref.@xcite ) . the fractional decrease of critical temperature , when it is small , can be estimated to be ( not including the oscillation by flux ) @xmath185 which causes a quadratic decrease in the critical temperature on top of the oscillations discussed in the present paper . if we take the same values shown in fig . [ fig : dirty ] , i.e. , @xmath186 , for @xmath187 the decrease is about @xmath188 at @xmath177 and about @xmath189 at @xmath190 . the largest decrease in the critical temperature shown in fig . [ fig : dirty ] is about @xmath191 , and the @xmath1 component is not swamped by the pair - breaking effect and can still be observed . although we have obtained the emergence of the @xmath1 oscillation and its amplitude by the microscopic calculations , the physics behind these effects can be illustrated via heuristic arguments associated with the corresponding cooper problem on a ring , together with a path - integral based instanton tunneling approach . we briefly discuss these points in appendix [ app : heuristic ] . the non - universal factor @xmath192 determines whether the finiteness of the ring radius leads to a decrease or an increase in the critical temperature near flux @xmath111 . although this factor is model dependent ( i.e. dependent on the form of the single - particle spectrum ) , for the quadratic spectrum we consider here , @xmath193 roughly counts the number of electrons divided by four , as there are two spin species and positive and negative ( angular ) momenta . if we restrict ourselves to the case in which all electrons are paired then @xmath194 , because for @xmath195 two electrons can still occupy the @xmath196 state . when all the levels at @xmath54 and below are filled at zero flux , @xmath197 . when there is one pair fewer or more ( or equivalently , when all pairs are occupied at @xmath111 ) , @xmath198 . this seems to result in an even - odd effect , not from the number of electrons @xcite but from the number of cooper pairs . however , whether this even - odd effect holds in general requires further investigation . . 1 . we would like to point out that the issue of flux - dependent supercurrents for s - wave rings was also studied by zhu and wang in ref . in addition to refs . @xcite , there is a more recent work on the same issue in d - wave superconductors in ref . @xcite . \2 . throughout our paper , we have essentially assumed that the switching of pairing configuration ( see fig . 2 ) occurs at flux values being an odd integer multiple of @xmath199 near superconducting - normal transition temperatures . this is consistent with our numerical results that by allowing the switching to be varied , the largest possible critical temperature is obtained when the above assumption is obeyed . in a very recent paper by vakaryuk in ref . @xcite , the author concludes that the switching can be flux dependent at zero temperature . if the two results are to be consistent , we are led to the conclusion that the switching is temperature dependent . this requires further investigation . _ acknowledgments_. the authors acknowledge informative discussions with david pekker and frank wilhelm , and are especially grateful to gianluigi catelani for his critical reading of this paper . this work was supported by doe grant no . defg02 - 91er45439 through the federick seitz material research laboratory at the university of illinois . tcw acknowledges the financial support from iqc , nserc , and orf , as well as the hospitality of perimeter institute , where part of this work was done . we would also like to acknowledge v. vakaryuk and a. j. leggett for communicating the results of ref . consider a ring on a plane with inner and outer radii @xmath200 and @xmath201 , respectively . assume that the thickness @xmath202 is much smaller than the mean radius @xmath203 and the zero - temperature coherence length @xmath79 . we reduce the two dimensional gorkov equations into effective one - dimensional equations by defining the averaged green function , @xmath204 and similarly for @xmath205 . under this averaging , the two - dimensional delta function becomes one - dimensional , @xmath206 in the laplacian operator , there is a term @xmath207 . when performing the above average , we get for this term @xmath208 which , under the condition of no current flowing radially through the ring boundary , gives zero identically . similarly , if we regard the anomalous green function as playing the role of the ginzburg - landau order parameter in the theory of superconductivity , no - flow of supercurrent radially gives the average to be zero for @xmath41 . furthermore , under the limit that the average of the product of two functions can be approximated by the product of two averaged functions , we obtain a set of reduced one - dimensional gorkov equations , with the coordinate variables being azimuthal angles @xmath209 and @xmath210 and the radii being set to the fixed value of the average radius . after appropriately renormalizing the green functions by the inverse of the average radius ( thus making the dimension consistent ) , we arrive at eqs . ( [ eqn : gorkov1d ] ) . we remark that even if the ring has the geometry of a torus , the same averaged 1d equations will result provided that the cross - section is relatively small , compared with the ring area and the coherence length . in this appendix , we supplement the details leading to the critical temperature equations in both clean limit and the disordered regime . continuing from eq . ( [ eqn : poissonsum ] ) , we make a shift in @xmath28 : @xmath211 , under which the integral becomes @xmath212[-i\omega_n-\frac{1}{2mr^2}(x+x_0)^2+\mu]},\ ] ] where @xmath213 . the integral over @xmath28 can be performed using contour integration . for example , for @xmath214 and @xmath215 , we can close the contour in the upper plane and evaluate the residues at @xmath216 and @xmath217 . we end up with ( noting the cancellation of the factor @xmath218 ) @xmath219}\cr & & \quad + \frac{\pi e^{-i2\pi k \phi - i2\pi k\sqrt{2mr^2(\mu - i\omega_n ) } } } { \sqrt{\frac{2}{mr^2}(\mu - i\omega_n)}\big[\omega_n-\frac{i x_0 ^ 2}{mr^2}+i x_0\sqrt{\frac{2}{mr^2}(\mu - i\omega_n)}\,\big]}.\end{aligned}\ ] ] including the contributions from the three other cases , we arrive at the self - consistency equation : @xmath220}\right.\cr & & \left.\quad+\sum_{k=1}^\infty\frac{8\pi\ , e^{i2\pi k\sqrt{2mr^2(\mu+i\omega_n ) } } \cos2\pi k\phi}{\sqrt{\frac{2}{mr^2}(\mu+i\omega_n)}\big[\omega_n+\frac{i x_0 ^ 2}{mr^2}-i x_0\sqrt{\frac{2}{mr^2}(\mu+i\omega_n)}\,\big ] } \right\},\end{aligned}\ ] ] where we have put the debye frequency @xmath61 as the upper cutoff in the matsubara sum . this equation can be re - written as @xmath221}\right.\cr & & \left.\quad+\sum_{k=1}^\infty\frac{2 e^{i2\pi k\sqrt{2mr^2(\mu+i\omega_n ) } } \cos2\pi k\phi}{\sqrt{1+i\frac{\omega_n}{\mu}}\big[\omega_n+\frac{i x_0 ^ 2}{mr^2}-i x_0\sqrt{\frac{2}{mr^2}(\mu+i\omega_n)}\,\big ] } \right\}. \label{eqn : selfconsistent}\end{aligned}\ ] ] furthermore , for typical temperatures we have @xmath222 . the second term causes the contribution of the @xmath62 terms to be exponentially small for large @xmath8 , i.e. there is a factor @xmath223 for sufficiently large @xmath8 , we can ignore the @xmath62 correction terms , in which case we have @xmath221 } \right\}.\end{aligned}\ ] ] the third term in the denominator is usually much larger than the second term , as the chemical potential @xmath54 is much larger than the level spacing @xmath224 , i.e. , @xmath225 . for typical values of @xmath61 and @xmath54 , we have @xmath63 . hence , we have @xmath226 the solution for @xmath26 to this equation gives the critical temperature @xmath126 . denoting by @xmath74 the critical temperature in the absence of flux ( so that @xmath227 ) , we have the corresponding equation @xmath228 taking the difference of equations ( [ eqn : bulkselfconsistency ] ) and ( [ eqn : thirdofselfconsistencybulk ] ) , we have @xmath229 if we extend both upper limits to infinity , we should compensate by the difference ( assuming @xmath230 ) , i.e. , @xmath231 therefore , we arrive at @xmath232 in terms of the digamma function @xmath70 in eq . ( [ eqn : digamma ] ) , we have an implicit formula for @xmath124 : @xmath233 using the quantities @xmath234 , @xmath235 , and @xmath236 , and defining @xmath237 , we can re - write eq . ( [ eqn : tcbulk2 ] ) as @xmath238 what is the correction to @xmath124 due to the finiteness of the radius ? to address this question we need to take into account the @xmath62 corrections to eq . ( [ eqn : selfconsistent ] ) . if we take @xmath63 and @xmath222 , the self - consistency equation ( [ eqn : selfconsistent ] ) can be approximated as @xmath239 taking the difference between this equation and the version corresponding to @xmath240 , and using the trick for converting the cutoff at the debye frequency in a logarithm ( see eqs . ( [ eqn : log])-([eqn : tcbulk2 ] ) , we arrive at @xmath241\right . \cr & & \!\!\!\!\!\!\!\!\!\!\left . - { \rm re}\big\{e^{i2\pi k\sqrt{2mr^2\mu } } e^{-\frac{2\pi k\rho\ , t}{\gamma } } { \rm hf } \big[\frac{1}{2}\!-\ ! \frac{i x_0 \gamma}{2\rho\ , t(\phi)},1,\frac{3}{2}\!-\ ! \frac{i x_0 \gamma}{2\rho\ , t},e^{-\frac{4\pi k\rho\ , t}{\gamma}}\big]\cos2\pi k\phi\big/\big(1\!-\ ! \frac{i x_0 \gamma}{\rho\ , t}\big)\big\}\right\},\end{aligned}\ ] ] where the @xmath121 dependence of @xmath97 on r.h.s . is suppressed . we have extended the upper limit of the sum over @xmath148 to infinity for the exponentially decaying terms ( which introduces a negligible small error ) , and we have used the formula @xmath242\big/(1 + 2a),\ ] ] where @xmath243 $ ] is the hypergeometric function @xmath244 . in this subsection , we calculate @xmath245 and @xmath246 and obtain the r.h.s . of the self - consistency equation ( [ eqn : kernel ] ) . for simplicity , we assume that the potential @xmath247 is short - ranged , so that its fourier transform @xmath248 can be treated as a constant , essentially independent of momentum transfer @xmath249 . the one - particle self - energy can be obtained from summing one - particle - irreducible diagrams ( and ignoring the crossed diagrams ) , and thus we obtain @xmath250 the real part of the self - energy has been ignored and we shall call @xmath251 the frequency - dependent scattering time . under the condition that the debye frequency is much smaller than the chemical potential , i.e. @xmath252 , and hence for the range of @xmath149 s that are relevant to superconductivity ( i.e. @xmath253 ) , we obtain @xmath254 \,e^{-2\pi k \sqrt{\frac{mr^2}{2\mu}}|\omega|}\big],\ ] ] where @xmath255 this form for @xmath251 is an approximant because it is calculated with @xmath137 rather than @xmath142 . to improve the approximation we then use the exact disordered green function @xmath142 to calculate the same self - energy diagrams again ( see , e.g. ref . @xcite ) , thus obtaining a self - consistency condition for @xmath251 ( that can be solved iteratively ) : @xmath256 \,e^{-2\pi k \sqrt{\frac{mr^2}{2\mu}}|\omega|\big(1+\frac{1}{2\tau(\omega)|\omega|}\big)}\big].\ ] ] as the @xmath257 terms are exponentially small , we can approximate @xmath251 on the right - hand side by @xmath156 to arrive at @xmath258 \,e^{-2\pi k \sqrt{\frac{mr^2}{2\mu}}|\omega|\big(1+\frac{1}{2\tau_0|\omega|}\big)}\big].\ ] ] returning to the kernel @xmath259 , we re - write eq . ( [ eqn : kernel ] ) , following gorkov @xcite , as @xmath260,\ ] ] where we have conveniently dropped the @xmath261 sign in @xmath142 , and @xmath262 and the argument @xmath263 in @xmath264 reflects the conservation of total ( azimuthal ) momentum of the two incoming ( and outgoing ) electrons in the ladder diagrams after disorder averaging . for the purpose of evaluating self - consistency equation ( [ eqn : self - consistency1 ] ) , our goal is to obtain @xmath246 for @xmath265 . by eliminating @xmath259 from eqs . ( [ eqn : k ] ) and ( [ eqn : l ] ) by we have an equation for @xmath266 : @xmath267 which gives @xmath268 where @xmath269 the self - consistency equation ( [ eqn : self - consistency1 ] ) then becomes @xmath270 where we have used eq . ( [ eqn : tau0 ] ) in the second equality . as with the evaluation of eq . ( [ eqn : doubleg ] ) in the clean limit ( see appendix [ app : detail ] ) , we obtain @xmath271 as @xmath272+\sum_{k>0}\frac{e^{-2\pi k \sqrt{\frac{mr^2}{2\mu}}|\omega|\eta}}{\tau}\cos(2\pi k\sqrt{2mr^2\mu}){\rm re}\,\big[\frac{e^{i2\pi k\phi}}{|\omega|\eta - i x_0}\big],\end{aligned}\ ] ] where @xmath273 , @xmath274 , and @xmath275 is a shorthand for @xmath251 . to illustrate the corrections arising from the finiteness of the radius , we re - write @xmath271 as @xmath276 where @xmath277 and @xmath278 are @xmath279 as the correction to @xmath280 is exponentially small [ see eq . ( [ eqn : tau1 ] ) ] , in the exponentials @xmath281 can be approximated by @xmath282 on the other hand , for @xmath280 not in the exponentials we shall approximate it by retaining the leading correction [ see eqs . ( [ eqn : tau1 ] ) and ( [ eqn : a ] ) ] via @xmath283 the quotient @xmath284 then becomes @xmath285 } { 2\tau|\omega|+\frac{1}{1 + 2\tau|\omega|}(2\tau x_0)^2-\big[a_\omega-\frac{2\tau b_\omega x_0}{1 + 2\tau|\omega|}\big ] } \approx \frac{1+\big[a_\omega-\frac{2\tau b_\omega x_0}{1 + 2\tau|\omega|}\big ] } { 2\tau|\omega|+\frac{1}{1 + 2\tau|\omega|}(2\tau x_0)^2 } .\ ] ] we remark that from this equation one can obtain the equation for the critical temperature for arbitrary mean - free path @xmath173 . to illustrate the remark made above , we consider large - radius limit in which we ignore corrections due to the finite radius . in this limit ( [ eqn : a1a ] ) becomes @xmath286 substituting this into eq . ( [ eqn : self - consistency2 ] ) we have @xmath287+\big(\frac{x_0}{2\pi t_\text{c}}\big)^2 } \label{eqn : secondofselfconsistencybulk2}.\end{aligned}\ ] ] in the clean limit @xmath288 , we see that this reduces to eq . ( [ eqn : secondofselfconsistencybulk ] ) , which we obtained in the absence of disorder . but here @xmath156 is arbitrary . subtracting eq . ( [ eqn : bulkselfconsistencyarbitraryl ] ) from the corresponding equation at @xmath240 ( i.e. @xmath289 ) and using the trick to get logarithm of the ratio of the critical temperatures as we did in eqs . ( [ eqn : log])-([eqn : tcbulk2 ] ) , we have @xmath290+\big(\frac{x_0}{2\pi t_\text{c}}\big)^2}-\frac{1}{n+\frac{1}{2}}\right).\end{aligned}\ ] ] by making the partial fractions of the first term in the summation and by using the definition of the digamma function ( [ eqn : digamma ] ) , we arrive at @xmath291,\end{aligned}\ ] ] where , for convenience , we have defined @xmath292 and @xmath293 . this is the equation for the critical temperature at arbitrary disorder for large radii of rings . now we return to the corrections due to the finiteness of the radius . in the strong disordered limit ( i.e. @xmath294 ) , eq . ( [ eqn : a1a ] ) becomes @xmath295 } + \frac{a_\omega-{2\tau b_\omega x_0 } } { 2\tau\big[|\omega|+2\tau x_0 ^ 2\big ] } .\ ] ] this is further approximated , using eq . ( [ eqn : tau ] ) as @xmath296 } + \frac{2a_\omega-{2\tau_0 b_\omega x_0 } } { 2\tau_0\big[|\omega|+2\tau_0 x_0 ^ 2\big ] } , \ ] ] where we have used eq . ( [ eqn : tau ] ) . the first term on the r.h.s . represents the bulk term and is the little - parks term in the dirty limit . the second term takes into account the finite radius , and contains flux dependence in period @xmath1 . the equation for the critical temperature will then contain the digamma function and hypergeometric function with real arguments , in contrast with the clean limit . this makes the transition to normal state continuous , as the solution for the critical temperature is unique and the assumption of vanishing order parameter used in the linearized self - consistency condition is valid . therefore , there can be quantum phase transitions tuned by flux and/or radius . as @xmath297 in the strong - disorder limit , the ratio @xmath284 becomes ( by ignoring the @xmath298 term ) @xmath299 } + \frac{2a_\omega } { 2\tau_0\big[|\omega|+2\tau_0 x_0 ^ 2\big ] } .\ ] ] from this we can obtain an equation for the critical temperature @xmath114 in the presence of flux @xmath6 , as we have done in the clean limit ( see appendix [ app : cleanfinite ] ) . by inserting eq . ( [ eqn : quotienta ] ) into the self - consistency equation ( [ eqn : self - consistency2 ] ) we obtain @xmath300}\cos(2\pi k \sqrt{2mr^2\mu})\cos2\pi k\phi}{n+\frac{1}{2}+\frac{\tau_0 x_0 ^ 2}{\pi t_c}}.\end{aligned}\ ] ] subtracting from this the corresponding @xmath240 equation , i.e. , @xmath301}\cos(2\pi k \sqrt{2mr^2\mu})}{n+\frac{1}{2}},\end{aligned}\ ] ] we obtain the following implicit equation for the critical temperature : @xmath302 where we have used the fact that when @xmath303 or higher , @xmath304 , the sum of the series being approximated is a logarithm , and we have extended the upper limit of @xmath148 for the correction terms to infinity . by using formula ( [ eqn : sumhypergeometric ] ) for the hypergeometric function , we finally arrive at @xmath305,\end{aligned}\ ] ] where we recall that @xmath306 . if we use @xmath307 , @xmath308 , and @xmath309 ( with @xmath310 ) , we have @xmath311.\end{aligned}\ ] ] we can re - write this equation using the relations @xmath312 , @xmath313 and @xmath314 , and thus arrive at @xmath315.\end{aligned}\ ] ] it is also possible to include corrections from the finiteness of the radius , and derive the equation for the critical temperature , as we did in the previous section . the results will contain the r.h.s . of eq . ( [ eqn : arbitrarydisorder ] ) as the zeroth order , as well as corrections due to the finiteness of the radius in terms of hypergeometric functions . however , the formulas are too cumbersome and we do not list them here . let us consider cooper s problem on a ring with a flux @xmath6 threading through it . the orbital wavefunction can be written in the same form as in eq . ( [ eqn : gnf ] ) . assuming that @xmath316 , and that the electron - electron interaction is factorizable , i.e. @xmath317 , we can write down the time - independent schrdinger equation in terms of the wavefunction amplitude @xmath318 as @xmath319 where @xmath320,\ ] ] and hence we arrive at @xmath321 the integer @xmath68 has to be chosen to minimize the ground state energy . thus , we see that the solution is periodic in @xmath121 with period 1 ( or in @xmath6 with period @xmath1 , namely the single particle flux quantum ) and that the little - parks period @xmath0 is exact only in the large-@xmath8 limit , in which case the summation over @xmath148 can be replaced by an integral and hence the period of @xmath121 is @xmath96 . this illustrates the role of the single particle oscillation . however , the amplitudes of the single - particle and little - parks oscillations have to be evaluated within a microscopic theory , as has been done in the main text . the instanton picture provides us another , heuristic , view of the emergence of @xmath1-period oscillations . the argument presented here is intended just to give some intuition . we refer to rajaraman @xcite for a pedagogical review of instanton techniques . a single instanton tunneling from @xmath95 through a potential to @xmath98 ( which is identified as @xmath95 ) on a circle gives an amplitude @xmath322 where @xmath323 is the classical euclidean action ( in the absence of any flux threading through the circle ) , @xmath324 is a jacobian factor , @xmath145 is a constant independent of @xmath275 as @xmath325 , and @xmath149 is the harmonic oscillator frequency near the bottom of the trapping potential . now , if there is a flux @xmath6 threading the ring , the amplitude will also acquire an additional phase factor @xmath326 , where @xmath327 and @xmath328 , if the particle carries charge @xmath19 . for a charge @xmath4 particle , the phase factor would be @xmath329 . we consider a ring size that is large enough that the electrons in a cooper pair generally traverse the ring together , and rarely split so as to wind separately around the ring . the ground state energy will give a qualitative estimate of the critical temperature of the associated superconductor . the total contribution of the amplitude for the instanton associated with the cooper pair is then @xmath330 which gives @xmath331 this gives a ground state energy of @xmath332 , which reveals the period @xmath0 , the little - parks period in critical temperature . the fact that this gives a dependence on flux being sinusoidal rather than quadratic results from the lack of accounting of the other many - body electrons and the existence of a condensate . now , occassionally ( in the sense of contributing feynman paths ) the electrons in a cooper pair separate and circumnavigate the ring ( relative to one another ) before re - associating . the contribution of such processes to the ground - state energy can be estimated via the instantons and anti - instantons of such events associated with them . a single instanton involving one electron going from @xmath95 to @xmath98 has the amplitude @xmath333 where the subscript @xmath19 indicates a single electron rather than a cooper pair , and the additional minus sign comes from the exchange of the two electrons . summing all the instanton and anti - instanton processes , we arrive at the contribution to the ground - state energy from the two electrons @xmath334 which results in the emergence of an @xmath1 contribution to the period of oscillation to critical temperature . we remark that it is owing to the separation of the lengthscales and hence time scales that we can separate the cooper - pair and single - electron contributions . the amplitudes of the two oscillations are related to the respective actions , and for large radius , the amplitude corresponding to single - particle oscillation is expected to be small , due to the binding resulting from the attractive interparticle interaction . 99 w. a. little and r. d. parks , phys . * 9 * , 9 ( 1962 ) . m. tinkham , _ introduction to superconductivity _ , mcgraw - hill ( 1996 ) , p.128-p.130 . see , e.g. , j. r. schrieffer , _ theory of superconductivity _ , perseus books ( 1983 ) , chapter 8 , p.240-p.244 . y. liu , yu . zadorozhny , m. m. rosario , b. y. rock , p. t. carrigan , and h. wang , science * 294 * , 2332 ( 2001 ) . h. wang , m. m. rosario , n. a. kurz , b.y . rock , m. tian , p. t. carrigan , and y. liu , phys . lett . * 95 * , 197003 ( 2005 ) . p. g. de gennes , c. r. acad . sci . ser . ii * 292 * , 279 ( 1981 ) . r. a. webb , s. washburn , c. p. umbach , and r. b. laibowitz , phys . * 54 * , 2696 ( 1985 ) . h. bluhm , n. c. koshnick , m. e. huber , and k. a. moler , phys . lett . * 97 * , 237002 ( 2006 ) . n. c. koshnick , h. bluhm , m. e. huber , and k. a. moler , science * 318 * , 1440 ( 2007 ) . k. czajka , m. m. maka , m. mierzejewski , and z. led , phys . b * 72 * , 035320 ( 2005 ) . f. loder , a.p . kampf , t. kopp , j. mannhart , c. w. schneider , yu . s. barash , nature phys . * 4 * , 112 ( 2008 ) . v. juricic , i. f. herbut , and z. tesanovic , e - print arxiv:0711.3790 ( 2007 ) . s. barash , e - print arxiv:0711.4338 ( 2007 ) . j. bardeen , l. n. cooper , and j. r. schrieffer , phys . rev . * 106 * , 162 ( 1957 ) . l. p. gorkov , soviet physics jetp * 9 * , 1364 ( 1959 ) ; _ ibid . _ * 10 * , 998 ( 1960 ) . in c.g.s unit , the single - particle flux quantum is @xmath49 . we shall set @xmath47 and @xmath46 . even though in this unit the flux quantum becomes @xmath335 , we shall refer to it by @xmath1 instead . see , e.g. , a. l. fetter and j. d. walecka , _ quantum theory of many - particle systems _ ( mcgraw - hill , new york , 1971 ) . although we take the ring to be of infinitesimally thin width , for small but finite width compared to the radius and the coherence length , this set of equations can be obtained by averaging over the radial direction and ignoring the fluctuations ; see appendix a. in our discussions we require that the mean average level spacing @xmath336 in the transverse direction is much greater than the superconducting gap @xmath73 , so that only the lowest level in the transverse direction is occupied . this leads to the condition that @xmath337 , where @xmath9 is the cooper - pair size @xmath338 . m. abramowitz and i. a. stegun , _ handbook of mathematical functions _ ( national bureau of standards , 1972 ) , p.259 and p.556 . g. sarma , j. phys . solids , * 24 * , 1029 ( 1963 ) . k. maki and t. tsuneto , prog . of theor . phys . * 31 * , 945 ( 1964 ) . note that here we assume the equilibrium normal state does not possess a persistent current . ignoring the finiteness correction , the transition to normal follows the curve abd in fig . [ fig : sfphase ] . if the normal state does possess a persistent current , the transition from superconducting to normal will follow the curve abe instead . the inclusion of the finiteness correction only modifies the detail locations of these curves . l. p. gorkov and a. a. abrikosov , soviet physics jetp * 8 * , 1090 ( 1959 ) . 39.2 , chapter 7 , in a. a. abrikosov , l. p. gorkov , and i. e. dzyaloshinski , _ methods of quantum field theory in statistical physics _ ( dover , 1975 ) . a. v. lopatin , n. shah , and v. m. vinokur , phys . lett . * 94 * , 037003 ( 2005 ) . this can be seen from the fact that the function @xmath339 , is greater than zero for @xmath340 when @xmath341 , whereas it crosses from negative values to positive at a certain value of @xmath342 when @xmath343 . d. c. ralph , c. t. black , and m. tinkham , phys . * 74 * , 3241 ( 1995 ) r. rajaraman , _ solitons and instantons _ , chapter 10 ( north holland , 1987 ) .

as a function of the magnetic flux threading the object , the little - parks oscillation in the critical temperature of a large - radius , thin - walled superconducting ring or hollow cylinder has a period given by @xmath0 , due to the binding of electrons into cooper pairs . on the other hand , the single - electron aharonov - bohm oscillation in the resistance or persistent current for a clean ( i.e. ballistic ) normal - state system having the same topological structure has a period given by @xmath1 . a basic question is whether the little - parks oscillation changes its character , as the radius of the superconducting structure becomes smaller , and even comparable to the zero - temperature coherence length . we supplement a physical argument that the @xmath1 oscillations should also be exhibited with a microscopic analysis of this regime , formulated in terms of the gorkov approach to bcs theory . we see that , as the radius of the ring is made smaller , an oscillation in the critical temperature of period @xmath1 emerges , in addition to the usual little - parks @xmath0-period oscillation . we argue that in the clean limit there is a superconductor - normal transition at nonzero flux , as the ring radius becomes sufficiently small , and that the transition can be either continuous or discontinuous , depending on the radius and the external flux . in the dirty limit , we argue that the transition is rendered continuous , which results in continuous quantum phase transitions tuned by flux and radius .

the advent of the @xmath8 factories , babar @xcite and belle @xcite , opens new perspectives for very precise measurements of non - leptonic @xmath8-decays @xcite and calls for a significant improvement of the theoretical predictions . in this respect , important progress has been recently achieved by systematic studies of factorization in @xmath8 decays @xcite . these studies confirmed the physical idea @xcite that factorization holds in heavy hadron decays , @xmath9 , for the leading terms of the @xmath10 expansion . they leave open , however , the central question of whether i ) the leading terms predict with sufficient accuracy the relevant @xmath8-meson decay rates or ii ) the power - suppressed corrections , which can not be evaluated without some model assumption , are phenomenologically important . this problem has been addressed in a series of papers @xcite@xcite . in particular , the main conclusion of ref . @xcite is that _ non - perturbative _ @xmath2 corrections from the leading operators of the effective weak hamiltonian , conventionally called charming ( or gim ) penguins , are very important in cases where the factorized amplitudes are either colour or cabibbo suppressed . one of the consequences of this observation is that factorization at the leading order in @xmath2 is unable to reproduce the observed @xmath0 and @xmath1 @xmath3s even taking into account the uncertainties of the input parameters . the results of ref . @xcite seem to be at variance with the conclusions of ref . @xcite where it is stated that , in the qcd factorization approach , `` an acceptable fit to the branching fractions is obtained even if we impose @xmath11 as implied by the standard constraints on the unitarity triangle '' and ref . @xcite quotes @xmath12 . ] . given the contradictory conclusions of the different studies , it is very important to clarify the situation by comparing input parameters , methods of analysis and results . in order to help the debate on this subject , we discuss in the following : * the theoretical framework of factorization and the calculation of the amplitudes at the leading order of the @xmath2 expansion ; * a comparison of the leading terms , including their uncertainties , with the measured @xmath0 and @xmath1 branching ratios ; * results for the @xmath0 and @xmath1 @xmath3s including charming ( and gim ) penguins ; * a comparison of the results obtained with charming and gim penguins @xcite with the model of the @xmath2 corrections adopted in @xcite . in this section we recall the basic ingredients necessary to compute the relevant amplitudes either whithin factorization or including the corrections which arise at higher order in the @xmath2 expansion . the physical amplitudes for @xmath1 and @xmath13 can be conveniently written in terms of rg - invariant parameters built using the wick contractions of the effective hamiltonian @xcite . in the heavy quark limit , following the approach of ref . @xcite , it is possible to compute these rg invariant parameters using factorization . the formalism of ref . @xcite has been developed so that it is also possible to include the perturbative corrections to order @xmath14 , i.e. at the next - to - leading order in perturbation theory . for the sake of discussion , it is instructive to start from the explicit expression of the @xmath15 amplitude . in terms of the parameters defined in @xcite , this amplitude reads @xmath16 we have @xmath17 where @xmath18 denotes the factorized matrix elements and @xmath19 the parameters introduced in @xcite . ( [ eq : uno ] ) and ( [ eq : due ] ) are exact . unfortunately , similar equations require the knowledge of several non - perturbative parameters , which at present can not be extracted from the data . to be predictive , we will then use our physical intuition to reduce their number . in eqs . ( [ eq : uno ] ) and ( [ eq : due ] ) : 1 . the ckm matrix elements can either be taken from other experimental measurements or from a fit to the non - leptonic @xmath3s , assuming that factorization is accurate enough ; 2 . the coefficients @xmath20 ( e.g. @xmath21 ) are renormalization group invariant , as the corresponding factorized matrix elements , and have been computed perturbatively at the nlo in refs . @xcite ; 3 . the coefficients @xmath22 and @xmath23 , which have also been computed to one - loop order , are instead scheme dependent . their scheme - dependence is cancelled by the hadronic matrix elements of the penguin operators @xmath24 and @xmath25 respectively . assuming factorization for the chirally enhanced contributions @xcite , the latter can be expressed in terms of the ratio @xmath26 which is formally of @xmath27 but numerically important ( an analogous parameter @xmath28 can be defined for @xmath29 decays ) . we will discuss the rle of these terms below . the leading amplitudes @xmath18 are computed in terms of decay constants and semi - leptonic form factors . the form factors can either be taken from theoretical calculations @xcite or fitted from the experimental @xmath3s ( the possibility of extracting them from the corresponding @xmath30 semileptonic form factor at small momentum transfer is at present rather remote ) . 5 . the tilded parameters , namely @xmath31 , @xmath32 and @xmath33 , are genuine , non - perturbative @xmath2 corrections which can not be computed at present . if we neglect zweig - suppressed contributions , by @xmath34 symmetry one can show that all the cabibbo - enhanced @xmath2 corrections to @xmath1 decays can be reabsorbed in @xmath35 . several corrections are contained in @xmath35 : this parameter includes not only the charming penguin contributions , but also annihilation and penguin contractions of penguin operators . it does not include leading emission amplitudes of penguin operators ( @xmath36@xmath37 ) which have been explicitly evaluated using factorization . had we included these terms , this contribution would exactly correspond to the parameter @xmath38 of ref . . the parameter @xmath35 ( @xmath39 ) encodes automatically not only the effect of the annihilation diagrams considered in @xcite , but all the other contributions of @xmath27 with the same quantum numbers of the charming penguins . in this respect it is the most general parameterization of all the perturbative and non - perturbative contributions of the operators @xmath40 and @xmath24 ( @xmath41 and @xmath42 ) , including the worrying higher - twist infrared divergent contribution to annihilation discussed in ref . the parameter @xmath35 has the same quantum numbers and physical effects as the original charming penguins proposed in @xcite , although it has a more general meaning . if one also includes @xmath0 decays we have several other parameters , for example @xmath43 and @xmath44 , in the formalism of ref . @xcite . a closer look to @xmath44 shows that this term is due either to zweig suppressed annihilation diagrams ( called cpa and dpa in ref . @xcite ) or to annihilation diagrams which are colour suppressed with respect to those entering @xmath35 . for this reason in ref . @xcite @xmath44 was taken to be zero . @xmath45 is equal to the corresponding parameter in @xmath46 decays if @xmath47 symmetry is assumed . in our analysis we have used the same value of @xmath48 for all @xmath46 and @xmath49 channels . @xmath43 will be discussed later on . we are now ready to discuss _ factorization _ for the leading terms of the @xmath2 expansion . factorization is the theory of non leptonic decays which is obtained in the limit @xmath50 . thus it consists in neglecting _ all _ terms of @xmath51 ( @xmath52 , @xmath53 , @xmath54 , etc . ) . at lowest order in perturbation theory , called also nave factorization , the @xmath55 are simple combinations of the wilson coefficients and do not depend on the hadron wave functions . the inconvenience of nave factorization is that physical amplitudes still have a marked dependence on the renormalization scale because , contrary to the wilson coefficients , the factorized matrix elements are scale independent . the scale dependence is reduced by working at @xmath56 , both for the wilson coefficients and the matrix elements . in refs . @xcite it has been shown that , at this order , all the dangerous infrared divergences can be reabsorbed in the definition of the hadronic wave functions . for the leading terms in the @xmath2 expansion there are strong arguments to support the idea that this will remain true at all orders in @xmath14 , see also ref . thus , in the limit @xmath57 , it is likely that factorization is preserved by strong interactions . at @xmath56 or higher , the coefficients @xmath55 depend on the specific detail of the hadron wave - fuctions . for this reason , the uncertainties relative to the wave functions , as the residual renormalization scale dependence , must be taken into account in the evaluation of the uncertainties for the theoretical predictions . the approximation in which we neglect all the @xmath2 corrections , but include the perturbative corrections to the leading contribution , is called qcd factorization or simply factorization . factorization implies an important consequence : predictions of non - leptonic decay rates are _ model independent _ to the extent that the few relevant hadronic parameters , namely the kaon and pion decay constants , @xmath58 , the semileptonic form factors , @xmath59 , and the hadronic wave functions are known . in cases like @xmath1 decays , where the factorized amplitudes are cabibbo suppressed , the corrections of @xmath27 , which unfortunately are _ model dependent _ , become important . at lowest order in @xmath14 , the chirally enhanced terms proportional to @xmath60 ( @xmath61 ) are computable by assuming that factorization can be applied beyond the leading order . a substantial difficulty arises , however , at @xmath62 . although the chirally enhanced corrections from @xmath63 are infrared finite , other contributions of the same order from different operators are infrared divergent , signaling that they belong to the class of the non - perturbative contributions which appear beyond factorization . these can not be predicted using the same hadronic quantities of the factorized amplitudes . for this reason , any phenomenological analysis which aims at including in a coeherent way the terms of @xmath64 is forced to introduce extra model - dependent non - perturbative parameters besides @xmath58 , @xmath59 and the hadronic wave functions . this implies that , _ at @xmath51 , model dependence is unavoidable _ ( even in the subsector of the chirally enhanced contributions ) and it is present in both the analyses of ref . @xcite and ref . @xcite , which we will compare below . different model - dependent assumptions were made in the two approaches : 1 . in ref . @xcite , @xmath65 and @xmath66 were neglected and @xmath34 symmetry was assumed for @xmath67 ( @xmath47 when it was used for @xmath68 decays ) . the same approximations were made for @xmath69 . the complex parameter @xmath35 ( @xmath69 ) was then fitted to reproduce the experimental @xmath3s . 2 . in ref . @xcite the effects of the chirally enhanced @xmath2 corrections were either computed perturbatively or encoded in two complex phenomenological parameters called @xmath70 and @xmath71 . an uncertainty of 100 @xmath72 to the `` default '' values ( e.g. @xmath73 ) was assigned to these parameters in order to determine allowed bands for the predicted @xmath3s . the bands include all other sources of uncertainties . we now compare the leading amplitudes to the experimental results in order to _ test factorization_. before using predictions based on factorization to test the standard model and look for signals of new physics , it is crucial to check how large are the errors induced by our ignorance of the @xmath51 corrections which we are unable to compute . our position , indeed , is that we have more confidence in the sm rather than in factorization . in order to test factorization , we ought to use all the information that we have from other measurements . thus , for example , whereas the size of the error on @xmath74 and @xmath75 can be debated , there is no question that these experimental inputs must be included in any analysis that aims at testing ( or using ) factorization . we also stress that the value of @xmath75 is not expected to be affected by the presence of new physics beyond the sm . the cp parameter @xmath4 does in general change if there is physics beyond the sm . it remains an interesting exercise , however , to verify whether , by taking the value of @xmath4 from the unitarity triangle analysis ( uta ) in the sm , the predicted @xmath3s are in agreement with the data . if , by using @xmath4 from the uta , one is unable to reproduce the experimental @xmath0 and @xmath1 @xmath3s , this implies that `` either there is new physics or @xmath2 corrections are important '' @xcite . in our analysis we have used the likelihood method which has been described in all details in ref . @xcite . without entering in the `` ideological '' controversy about frequentistic and bayesian methods , we only note here that in @xcite it has been shown that , at 95 % c.l . , the bayesian analysis give the same results as the frequentistic babar scanning method ( and its variations ) when the same inputs are used . thus we will present our contour plots , corresponding to fig . 17 of ref . @xcite , both with factorization plus chirally enhanced contributions and with the non - factorizable charming ( and gim ) penguin corrections . besides this , we will also give tables with the relevant @xmath3s , both in the factorization approximation with chirally enhanced terms and with the charming ( and gim ) penguin corrections included . we end this section with some remarks . in our approach , we have first checked that , within factorization and the sm , it is impossible to fit the experimental @xmath3s . the @xmath2 terms , that we are then forced to include in order to reproduce the experimental results , are non - perturbative quantities , infrared divergent in perturbation theory , on which we do not have any knowledge _ a priori_. for this reason we decided to fit them on the data . the experimental numbers are nicely reproduced and the corrections to factorization are well consistent with the expected size ( i.e. @xmath35 is of @xmath51 with respect to the leading contributions ) . in ref . @xcite the subleading power corrections are varied in predefined intervals and the change in the predicted @xmath3s is interpreted as uncertainty on the factorized amplitudes . in our opinion the uncertanties on factorization are only those coming from the ckm matrix elements or the form factors , etc . the @xmath2 terms instead are really contributions beyond factorization : if they are necessary to reproduce the data then it is not possible to make model independent predictions . this would remain true even if we knew without any uncertainty the hadronic parameters entering at the lowest order of the @xmath2 expansion s are dominated by the @xmath2 corrections . ] . thus we are in the bermuda triangle : i ) without the @xmath76 and @xmath77 terms , that is within qcd factorization , we can not reproduce the data ; ii ) the inclusion of the computable subset of @xmath77 terms only is inconsistent since there is no reason to exclude the other non - perturbative non - computable contributions of the same order . in any case , we will show that , by using all the available experimental information , also this case is very difficult to reconcile with the data ; iii ) the complete set of @xmath77 corrections leads us beyond factorization and the results are model dependent . indeed there is no proof that the one - loop finite chirally enhanced terms remain infrared finite at higher orders in @xmath14 . moreover , if the corrections of @xmath78 are phenomenologicaly important , it is difficult to understand why , at the same level of numerical accuracy , other non - chirally enhanced non - perturbative @xmath2 terms should not also be taken into account . the sad conclusion is that the very nice theory of qcd factorization developed in @xcite is insufficient to fit the data because power corrections , which are model dependent , are important in @xmath79 and @xmath80 decays . finally , model dependence does not implies that we are unable to make any prediction . if the assumptions made in our approach are reasonable . ] , by fitting @xmath81 to the data and with the increasing experimental precision we may hope to extract also the value of @xmath4 or to constrain @xmath82 in this section we present our analysis and a detailed comparison with the results of ref . @xcite . in order to obtain our results we used the likelihood method as in @xcite . the input parameters , given in table [ tab : inputs ] , are also the same but for a few differences : * we added the @xmath56 corrections to the coefficients of the penguin and electropenguin operators computed in @xcite , which appeared after the completion of @xcite . in this respect the criticisms of ref . @xcite do not apply to the present analysis . we will see below that , even including these new ingredients , the main physics conclusions of ref . @xcite are confirmed . * as for the matrix elements of @xmath63 , we include the `` computable '' factorizable chirally enhanced terms in the definition of @xmath81 , which in this way contains all the possible cabibbo enhanced , model - dependent corrections of @xmath51 . in practice this corresponds to fit @xmath67 as in ref . @xcite with @xmath83 . there is no substantial difference between the old choice and the new one , since the contribution of the chirally enhanced terms and of @xmath31 have exactly the same quantum numbers . * although this is a minor source of uncertainty we also allow a variation of the renormalization scale and of the parameters of the hadronic wave functions . we have also verified that by using the inputs of ref . @xcite we obtain essentially the same results , and hence arrive to the same physics conclusions . in this section we present : 1 . a brief discussion of the results obtained in qcd factorization , namely with all the terms of @xmath51 set to zero . the results obtained in our approach by fitting @xmath35 and using @xmath4 as determined from the unitary triangle analysis in ref . @xcite @xmath84 on the basis of this study we predict the @xmath8@xmath85 asymmetries of the @xmath3s , such as @xmath86 3 . the results obtained by letting @xmath4 free and a comparison of our results with those of ref . @xcite . in this subsection we compare the model independent results obtained with qcd factorization , namely including only the terms which survive when @xmath87 , with the experimental data . in this case there is still a residual model dependence due to our ignorance of the semileptonic form factors @xmath59 and , at order @xmath14 , to the ignorance of the hadron wave functions . we vary the semileptonic form factors with flat p.d.f . in the intervals given in table [ tab : inputs ] and the parameters of the hadron wave functions in the intervals given in table 2 of ref . we also vary the renormalization scale between @xmath88 and @xmath89 , see table 1 of @xcite . the data show a generalized disagreement with the qcd factorization predictions . in particular the allowed region in the @xmath90@xmath91 plane and the value of @xmath4 do not have any overlap with the corresponding ones from the unitarity triangle analysis @xcite . this remains true even if we double the uncertainty on @xmath92 . we conclude that qcd factorization can not be reconciled with data . .input values used in the numerical analysis . the form factors are taken from refs . @xcite , the ckm parameters from ref . @xcite and the brs correspond to our average of cleo , babar and belle results @xcite . all the @xmath3s are given in units of @xmath93 . [ cols="^,^,^,^",options="header " , ] we now discuss the effect of @xmath94 on the final results . the addition of these parameters , in the range proposed in ref . @xcite , leaves the situation substantially unaltered as shown in fig . [ fig : lorolastloro ] . this holds true also for the @xmath3s , which are given in table [ tab : one ] with the label bbns . the reason is that on the one hand @xmath71 and @xmath70 do not have the same quantum numbers , and hence effects , of charming penguins , on the other the range chosen _ a priori _ , on the basis on one - loop perturbation theory , is not large enough to improve the agreement with the measured @xmath3s ( it essentially increases the uncertainty on the predictions ) . of course by choosing a low value of the strange quark mass and of @xmath95 ( without using the experimental information coming from its measurements ) , a large value of @xmath96 and a small value for @xmath97 etc . it is still possible to find some point in parameter space where the @xmath98 is good . that this can be used to fit @xmath4 and test the sm is hard to believe though . the situation would be different if @xmath94 are let free to vary and fitted to the data . we have done this exercise and found that the preferred value of @xmath99 is much larger than the values allowed in the interval chosen in @xcite , whereas @xmath100 is not determined by the fit . we conclude that since @xmath71 and @xmath70 are infrared divergent quantities , the value of which can not be predicted , and since without the inclusion of non - perturbative contributions of @xmath51 is not possible to reproduce the experimental data , we are bound to use model dependent assumptions in the analysis of non - leptonic @xmath1 and @xmath0 decays . we have analyzed the predictions of qcd factorization for @xmath0 and @xmath1 decays . even taking into account the uncertainties of the input parameters , we find that qcd factorization is unable to reproduce the observed @xmath3s . the introduction of charming and gim penguins @xcite allows to reconcile the theoretical predictions with the data . instead of varying the non - perturbative phenomenological parameters in preassigned ranges , we prefer to try to fit them on the data . with the present theoretical and experimental accuracy , we find that it is still not possible to determine the cp violation angle @xmath4 . the situation is expected to improve in the near future with more accurate experimental measurements of the relevant @xmath3s . contrary to factorization , we predict large asymmetries for several of the particle antiparticle @xmath3s , in particular @xmath101 , @xmath102 and , possibly , @xmath103 . this opens new perspectives for the study of cp violation in @xmath8 systems . we thank c. sachrajda for useful discussions on this work . g.m . and l.s . thanks the th division at cern where part of this work has been done . 88 , edited by p.f . harrison and h.r . quinn , slac report slac - r-504 , october 1998 . f. takasaki , in _ proc . of the 19th intl . symp . on photon and lepton interactions at high energy lp99 j.a . jaros and m.e . peskin , int . j. mod . a * 15s1 * ( 2000 ) 12 , hep - ex/9912004 . f. ferroni , talk given at this workshop . h - n li and h.l . yu , phys . * 74 * ( 1995 ) 4388 and phys . d * 53 * ( 1996 ) 2480 ; c.h . chang and h - n li , phys . rev . d * 55 * ( 1997 ) 5577 ; t.w . yeh and h - n li , phys . d * 56 * ( 1997 ) 1615 ; h.y . cheng , h - n li and k.c . yang , phys . d * 60 * ( 1999 ) 094005 ; for a recent review see h - n li , hep - ph/0103305 . m. beneke , g. buchalla , m. neubert and c.t . sachrajda , phys . rev . * 83 * ( 1999 ) 1914 ; nucl . b * 591 * ( 2000 ) 313 ; hep - ph/0007256 . bjorken , nucl . b ( proc . suppl . ) * 11 * ( 1989 ) 325 ; + m. j. dugan and b. grinstein , phys . b * 255 * ( 1991 ) 583 ; + h. d. politzer and m. b. wise , phys . b * 257 * ( 1991 ) 399 . m. ciuchini , e. franco , g. martinelli and l. silvestrini , nucl . b * 501 * ( 1997 ) 271 , hep - ph/9703353 . m. ciuchini , r. contino , e. franco , g. martinelli and l. silvestrini , nucl . b * 512 * ( 1998 ) 3 , hep - ph/9708222 . p. colangelo , g. nardulli , n. paver and riazuddin , z. phys . c * 45 * ( 1990 ) 575 . c. isola , m. ladisa , g. nardulli , t. n. pham and p. santorelli , hep - ph/0101118 . a. j. buras and r. fleischer , phys . b * 341 * ( 1995 ) 379 , hep - ph/9409244 . a. ali and c. greub , phys . d * 57 * ( 1998 ) 2996 , hep - ph/9707251 ; + a. ali , g. kramer and c. lu , phys . d * 58 * ( 1998 ) 094009 , hep - ph/9804363 ; phys . rev . d * 59 * ( 1999 ) 014005 , hep - ph/9805403 . w. n. cottingham , h. mehrban and i. b. whittingham , hep - ph/0102012 . m. ciuchini , e. franco , g. martinelli , m. pierini and l. silvestrini , hep - ph/0104126 . m. beneke , g. buchalla , m. neubert and c.t . sachrajda , hep - ph/0104110 . m. ciuchini _ et al . _ , hep - ph/0012308 . a. hocker , h. lacker , s. laplace and f. le diberder , hep - ph/0104062 . a. j. buras and l. silvestrini , nucl . phys . b * 569 * ( 2000 ) 3 , hep - ph/9812392 . s. descotes and c.t . sachrajda , shep/01 - 27 , hep - ph/0109260 . a. abada , d. becirevic , p. boucaud , j. p. leroy , v. lubicz and f. mescia , hep - lat/0011065 . see also l. del debbio , j. m. flynn , l. lellouch and j. nieves [ ukqcd collaboration ] , phys . b * 416 * ( 1998 ) 392 , hep - lat/9708008 . a. khodjamirian , r. ruckl , s. weinzierl , c. w. winhart and o. yakovlev , phys . d * 62 * ( 2000 ) 114002 , hep - ph/0001297 . for an earlier determination of the form factors , see also p. ball , jhep*9809 * ( 1998 ) 005 , hep - ph/9802394 . y. keum , h. li and a. i. sanda , hep - ph/0004004 ; y. y. keum , h. li and a. i. sanda , phys . d * 63 * ( 2001 ) 054008 , hep - ph/0004173 . m. beneke , hep - ph/0009328 . r. godang _ et al . _ [ cleo collaboration ] , phys . * 80 * ( 1998 ) 3456 , hep - ex/9711010 . d. cronin - hennessy _ et al . _ [ cleo collaboration ] , hep - ex/0001010 . d. m. asner _ [ cleo collaboration ] , hep - ex/0103040 . g. cavoto , babar collaboration , talk given at the xxxvi rencontres de moriond qcd . b. casey , belle collaboration , talk given at the xxxvi rencontres de moriond qcd . c. w. bauer , d. pirjol and i. w. stewart , hep - ph/0107002 . m. beneke , hep - ph/0109243 .

by using the recent experimental measurements of @xmath0 and @xmath1 branching ratios , we find that the amplitudes computed at the leading order of the @xmath2 expansion disagree with the observed @xmath3s , even taking into account the uncertainties of the input parameters . beyond the leading order , charming and gim penguins allow to reconcile the theoretical predictions with the data . because of these large effects , we conclude , however , that it is not possible , with the present theoretical and experimental accuracy , to determine the cp violation angle @xmath4 from these decays . we compare our results with those obtained with the parametrization of the chirally enhanced non - perturbative contributions by bbns . we also predict large asymmetries for several of the particle antiparticle @xmath3s , in particular @xmath5 , @xmath6 and @xmath7 . address = dip . di fisica , univ . di roma iii and infn , sezione di roma tre , via della vasca navale 84 , i-00146 roma , italy , email= , thanks= address = dip . di fisica , univ . `` la sapienza '' and infn , sezione di roma , p.le a. moro , i-00185 rome , italy , email= , thanks= address = dip . di fisica , univ . `` la sapienza '' and infn , sezione di roma , p.le a. moro , i-00185 rome , italy , email= , thanks= address = dip . di fisica , univ . `` la sapienza '' and infn , sezione di roma , p.le a. moro , i-00185 rome , italy , email= , thanks= address = dip . di fisica , univ . `` la sapienza '' and infn , sezione di roma , p.le a. moro , i-00185 rome , italy , email= , thanks=

lkh@xmath0 234 ( v373 cep ) is a b7-type herbig be star in the ngc 7129 cluster ( d @xmath6 1.25 kpc , * ? ? ? the star is @xmath8 8.5 m@xmath9 , @xmath8 1700 l@xmath9 @xcite , and has an age of @xmath8 10@xmath10 years @xcite . lkh@xmath0 234 is bright in far - ir bands and is surrounded by reflection nebulae @xcite . it is one of the objects in the catalog of embedded clusters @xcite , and is a well - known water maser emission source @xcite . lkh@xmath0 234 region is complex , with multiple outflows from different ysos . @xcite discovered a large - scale outflow in j = 1@xmath10 @xmath11co , which is mostly redshifted with low - velocity ( @xmath8 10 km s@xmath7 ) , to the northeast of lkh@xmath0 234 . shocked h@xmath2 flows are also detected in the co outflow region @xcite . mid - ir spectroscopy showed that this shocked h@xmath2 is collisionally excited by a j - type shock @xcite . @xcite found a blueshifted optical [ ] jet ( hh 167 ) , which extends more than 30@xmath12 with a p.a . of 252@xmath13 . @xcite argue that this jet is the counterpart of the red co lobe . @xcite showed that there is near - ir h@xmath2 emission at the position of the [ ] jet , and @xcite confirmed an h@xmath2 jet in high angular resolution images . the h@xmath2 jet coincides with knots a , b and c of the [ ] jet @xcite . @xcite noticed two jet - like features in their stellar coronagraphic images in the j@xmath1 and h@xmath1bands . one of the jet - like features is coincident with a `` green blob '' in the middle of the reflection nebula shown in their jhk color composite image . the position of the green blob is in agreement with the [ ] emission in @xcite . in addition , @xcite suggested a parsec - scale jet over @xmath8 22@xmath14 ( @xmath8 8 pc ) as projected on the sky , including hh 815 @xmath1 822 and hh 103 a. in figure [ fig : sourcemap ] , we show the source candidates and the axes of outflows on the images taken from @xcite and @xcite . also , table 3 in @xcite established the association of sources and source labels from previous studies , which helps the understanding of this region . polarimetric observations at 2 @xmath4 by @xcite revealed the existence of an embedded young stellar companion 3@xmath12 northwest of lkh@xmath0 234 . their polarization map also showed that the companion is the most likely illuminating source of the reflection nebula . @xcite detected a 10 @xmath15 m source ( irs 6 ) at the position coinciding with the center of the polarization vectors in @xcite . @xcite also detected a mid - ir source nw at the position of irs 6 . since the axis of the h@xmath2 jet ( p.a . = 227@xmath13 ) is not aimed at irs 6 , the possible existence of another embedded source was suggested . irs 6 is not driving the h@xmath2 jet , but it was regarded as the source of the co/ [ ] outflow @xcite . millimeter observations by @xcite revealed a new embedded source , firs1-mm1 @xmath8 4@xmath12 northeast of lkh@xmath0 234 . firs1-mm1 lies within 1@xmath12 the jet axis , so it is suggested as the source of the h@xmath2 jet @xcite . many radio observations have shown strong continuum emission near lkh@xmath0 234 ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? the strongest radio source , vla 3 , is associated with irs 6 . @xcite showed that the vla 3 is a binary system ( 3a and 3b ) having thermal radio jets . in the 1.3 cm and 3.6 cm continua and h@xmath2o maser observations , the water maser sources around another radio source vla 2 are tracing the axis of [ ] outflow . the proper motion of h@xmath2o masers showed bipolar motions centered on vla 2 along the axis of [ ] outflow . these suggested that vla 2 is the driving source of [ ] outflow @xcite . @xcite detected nw 1 and 2 at the positions of irs 6 and vla 2 , respectively in a mid - ir observation . in figure [ fig : sourcemap ] , the positional uncertainties are less than 02 and 005 for the radio sources and the mid - ir sources ( nw 1 and 2 ) . for irs 6 , the cross indicates an uncertainty . we note that an additional error could be caused by astrometric matching between different observations , which is less than 05 . from the previous studies @xcite , we can say that the [ ] outflow is driven by vla 2 ( = nw 2 ) and that firs1-mm 1 is well aligned with the near - ir h@xmath2 jet axis . currently there is no evidence of lkh@xmath0 234 itself as an outflow driving source . a large fraction of stars form in binary or multiple star systems @xcite . for all stars , outflows and mass - accretion are an essential part of their formation and early evolution @xcite . while studies of single star - disk systems have brought much knowledge about outflows and mass - accretion from young stellar objects , the complicated nature of multiple - star systems makes it more difficult to understand their characteristics in detail . high - resolution spatial - kinematic analysis toward outflows in young multiple systems can help us to understand their complicated velocity distribution and physical conditions . in this paper , we report the first high - resolution near - ir spectroscopic observations of the multiple outflows around lkh@xmath0 234 using the recently developed immersion grating infrared spectrograph ( igrins , * ? ? ? * ; * ? ? ? we detected emission lines from [ ] and in ro - vibrational transitions of h@xmath2 including [ ] @xmath31.644 @xmath4 and h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 lines . from our result , we suggest a newly confirmed [ ] outflow , possibly driven by vla 3b . in section [ sec : observation ] , we describe the observations and data reduction . section [ sec : result ] shows the obtained position - velocity diagrams ( pvds ) and line ratios . we discuss the characteristics of the [ ] and h@xmath2 emission , and the driving sources of multiple outflows in section [ sec : discussion ] . we summarize the results in section [ sec : summary ] . the data were obtained during a commissioning run of igrins mounted on the 2.7 m harlan j. smith telescope at the mcdonald observatory of the university of texas . the date of observation was july 13 , 2014 ( ut ) . igrins covers the whole h@xmath1 ( 1.49 @xmath1 1.80 @xmath15 m ) and the k@xmath1bands ( 1.96 @xmath1 2.46 @xmath15 m ) simultaneously , with a high spectral resolution r ( @xmath16 ) of @xmath8 40,000 ( @xmath17@xmath18 @xmath6 7.5 km s@xmath7 with @xmath8 3.5 pixels ) . each of h@xmath1 and k@xmath1band cameras uses a ( 2k @xmath19 2k ) hawaii-2rg array for a detector @xcite . the pixel scale along the slit , which becomes larger in higher orders was 024 @xmath1 029 pixel@xmath7 . the slit size was 10 ( w ) @xmath19 148 ( l ) . auto - guiding was performed during each exposure with a k@xmath1band slit - viewing camera equipped with a ( 2k @xmath19 2k ) hawaii-2rg array ( pixel scale = 012 pixel@xmath7 ) . the guiding uncertainty on average was smaller than 04 . the seeing condition was about 11 at k@xmath1band . the observations were made at three slit positions covering lkh@xmath20 234 and hh 167 . in figure [ fig : sourcemap ] , the slit positions are marked on the jhk color composite and h@xmath2 narrow - band images . the white rectangles represent slit positions 1 , 2 , and 3 ( hereafter sp 1 , 2 , and 3 ) . the position angle ( p.a . ) of the slit was 256@xmath13 in all positions . we confirmed the slit positions and p.a . by matching the positions of stars on the slit - view images and the 2mass ks image . the total on - source integration time was 600 s for each slit position . the sky frames were obtained with the same exposure time as on - source frames . we observed hr 6386 ( k @xmath6 6.52 , spt @xmath6 a0v ) as a standard star . th - ar and halogen lamp frames are acquired for wavelength calibration and flat - fielding , respectively . we performed the basic data reduction with the igrins pipeline package ( plp ) . the plp performs sky subtraction , flat - fielding , bad pixel correction , aperture extraction , and wavelength calibration . to make position - velocity diagrams , we conducted additional processes on the data using iraf ( the image reduction and analysis facility ) . we resampled the spectra with a uniform wavelength interval per pixel along the dispersion direction by the transform task ( linearization ) . after we removed the brackett series absorption lines from the standard star spectra using the splot task , we did the wavelength sensitivity correction and flux calibration with standard star spectra . the telluric line correction was performed with the telluric task . we used the background task to subtract the continuum emission from lkh@xmath0 234 . in figure [ fig : sourcemap]c , the y = 0@xmath12 position along the slit is indicated with a dash - dotted line , which crosses to the position of the lkh@xmath0 234 in sp 1 and perpendicular to the p.a . of the slits . the notation of knots a , b , and c are from @xcite . although the inclination angle of the jet is not known , the positional change on the sky plane of the knots is supposed to be small ( @xmath21 1 ) due to large ( 1.25 kpc ) distance from us . figure [ fig : profiles ] shows line profiles of all detected 5 [ ] emission lines and 8 selected h@xmath2 emission lines toward knot a at sp 1 , 2 , and 3 . in figure [ fig3 ] , we show the position velocity diagrams of the h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 and [ ] @xmath31.644 @xmath4 lines at the three slit positions . the line profiles at 05 interval along the y direction are shown in figure [ fig4 ] . in figure [ fig : profiles ] , the fluxes are integrated over knot a ( @xmath165 @xmath21 y @xmath21 @xmath105 ) . the [ ] lines at sp 1 and 2 show similar profiles with a peak velocity ( @xmath22 ) of @xmath8 @xmath1110 km s@xmath7 and a shoulder toward lower velocity . at sp 3 , only [ ] @xmath31.644 @xmath4 line is detected . at each slit position , all h@xmath2 lines show similar profiles . at sp 1 and 3 , the h@xmath2 emission lines have asymmetric line profiles . at sp 1 , the profiles peak at v@xmath5 @xmath8 @xmath111 km s@xmath7 and show blueshifted wings . the profiles at sp 3 are asymmetric relative to the peak velocity ( v@xmath5 @xmath8 @xmath113 km s@xmath7 ) , showing a gradual slope on the red side of the line . at sp 2 , they show double peaks at v@xmath5 = @xmath130 and @xmath15 km s@xmath7 . the [ ] and h@xmath2 emission profiles differ significantly ; h@xmath2 emission lines are strong at low - velocity , close to the systemic velocity of v@xmath5 = @xmath110.2 km s@xmath7 @xcite , while [ ] emission lines are prominent at higher velocity . in the following section , we compare [ ] @xmath31.644 @xmath4 and h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 emission lines at each slit position in detail . in figure [ fig3 ] , contours and color gradients represent h@xmath2 and [ ] emission , respectively . sp 1 includes the southern part of knot a and the center of knot b , as shown in figure [ fig : sourcemap ] . the h@xmath2 emission in knot a shows multiple intensity peaks . we marked two strong peaks as a1 and a2 . they are at y = @xmath135 and @xmath148 , and their peak velocities are @xmath8 @xmath125 and @xmath111 km s@xmath7 , respectively . a weak , but high@xmath1velocity ( @xmath1110 km s@xmath7 ) emission is also detected at y = @xmath150 , at a similar position as knot a2 . velocity widths at half intensity ( @xmath23 ) are @xmath8 37 and 23 km s@xmath7 for a1 and a2 , respectively . the @xmath22 of a2 is very similar to the systemic velocity ( i.e. , @xmath110.2 km s@xmath7 ) . a plateau extended from knot a is shown at y = @xmath153 and v@xmath5 = @xmath150 km s@xmath7 . we detected a bright , high - velocity [ ] knot at y = @xmath147 with a @xmath22 @xmath8 @xmath1113 km s@xmath7 . the position and velocity of this [ ] knot are almost consistent with high - velocity h@xmath2 emission at y = @xmath150 mentioned above . the [ ] emission also shows an extended velocity component which peaks at @xmath173 km s@xmath7 . the fwzi of the [ ] profile which contains both high - velocity and extended components is @xmath8 130 km s@xmath7 . from their double - peak line profile ( figure [ fig4 ] ) , we estimated the velocity widths and peak intensities by a multiple - gaussian fitting . @xmath23 are 33 and 41 km s@xmath7 for high - velocity and extended components , respectively . the peak intensity level of the extended component is about 3 times weaker than that of the bright peak ( @xmath8 40@xmath24 ) . at y @xmath8 @xmath168 , both h@xmath2 and [ ] emission show peaks at @xmath1130 km s@xmath7 , which is the highest velocity in pvd . the position of this fast peak is located on the boundary region between knot a and knot b. we detected no counter component of low velocity in the h@xmath2 emission . knot b reveals three different velocity peaks in h@xmath2 emission . they show an increase in @xmath25y@xmath25 with larger @xmath26 values . their positions are y = @xmath192 , @xmath194 , and @xmath1102 , and @xmath22 are @xmath113 , @xmath157 , and @xmath1118 km s@xmath7 , respectively . all three peaks have the same , narrow velocity widths of @xmath8 23 @xmath27 1 km s@xmath7 . the lowest velocity emission at @xmath113 km s@xmath7 , which is close to the systemic velocity , is 8 times and 6 times brighter than those of the @xmath157 and @xmath1118 km s@xmath7 peaks , respectively . in [ ] , two weak peaks are detected at y = @xmath194 and @xmath1 99 with a @xmath22 of @xmath159 and @xmath1120 km s@xmath7 . the @xmath23 is wider ( 47 km s@xmath7 ) in its higher velocity peak than the slower peak ( 24 km s@xmath7 ) . the positions and velocities of these peaks are consistent with @xmath157 and @xmath1118 km s@xmath7 peaks in h@xmath2 emission . no [ ] emission corresponds to the position of the @xmath113 km s@xmath7 peak in h@xmath2 . the [ ] emission usually arises from a similar shock region as the optical [ ] emission @xcite . the spectroscopy of [ ] @xmath286716 , 6731 in @xcite showed @xmath29 of @xmath179 and @xmath189 km s@xmath7 for knots a and b ( velocities are converted from their heliocentric velocity ) . the peak velocities obtained from our [ ] observations are different from [ ] . knot a shows @xmath8 @xmath1113 km s@xmath7 and knot b is detected in multiple velocities of @xmath159 and @xmath1120 km s@xmath7 . although the intensity of knot b in [ ] is comparable to that of knot a , [ ] in knot b is about 6 times weaker than knot a. one similarity between [ ] and [ ] spectra is that both show no emission at the systemic velocity . the differences between h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 and [ ] @xmath31.644 @xmath4 emission and their discrete multiple peaks will be discussed in detail in section [ sec : discussion ] . sp 2 lies @xmath8 12 northwest of sp 1 ( figure [ fig : sourcemap ] ) . this position includes the central region of knot a in h@xmath2 emission . the h@xmath2 and [ ] emission in this position are strongest among the three slit positions . sp 2 grazes knot b at y @xmath21 @xmath168 . in h@xmath2 emission , knot a shows multiple velocity peaks at y = @xmath135 and @xmath152 with @xmath22 @xmath8 @xmath130 and @xmath15 km s@xmath7 ( figure [ fig3 ] ) . since their positions are different from a1 and a2 in sp 1 , we marked them as a1@xmath14 and a2@xmath14 . the @xmath22 of a1@xmath14 is slightly faster than a1 , and a2@xmath14 is redshifted compared to the systemic velocity . the velocity widths of a1@xmath14 and a2@xmath14 ( @xmath8 34 and @xmath8 25 km s@xmath7 ) are similar to those of a1 and a2 , within an error range of @xmath27 3 km s@xmath7 . weak emission at a high - velocity of @xmath1110 km s@xmath7 is also detected at @xmath14@xmath307 . it is noticeable that the redshifted h@xmath2 emission ( v@xmath5 @xmath31 @xmath110.2 km s@xmath7 ) from knot a is extended to @xmath8 @xmath3230 km s@xmath7 . the [ ] emission from knot a is similar to that of sp 1 in velocity , showing double - velocity peaks . it shows a high - velocity peak of @xmath1112 km s@xmath7 at y= @xmath143 and an extended line profile toward lower - velocity . the peak of the extended component shows a @xmath22 of @xmath178 km s@xmath7 and is @xmath8 2.5 times weaker than the high - velocity peak . their velocity widths estimated by a multiple - gaussian fitting are @xmath8 32 and 46 km s@xmath7 , respectively . the fwzi of this [ ] emission is the same with that of sp 1 ( @xmath8 130 km s@xmath7 ) . [ ] peak in sp 2 is @xmath3204 in y from the corresponding peak in sp 1 . this may be caused by the different p.a . of the [ ] outflow and our slits . weak h@xmath2 emission ( @xmath24 @xmath8 5 ) is detected at y = @xmath16@xmath308 and v@xmath5 = @xmath1130 km s@xmath7 , which coincides in position and velocity with the highest velocity peak of h@xmath2 and [ ] at sp 1 . at y @xmath21 @xmath168 , a part of knot b shows a similar shape to that of sp 1 in h@xmath2 emission : strong around the systemic velocity , high velocity peaks and a blueshifted wing . however , there is no relevant peak feature around the systemic velocity . [ ] emission is not detected in knot b. at this position , we obtain a spectrum of the northwest part of knot a , while the slit does knot cover any of the emission from knot b ( figure [ fig : sourcemap ] ) . knot a shows two peaks , as in the previous two slit positions . both peaks lie near the systemic velocity and we mark them as a1@xmath12 and a2@xmath12 . a1@xmath12 peaks at y = @xmath1335 and shows a less negative peak velocity ( @xmath112 km s@xmath7 ) than a1 and a1@xmath14 , with a velocity width of 36 km s@xmath7 . a2@xmath12 shows multiple velocities with peaks at @xmath15 and @xmath113 km s@xmath7 at y @xmath8 @xmath150 . the velocity widths of the two peaks are 23 km s@xmath7 and @xmath8 41 km s@xmath7 , respectively . in sp 3 , an extension of a redshifted component at knot a in the h@xmath2 emission is more noticeable than in sp 2 . it is most extended at y = @xmath145 and the velocity reaches over @xmath3240 km s@xmath7 . [ ] emission in sp 3 is much weaker than in sp 1 and 2 , by a factor of @xmath8 10 and @xmath8 25 , respectively . figure [ fig : feiipvd ] shows the pvds of all detected [ ] emission from sp 1 , sp 2 and sp 3 . it includes the @xmath31.533 , @xmath31.600 , @xmath31.644 , @xmath31.664 , and @xmath31.677 @xmath4 lines . all five lines are detected at sp 1 and 2 , while sp 3 only shows emission in @xmath31.644 line . in sp 1 and 2 , the morphologies and velocities are almost the same in all of the lines in each slit position . one exception is in sp 1 , where the highest velocity peak at v@xmath5 @xmath8 @xmath1130 km s@xmath7 , y = @xmath168 and weak emission at y = @xmath194 and @xmath199 are only detected in @xmath31.644 @xmath4 . measured line fluxes normalized to the [ ] @xmath31.644 @xmath4 line are listed in table [ tbl : feiiflux ] . since the positions and velocities of peaks in all [ ] lines are consistent , the fluxes are estimated within the regions at y @xmath8 47 @xmath27 04 , v@xmath5 @xmath8 @xmath1113 @xmath27 10 km s@xmath7 and at y @xmath8 43 @xmath27 04 , v@xmath5 @xmath8 @xmath1112 @xmath27 10 km s@xmath7 in sp 1 and sp 2 , respectively . the line fluxes in sp 1 and sp 2 are very similar . near - ir [ ] emission lines can be used as effective tracers of electron density ( @xmath33 ) in stellar outflows @xcite . @xcite developed a non - lte model applicable to jets from ysos , considering the first 16 fine structure levels of the fe@xmath34 ion . the flux ratios between lines obtained in our observations are relatively independent of gas temperature , because the lines are all from the fine structure level of @xmath35 term , having excitation energies in the range of 10,000 @xmath1 12,000 k @xcite . to investigate the electron density , we show the line ratios superposed on the model grids from @xcite in figure [ fig : ne ] . in sp 1 and 2 , the electron densities ( log @xmath33 ) averaged from the three ratios of @xmath31.600 , @xmath31.533 , @xmath31.677 @xmath4 lines against the @xmath31.644 @xmath4 line are 4.0 @xmath36 and 4.1 @xmath37 , respectively . the uncertainty in @xmath31.644 @xmath4 / @xmath31.533 @xmath4 ratio is larger ( figure [ fig : ne ] ) , due to residuals after a subtraction of the oh sky emission in @xmath31.533 @xmath4 line . the @xmath33 of knot a we obtained from the optical [ ] doublet ratio @xcite is about 0.3 @xmath19 10@xmath38 @xmath39 , which is smaller than that estimated from near - ir ion emission lines here . this result is consistent with the tendency in @xcite . it indicates that the [ ] lines are able to probe a denser region in the jet because they have a higher critical density ( @xmath8 10@xmath38 @xmath39 ) than that of the [ ] ( @xmath8 10@xmath40 @xmath39 ) . the electron densities of 0.5 @xmath1 3.2 @xmath19 10@xmath38 @xmath39 , obtained here are similar to or smaller than those estimated from [ ] emission from t - tauri stars and intermediate - mass stars in @xcite . in addition , these are also slightly lower than values from hh outflows from class 0@xmath1i , which range from 10@xmath38 to 10@xmath10 @xmath39 @xcite . table [ tbl : h2flux ] lists the line fluxes of all 14 emission lines detected in these observations . fluxes are estimated in each peak position in figure [ fig3 ] , and normalized to the h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 line . figure [ fig : h2pvd ] shows the pvds of 8 selected h@xmath2 emission lines . in all slit positions , the different h@xmath2 emission lines show similar velocity features , as in [ ] . in all h@xmath2 lines at sp 1 , 2 , and 3 , we detected emission from both knot a and knot b which are bright at low - velocity . the three high - velocity components at y = @xmath168 , @xmath194 , and @xmath1102 with @xmath22 of @xmath1130 , @xmath113 , and @xmath1118 km s@xmath7 shown in @xmath3 2.122 @xmath4 are also detected in @xmath32.034 , @xmath32.223 , @xmath32.407 , and @xmath32.424 @xmath4 lines . in @xmath32.407 @xmath4 at sp 2 , we detected a weak ( 5@xmath24 level ) emission which is consistent with a peak at y = @xmath147 with @xmath1110 km s@xmath7 in @xmath32.122 @xmath4 . figure [ fig : h2pop ] shows h@xmath2 population diagrams calculated from the fluxes in table [ tbl : h2flux ] . the level populations of hydrogen molecular gas estimated from ro - vibrational transitions allow us to study the excitation state and temperature of the gas @xcite . we calculated the upper level column density from observed line flux after a reddening correction . the extinction can be estimated using the ratios of the emission lines originated from the same upper levels . in our calculation , we used the ratios of three pairs of 1@xmath10 s(1 ) / 1@xmath10 q(3 ) , 1@xmath10 s(0 ) / 1@xmath10 q(2 ) , and 1@xmath10 s(2 ) / 1@xmath10 q(4 ) . we adopted the transition probabilities from @xcite . we apply the extinction law , a@xmath41 = a@xmath42(0.55@xmath4/@xmath3)@xmath43 @xcite . in our estimation , a@xmath44 and a@xmath45 are very small ( @xmath21 0.1 ) . we used a@xmath42 = 3.4 which is an intermediate from the range of 3.1 @xmath1 5.1 used in previous studies @xcite . for the data in figure [ fig : h2pop ] , we applied weighted least - square fitting to estimate rotational temperature ( t@xmath46 ) from an upper level of @xmath18 = 1 ( circle ) and 2 ( square ) , considering 1/@xmath47 for weights , where @xmath24 is the uncertainty in the level population . we excluded one transition from @xmath18 = 3 ( triangle ) from the fit due to its large uncertainty . solid and dashed lines represent the fitting lines for @xmath18 = 1 and 2 , respectively . in sp 1 , t@xmath46 of all peaks estimated in @xmath18 = 1 is 2500 @xmath27 200 k. the temperatures in @xmath18 = 2 show uncertainty , because we have only three data points for the fitting . t@xmath46 of peaks a1 and b in @xmath18 = 2 are similar , 3200 @xmath27 1500 k. in a2 , t@xmath46 in @xmath18 = 2 is 2500 @xmath27 1100 k which is close to the value from @xmath18 = 1 . in sp 2 , t@xmath46 in a1@xmath14 is almost the same as in a1 , in both @xmath18 = 1 and 2 . peak a2@xmath14 shows a higher t@xmath46 than a2 in @xmath18 = 1 and 2 , but the differences are within the uncertainties . in sp 3 , t@xmath46 from a1@xmath12 and a2@xmath12 in @xmath18 = 1 are higher than those of sp 1 and 2 ; with t@xmath46 @xmath31 2700 @xmath27 250 k. in @xmath18 = 2 , t@xmath46 is 3000 @xmath27 1500 k for both a1@xmath12 and a2@xmath12 . from sp 1 to 3 , t@xmath46 in @xmath18 = 1 shows a small increase , but within uncertainties . for @xmath18 = 2 , there is no clear trend with slit position change . in all three slit positions , in both @xmath18 = 1 and 2 the derived t@xmath46 is @xmath8 2500 @xmath1 3000 k. this means that the gases are thermalized in a single ro - vibrational temperature , because both level populations follow same t@xmath46 . we note that the temperature estimation differs when we consider different a@xmath42 in the flux correction . it becomes @xmath8 200 k lower and less than 100 k higher for the cases of a@xmath42 @xmath6 0 and 5.1 , respectively , compared to the estimation using a@xmath42 = 3.4 . we also note that the populations of ortho and para transitions are aligned in a single line . this indicates that the emission lines are not from the fluorescent h@xmath2 by uv excitation ( e.g. , * ? ? ? thermalization has been observed in the shocked gas in the outflows from low- and high - mass stars ( e.g , hh 111 , hh 240 @xmath48 241 in @xcite , orion kl peak1 in @xcite ) . we can test the properties of shock with a population diagram by comparison with model data . @xcite have investigated various shock models to prove a shock nature in orion peak 1 , and they showed that the combining of shock models could explain their observational results except at the highest excitation level . since we assume the presence of a bow shock in this region ( see section [ sec : discussion ] ) , we plotted the bow shock model with @xmath49 = 100 km s@xmath7 from @xcite in figure [ fig : h2pop ] ( dotted lines ) . this model is more consistent with fitting lines from @xmath18 = 2 than those from @xmath18 = 1 . on the other hand , it is hard to discriminate the type of shock from our result because there is no significant difference between various shock models in the energy levels of 0.5 @xmath1 2 @xmath1910@xmath38 k @xcite . in table [ tbl : h2ratio ] , we listed the h@xmath2 line ratios at all peak positions that are sensitive to the type of shock . the ratios in the models of c- , j - type shocks and uv pumping are taken from @xcite . the ratios in our observation are similar to those of outflows from t - tauri stars @xcite . the 2@xmath11 s(1 ) / 1@xmath10 s(1 ) ratio is close to c - type shock in all cases , indicating similar shock conditions along outflow . the other three ratios do not help discriminate between different shocks , due to the large uncertainties . there are no significant differences at all three slit positions . we note that the 1@xmath10 s(1 ) / 1@xmath10 q(1 ) ratios in our data are about 1.5 @xmath1 2.5 times higher than ratios from all models . 1@xmath10 q(1 ) @xmath32.407 @xmath4 emission is affected by a deep telluric absorption at @xmath8 @xmath140 km s@xmath7 ( ` @xmath50 ' symbols in figure [ fig : h2pvd ] ) , so it may not be reliable . as shown in section [ sec : result ] , the h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 and [ ] @xmath31.644 @xmath4 emission lines have are very different velocity structure . the h@xmath2 emission is dominant at low - velocity while [ ] emission dominates at high - velocity . this trend was found in outflows from both ctts and class 0@xmath1i ysos ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? the trend makes sense in the context of an interpretation where the shocked h@xmath2 emission arises from gas entrained by a high - velocity outflow @xcite . in our pvds , we detected h@xmath2 emission at the systemic velocity along the whole slit , in all three slit positions . this emission probably originates from ambient molecular hydrogen gas in this region , which corresponds to the presence of far - uv radiation by producing a pdr @xcite . however , taking account of the h@xmath2 lines ratios ( table [ tbl : h2ratio ] ) , we should not rule out the excitation by shock as the emission source . we note that , in this case , the velocity width at the top of the pvds should be larger than current value ( @xmath810 km s@xmath7 ) , because the angle of the outflow axis may be smaller than 45@xmath13 with respect to the line of sight according to our interpretation in bow shock features described below . discrete multiple velocity components revealed from the h@xmath2 emission in figure [ fig3 ] are the typical high- and low - velocity features that arise from the bow shock in outflows @xcite . if the inclination angle between the bow shock axis and the line of sight is in a range of @xmath8 0@xmath13 @xmath1 45@xmath13 , the emission from the apex and the wing of the bow are seen as separate high- and low - velocity peaks . the weak h@xmath2 and strong [ ] emission at high - velocity ( v@xmath5 @xmath8 @xmath1120 km s@xmath7 ) show good agreement in position and velocity , indicating that the [ ] emission lines usually arise from bow apex , where the jet velocity is faster than surrounding region @xcite . the velocity difference of @xmath8 100 km s@xmath7 between the high- and low - velocity peaks in the h@xmath2 lines is similar to that observed in the jet of l1551-irs 5 @xcite , which has an inclination angle of @xmath8 45@xmath13 with respect to the line of sight . in knot b at sp 1 , we see three discrete velocity peaks in h@xmath2 where the velocity of the peak increases with increasing @xmath25y@xmath25 . the more blueshifted peaks lie farther from the star . the total offset along the outflow is @xmath8115 , after consideration of the different angle between our slit ( 256@xmath13 ) and the outflow axis ( 227@xmath13 ) . one possible interpretation for this position shift is a spatial difference between the faster gas in the bow apex and the slower portion in the bow wing . we can not rule out , however , the possibility that this shift is caused by distinct knots originally located in different positions . in contrast to the blueshifted gas seen at all slit positions , the redshifted component ( v@xmath5 @xmath31 @xmath110.2 km s@xmath7 ) seen in h@xmath2 at sp 2 and 3 seems to arise from another , spatially unresolved outflow . since the slit positions are pointing at the blue lobe of the jet ( see section [ sec : intro ] and [ sec : observation ] ) , at locations where the blueshifted material is well - separated in phase space from any ambient emission , the detection of redshifted emission implies the existence of a distinct outflow , separated from the high - velocity blueshifted jet . this outflow may have an axis almost parallel to the plane of the sky , with a wide outflow opening angle , because it shows both blue and redshifted components at low - velocity ( @xmath150 km s@xmath7 @xmath21 v@xmath5 @xmath21 @xmath3250 km s@xmath7 ) . for a further discussion , we need additional clues on the position and orientation of the redshifted component , which would need to come from further observations with high spectral resolution and with higher spatial resolution than we can obtain with our present instrument / telescope combination . as shown in section [ sec : intro ] and figure [ fig : sourcemap ] , the lkh@xmath0 234 region is complicated with several outflow sources observed at mid - ir , millimeter , and radio wavelengths . in this section , we summarize three separate outflows and their source candidates , and relate them to our own spectroscopic observations . the [ ] jet from vla 3 ( nw 1 , irs 6 ) : at sp 1 and 2 , we detected the bright [ ] emission with a velocity of @xmath8 @xmath1120 km s@xmath7 at the position of knot a ( figure [ fig3 ] ) . here , we suggest that this [ ] emission possibly originates from the outflow driven by radio source vla 3b , according to following evidence . the pvds at sp 1 and 2 show that the [ ] knot lies between y @xmath6 @xmath12@xmath12 and y @xmath6 @xmath16@xmath12 . as shown in figure [ fig : sourcemap ] , its position agrees well with the `` green blob '' feature seen in the center of the c - shaped reflection nebula in the jhk color image of @xcite , a feature that is probably caused by [ ] emission in the h@xmath1band . the narrow band [ ] @xmath31.644 @xmath4 image in @xcite , which showed emission at the same position , supports this conclusion . the configuration of an [ ] jet detected along the central axis of a cavity in a reflection nebula is very similar to the case of l1551-irs 5 @xcite . @xcite showed two jet - like features in their j@xmath1 and h@xmath1band images and they mentioned that those features point at yso candidate g. they suggested that the jet - like feature containing the green blob is associated with the optical [ ] jet . we suggest another possible origin of the [ ] emission in figure [ fig3 ] , vla 3b . the 3.6 cm continuum map of @xcite showed that vla 3b has an elongated thermal radio jet extending northeast - southwest . in figure [ fig : sourcemap]d , their source - subtracted 3.6 cm map is shown . we estimated a p.a . of @xmath8 230@xmath13 for this jet . `` axis3 '' in figure [ fig : sourcemap ] denotes the axis of the radio jet in vla 3b . this line passes through the positions of the [ ] knot detected in our observations and the green blob in the jhk image . the very similar major axis position angles of the [ ] emission in @xcite and the radio thermal jet also support our suggestion , although the reliability of their [ ] image close to lkh@xmath0 234 should be a cause of caution . taking all factors into account , however , we conclude that this [ ] emission is from a jet driven by vla 3b , with a velocity of v@xmath5 @xmath8 @xmath1120 km s@xmath7 . @xcite suggested that vla 3b could be a low - mass yso , while @xcite suggested nw 1 as a b6 @xmath1 b7 type yso from the sed . an outflow cavity is opening toward the southwest from vla 3b . the mid - ir source irs 6 lies in the cavity with a @xmath8 05 offset from vla 3b . the offset implies that the mid - ir emission comes from a region less affected by dust extinction . we note that the p.a . of the [ ] jet is very similar to that of the h@xmath2 jet ( 227@xmath13 ) , as shown in figure [ fig : sourcemap ] . this may be an additional example of multiple jets sharing a similar orientation ( e.g. , * ? ? ? * ) , as pointed out by @xcite . \2 . the h@xmath2 jet from firs1-mm1 : the most likely source of the h@xmath2 jet @xcite and inner [ ] jet @xcite is firs1-mm1 @xcite , which is indicated as a white pentagon in figure [ fig : sourcemap ] . more accurately , it seems driving the knot b and c , because the position of firs1-mm1 is well - aligned with the line through those two knots ( p.a . @xmath8 227@xmath13 ) , which is marked as `` axis2 '' in the figure [ fig : sourcemap ] . in figure [ fig3 ] at sp 1 , the h@xmath2 emission shows a peak at y = @xmath192 . this peak position represents that sp 1 is superposed on the center position of knot b of h@xmath2 jet , as we confirm in figure [ fig : sourcemap ] . we used our high - resolution observation to reveal , for the first time , that knot b shows multiple velocity peaks , which imply the presence of a bow shock ( see also section [ sec:4.1 ] ) . the outer [ ] jet from vla 2 ( nw 2 ) : the proper motion and the locations of h@xmath2o masers around radio continuum vla 2 @xcite confirmed that vla 2 is the most likely source of redshifted co outflow @xcite and the outer [ ] jet ( knot d @xmath1 e in * ? ? ? * ) , showing good agreement in direction . in the figure , the axis of [ ] outflow is shown as `` axis1 '' with p.a . of @xmath8 252@xmath13 . although sp 3 is located along the direction of the outer [ ] jet from vla 2 at y @xmath8 @xmath126 , we could not obtain information related to the outer [ ] jet because there is no detection of any significant [ ] emission feature along sp 3 , and the slit position only covers the inner [ ] jet region @xcite . we have presented results from the first high - resolution near - ir spectroscopy toward the multiple outflows around the herbig be star lkh@xmath0 234 . the multiple velocity peaks we observe in h@xmath2 emission lines are consistent with a generic bow shock model . both knots a and b show this bow shock feature . furthermore , the positional difference ( @xmath8 1@xmath12 ) between low- and high - velocity components may be caused by a difference between the wing and apex of the bow . the molecular hydrogen emission is dominant at low - velocity with a radial velocity within 50 km s@xmath7 of the systemic velocity , while [ ] emission is only presnet in the higher - velocity ranges ( v@xmath5 @xmath8 @xmath1100 km s@xmath7 to @xmath1130 km s@xmath7 ) . this trend has been observed in previous studies and may be understood from the assumption that the h@xmath2 emission originates from shocked gas entrained by a fast outflow . we also detected narrow h@xmath2 emission along the whole slit length at systemic velocity , which indicate the background pdr . \5 . from the ratios of [ ] emission lines , we estimate an electron density of @xmath8 1.1 @xmath19 10@xmath38 @xmath39 . this is similar to or slightly smaller than the values in outflows from t - tauri stars or class 0@xmath1i sources . the population diagrams of hydrogen molecules show that the gas is thermalized at a temperature of 2,500 @xmath1 3000 k in this region . this indicates that the emission arises from shock excited gas . the ratios between h@xmath2 lines at knot a and b are close to those from c - type shock models @xcite . this work used the immersion grating infrared spectrograph ( igrins ) that was developed under a collaboration between the university of texas at austin and the korea astronomy and space science institute ( kasi ) with the financial support of the us national science foundation under grant ast-1229522 , of the university of texas at austin , and of the korean gmt project of kasi . osterbrock , d. e. 1989 , astrophysics of gaseous nebulae and active galactic nuclei ( research supported by the university of california , john simon guggenheim memorial foundation , university of minnesota , et al . ; mill valley , ca , univ . science books ) , 422 cccc line & @xmath3(@xmath15 m ) & & + @xmath51 & 1.53389 & 0.12 @xmath27 0.05 & 0.14 @xmath27 0.06 + @xmath52 & 1.59991 & 0.10 @xmath27 0.04 & 0.11 @xmath27 0.04 + @xmath53 & 1.64400 & 1.00 @xmath27 0.29 & 1.00 @xmath27 0.18 + @xmath54 & 1.66422 & 0.09 @xmath27 0.03 & 0.10 @xmath27 0.04 + @xmath55 & 1.67733 & 0.17 @xmath27 0.04 & 0.18 @xmath27 0.06 + ccccccccc 1@xmath10 s(9 ) & 1.68772 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 + 1@xmath10 s(7 ) & 1.74803 & 0.04 @xmath27 0.02 & 0.04 @xmath27 0.02 & 0.05 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.02 + 1@xmath10 s(6 ) & 1.78795 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.03 @xmath27 0.01 & 0.03 @xmath27 0.02 & 0.03 @xmath27 0.02 + 1@xmath10 s(2 ) & 2.03376 & 0.19 @xmath27 0.04 & 0.19 @xmath27 0.04 & 0.19 @xmath27 0.02 & 0.21 @xmath27 0.03 & 0.23 @xmath27 0.04 & 0.23 @xmath27 0.06 & 0.22 @xmath27 0.05 + 2@xmath11 s(3 ) & 2.07351 & 0.07 @xmath27 0.04 & 0.07 @xmath27 0.04 & 0.09 @xmath27 0.01 & 0.08 @xmath27 0.02 & 0.07 @xmath27 0.03 & 0.09 @xmath27 0.03 & 0.06 @xmath27 0.03 + 1@xmath10 s(1 ) & 2.12183 & 1.00 @xmath27 0.14 & 1.00 @xmath27 0.13 & 1.00 @xmath27 0.05 & 1.00 @xmath27 0.14 & 1.00 @xmath27 0.14 & 1.00 @xmath27 0.14 & 1.00 @xmath27 0.15 + 2@xmath11 s(2 ) & 2.15423 & 0.04 @xmath27 0.02 & 0.06 @xmath27 0.02 & 0.04 @xmath27 0.01 & 0.03 @xmath27 0.01 & 0.03 @xmath27 0.01 & 0.05 @xmath27 0.02 & 0.03 @xmath27 0.02 + 3@xmath12 s(3 ) & 2.20139 & 0.01 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.02 @xmath27 0.01 & 0.03 @xmath27 0.02 & 0.02 @xmath27 0.02 + 1@xmath10 s(0 ) & 2.22329 & 0.23 @xmath27 0.05 & 0.22 @xmath27 0.05 & 0.24 @xmath27 0.02 & 0.19 @xmath27 0.03 & 0.20 @xmath27 0.04 & 0.22 @xmath27 0.05 & 0.21 @xmath27 0.05 + 2@xmath11 s(1 ) & 2.24771 & 0.08 @xmath27 0.02 & 0.11 @xmath27 0.03 & 0.10 @xmath27 0.01 & 0.08 @xmath27 0.02 & 0.06 @xmath27 0.02 & 0.09 @xmath27 0.03 & 0.06 @xmath27 0.03 + 1@xmath10 q(1 ) & 2.40659 & 0.40 @xmath27 0.08 & 0.47 @xmath27 0.08 & 0.47 @xmath27 0.03 & 0.37 @xmath27 0.06 & 0.32 @xmath27 0.06 & 0.37 @xmath27 0.07 & 0.37 @xmath27 0.07 + 1@xmath10 q(2 ) & 2.41344 & 0.14 @xmath27 0.04 & 0.15 @xmath27 0.04 & 0.14 @xmath27 0.02 & 0.12 @xmath27 0.03 & 0.11 @xmath27 0.03 & 0.13 @xmath27 0.04 & 0.11 @xmath27 0.04 + 1@xmath10 q(3 ) & 2.42373 & 0.27 @xmath27 0.06 & 0.24 @xmath27 0.05 & 0.25 @xmath27 0.02 & 0.20 @xmath27 0.03 & 0.18 @xmath27 0.04 & 0.22 @xmath27 0.05 & 0.19 @xmath27 0.05 + 1@xmath10 q(4 ) & 2.43749 & 0.08 @xmath27 0.01 & 0.09 @xmath27 0.01 & 0.07 @xmath27 0.01 & 0.06 @xmath27 0.01 & 0.05 @xmath27 0.01 & 0.07 @xmath27 0.03 & 0.06 @xmath27 0.03 + ccccccccccc 2@xmath11 s(1 ) / 1@xmath10 s(1 ) & 0.08 @xmath27 0.02 & 0.11 @xmath27 0.03 & 0.10 @xmath27 0.01 & 0.08 @xmath27 0.02 & 0.06 @xmath27 0.02 & 0.09 @xmath27 0.03 & 0.06 @xmath27 0.03 & 0.05 & 0.24 & 0.55 + 1@xmath10 s(2 ) / 1@xmath10 s(0 ) & 0.81 @xmath27 0.23 & 0.86 @xmath27 0.24 & 0.82 @xmath27 0.10 & 1.07 @xmath27 0.18 & 1.16 @xmath27 0.26 & 1.07 @xmath27 0.34 & 1.02 @xmath27 0.34 & 1.56 & 2.08 & 1.09 + 2@xmath11 s(1 ) / 2@xmath11 s(3 ) & 1.18 @xmath27 0.74 & 1.50 @xmath27 0.93 & 1.05 @xmath27 0.17 & 0.97 @xmath27 0.35 & 0.87@xmath27 0.43 & 0.99 @xmath27 0.47 & 0.97 @xmath27 0.62 & 1.08 & 0.73 & 1.58 + 1@xmath10 s(1 ) / 1@xmath10 q(1 ) & 2.51 @xmath27 0.49 & 2.11 @xmath27 0.36 & 2.12 @xmath27 0.15 & 2.67 @xmath27 0.55 & 3.09 @xmath27 0.43 & 2.69 @xmath27 0.51 & 2.71 @xmath27 0.52 & 1.29 & 1.59 & 1.00

we present the results of high - resolution near - ir spectroscopy toward the multiple outflows around the herbig be star lkh@xmath0 234 using the immersion grating infrared spectrograph ( igrins ) . previous studies indicate that the region around lkh@xmath0 234 is complex , with several embedded ysos and the outflows associated with them . in simultaneous h@xmath1 and k@xmath1band spectra from hh 167 , we detected 5 [ ] and 14 h@xmath2 emission lines . we revealed a new [ ] jet driven by radio continuum source vla 3b . position - velocity diagrams of h@xmath2 1@xmath10 s(1 ) @xmath32.122 @xmath4 line show multiple velocity peaks . the kinematics may be explained by a geometrical bow shock model . we detected a component of h@xmath2 emission at the systemic velocity ( v@xmath5 @xmath6 @xmath110.2 km s@xmath7 ) along the whole slit in all slit positions , which may arise from the ambient photodissociation region . low - velocity gas dominates the molecular hydrogen emission from knots a and b in hh 167 , which is close to the systemic velocity , [ ] emission lines are detected at farther from the systemic velocity , at v@xmath5 @xmath6 @xmath1100 @xmath1 @xmath1130 km s@xmath7 . we infer that the h@xmath2 emission arises from shocked gas entrained by a high - velocity outflow . population diagrams of h@xmath2 lines imply that the gas is thermalized at a temperature of 2,500 @xmath1 3,000 k and the emission results from shock excitation .

a large part of modern physics is devoted to nonlinear classical and quantum phenomena in various systems . such effects as the generation of the second harmonic or optical rectification are known from classical physics , while quantum electron pumping through a small sample due to interference of wave functions is a quantum nonlinear effect . experiments on nonlinear electrical transport often combine classical and quantum contributions . a macroscopic sample without inversion center @xcite exhibits a current - voltage characteristic which with increasing voltage departs from linearity due to terms proportional to the square of the applied voltage . if now an oscillating ( ac ) voltage is applied , a zero - frequency current ( dc ) is generated . if the sample is sufficiently small , quantum effects can appear due to the wave nature of electrons . the uncontrollable distribution of impurities or small variations in the shape of the sample result in quantum contributions to the dc which are random . for a mesoscopic conductor with terminals @xmath0 we can describe the quadratic current response in terms of second order conductances @xmath1 . they relate voltages @xmath2 applied at contacts or neighboring gates @xmath3 at frequency @xmath4 to the current at zero frequency at contact @xmath5 , @xmath6 the second order conductances include in detail the role of the shape and the nearby conductors ( gates ) . they depend on external parameters like the frequency of the perturbation , temperature , magnetic field or the connection of the sample to the environment . we concentrate here on the quantum properties of nonlinear conductance through coherent chaotic samples . chaos could result from the presence of impurities ( disorder ) or random scattering at the boundaries ( ballistic billiard ) . due to electronic interference the sign of this effect is generically random even for samples of macroscopically similar shape . @xcite when averaged over an ensemble , the second order conductances vanish . as a consequence , for a fully chaotic sample there is no classical contribution to the dc and the nonlinear response is the result of the sample - specific quantum fluctuations . interestingly enough , from a fundamental point of view these fluctuations of nonlinear conductance are sensitive to the presence of coulomb interactions and magnetic field . while interactions strongly affect the fluctuations amplitude , their sign is easily changed by a small variation of magnetic flux @xmath7 , similarly to universal conductance fluctuations ( ucf ) in linear transport . more importantly , without interactions the current ( [ eq : iv ] ) through a two - terminal sample is a symmetric function of magnetic field , just like linear conductance . however , the idea that coulomb interactions are responsible for magnetic - field asymmetry in nonlinear current was recently proposed theoretically @xcite and demonstrated experimentally in different mesoscopic systems . @xcite ( various aspects of nonlinear quantum @xcite and classical @xcite charge and spin transport @xcite have been discussed later on . ) it is useful to consider ( anti ) symmetric second order conductance @xmath8 defined as @xmath9 where @xmath10 is a combination of voltages at the gates and contacts varied in the experiment and @xmath11 accounts for the spin degeneracy . we emphasize that , depending on the way voltages are varied , experiments probe different linear combinations of second order conductance elements @xmath1 of eq . ( [ eq : iv ] ) . from now on we will simply call @xmath12 conductances and if no confusion is possible leave out the expression `` second order '' . in the presence of a dc perturbation the mesoscopic averages of antisymmetric @xcite and symmetric @xcite conductances vanish , and it is their sample - to - sample fluctuations that are measured . experiments are usually performed for strongly interacting samples and the magnetic - field components @xmath13 allow one to evaluate the strength of interactions . @xcite in previous theoretical works on nonlinear transport through chaotic dots several important issues have been discussed using random matrix theory ( rmt ) . @xcite snchez and bttiker @xcite found the fluctuations of @xmath14 in a dot with arbitrary interaction strength at zero temperature and broken time - reversal symmetry due to magnetic field . polianski and bttiker considered the statistics of both @xmath14 and @xmath15 for arbitrary flux @xmath7 , the temperature @xmath16 , and the dephasing rate . @xcite the fluctuations of relative asymmetry @xmath17 and the role of the contact asymmetry on this quantity were discussed in ref .. the results of rmt approach were compared with experimental data of zumbhl @xcite and angers @xcite previously we considered statistics of @xmath8 for the dots where only one dc voltage was varied . however , to avoid parasitic circuit effects some experiments are performed varying several voltages simultaneously . surprisingly , the importance of the chosen combination of varied voltages ( bias mode ) was not addressed before in the literature . it turns out that an experiment where only one of the voltages is varied @xcite or two voltages are asymmetrically shifted @xcite measure different combinations of nonlinear conductances @xmath1 . for example , in a weakly interacting dot in the first mode we found that @xmath18 , @xcite but in the second bias mode the fluctuations of nonlinear current are strongly reduced , so that @xmath19 . it is also important to generalize the previous treatment of the nonlinear current to mesoscopic systems biased by an ac - voltage at _ finite _ frequency . the resulting dc is sometimes called `` photovoltaic current '' . we expect that in such mesoscopic ac / dc converters the interactions lead to significant magnetic field - asymmetry in the dc - signal . the rectification effect of mesoscopic diffusive metallic microjunctions was theoretically considered by falko and khmelnitskii @xcite assuming that electrons do not interact . therefore , a magnetic - field asymmetry was not predicted and was also not observed in subsequent experiments . @xcite the fact that the interactions induce a magnetic field - asymmetry of the photovoltaic current when the size of the sample is strongly reduced was recently demonstrated in aharonov - bohm rings by angers @xcite however , it turns out that for an ac perturbation another quantum interference phenomenon , also quadratic in voltage , random in sign and magnetic field - asymmetric , contributes to the dc . due to _ internal _ ac- perturbations of the sample , the energy levels are randomly shifted and a phenomenon commonly referred to as `` quantum pumping '' @xcite appears . brouwer demonstrated that two voltages applied out of phase generate pumped current linear in frequency , while a single voltage pumps current quadratic in frequency @xmath4 . @xcite although theory usually considers small ( adiabatic ) frequencies , a photovoltaic current could be induced by voltages applied at arbitrary frequency . at small @xmath4 the pumping contribution vanishes and only the rectification effect survives . in contrast , it is not clear what the ratio of pumping current to rectification current is at large @xmath4 . to distinguish between different mechanisms it is therefore important to consider rectification in a wide range of frequencies in detail . at the locally applied gate , which slightly changes the shape of the dot ( shown dashed ) , or microwave antenna emitting photons with energy @xmath20 into the dot . bottom : rectification sources include external bias @xmath21 , top gate voltage @xmath22 with capacitance @xmath23 , and parasitic coupling of @xmath24 due to stray capacitances @xmath25 . microwave antenna can emit photons to the contacts and lead not only to photon - assisted ac transport but also to a rectified dc.,title="fig : " ] we point here to a crucial difference between rectification and pumping contributions to the photovoltaic effect . rectification results from external perturbations or the perturbations that can be reduced to the exterior by a gauge transformation . typical examples are external ac - bias , or gate voltage which shifts all levels uniformly , @xcite or a bias induced by parasitic ( stray ) capacitance which connects sources of possible internal perturbations to macroscopic reservoirs , @xcite see the bottom panel in fig . [ fig : dot ] . pumping , on the other hand , is due to internal perturbations like those of a microwave antenna @xcite or a locally applied gate voltage , @xcite see the top panel in fig . [ fig : dot ] . internal and external sources affect the schrdinger equation and its boundary conditions , respectively . in experiment pumping and rectification , often considered together under the name of photovoltaic effect , @xcite are hard to distinguish . can one clearly separate quantum pumping from rectification effects ? to distinguish them it was proposed to use magnetic field asymmetry of dc as a signature of a true quantum pump effect . in refs . and rectification by ( non - interacting ) quantum dot was due to stray capacitances of reservoirs with pumping sources . the rectified current was found to be symmetric with respect to @xmath26.@xcite while such field - symmetric rectification dominated in the experiments of switkes @xcite and dicarlo @xcite at mhz frequencies , an asymmetry @xmath27 observed at larger ghz frequencies seemed to signify a quantum pump effect . @xcite it was noted that the coulomb interactions treated self - consistently do not lead to any drastic changes in the mesoscopic distribution of a pumped current.@xcite probably , that is why the effect of interactions on the rectification have not been considered yet , even though the coulomb interaction in such dots is known to be strong.@xcite however , as it turned out later , coulomb interactions are responsible for magnetic - field asymmetry in nonlinear transport through quantum dots . @xcite similarly this could be expected for rectification as well . then the magnetic field asymmetry alone can not safely distinguish pumping from rectification . therefore we thoroughly examine the frequency dependence of the magnetic - field ( anti)symmetric conductances @xmath8 . here we neglect any quantum pumping effects and their interference with rectification . @xcite while the role of coulomb interactions and the full frequency dependence in quantum pumping are yet to be explored , here we answer two important questions concerning a competing mechanism , rectification : ( 1 ) in the dc limit @xmath28 for a strongly interacting quantum dot @xmath14 and @xmath15 are of the same order . is this also the case at finite frequencies ? ( 2 ) how are the experimental data affected by the bias mode for alternating voltages ? a number of very recent experiments on nonlinear dc transport @xcite and ac rectification @xcite have used submicron ring - shaped samples with a relatively large aspect ratio . in this work we develop a model of a ring which includes chaotic dynamics due to possible roughness of its boundary and/or the presence of impurities . similarly to quantum dots , the two - terminal nonlinear conductance of such a ring is field - asymmetric because field - asymmetry exists in each arm . in particular , this leads to deviations of the phase in ab oscillations from @xmath29 which characterizes linear conductance obeying onsager symmetry relations . experiments find that the amplitude and phase of ab oscillations exhibit rather curious properties . for example , the dc experiment of leturcq @xcite finds that during many ab oscillations with period @xmath30 the phase is well - defined . the experiment demonstrates that a nearby gate can vary the phase of the ab oscillations over the full circle . the amplitude of the second harmonic @xmath31 is strongly suppressed . on the other hand , the dc experiment @xcite and ac experiment @xcite of angers find that the phase can be defined only for few oscillations at low magnetic fields . for high frequencies , the phase fluctuates strongly as function of frequency . both in the nonlinear and the rectified current the amplitude of the second harmonic @xmath31 in ab oscillations is always comparable with the first harmonic @xmath30 . this is in contrast with the experiments in ref .. although we do not fully address all these questions here , our model of a chaotic ring allows us to consider them at least on a qualitative level . to introduce the reader to the problem of nonlinear transport in sec . [ sec : bias ] we first qualitatively discuss the coulomb interaction effect in the simplest dc problem . in reality the statistical properties of conductances @xmath1 in eq . ( [ eq : iv ] ) are sensitive to electronic interference but to assess the role of coulomb interactions we can consider a specific sample . in contrast to linear transport , it turns out that the nonlinear current strongly depends on the way voltages at the contacts and/or nearby conductors are varied from their equilibrium values ( bias mode ) . for example , we find that the experiments when only one voltage at the contact is varied @xcite or when two contact voltages are shifted oppositely @xcite measure different nonlinear currents . indeed , for a current @xmath32 , bilinear in voltages , its second derivative should depend on the chosen direction in the space of voltages @xmath33 . interestingly , a sample with weak interactions is very sensitive to the choice of the bias mode , which we attribute to the strong effect of capacitive coupling of the sample with nearby conductors . to make our arguments quantitative and consider the role of magnetic flux @xmath7 for a quantum dot which is ( generally ) ac - biased at arbitrary frequency @xmath4 , in sec . [ sec : dc ] we take electronic interference into account . having done that , we illustrate the interplay between interactions and interference on several important examples . first , we consider nonlinear transport due to a constant applied voltage and then consider rectification of ac voltages . for a two - terminal dot , in a generally asymmetric circuit ( capacitive couplings included ) , in sec . [ sec:2terminal ] we find the statistics of ( anti ) symmetric conductances @xmath8 defined in eq . ( [ eq : ivfield ] ) . both @xmath14 and @xmath15 vanish on average . quantum fluctuations of @xmath15 strongly depend on the interaction strength , circuit asymmetry and bias mode . this is in accordance with our qualitative picture . on the other hand , the antisymmetric component @xmath14 depends only on interactions . our arguments agree with recent experiments in quantum dots:@xcite depending on the bias mode different features of the nonlinear conductance tensor are probed . the fluctuations of nonlinear current can be minimized or maximized ( on average ) , which becomes important for weakly interacting electrons . curiously , for symmetric coupling ( transmission and capacitance ) of contacts and dot the bias mode in which the voltages at the contacts are changed in opposite directions generally _ minimizes _ fluctuations of @xmath15 . consequently , such a mode is more advantageous for the observation of @xmath14 or a cleaner linear signal . near the end of sec . [ sec:2terminal ] we also demonstrate how to take into account possible classical circuit - induced asymmetry @xcite due to the finite classical resistance of the wires . in sec . [ sec : rectify ] we present results elucidating the role of interaction in rectification through two - terminal dots . usually there are two important time - scales : the dwell time @xmath34 an electron spends inside the dot and the charge relaxation time @xmath35 of the dot . for a given geometry , the dwell time depends on the coupling of the dot with reservoirs , but the charge relaxation time is also sensitive to the interaction strength . we have @xmath36 for strong interactions and @xmath37 in the weak interaction limit . our results for fluctuations of @xmath38 are obtained for arbitrary frequency @xmath4 . although the fluctuations of both @xmath39 and @xmath40 monotonically decrease when @xmath41 , as functions of frequency @xmath4 they behave differently . at nonadiabatic frequencies @xmath42 the nearby gate short - circuits currents . this effect is even in magnetic field and thus affects only @xmath15 . as a result , for a high - frequency voltage the asymptotes of @xmath14 and @xmath15 are generally different and strongly depend on the bias mode . since the regime of parameters is quite realistic , we expect that the predicted difference of @xmath40 and @xmath39 should be experimentally observable . in the noninteracting limit our results qualitatively agree with those in diffusive metallic junctions . our model of a ring consisting of a chaotic dot with a ballistic arm which encloses an ab flux is presented in section [ sec : phase ] . although it is impossible to find the full mesoscopic distribution of the ab phase @xmath43 , its shape can be discussed qualitatively . since @xmath44 is similar to the asymmetry parameter @xmath17 in quantum dots , its distribution can become very wide for a particular choice of the bias mode . on average @xmath45 in our model , and we find the dependence of the fluctuations of @xmath46 on temperature , interactions , and number of channels of the contacts and the arm . our treatment allows a straightforward generalization to treat ac voltages applied to the ring . the technical calculations are presented in the appendix . [ ] [ ] [ 0.8]@xmath23[][][0.8]@xmath47 at reservoirs connected by @xmath48 ballistic channels and capacitances @xmath49 and by voltages @xmath50 applied at additional gates with capacitances @xmath51 . transport through the dot is sensitive to the total magnetic flux @xmath7 through the area of the dot . ( center and right ) forward and reverse connection of ref . exchange voltages at the contacts and classical resistors @xmath52.,title="fig : " ] the 2d quantum dot , see the left panel in fig . [ fig:3dot ] , is biased with several voltages @xmath53 at @xmath54 ballistic quantum point contacts ( qpcs ) with @xmath55 orbital channels . the reservoirs can be capacitively coupled to the dot via capacitances @xmath56 . an additional set of voltages @xmath57 is applied to ( several ) gates with capacitances @xmath51 . all perturbations are assumed to be at the same frequency @xmath4 , which is not necessarily small ( adiabatic ) . the dot is in the universal regime , @xcite when the thouless energy @xmath58 is large . the dots with area @xmath59 ( taken circular ) are either diffusive with mean free path @xmath60 , or ballistic , with @xmath61 and chaotic classical dynamics ( in the latter case the substitution @xmath62 should be used ) . the mean level spacing ( per spin direction ) @xmath63 and the total number of ballistic channels @xmath64 together define the dwell time @xmath65 . we also require that @xmath66 when we can treat the nonlinearity only to @xmath67 . scattering is spin - independent and this spin degeneracy is accounted for by the coefficient @xmath11 . the noninteracting electrons are treated using the scattering matrix approach and random matrix theory ( rmt ) for the energy - dependent scattering matrix @xmath68 . for details we refer the reader to reviews . @xcite in this approach the fundamental property of a dot is its scattering matrix @xmath69 distributed over circular ensembles of proper symmetry , see ref . ( an alternative method is the hamiltonian approach based on the properties of the dot s hamiltonian @xmath70 taken from a gaussian ensemble . @xcite ) transport properties of chaotic dots in rmt for matrices @xmath69 or @xmath70 are usually expressed in terms of an effective , magnetic field - dependent number of channels . predictions based on this approach are in good agreement with experiment . for multichannel samples with @xmath71 we use the diagrammatic technique described in refs . and . however , when interactions are present , this treatment should be modified . the approach which assumes that in a pointlike scatterer the interactions appear in the form of a self - consistent potential was introduced by bttiker and co - authors @xcite on the basis of gauge - invariance and charge conservation . this ( hartree ) approach neglects contributions leading to coulomb blockade ( fock terms ) , but is a good approximation for open systems . if the screening in the dot inside the medium with dielectric constant @xmath72 is strong , @xmath73 , an rpa treatment of coulomb interactions is sufficient . for large dots , @xmath74 , the details of screening potential on the scale @xmath75 are not important and we can assign an electric potential @xmath76 defined by excess electrons at @xmath77 at any point @xmath78 of the sample . if additionally the number of ballistic channels @xmath64 is much smaller than the dimensionless conductance of a closed sample , @xmath79 , the potential drops over the contacts and therefore in the interior of the dot it can be taken uniform ( `` zero - mode approximation '' ) . @xcite this potential shifts the bottom of the energy band in the dot and thus modifies the @xmath69-matrix . as a consequence , electrons with kinetic energy @xmath80 have an electro - chemical potential @xmath81 in the contact @xmath5 and @xmath82 in the dot . ( we point out that we neglect the quantum pumping in the dot and consequently the @xmath69-matrix depends only on one energy . ) recently , brouwer , lamacraft , and flensberg demonstrated that this self - consistent approach gives the leading order in an expansion in the inverse number of channels @xmath83 . @xcite therefore , our analytical results present the leading order effect , valid for @xmath83 . in the self - consistent approach the influx of charge changes the internal electrical potential of the dot @xmath84 , which in turn affects the currents incoming through each conducting lead and/or redistributes charges among the nearby conductors ( gates ) . such capacitive coupling can often be estimated simply from the geometrical configuration . for example , the capacitance of a dot covered by a top gate at short distance @xmath85 is @xmath86 and a single quantum dot has @xmath87 . the ratio of charging energy @xmath88 to mean level spacing @xmath89 characterizes the interaction strength . it is proportional to the ratio of the smallest geometrical scale to the effective bohr s radius , @xmath90 . we refer to interactions as strong if @xmath91 and weak if @xmath92 . and @xmath93 , the dashed curves correspond to equal currents . thin line shows fixed @xmath94 and @xmath95 is a function of source voltage @xmath96 . thick line corresponds to fixed @xmath97 , such that @xmath95 depends only on @xmath98 . full and empty dots on the right figure correspond to the forward or reverse configurations shown in fig . [ fig : dot].,title="fig : " ] we suppose for simplicity that at equilibrium the voltages @xmath99 are set . in the following we consider the situation when the ( single ) gate voltage @xmath100 is held fixed at its equilibrium value . experiments can be performed in different _ bias modes _ , usually either ( i ) with fixed drain voltage @xmath94 or ( ii ) at fixed @xmath97 ( the variations of the voltages at the contacts are equal in magnitude but opposite in sign ) . these different modes correspond to straight lines in the @xmath101 plane shown in fig . [ fig : vaxes ] . let us consider the nonlinear current as a function @xmath102 , where @xmath103 and @xmath93 are deviations of contacts voltages from equilibrium . for generality we consider below a situation when the linear combination @xmath104 is held fixed and the only variable is @xmath105 this corresponds to a rotation of the original @xmath106 axes such that the new coordinate axis @xmath10 makes an angle @xmath107 with the @xmath108 line , as illustrated in fig . [ fig : vaxes ] . the value of @xmath107 fully characterizes the bias mode . now the two modes introduced above are simply ( i ) @xmath109 which implies @xmath110 ; and ( ii ) @xmath111 , which implies @xmath112 and corresponds to an asymmetric variation of the voltages . the linear current depends only on @xmath113 ( dashed lines on the left panel in fig . [ fig : vaxes ] correspond to the lines of equal currents ) and in any bias mode the measured linear current @xmath114 is the same for a given @xmath113 . if we consider the nonlinear current @xmath115 as a function of @xmath116 , it is by construction a bilinear function of @xmath116 . as in the linear case the current must vanish if the voltages are the same and thus @xmath117 for @xmath118 . therefore , the bilinear function must be of the form @xmath119\ , ( x - y)\end{aligned}\ ] ] with unknown ( generally fluctuating ) parameters @xmath120 and @xmath121 $ ] . it is important that the qualitative behavior of @xmath102 depends on the interaction strength : one could expect that transport depends not only on voltages in the leads , but also on the internal nonequilibrium potential @xmath122 of the sample . this potential can be found if potentials in all reservoirs and the nearby gate are known . in the limit of weak interactions the equilibrium point @xmath100 is important , and if we reverse the bias voltage , @xmath123 the current is fully reversed , that is @xmath124 . for the current defined in eq . ( [ eq : simplei ] ) it is possible only when @xmath125 . another way to see this is to use the usual expression for the total current in terms of scattering matrices . in this formula the current depends on the difference between fermi distributions in the leads @xmath126 , and its expansion up to the second order yields @xmath127 . the lines of equal current are curved and directions @xmath128 correspond to zero current directions . thus the dependence of current on the angle @xmath107 is strong . in addition this approach predicts that the current through a two - terminal sample is symmetric with respect to the magnetic flux inversion . in contrast , for strong interactions , the value of @xmath100 is irrelevant and the nonequilibrium electrical potential @xmath122 is independent of @xmath100 . in this case current depends only on the voltage difference @xmath113 and thus @xmath129 for linear transport . therefore we do not expect any nontrivial dependence of the nonlinear current on the choice of the bias mode . it is noteworthy that qualitative considerations can predict neither the sign , nor the magnitude of @xmath120 . the only general conclusion which we can make for a weakly or strongly interacting dot is @xmath130 and @xmath131 , respectively . experiments extract derivatives of @xmath115 with respect to the applied voltages . importantly , this derivative depends on the chosen direction @xmath107 . the nonlinear current measured in this bias mode is @xmath132 the current is zero when @xmath133 and @xmath134 , and the bisectrix of the angle between the two zero - current directions at @xmath135 maximizes @xmath136 . sometimes experiments extract information on nonlinearity from measurements in different connections schematically shown in the central and right panels in fig . [ fig:3dot ] : `` forward '' connection corresponds to @xmath137 , while `` reverse '' connection for the same voltage configuration corresponds to @xmath138 . the gate voltages @xmath139 are kept fixed . in fig . [ fig : vaxes ] these forward and reverse points are indicated by black and white dots , respectively . to find the nonlinear conductance marlow @xcite and lfgren @xcite determine the difference of conductance at these measurement points . lfgren @xcite use the term `` rigidity '' for samples for which @xmath140 in the points @xmath141 and @xmath142 . @xcite equation ( [ eq : simplei ] ) gives the nonlinear contribution @xmath143 to the full conductance @xmath144 : @xmath145\,.\end{aligned}\ ] ] thus for a sample which is called rigid this implies @xmath146 . since @xmath147 would mean that there is no second - order response , we must have @xmath148 which is the case for samples with strong interaction . in other words , `` rigidity '' in samples which exhibit @xmath149 current is equivalent to strong coulomb interactions . on the other hand , comparison of data at another pair of points @xmath150 and @xmath151 gives @xmath152 and provides _ additional _ information about the two fluctuating quantities @xmath153 . reference expects that a left - right ( lr)-symmetric system has @xmath154 . therefore rigid and lr - symmetric sample should necessarily have @xmath155 and thus could not exhibit a second - order current @xmath149 . this point is discussed more quantitatively in sec . [ sec:2terminal ] . it is important to note that to find the linear dc current one needs to know only @xmath156 , while for the nonlinear current in general one needs two variables @xmath157 or any independent pair of their linear combinations . the projection of the vector @xmath158 on the @xmath159const plane uniquely defines the nonlinear current . this projection can be parametrized by the pair of cartesian @xmath160 or axial coordinates @xmath161 . however , if in the experiment the voltages @xmath162 were fixed , this would not be enough to define @xmath160 uniquely . in this case ref . points to the importance of the reference point @xmath100 . indeed , one could arrive at the point with a given @xmath163 from any equilibrium point and the measured current would depend on @xmath100 . we prefer to characterize the measurement by the pair @xmath164 instead of three variables @xmath158 because of the simplicity of the final results . the weaker the interaction ( or the stronger the capacitive coupling of the sample to the nearby gate ) the more important the role of @xmath107 chosen in experiment . we illustrate this important conclusion by quantitative results for nonlinear conductance @xmath165 in the following sections . we point out that conductance with respect to the voltage difference @xmath166 is often used , even when a linear combination @xmath10 is actually varied in experiment . voltages @xmath10 and @xmath167 are related , @xmath168 , and one can straightforwardly find @xmath169 . now we quantify the qualitative arguments of sec . [ sec : bias ] and consider the more general situation of a dc current generated by an ac bias . if at first we neglect coulomb interactions , the nonlinear dc current @xmath170 in response to the fourier components @xmath171 of the ac voltages applied at the contacts @xmath172 , can be expressed with the help of the dc - conductance matrix @xmath173 of the dot at the energy @xmath72 @xcite @xmath174.\ ] ] if we now include interactions using a self - consistent potential @xmath175 this formula is modified : @xcite in eq . ( [ eq : pedersen ] ) the fourier components of the voltages at _ all _ contacts are shifted down by the fourier component of the internal potential @xmath176 @xmath177\nonumber \\ & \times & \frac{f(\e)-f(\e+\hbar\oo)}{\hbar\oo}.\label{eq : sumg}\end{aligned}\ ] ] in eq . ( [ eq : uomega ] ) the index @xmath178 runs not only over real leads @xmath179 , but also over all gates @xmath180 . however , when @xmath181 the ac conductance @xmath182 is absent and only capacitive coupling @xmath183 remains in the numerator . we point out that the matrix @xmath184 of dynamical ac conductance at frequency @xmath4 given in eq . ( [ eq : sumg ] ) should not be confused with the degenerate matrix @xmath185 of energy - dependent dc conductances of electrons with kinetic energy @xmath72 given in eq . ( [ eq : gdc ] ) . the results of ref . can be expressed in terms of the dc conductances @xmath186 and frequency - dependent characteristic potentials @xmath187 , @xmath188 stands for the real part of @xmath187 , which is in general a complex quantity . in contrast to eq . ( [ eq : pedersen ] ) , eq . ( [ eq : current4omega ] ) is expressed via differences of voltages applied to all present conductors . therefore , the current is gauge - invariant . the charge conservation , @xmath189 , is obvious from eq . ( [ eq : gdc ] ) . from this point on we consider eq . ( [ eq : current4omega ] ) , a specific expression of eq . ( [ eq : iv ] ) , in detail for several regimes . in sec . [ sec:2terminal ] we discuss the nonlinear current due to dc applied voltages ( previously considered in ref . ) and the importance of different bias modes in experiments in two - terminal quantum dots . in sec . [ sec : rectify ] we consider the frequency dependence of @xmath40 and @xmath39 . in the static limit @xcite @xmath190 the integrand in the first line of eq . ( [ eq : current4omega ] ) simplifies to @xmath191 and for @xmath192 the derivatives @xmath187 are real and expressed via subtraces of the hermitian wigner - smith matrix @xmath193 @xcite @xmath194 for a two - terminal sample the nonlinear current through the first lead is @xmath195+(u_2-u_1)(v_1-v_2)^2\right].\end{aligned}\ ] ] the characteristic potentials in the last term of eq . ( [ eq : current ] ) are sensitive to the asymmetry of the contacts . indeed , in a strongly interacting dot @xmath196 and @xmath197 . the current magnitude grows with asymmetry due to the last term in eq . ( [ eq : current ] ) . on the other hand , the sign of @xmath198 is random because of quantum fluctuations of @xmath199 around zero . @xcite as a consequence , if in an experiment the fermi level is shifted by @xmath200 ( or the shape of the dot is changed ) the sign of nonlinearity can be inverted . different modes of bias having been discussed in sec . [ sec : bias ] , we concentrate here on the ( anti)symmetric conductances through the quantum dot at fixed gate voltages . when the reservoir voltages are varied in the @xmath107 direction , the nonlinear current is given by the expression @xmath201\cos\eta\tilde v^2,\end{aligned}\ ] ] and one can define exactly the unknown parameters @xmath153 which we introduced in the qualitative argument leading to eq . ( [ eq : iexample ] ) . depending on @xmath107 one measures different linear combinations of conductances . if we consider conductances @xmath202 in units of @xmath203 , eqs . ( [ eq : ivfield ] ) and ( [ eq : deriviv ] ) yield @xmath204}\end{aligned}\ ] ] expressed in terms of fluctuating functions @xmath205 and a traceless matrix @xmath206 : @xmath207,\\ \label{eq : chi2s } \chi_{2,s}(\e ) & = & \delta\left(\frac{c_0\tan\eta+c_2-c_1}{e^2\nu_s } + \frac{n_2-n_1}{n}\frac{\tr \s^\dagger\dd_\e\s}{2\pi i } \right.\nonumber \\ & & \left . + \frac{1}{2\pi i } \tr\lambda\{\s^\dagger,\dd_\e\s\}\right).\end{aligned}\ ] ] standard calculations using the wigner - smith and/or @xmath69-matrix averaging @xcite yield @xmath208 . this result signifies that the nonlinear current through a quantum dot is indeed a quantum effect . as a consequence the size of the measured nonlinearity must be evaluated from correlations of @xmath8 . the functions @xmath209 and @xmath210 are uncorrelated , and their autocorrelations @xcite readily allow one to find statistical properties of @xmath211 . our results can be expressed in terms of diffuson @xmath212 or cooperon @xmath213 in a time representation , @xmath214 and @xmath215 . both can be introduced using the @xmath69-matrix correlators @xcite ( correlations of retarded and advanced green functions lead to the same expression up to a normalization constant @xcite ) . we have @xmath216 we also introduce the electrochemical capacitance @xmath217 @xcite which relates the non - quantized mesoscopically averaged excess charge @xmath218 in the dot in response to small shift of the voltages @xmath219 at all gates . in addition the charge relaxation time @xmath220 of the dot is conveniently introduced by this electrochemical capacitance and the total contact resistance , @xmath221 the denominator of eq . ( [ eq : defg ] ) is a self - averaging quantity , @xmath222 . using the diffusons and cooperons defined in eq . ( [ eq : cum1 t ] ) we find the following correlations of @xmath14 and @xmath15 : @xmath223 there are two very different contributions to eq . ( [ eq : main ] ) , @xmath224 due to quantum interference and @xmath225 defined by the classical response of the internal potential to external voltage . the terms denoted by @xmath226 are sensitive to temperature , magnetic field , and decoherence . asymptotical values of @xmath227 in the low temperature , @xmath228 , or high temperature limits , @xmath229 , are @xmath230 and @xmath231 , respectively . the term denoted by @xmath225 and given by eq . ( [ eq : x ] ) contains only quantities specifying the geometry of the sample and gates and the bias mode . in a real experiment the coupling due to capacitances @xmath232 is usually stronger then that of the external gates , @xmath233 . symmetrization of the circuit @xmath234 can diminish the value of @xmath225 . if in addition @xmath235 and @xmath111 ( used in the experiments @xcite ) we have @xmath236 . thus such a symmetric setup and bias mode minimize the fluctuations of the nonlinear current and actually would be best for an accurate measurement of _ linear _ transport . indeed , this regime is not affected by the fluctuations of capacitive coupling @xmath237 of the dot with the nearby gate and thus minimizes fluctuations of @xmath15 around 0 . fluctuations of @xmath8 are given by different expressions , see the first line of eq . ( [ eq : main ] ) , where the first term is due to @xmath238 or @xmath239 . importantly , @xmath239 contains both quantum @xmath240 and classical @xmath225 contributions . if the classical term dominates , @xmath241 , the current is mostly symmetric , @xmath242 . this could be expected either for a weakly interacting dot or a very asymmetric setup , @xmath243 .@xcite however , if the classical term is reduced due to , e.g. , the bias mode , the fluctuations of @xmath14 and @xmath15 become comparable . this experimentally important conclusion remains valid for _ any interaction strength_. ( particularly , it leads to a very wide distribution of the aharonov - bohm phase considered in sec . [ sec : phase ] . ) experiments of zumbhl @xcite and leturcq @xcite are performed in this regime when @xmath111 and @xmath236 . data in ref . demonstrate that the part of the total current symmetrized with respect to magnetic field is by far dominated by linear conductance . from eq . ( [ eq : main ] ) we expect mesoscopic fluctuations in linear conductance to be @xmath244 times larger then those of @xmath245 . thus only when the number of channels is decreased will the nonlinear @xmath15 become noticeable . a clear observation of @xmath15 without linear transport contribution was performed in a dc aharonov - bohm experiment by angers @xcite in the mode @xmath246 ( only one contact voltage was varied ) . this allowed to evaluate the interaction strength from the ratio of @xmath247 . experiments of marlow @xcite and lfgren @xcite measure the full two - terminal conductance and extract nonlinear conductance properties related to various spatial symmetries of the dot . although the current through a weakly interacting sample is field - symmetric , this is not true in general . samples of ref . differ in `` rigidity '' and degree of symmetry . rigid samples , @xmath248 , with left - right(lr ) and up - down ( ud)-symmetry should have @xmath249 and @xmath250 respectively , according to the expectations of lfgren @xcite ( indices @xmath251 and @xmath252 mean the symmetric and antisymmetric part in magnetic field ) . due to quantum fluctuations , in experiment none of these symmetry - relations can be exactly fulfilled , see eq . ( [ eq : main ] ) . according to eq . ( [ eq : deriviv ] ) , the difference in the full conductances @xmath253 measured between different points probes different characteristic potentials . reference defines three differences @xmath254 for three pairs of points in the forward and reverse connection discussed after eq . ( [ eq : ivangle ] ) . using eq . ( [ eq : main ] ) we find ( i ) @xmath255 , ( ii ) @xmath256 , and ( iii ) @xmath257 . the ensemble average of these differences vanishes and their fluctuations for @xmath258 are given by @xmath259 where @xmath260 is found from eq . ( [ eq : x ] ) at @xmath261 . in weakly interacting dots @xmath262 and only magnetic - field symmetric signals @xmath263 and @xmath264 survive . in strongly interacting ( `` rigid '' ) dots @xmath265 and @xmath266 becomes similar to @xmath264 . we point out that even if the rigid samples are made symmetric with respect to left - right inversion , the quantum fluctuations of the sample properties are unavoidable and @xmath267 at @xmath268 . for high magnetic fields and arbitrary interactions @xmath269 and experiment should observe @xmath270 . clearly fluctuations exist also for large magnetic fields beyond the range of applicabilty of rmt . experimental data ( see inset of fig . 6 in ref . ) show that @xmath271 . it is hard to make a quantitative comparison with refs . and , since the quantum fluctuations in the nonlinear conductance exist possibly on the background of classical effects due to macroscopic symmetries . we expect that quantum effects become more pronounced as contacts are narrowed . to conclude this subsection we briefly discuss here the case of a macroscopically asymmetric setup . if the experiment were aimed to measure large @xmath14 compared to @xmath15 , one would try to minimize @xmath15 by adjusting the setup . such a procedure minimizes the value of @xmath225 in eq . ( [ eq : x ] ) . for @xmath272 the role of asymmetric contacts @xmath243 was discussed in ref .. analogously , one could consider a more general case of @xmath232 and an arbitrary bias mode @xmath107 . this is especially important if the difference @xmath273 can not be neglected due to occasional loss of contact symmetry . the results of an experiment could also be affected by the presence of classical resistance loads @xmath52 between macroscopic reservoirs and the dot ( shown in fig . [ fig:3dot ] ) . swapping of such resistances in the experiment , when connection is switched between `` forward '' and `` reverse '' @xcite affects the voltage division between loads . if we assume the capacitive connection of the dot and reservoirs is still the same , the modification of the expression for @xmath187 in eq . ( [ eq : uomega ] ) is straightforward , @xmath274 . naturally , at large @xmath275 , @xmath276 , the main drop of the voltage occurs over the resistor @xmath275 and not over the qpcs . as a consequence , if @xmath277 , values of @xmath278 can become unequal due to @xmath279 and this leads to the classical circuit asymmetry which we do not consider here . here we consider the dc generated by a quantum dot subject to an ac bias at the frequency @xmath4 . in experiment at high bias frequency @xmath280 current is usually measured at zero frequency . in contrast , at small bias frequency @xmath281 higher harmonics ( for instance the second harmonic @xmath282 ) can be measured . however , up to corrections small due to @xmath281 , the second harmonic is just equal to the rectified current , @xmath283 . therefore , to leading order , our results for the rectified current describe both experiments . generally , there are several important time - scales characteristic for time - dependent problems in chaotic quantum dots . to see how they appear let us first consider frequency - dependent linear transport of noninteracting electrons . its statistics usually depend only on the flux - dependent time scales @xmath284 , see eq . ( [ eq : channels ] ) . if we consider an analog of ucf @xmath285 for the frequency - dependent conductances introduced in eq . ( [ eq : sumg ] ) , we find @xmath286\sinh^2 \pi t\tau/\hbar}.&&\end{aligned}\ ] ] the presence of @xmath287 in the diffuson and cooperon contributions in the second line of eq . ( [ eq : linear ] ) is due to the energy dependence of the scattering matrix @xmath68 , which usually brings up imaginary corrections to the matrix - element correlators . in a dc - problem @xmath28 it is usually useful to introduce a dimensionless number of channels @xmath288 modified by the magnetic field , see eq . ( [ eq : channels ] ) . in this limit at @xmath289 the integration in eq . ( [ eq : linear ] ) becomes straightforward and summation is then performed over @xmath290 . for equal magnetic fields , @xmath291 , we have @xmath292 , but @xmath293 is strongly modified by large fields , @xmath294 , which suppresses the weak localization correction and diminishes ucf . however , for an ac problem ( especially for @xmath280 ) it is more convenient to express results in terms of dimensionless quantities @xmath295 . for example , from eq . ( [ eq : linear ] ) the statistics of conductance can be easily evaluated : @xmath296 and the real and imaginary parts of conductance are similar and uncorrelated at high frequency @xmath42 . inclusion of interactions introduces an ( additional ) dependence on @xmath220 , the charge - relaxation time defined in eq . ( [ eq : excess ] ) . to leading order in @xmath83 the effect of interactions is often to substitute @xmath297 in the noninteracting results , e.g. , for the linear conductance @xcite or shot noise . @xcite interestingly , the subleading corrections depend on both @xmath220 and @xmath34 , e.g. , in the weak localization correction in the absence of magnetic field.@xcite when the magnetic field is increased to values which finally break time - reversal symmetry , the appearance of different time scales @xmath284 is expected , see e.g. , eq . ( [ eq : linear ] ) . therefore at intermediate magnetic fields , when @xmath298 , and the interactions taken into account , @xmath299 , the solution of an ac problem is expected to show a complicated dependence on all these time scales . indeed , if we consider the rectified current such an interplay between @xmath284 and @xmath220 does appear . we find @xmath208 and present below results for correlations of @xmath14 and @xmath15 : @xmath300\left ( \frac{4\pi\cos^2\eta } { \delta}\frac{c_\m}{c_\sigma}\right)^2\frac{n_1 ^ 3 n_2 ^ 3}{n^6 } \label{eq : vargs}.\end{aligned}\ ] ] here the functions @xmath301 are finite - frequency generalizations of eq . ( [ eq : fraw ] ) @xmath302 the subscripts @xmath303 of @xmath304 illustrate the origin of these functions : they result from averaging of different scattering properties over the energy band defined by @xmath305 . the function @xmath306 is a characteristic of the internal potential @xmath307 , see eq . ( [ eq : uomega ] ) . the function @xmath308 results from the energy averaging of the dc conductance @xmath185 . such averaging appears because both @xmath309 defined in eq . ( [ eq : sumg ] ) and @xmath185 in eq . ( [ eq : current4omega ] ) are coupled to the fermi distribution . the function @xmath310 is @xmath311 and in the static limit @xmath28 it is given by eq . ( [ eq : x ] ) . we point out that when the interactions are negligible , @xmath312 , the role of the bias mode is significant . a quantum dot with ( fully broken ) time - reversal symmetry can be labeled by dyson symmetry parameter ( @xmath313 ) @xmath314 . when the setup is ideal , @xmath315 , and @xmath316 , the fluctuations of @xmath8 at large frequencies @xmath42 are @xmath317 in chaotic quantum dots the role of the thouless energy @xmath318 of the open systems is often played by the escape rate @xmath319 . if we take this into account , our result ( [ eq : fk ] ) qualitatively agrees with that of falko and khmelnitskii @xcite obtained for open diffusive metallic junctions . however , when @xmath320 , the fluctuations of @xmath15 are much smaller and for @xmath321 they become comparable with those of the antisymmetric conductance ( [ eq : fkasym ] ) . however , very often experiments are performed in samples , where the interaction is not weak . since @xmath14 and @xmath15 are comparable for strong coulomb interactions in the static limit @xmath322,@xcite we concentrate here on this experimentally relevant regime of @xmath323 and take an ideal symmetric setup , @xmath235 and @xmath315 . then we have @xmath324 below we consider in detail the case @xmath316 and how this bias mode affects the behavior of @xmath325 . several frequency regimes can be separated : adiabatic @xmath326 , intermediate , where @xmath327 , and high frequencies @xmath328 . the asymptotes of the functions defined in eqs . ( [ eq : fu ] ) , ( [ eq : fg ] ) , and ( [ eq : xomega ] ) in these regimes are presented in table [ tab : table ] for reference . for adiabatic frequencies @xmath326 the integrands in eqs . ( [ eq : fu ] ) and ( [ eq : fg ] ) do not oscillate on the short time scale @xmath329 . at such small frequencies @xmath330 are equal to @xmath227 of eq . ( [ eq : fraw ] ) and @xmath331 can be neglected . this is essentially the zero frequency regime considered before for nonlinear dc transport . as the frequency grows , an intermediate regime is reached when max @xmath332 and @xmath333 start to differ . the scattering properties at large energy difference @xmath334 are uncorrelated and the response of the dot is randomized . therefore both the conductance averaged over a large energy window @xmath335 and the response of the internal potential @xmath307 to the ac voltage at @xmath336 are strongly suppressed , see table [ tab : table ] . as a result , if @xmath310 is still negligible , both @xmath337 and @xmath338 decrease with growing frequency as @xmath339 . .asymptotes of @xmath340 at @xmath341 [ tab : table ] [ cols="^,^,^,^ " , ] it is noteworthy that a recent experiment in ab rings @xcite finds that @xmath342 grows with frequency until @xmath343 and then decreases @xmath344 . while we predict a monotonic decrease of @xmath345 , this growth could be the result of quantum pumping or an interference of the pumping and rectification ( both effects were neglected here ) . in this section we consider nonlinear transport through a chaotic aharonov - bohm ( ab ) ring . the nonlinear conductance @xmath143 exhibits periodic ab oscillations and non - periodic fluctuations , similarly to the linear conductance @xmath346 . however , since coulomb interactions produce asymmetry of @xmath143 with respect to magnetic field inversion , the phase of these oscillations is not pinned to @xmath347 . as a quantum effect this ab phase is characterized by a mesoscopic distribution . the width of this distribution represents a typical fluctuation . we first discuss what kind of distribution could be expected in a chaotic ab ring and then calculate the fluctuation of the ab phase . let us assume that @xmath143 as a function of magnetic flux @xmath7 can be expanded into the series of well - defined fourier harmonics similarly to the linear conductance @xmath346 : @xmath348 the phase @xmath46 of the main ( first ) harmonic @xmath349 is obtained from the ratio of the ( anti ) symmetrized conductances defined in eq . ( [ eq : ivfield ] ) @xmath350 we can not find the full mesoscopic distribution of the phase @xmath351 . we can gain some insight in the behavior of this phase by investigating a similar quantity , namely , the asymmetry parameter @xmath17 considered previously for chaotic dots . @xcite based on eq . ( [ eq : tan ] ) we argue that the statistical properties of @xmath352 and the ab phase @xmath46 should be similar . in quantum dots the parameter @xmath353 is given by the ratio @xmath354 , see eqs . ( [ eq : defg ] ) , ( [ eq : chi2a ] ) , and ( [ eq : chi2s ] ) . the functions @xmath355 at @xmath356 are convolved separately with @xmath357 , and at @xmath358 ( which we consider below ) they are evaluated at the fermi energy . the properties of @xmath355 and the dependence of @xmath359 on the bias mode were described after eq . ( [ eq : x ] ) . the function @xmath359 can have a nonzero ( classical ) average @xmath360 defined by the interaction strength , geometry of the setup , and the bias mode @xmath107 . since @xmath361 and the fluctuations of @xmath355 are small as @xmath362 , the mesoscopic distribution of @xmath363 is narrow and concentrated close to 0 . however , @xmath364 is possible if @xmath236 , e.g. , for symmetric contacts and the bias mode @xmath111 . in this case , the distribution of @xmath352 becomes wide regardless of the interaction strength . [ t]@xmath365[l]@xmath366 [ l][][0.8]@xmath367 [ l][][0.8]@xmath368 [ l][][.7]@xmath369 [ l][][.7]@xmath370 of @xmath371 . ( main plot ) if the contacts are asymmetric ( bold curve , @xmath368 ) the distribution is narrow , while for symmetric contacts ( dashed , @xmath367 ) it is almost uniform . as shown in the inset , for symmetric contacts at large @xmath64 the distribution becomes uniform , compare bold curve for @xmath370 and dashed for @xmath369.,title="fig:",width=302 ] + the role of the classical contribution on the shape of @xmath372 is demonstrated in the main plot in fig . [ fig : delta ] for @xmath111 , where the distributions for asymmetric , @xmath373 , and symmetric contacts , @xmath374 , are presented . while the distribution is almost uniform , when the classical contribution @xmath225 is absent , it is highly peaked near zero when @xmath225 dominates . if @xmath225 is absent , the correlations between @xmath14 and @xmath15 are significant at small @xmath64 . this leads to a nonuniform distribution of @xmath372 , which is peaked at @xmath375 and @xmath376 when @xmath370 , see the inset in fig . [ fig : delta ] . when @xmath64 grows , the correlations between @xmath14 and @xmath15 vanish and therefore the distribution becomes uniform . such a distribution could be easily obtained if we make the natural assumption that @xmath8 are independent and distributed by the gaussian law with the same width . these numerics were performed for @xmath111 , when the mesoscopic distribution of @xmath17 becomes insensitive to the interaction strength . the role of interactions appears only if @xmath316 , when the classical contribution @xmath225 becomes dominant . similarly , we expect that the distribution of the phase of ab oscillations is also strongly affected by the bias mode . if the bias mode is chosen such that the classical contribution @xmath225 vanishes , the phase @xmath46 strongly fluctuates _ even for weak interactions_. it would be very interesting to check this surprising conclusion experimentally . let us now consider the fluctuations of the ab phase . since the scattering theory turned out to be very useful for the discussion of the nonlinear/ rectified current through a chaotic quantum dot , we extend this theory to rings . we make two key assumptions ( discussed in the appendix in more detail ) that the magnetic flux through the annulus of the ring is smaller then the flux quantum @xmath377 and that the mean free path @xmath378 , the radius @xmath379 , the width of the ring @xmath380 and the contacts @xmath381 satisfy the condition @xmath382 . in this case the rmt can be applied to such chaotic rings as well . unlike the experiments on large open rings with high aspect ratio @xmath383,@xcite the recent experiments @xcite are performed in rings of submicron size , which are effectively zero - dimensional . the treatment of such rings is similar to chaotic quantum dots , and the fluctuations of @xmath13 can be expressed in terms of the diffuson @xmath212 and the cooperon @xmath213 , see eq . ( [ eq : main ] ) . the only problem is to find the expression for the effective number of channels as a function of magnetic field , similar to eq . ( [ eq : channels ] ) . channels . the model consists of a quantum dot with @xmath54 channels combined with a ballistic arm with @xmath384 channels.,title="fig:",width=226 ] + the model we propose for a chaotic ab ring combines chaos and a ring geometry : a chaotic dot is attached to a long ballistic arm which serves to include an ab flux large compared to the fraction of the flux through the sample . this model is shown in fig . [ fig : model ] , where the ring with @xmath385 ballistic channels in the contacts 1,2 is modeled by a dot with @xmath386 channels and a ballistic arm with @xmath384 channels in contacts 3,4 . the parameter @xmath387 , the ratio of @xmath388 to the total number of channels @xmath54 , can vary between 0 when the arm is much narrower then the contacts and 1 in the opposite limit . the electronic phase is randomized in the quantum dot , but when electrons propagate along the arm their phase is determined by the geometry and applied magnetic field . this model is a reasonable approximation for the real experiment , it takes into account the long time spent by electron inside the ring and the randomness of its motion . the discussion of the model and the details of calculation of @xmath389 are presented in the appendix . in experiment the fourier transform is often taken over the total flux ( or applied magnetic field ) and the flux through the hole @xmath390 can not be separated from the flux through the dot @xmath391 . then the dependence of the diffuson and cooperon on magnetic field is non - periodic , which is indeed observed in the form of nonperiodic fluctuations in the ( non-)linear conductance and phase slips of ab oscillations . a possible weakness of this model is in its spatial separation of chaotic scattering and the main part of magnetic field , but in the limit when the arm is much wider then the contacts @xmath392 and @xmath393 such a separation is not important and the averaged properties of ab oscillation phase become independent of the arm s width . if the flux @xmath394 through the dot is much smaller then the flux @xmath395 through the hole , the nonperiodic fluctuations and the periodic ab oscillations are well - separated , which is usually the case in experiment.@xcite in view of this separation we can neglect the flux through the chaotic dot , @xmath396 , to find the statistics of the ab phase . we assume that the averaging is taken over a magnetic field range containing many ab oscillations but still small compared to the characteristic field of the nonperiodic fluctuations . in such a simplified model of a chaotic ab ring @xmath288 are given by eq . ( [ eq : dcfinal ] ) with @xmath397 and the parameter @xmath398 . the effective number of channels is @xmath399 using this expression for the @xmath288 we can evaluate the quantum fluctuations of linear conductance in ab rings . at low temperature a typical fluctuation of @xmath346 at @xmath400 is @xmath401 and the amplitude of ab oscillations is @xmath402 , which reaches maximum when the widths of the arm and the contacts are equal , @xmath403 . the first two moments of @xmath44 can be found analytically . it is zero on average , @xmath404 , since the numerator and denominator in eq . ( [ eq : tan ] ) are independent random quantities . equation ( [ eq : dcsimple ] ) show that @xmath405 are the same functions of @xmath406 , so that all necessary ingredients can be expressed in terms of the functions @xmath407 and @xmath408 of @xmath409 defined in eqs . ( [ eq : fu ] ) and ( [ eq : fg ] ) . we omit now the index @xmath212 for brevity and denote the average over magnetic field by @xmath410 , to find @xmath411/ \left[\overline{({\cal f}_{u } ( \phi)+x(\oo)){\cal f}_{g } ( \phi)\cos\phi } \right.\nonumber \\ & & \mbox { } \left.+ \overline{\frac{{\cal f}_{u } ( \phi)}{2}}\overline{{\cal f}_{g } ( \phi)\cos\phi}+ \overline{\frac{{\cal f}_{g } ( \phi)}{2}}\overline{{\cal f}_{u } ( \phi)\cos\phi}\right],\end{aligned}\ ] ] where the function @xmath310 is defined by the setup geometry in eq . ( [ eq : xomega ] ) . again , in the static limit @xmath28 we have @xmath412 and @xmath225 defined by eqs . ( [ eq : fraw ] ) and ( [ eq : x ] ) . in this case ( [ eq : tandelta ] ) can be rewritten as @xmath413\overline{\cos\phi{\cal f}(\phi)}}{\overline{\cos\phi{\cal f}^2(\phi)}}.\end{aligned}\ ] ] in the limits of high , @xmath414 , and low temperature , @xmath415 the asymptotical values of @xmath416 are @xmath417 very important is the case of symmetric contacts , @xmath235 , and antisymmetric bias mode , @xmath111 , which is used in ref .. then @xmath225 vanishes and the average @xmath418 becomes independent of interaction strength and as a function of @xmath16 it is very weak . that is not the case if @xmath419 , for example , when only one of the voltages changes , @xmath261.@xcite then the statistics of the ab phase becomes temperature and interaction dependent due to the presence of @xmath225 . the limit @xmath420 corresponds to a uniformly chaotic ring , which we suppose to be closer to the experimental situation . then the dependence on @xmath54 drops out and the high / low temperature asymptotic read @xmath421 this result clearly demonstrates that the phase of the oscillations is expected to deviate strongly from 0 , especially if the temperature is low and the number of channels in the contacts is diminished . the temperature is taken into account only in the form of temperature - averaging and the dephasing ( previously considered for nonlinear transport of noninteracting electrons in refs . ) is not included . we expect our model for chaotic ab rings to work both for experiments at small frequencies @xcite and for large frequencies.@xcite similarly to quantum dots , the generalization on the finite - frequency case is obvious , if we use eq . ( [ eq : xomega ] ) . even in cases where rmt can not be assured to be valid for open diffusive rings , the dependence of the ab phase on interaction strength , temperature , and number of external channels given by eq . ( [ eq : anglewidearm ] ) should be correct qualitatively . the experiment of leturcq @xcite is performed in a bias mode @xmath111 when @xmath422 . ( [ eq : anglewidearm ] ) gives @xmath423 . the phase of the oscillations is evaluated from data according to eq . ( [ eq : tan ] ) over a large range of fields . in experiment the ab phase is varied continuously as a function of the gate voltage at one of the arms of the ring . the data demonstrate that the phase @xmath46 indeed changes in a wide range and is usually far from 0 . this substantiates our conclusion that in the mode when the classical contribution is minimized , @xmath236 , the mesoscopic distribution of @xmath46 is very wide . experiment of angers @xcite varies voltage in a different way , @xmath109 , and therefore has @xmath424 . we would expect the phase @xmath425 to take values closer to @xmath375 and the antisymmetric component of the oscillations be relatively smaller even for large fields . although phases close to 0 are indeed observed , the field averaging is taken only over first few oscillations . in this range @xmath14 , the numerator in eq . ( [ eq : tan ] ) is still small and grows linearly with magnetic field . averaging over a larger field - range similar to ref . could not be performed because of the phase slips . another interesting question is a difference in data @xcite for the relative magnitudes @xmath426 of the second @xmath31 and main harmonic @xmath30 , see eq . ( [ eq : expansion ] ) . in the nonlinear transport regime this harmonic is small compared to its contribution in the linear transport , @xmath427,@xcite while in ref . they were comparable , @xmath428 . our model also predicts the mesoscopically averaged contribution of @xmath31 into linear and nonlinear conductance to be comparable with that of @xmath30 . our approach assumes full quantum coherence of the ring , and probably the difference in data is due to decoherence . in this paper , we consider mesoscopic chaotic samples ( quantum dots or rings ) and find the statistics of their nonlinear conductance @xmath143 . this transport coefficient characterizes nonlinear dc current due to dc - bias or a rectified current due to ac bias or photon - assisted transport . for chaotic samples , the nonlinear effect is of quantum origin , which is clear from the fact that its ensemble average over similar samples vanishes . the linear response of the sample in two - terminal measurements is always symmetric with respect to magnetic field inversion . however , the coulomb interactions lead to magnetic field asymmetry of the nonlinear dc response , which fluctuates due to the electronic interference . for the quantum dots we consider the fluctuations of ( anti ) symmetrized components @xmath8 of the nonlinear conductance . in chaotic rings the statistics of the phase of ab oscillations in the nonlinear transport regime , closely related to the ratio @xmath429 , is of interest . unlike the linear conductance measurements , in mesoscopic nonlinear transport experiments the way voltages are varied ( `` bias mode '' ) turns out to be important , especially for a weakly interacting sample . we demonstrate this fact qualitatively and discuss the role of coulomb interactions . quantitative self - consistent treatment of interactions allows us to consider magnetic - field asymmetry in chaotic quantum dots with many channels . using eqs . ( [ eq : main])([eq : x ] ) we show that the fluctuations of @xmath15 are strongly affected by the geometry of the setup and discuss how the bias mode influences data of recent dc experiments . another important issue is rectification of ac bias , which is quadratic in applied voltage , random , and asymmetric with respect to the magnetic flux inversion . the photovoltaic dc current can be due to rectification of external perturbations or quantum pumping by internal perturbations . both rectification and quantum pumping share the aforementioned properties , and it is important to clearly separate them especially when the frequency of perturbations is high ( nonadiabatic ) . we consider here only the effects of the external perturbations and discuss the dependence of the fluctuations of @xmath8 on frequency @xmath4 . we show that the fluctuations of both @xmath14 and @xmath15 , presented in eqs . ( [ eq : vargs])([eq : xgeneral ] ) , decrease monotonically as @xmath41 . however , contrary to naive expectations , their asymptotical behavior can be very different . since at high frequencies the response of the dot to the external bias becomes rather capacitive then resistive , the coupling to the nearby gates can be strongly enhanced . if the experiment is performed in a bias mode where such coupling contributes , the symmetrized @xmath430 can become much larger then @xmath431 valid for a strongly interacting quantum dot . the same conclusion holds in the weakly interacting limit , when @xmath432 and @xmath433 . in addition , we show that recent experiments in chaotic aharonov - bohm rings might be considered similarly to quantum dots . the multiply connected geometry alone leads to ab oscillations , yet the mesoscopic distribution of their phase is expected to be qualitatively similar to that of @xmath434 in quantum dots . therefore , the bias mode should strongly affect the shape of mesoscopic distribution of the ab phase . the model of an ab ring , which we develop , consists of a dot and a long ballistic arm and takes into account both chaos and a ring geometry . as an application of our model we consider fluctuations of the ab phase . unlike the ab phase in the linear conductance , pinned to @xmath435 by the onsager symmetry relations , the fluctuations of the ab phase in nonlinear transport are shown to depend on the bias mode , interaction strength , and temperature . we thank hlne bouchiat , piet brouwer , renaud leturcq , david snchez , maxim vavilov , and dominik zumbhl for valuable discussions . we also thank the authors of ref . for sharing their results with us before publication . this work was supported by the swiss national science foundation , the swiss center for excellence manep , and the strep project subtle . in this appendix we determine the diffuson and cooperon contributions to the @xmath69-matrix correlators of the random scattering matrix of a chaotic aharonov - bohm ( ab ) ring . this calculation is performed using random matrix theory ( rmt ) . first we explain what approximations should be made to ensure validity of rmt . our starting point is the assumption that the @xmath69-matrix of the ring is uniformly distributed over the unitary group . this means that the ring is essentially zero - dimensional , similarly to quantum dots . rmt is applicable if all energy - scales are much smaller then the thouless energy @xmath318 and the total flux through the annulus of the ring is much smaller then @xmath377 . assume the ring of radius @xmath379 and width @xmath436 to be diffusive with diffusion coefficient @xmath437 . to evaluate @xmath318 we neglect with transversal motion of an electron and find @xmath438 as a solution to laplace equation along the circumference of the ring . rmt can be applied to a closed ring if the dimensionless conductance is large , @xmath439 , which is usually satisfied for a weak disorder even if @xmath436 . an open ring with ballistic contacts of the width @xmath381 gains a new energy parameter , the escape rate @xmath440 , where @xmath64 is the total number of ballistic channels . the scattering matrix @xmath69 is uniformly distributed and independent of the exact positions of the contacts ( and therefore the length of the arms ) if @xmath441 . in this case the main drop of the potential occurs in the contacts . if a magnetic field is applied , the rmt is valid if the total flux through the annulus of the ring is much less then the flux quantum , @xmath442 . due to narrow contacts the time - reversal symmetry ( trs ) of the @xmath69-matrix can be broken at a much smaller scale , @xmath443 . since in our rings @xmath444 , a full crossover to the broken trs can be considered . how well are these conditions fulfilled in the experiment ? in ref . chaos was mainly due to diffusive scattering on the boundary and @xmath445 . the width of the arm is 2 - 4 channels , while the number of channels in the contacts is @xmath446 , estimated from the linear conductance measurements , so @xmath447 . in semiballistic samples of ref . ( obtained by etching , and therefore having diffusive boundary scattering ) @xmath448 and the mean free path is estimated @xmath449m@xmath450 m , the side length . therefore , we have a similar estimate for the ratio @xmath451 . although this ratio is not parametrically large due to , e.g. , weak disorder @xmath452 , we believe that such ab rings still can be assumed zero - dimensional due to their good conducting properties together with relatively narrow contacts . in our calculations we make a further simplification by spatially separating chaotic scattering which randomizes the electronic phase and the long ballistic arm attached to it . to find the correlators of the @xmath69-matrix elements we use a simplified model , see fig . [ fig : abdot ] , which combines chaos and a ring geometry . a chaotic @xmath54-channel dot is attached to a long multi - channel ballistic arm with @xmath453 orbital channels . we assume that the size of the dot @xmath454 and the length of the arm @xmath455 are such that @xmath456 to ensure that in the hierarchy of different fluxes the main flux @xmath395 is concentrated in the region embraced by the arm , the flux through the dot @xmath394 is much smaller , but still much larger then the flux through the cross section of the arm . the amplitude of ab oscillations depends on the width of the arm @xmath457 . the wider the arm ( relatively to the contacts ) the closer the results should be to a uniformly chaotic ring . for the case when @xmath420 we expect it to be valid for the chaos uniformly distributed over the ring . indeed , in this case an electron makes @xmath458 windings around the arm before exiting . in this appendix it is more convenient for us to work with an energy - dependent matrix @xmath68 , and the final transformation to time - representation is rather obvious . the total scattering matrix @xmath69 is of size @xmath459 due to scattering channels in the contacts 1 and 2 . chaotic scattering in the @xmath54-channel quantum dot is characterized by the @xmath460 matrix @xmath461 . the scattered electron can either exit the sample through the @xmath385 channels ( projection operator @xmath462 ) or propagate into the arm with @xmath384 channels . electrons propagate through this arm ballistically and gain phases which depend on the flux through the hole . in the absence of backscattering the electronic amplitudes at energy @xmath72 are related to the path length @xmath455 and magnetic field phase @xmath365 : @xmath463 the scattering matrix of the arm is @xmath464 . each time an electrons enters the arm either through the third or fourth lead , the matrix @xmath465 contributes to the scattering amplitude of the process . the total scattering matrix @xmath69 is determined from the following equation : @xmath466 where multiple @xmath467 windings are taken into account . both @xmath468 and @xmath469 are field and energy dependent . once we are interested only in pair correlators of @xmath470 for @xmath471 , the diffuson @xmath212 and cooperon @xmath213 of our scattering matrix are expressed via correlators of the dot , @xmath472,@xmath473 , and tr @xmath474 . the correlators of the @xmath461-matrix are known , see eq . ( [ eq : cum1 t ] ) for their time representation , and for @xmath212 and @xmath213 we derive @xmath475 the flux penetrating the dot is denoted as @xmath394 and the phase @xmath476 gained in the arm depends on the flux @xmath395 through the hole . the traces read @xmath477}.\end{aligned}\ ] ] since we assumed that the area of the arm is small compared to that of the dot , the energy - dependence of eq . ( [ eq : tr ] ) can be neglected compared to that of @xmath478 in eq . ( [ eq : dcu ] ) . we also assumed that since the arm is much longer than the size of the dot , @xmath479 , the phases @xmath480 of open trajectories in the arm correspond to the flux @xmath481 through the hole . therefore , the effective number of channels @xmath288 , similar to eq . ( [ eq : channels ] ) for quantum dots is @xmath482 the energy - dependent cooperon and diffuson in energy representation are given by @xmath483 , x=\coop,\diff$ ] . notice that when @xmath291 the cooperon @xmath213 is nonperiodic in the total flux @xmath484 due to finite flux through the material of the sample , @xmath485 . c. a. marlow , r. p. taylor , m. fairbanks , i. shorubalko , and h. linke , phys . * 96 * , 116801 ( 2006 ) . r. leturcq , d. snchez , g. gtz , t. ihn , k. ensslin , d. c. driscoll , and a. c. gossard , phys . lett . * 96 * , 126801 ( 2006 ) . d. m. zumbhl , c. m. marcus , m. p. hanson , a. c. gossard , phys . lett . * 96 * , 206802 ( 2006 ) . a. v. andreev and l. i. glazman , phys . * 97 * , 266806 ( 2006 ) . b. braunecker , d. e. feldman , and f. li , phys . b * 76 * , 085119 ( 2007 ) . a. lfgren , c. a. marlow , t. e. humphrey , i. shorubalko , r. p. taylor , p. omling , r. newbury , p. e. lindelof , and h. linke , phys . b * 73 * , 235321 ( 2006 ) . a. a. bykov , z. d. kvon , l. v. litvin , yu . v. nastaushev , v. g. mansurov , v. p. migal , and s. p. moschenko , pisma zh . . fiz . * 58 * , 538 ( 1993 ) [ jetp lett . * 58 * , 543 ( 1993 ) ] ; a. a. bykov , l. v. litvin , n. t. moshegov , and a. i. toropov , superlattices microstruct . * 23 * , 1285 ( 1998 ) . m. g. vavilov , l. dicarlo , and c. m. marcus , phys . rev . b * 71 * , 241309(r ) ( 2005 ) showed that the interference between parasitic rectification and quantum pumping produces current asymmetric to @xmath486 even in noninteracting dot .

we investigate the nonlinear current - voltage characteristic of mesoscopic conductors and the current generated through rectification of an alternating external bias . to leading order in applied voltages both the nonlinear and the rectified current are quadratic . this current response can be described in terms of second order conductance coefficients and for a generic mesoscopic conductor they fluctuate randomly from sample to sample . due to coulomb interactions the symmetry of transport under magnetic field inversion is broken in a two - terminal setup . therefore , we consider both the symmetric and antisymmetric nonlinear conductances separately . we treat interactions self - consistently taking into account nearby gates . the nonlinear current is determined by different combinations of second order conductances depending on the way external voltages are varied away from an equilibrium reference point ( bias mode ) . we discuss the role of the bias mode and circuit asymmetry in recent experiments . in a photovoltaic experiment the alternating perturbations are rectified , and the fluctuations of the nonlinear conductance are shown to decrease with frequency . their asymptotical behavior strongly depends on the bias mode and in general the antisymmetric conductance is suppressed stronger then the symmetric conductance . we next investigate nonlinear transport and rectification in chaotic rings . to this extent we develop a model which combines a chaotic quantum dot and a ballistic arm to enclose an aharonov - bohm flux . in the linear two - probe conductance the phase of the aharonov - bohm oscillation is pinned while in nonlinear transport phase rigidity is lost . we discuss the shape of the mesoscopic distribution of the phase and determine the phase fluctuations .

not long ago only science fiction authors ventured to use a term `` teleportation '' . however in the last few years the situation drastically changed . in a landmark work @xcite a procedure for teleporting an unknown quantum state from one location to another was described . recent experiments have proved that this process can actually happen @xcite . now invention of qt is expected to have a great influence on the future computation and communication hardware comparable with the impact of radio network on modern technique . it may have important applications in superfast quantum computers ( theoretical at present ) @xcite-@xcite as well as in utilizing quantum phenomena to ensure a secure data transmission ( by means of so - called quantum cryptography ) @xcite-@xcite . practical realization of quantum information processing requires special quantum gates which can not be performed through unitary operations , but may be constructed with the use of quantum teleportation for a basis element @xcite . recently a one - to - one correspondence between quantum teleportation and dense coding schemes were established as well @xcite . besides a relevancy to such applications as quantum computing , qt is also a new fundamental concept in quantum physics . experimental demonstrations show that qt is an experimentally achievable technique to study the phenomenon of quantum entanglement . indeed , the very phenomenon of qt appeared to be possible only due to the einstein - podolsky - rosen correlations ( see below ) , which till now are confirmed exactly only for photons . the same is true for qt , because only entangled optical beams have been so far used to teleport quantum states of massless matter . since quantum information processing involves material particles such as atoms and ions , teleportation of heavy matter is considered now as the next necessary step for obtaining a complete set of quantum processing tools @xcite-@xcite . we propose here a new experimental scheme for qt of heavy matter based on a standard experimental nuclear physics technique and expected to be fulfilled in the nearest one or two years . to the best of our knowledge other methods require at least ten years to be successful . in 1935 albert einstein and his colleagues boris podolsky and nathan rosen ( epr ) developed a gedanken experiment to show as they believed a defect in quantum mechanics ( qm)@xcite . this experiment has got the name of epr - paradox . an essence of epr - paradox is as follows . there are two particles that have interacted with each other for some time and have constituted a single system . in the qm that system is described by a certain wave function . when the interaction is terminated and the particles fled far away from each other they are as yet described by the same wave function . however individual states of each separated particle are completely unknown . moreover , definite individual properties do not exist in principle as the qm postulates prescribe . it is only after * one * of the particles is registered by a detection instrument that the states arise to existence for * both * of them . furthermore , these states are generated simultaneously regardless of the distance between the particles at the moment . it looks like one particle informs instantly the other of its state . the real ( not just `` gedanken '' ) experiments on teleportation of information of this type , or `` a spooky - action - at - a - distance '' , as a. einstein called it , were carried out only 30 - 35 years later , in the seventies - eighties@xcite . experimenters , however , managed to achieve full and definite success only for photons , though attempts to perform experiments with atoms@xcite and protons were also undertaken@xcite . for the case of two photons the experiments were carried out for various distances between them at the moment of registration , and the epr - correlations were shown to survive up to as large distances as more than ten kilometers@xcite . in the case of protons , an experiment was carried out only for much less distances of about a few centimeters and the condition of causal separation , @xmath2 , was not met . thus it was not fully persuasive , as have been recognized by the authors of the work@xcite themselves . the next step in this direction that suggested itself was not merely the `` action - at - a - distance '' , but transmission of a quantum state from one quantum object to another . namely , this process was called qt . in spite of the successful epr - effect experiments it was until recently even this kind of teleportation was believed to be impossible at all . at first sight it seems as heisenberg uncertainty principle would forbid the very first step of the teleportation which was meant as an extraction of complete information about the inner properties of a quantum object to be teleported . but it can not be done because of an impossibility to measure simultaneously exact values for the so - called complementary variables of a quantum microscopic object ( e.g. spatial coordinates and momenta ) . nevertheless , in 1993 , a group of physicists ( c.bennet and his colleagues ) managed to get round this difficulty@xcite . they showed that measurement of full quantum information is not necessary for quantum states transferring from one object to another . instead , it was proposed to create that a so - called epr - channel of communication on the basis of epr - pair of two quantum particles . let it be photons b and c , shown in fig.1 . after they have interacted in a way to form a single system , decaying afterward , the photon b is directed to the `` point of departure '' , where it meets a within a registration system . the system is arranged in a mode ( see below ) to `` catch '' only those events which leave no choice to c but to take a state that a had initially ( before its interaction with b in the detector at the `` point of departure '' ) . this experimental technique is very fine but well known to those skilled in the epr - art . what is important from the principal point of view , it is `` disappearing '' of a in the place , notified in fig.1 as `` zone of scanning '' ( zs ) . indeed , interaction of b and a destroys the a photon , in a sense that none of the two photons outgoing from zs has definite properties of a. they constitute a new pair of photons , which only as a whole has some quantum state , and the individual components of the pair are deprived of this property . therefore , in some sense the photon a really disappears at zs . exactly at the same moment the photon c obtains the properties a had in the beginning . once it is happened , in view of the principle of identity of elementary particles , we can say that a , disappearing at zs , reappears at another location . thus , the quantum teleportation is accomplished . this process has several paradoxical features . in spite of the absence of contacts between objects ( particles , photons ) a and c , a manages to pass its properties to c. it may be arranged in such a way that the distance from a to c is large enough to prevent any causal signals between them ! furthermore , in contrast to the transportation of ordinary material cargo , when a delivery vehicle first visits the sender to collect a cargo from it , quantum properties are delivered in a backward fashion . here the photon b plays a role of the delivery vehicle , and one can see that b first interacts with the recipient ( c photon ) and only after that it travels to the sender ( a ) for the `` cargo '' . finally , to reconstruct initial object completely it is necessary to inform a receiver at the destination about a result of the measurement in zs . this allows him to accomplish processing of quantum signal ( incoming with the particle c ) in a due manner . therefore , one more channel of communication is needed for an ordinary or classical information transmission . only receiving a message ( using the classical communication line ) that a and b form a * new epr pair with zero total spin * , an observer at destination may be sure that the properties of c are identical to those of a before teleportation . in the case when a @xmath3 b system has non a zero total spin , some additional transformation of quantum signal is needed ( see below ) . the new idea was immediately recognized as an important one and several groups of experimenters set to implement it concurrently . nevertheless , it took more than four years to overcome all technological obstacles on the way@xcite . that was because such experiments , being the records , are always a step beyond the limits of experimental state of the art achieved before . the purpose of this paper is to show that experimental setups and instruments developed for conventional nuclear - physics studies allow one to design a new way of performing non - zero mass matter teleportation , with a prospect to implement the project in a rather short time . for example , in accordance with our estimates , teleportation of protons could be achieved in one or two years . is initial proton from the accelerator , lh@xmath4 is a liquid hydrogen target , which may be also replaced by ordinary polyethylene ( ch@xmath4 ) foils , protons p@xmath5 and p@xmath6 constitute an entangled epr - pair , ph@xmath4 denotes polarized hydrogen target , c is a carbon target which operates as an analyzer of the proton polarization using the left - right asymmetry of scattering , f-1 and f-2 are large - aperture position - sensitive particle detectors ( the so - called fobos - facilities ) . proton spin - state is being teleported from the ph@xmath4 target placed at x@xmath7 to the point x@xmath8 . k is a point where the spin of p@xmath5 gets a definite orientation ( which is just the same that one of the protons p@xmath8 in the ph@xmath4 target had before the scattering of p@xmath6 from it ) . the proton p@xmath8 losses its definite quantum state , as it forms a new epr - pair together with the scattered proton p@xmath6 . the role of classical communication channel including a data - processing center is explained in the text . ] in fig.2 , the layout of an experiment on teleportation of spin states of protons from a polarized ph@xmath4 target into the point of destination ( target c ) is shown . a proton beam p@xmath7 of a suitable energy within the range 20 - 50 mev bombards the lh@xmath4 hydrogen target @xcite . according to the known experimental data , the scattering in the lh@xmath4 target onto the direction of the second target ( corresponding the angle @xmath9 at the c.m . ) occurs within an acceptable accuracy through the singlet intermediary state @xcite . thus , the outgoing protons p@xmath4 and p@xmath10 form the two - proton entangled system fully analogous to the epr - correlated photons used in the experiments on the teleportation of massless matter , as it was discussed in the preceding section . at this moment the system is in a state latexmath:[\[|\psi_{23}\rangle=\frac{1}{\sqrt{2}}\left(|\uparrow_2\rangle|\downarrow_3\rangle- one of the scattered protons , p@xmath4 , then travels to the point of destination ( the target - analyzer c ) , while the other , p@xmath10 , arrives to a point where teleportation is started , i.e. , to ph@xmath4-target . the last one is used as a source of particles to be teleported . therefore , protons within this target play the same role asthe photons a in the above section . but there are two features differentiating the case of protons from the photon one . first , the protons p@xmath8 are within the motionless target ( and thus they are motionless themselves ) with a much more proton density ; besides , the protons within the ph@xmath4 target have quite definite quantum state , determined by a direction of polarization , @xmath12 which could be oriented accidentally and , thus , unknown to the experimenters . in the case , when the scattering in the polarized ph@xmath4 target occurs in the same kinematics conditions as in the lh@xmath4 target ( i.e. , at the c.m . angle @xmath9 ) , the total spin of the particles p@xmath8 and p@xmath10 also must be equal to zero after collision . to detect the events , a removable circular module f-1 of the facility `` fobos '' is supposed to be used @xcite . due to this fact , the detection efficiency is hoped to be much enhanced . if all the above conditions are provided , the protons reaching a point k will suddenly receive the same spin projections as the protons in the polarized @xcite ph@xmath4 target . indeed , using a so - called bell s basis , @xmath13 @xmath14 the state of three - particle system before the last scattering may be written in the form @xmath15 . \end{array}\ ] ] the last scattering and measurement with f-1 select from this state the term containing @xmath16 , and therefore the state of the particle 2 will be @xmath17 . thus , if the coincidence mode of the detection is provided via any classical channel , then a strong correlation has to take place between polarization direction in the ph@xmath4 target and the direction of the deflection of p@xmath4-protons scattered in the carbon target c. here the carbon foil c plays a role of the polarization analyzer , i.e. , one measures the asymmetry of the left - right counting rates to determine a spin state orientation of p@xmath4 before the scattering @xcite . in particular , if one succeeds to make a distance between the detectors f-1 and f-2 to be sufficiently large and the difference between the moments of registration in f-1 and f-2 to be short enough , then it will be possible to meet the important criteria of the causal independence between the events of the `` departure '' of the quantum state from ph@xmath4 target and `` arrival '' of this `` cargo '' to the recipient ( proton p@xmath4 ) at the point k. the measurements consist of recording signals entering two independent but strictly synchronized memory devices with the aim to select afterward those events alone that for sure appeared to be causal separated . thus , experimental setup shown in fig . 2 also allows one , at least in principle , to fill the gap in verification of the epr - effect for heavy matter . in the experiments that were carried out until now it was managed to use only one quantum information transmission channel corresponding to registration of bell s state @xmath16 . is it possible to involve other channels utilizing the states @xmath18 , @xmath19 and @xmath20 ? to answer this question let us consider a general expression for scattering amplitude of two particles , not necessarily identical ones , with the spin value @xmath0 @xcite , @xmath21 using a relation @xmath22 , \ ] ] in the case of the coordinate system to be fixed for a definiteness in the following way @xmath23 the expression for @xmath24 can be represented in the form @xmath25 + \frac{c}{2}\left[s^2_y-\frac12\right ] + \frac{d}{2}\left[s^2_z-\frac12\right]+es_z - fs_z,\ ] ] where @xmath26 the scattering operator @xmath24 can be now expressed in terms of the bell s state transition operators making use of the following formulas @xmath27 and a decomposition of the unity @xmath28 . as a result one obtains @xmath29 where @xmath30 c= a+ , d = a + . @xmath31 in the case @xmath32 expression ( 1 ) is a usual spectral decomposition for the operator @xmath33 , which can be interpreted then as a quantum observable corresponding to measurement of one of the bell s state . therefore , to register a definite bell s state one has to find such experimental conditions at which all coefficients but one of a , b , c , or d in the expression ( [ f ] ) turn into zero . for these purposes , the type and energy of colliding particles , as well as the angle which scattered particles are recorded at , could be altered . since the number of necessary conditions formulated above is less than the number of free coefficients in ( [ f ] ) , it is clear that registration of each bell s state is possible at least theoretically . directions which spin projections of the scattered particles should be measured along for detecting the states @xmath34 , @xmath35 and @xmath36 form three orthogonal spatial vectors . it follows from the relations @xmath37 where @xmath38 are orthonormalized states with the definite values of the spin and its projections , @xmath39 , corresponding to @xmath40 , represent the group of permutation for the bell s states considered ( putting aside an unimportant phase factor -1 ) . thus the possibility of registration of @xmath34 state also opens the way to register two other states @xmath36 , @xmath35 by means of change on @xmath41 of the direction along which the spin projection is measured . for identical spin 1/2 particles the scattering operator ( [ f ] ) has some additional symmetries , so that in c.m.s . one has @xmath42 @xmath43 @xmath44 for nucleon - nucleon scattering we have @xmath45 as total spin squared of such a system is conserved and the last two terms in ( [ f ] ) describe transitions between bell s state with different @xmath46 . thus , e.g. , for two identical nucleons at @xmath47 one obtains @xmath48 and @xmath34 is rather simple due to the characterization of these states by the definite values of total spin and its projections @xmath49 , @xmath50 , and @xmath51 , @xmath50 , respectively ) . the result of spin projection measurement for the particles 1 and 3 is @xmath52 for any choice of z axis direction , provided their initial state is @xmath53 . for particles in the @xmath34 state such correlations take place only if the spin projections are measured along a definite axis @xmath54 . if the axis of measuring is deflected at an angle @xmath55 from this direction the probability to have @xmath56 will decrease as @xmath57 . one may expect that at the energies considered , there is a scattering angle interval corresponding to @xmath58 and , therefore , to the @xmath34 final state of two protons . it seems more difficult to identify states @xmath35 and @xmath36 . in this case , it is necessary first to find out a direction @xmath59 ( which is perpendicular to @xmath54 ) for which measurements of spin projections give either @xmath60 and @xmath61 or @xmath62 and @xmath63 with the same probability @xmath64 . now measurement of the spin projection of the particle 2 allows one to determine what of two two possible states , @xmath19 or @xmath20 , the scattering has really occurred into . referring to the principle of identity of elementary particles of the same sort with the same quantum characteristics , i.e. , the protons in our case , we can say that protons from a polarized target ph@xmath4 are transmitted to the destination point c ( through the point k ) . thus , in the nearest future , teleportation of protons can come from the domain of dreams and fiction to the reality in physicists laboratories . algorithms for quantum computation : discrete logarithms and factoring . in : proc . , 35th annual symposium on foundations of computer science , santa fe , nm , 1994 , ieee computer society press , p.124 .

since its discovery in 1993 , quantum teleportation ( qt ) is a subject for intense theoretical and experimental efforts . experimental realizations of qt have so far been limited to teleportation of light . the present letter gives a new experimental scheme for qt of heavy matter . we show that the standard experimental technique used in nuclear physics may be successfully applied to teleportation of spin states of atomic nuclei . it was shown that there are no theoretical prohibitions upon a possibility of a complete bell measurement , so that implementation of all four quantum communication channels is at least theoretically available . a general expression for scattering amplitude of two @xmath0-spin particles was given in the bell operator basis , and peculiarities of bell states registration are briefly discussed . 3000 3000 40by -15pt # 1#2@xmath1#2

the recent development of quantum technologies strives to resolve the quest for the best entanglement source in quantum optical systems . though entanglement is observed in a variety of systems , entanglement in atomic systems are favored as more scalable and practical systems , compared to their `` photonic only '' counterparts due to the development of reliable state - of - the - art technologies to control the atoms one - at - a - time single atom which can be precisely scaled to many atoms @xcite . many exciting developments of entanglement sources are involved in atomic systems such as entanglement via atom - cavity coupling @xcite , atom - atom entanglement via cavity @xcite , entanglement in trapped ions / atoms @xcite , atomic entanglement in an optical lattice by controlled collision @xcite and also atomic entanglement via external fields @xcite . recently , it has also been shown that well separated atomic ensembles can also be entangled via coherent coupling between them nature ensemble entangle . scully has extensively discussed entanglement in two , three and many atoms via a single photon @xcite and has shown that such an ensemble can produce directional spontaneous emission @xcite . amongst the different atomic entanglement generation processes , an interesting and useful category is spontaneously generated entanglement ( sge ) sources via interaction of atoms with a common bath of cavity field @xcite , vacuum @xcite , heat bath @xcite or even a spin chain @xcite . usually , the baths have very short correlation time and hence potentially cause disentanglement @xcite and decoherence @xcite in an entangled system . agarwal and patnaik @xcite have shown that coherences in two multilevel atoms can be generated from their interaction with a common vacuum bath via the retarded dipole - dipole ( _ dd _ ) coupling when they are placed in the close proximity of each other . effect of such vacuum induced coherence ( vic ) on the collective resonance fluorescence is discussed in @xcite . sge is particularly interesting from the application point of view because : practical quantum devices are _ often unavoidably coupled _ to the environmental bath and hence sge can occur naturally . . ] most of the works listed above are focused on sge in two - level atoms . study of multilevel systems are important because in certain situations , participation of additional internal atomic levels in the process of generating entanglement or causing disentanglement is unavoidable . for example , when two atoms , having a triplet @xmath0-state as their excited anil or ground @xcite state , are placed in close proximity , i.e. , the interatomic distance is less than the wavelength of the atomic transitions involved , @xmath1 , even the dipoles involving the orthogonal @xmath2 transitions can radiatively couple to generate additional coherences . recently , keitel and coworkers @xcite have explicitly shown that the two - level approximation fails in such a situation . furthermore , multilevel systems can open up new channels in bath assisted sge in a vary natural way and even can give more control parameters @xcite . to the best of our knowledge , only a few studies addresses entanglement in three - level atoms interacting with a continuum via the radiative coupling @xcite . in this paper , we investigate the steady state sge between two _ radiatively coupled and incoherently pumped atoms _ having their energy levels in a v configuration with non - degenerate excited states ; see fig . we derive a master equation and trace over the field part to obtain the equations for the atomic dynamics . we obtain an analytical solution to show that multilevel systems are preferable compared to two - level systems for sge because they add additional coupling channels to enhance the entanglement . we demonstrate that the sge can be sustained to achieve a steady state entanglement by incoherently pumping the atoms . it may be noted that we are working outside the regime of vic . in our two - atom system vic could be generated if the excited states of both the atoms are degenerate or near degenerate @xcite . the organization of the paper is the following : in sec . ii we derive a master equation for the two atoms interacting with common vacuum . tracing over the vacuum bath parameters , we obtain the equations for the system dynamics . in sec . iii , we present the time evolution of the entanglement between the two atoms that occurs only for a short period of time . in sec . iv , we derive the atomic density matrix equations when atoms are incoherently pumped . we show that a steady state entanglement can be obtained between the two atoms purely via incoherent processes . we summarize and discuss our result in sec . v. we consider two identical three level @xmath3 systems ( say @xmath4 and @xmath5 ) in free space having two excited states @xmath6 and @xmath7 ( @xmath8 ) , and a ground state @xmath9 , as depicted in fig . 1 . both the atoms couple to the same vacuum field . while we do not wish to loose the generality of our results , our scheme can correspond to two @xmath10ca atoms in a magneto - optical trap ( mot ) in presence of a static magnetic field . the ground state can correspond to @xmath11 state and the excited states can correspond to the magnetic sublevels @xmath12 of _ ca _ atom . the static magnetic field would remove the degeneracy of the @xmath12 sublevels and the states @xmath13 levels . note that we restrict to the situation where the cross couplings between @xmath14 and @xmath15 transitions are eleminated by considering the non - degenerate excited states . thus the photon emitted from @xmath16 ( @xmath17 ( @xmath18 } \\ & + \sum_{k^{\prime } s^{\prime } } d_{\mu g}^{\alpha } \sigma _ { \mu g}^{\alpha } a_{k^{\prime } s^{\prime } } e^{i[\vec{k^{\prime } } \cdot \vec{x}_{\alpha } + ( \omega _ { 2}-\omega _ { k^{\prime } s^{\prime } } ) t]}+h.c.\big ) , \end{split } \label{eq1}\]]where , the vacuum rabi coupling coefficients corresponding to atom @xmath19 are @xmath20and @xmath21 is the dipole matrix element corresponding to the transition operator @xmath22 ( @xmath23 ) , @xmath24 is the unit polarization vector of the vacuum mode with frequency @xmath25 ( @xmath26 ) , @xmath27 ( @xmath28 ) is the photon annihilation operator corresponding to the vacuum field with wave vector @xmath29 and polarization @xmath30 , @xmath31 ( @xmath32 ) is the atomic frequency corresponding to @xmath33 ( @xmath34 ) transitions , and @xmath35 is the position of the atom @xmath19 . we use the zwanzig projection operator method @xcite to trace over the field degrees of freedom and obtain a reduced density matrix equation for the atoms . we use the born and markoff approximation to obtain a memoryless master equation . referring to ref . @xcite and without duplicating the lengthy calculation , we write the reduced density matrix equation for the atoms as @xmath36+(\mathcal{l}_{s}+\mathcal{l}_{dd})\rho , \label{mastereq}\]]where @xmath37is the part of the _ dd_-interaction that contributes to the level shift . the coupling coefficients are @xmath38here @xmath39 . further , the liouvillian operators @xmath40 are : @xmath41 \\ & + \gamma _ { 2}[(2\sigma _ { g\mu } ^{a}\rho \sigma _ { \mu g}^{a}-\sigma _ { \mu \mu } ^{a}\rho -\rho \sigma _ { \mu \mu } ^{a})+a\rightarrow b ] , \end{split}%\]]corresponding to spontaneous emission of the atoms , and @xmath42 \\ & + [ \gamma _ { 2}(2\sigma _ { g\mu } ^{b}\rho \sigma _ { \mu g}^{a}-\sigma _ { \mu g}^{a}\sigma _ { g\mu } ^{b}\rho -\rho \sigma _ { \mu g}^{a}\sigma _ { g\mu } ^{b})+h.c . ] , \end{split}%\]]corresponding to the _ dd _ coupling mediated by the vacuum . note that the subscript in @xmath43 is dropped for brevity . here the spontaneous decay rates are given as @xmath44and the atom - atom coupling coefficients are obtained as @xmath45further the index @xmath19 has been dropped as we consider that the atomic dipoles corresponding to the same atomic transitions are parallel to each other , i.e. , @xmath46 . clearly , the radiative coupling terms @xmath47 and @xmath48 have numerical significance only in the limit @xmath49 and @xmath50 . in the other limit , when the interatomic distance @xmath51 is too large , only the spontaneous emission terms survive and the atoms behave as two independent atoms . we refer to @xcite for the detail steps of the calculation . now let us assume that initially , the two - atom state is @xmath52 , where the notation @xmath53@xmath54@xmath55 @xmath56 @xmath57 @xmath58 and @xmath59 , and we number them @xmath60 through @xmath61 in the same order as above to simplify the notations for the density matrix elements @xmath62 corresponding to our initial state @xmath52 is represented as @xmath63 in the new notation . the full density matrix equation involves 81 matrix elements but for the above initial condition , many elements would be identically zero and only 10 density matrix elements survive . we consider the geometry where dipole matrix elements are orthogonal to each other and are real ( as discussed in sec . iii of @xcite ) , such that the parameters @xmath64 are real numbers seen eq . ( 26 ) in @xcite . in the following , we explicitely write the dynamics equations only for those surviving density matrix elements as@xmath65note that the conjugate matrix elements @xmath66 and @xmath67 ( conjugates of @xmath68 and @xmath69 , respectively ) also evolve . using the laplace transform method , we solve the above coupled equations for the density matrix elements with the initial condition @xmath70 to obtain their time evolution as @xmath71 , \notag \\ \rho _ { 37}(t ) & = & \frac{\gamma _ { 2}e^{-2\gamma _ { 1}t}}{2}\times \notag \\ & & \big[\frac{\gamma _ { 1}e^{-2\gamma _ { 2}t}-\gamma _ { 1}\cosh ( 2\gamma _ { 1}t)+\gamma _ { 2}\sinh ( 2\gamma _ { 1}t)}{\gamma _ { 1}^{2}-\gamma _ { 2}^{2 } } \notag \\ & & -\frac{ig_{1}\cos ( 2g_{1}t)-i\gamma _ { 2}\sin ( 2g_{1}t)-ig_{1}e^{-2\gamma _ { 2}t}}{g_{1}^{2}+\gamma _ { 2}^{2}}\big ] , \\ \rho _ { 66}(t ) & = & \frac{\gamma _ { 1}e^{-2\gamma _ { 2}t}}{2}\times \notag \\ & & \big[\frac{\gamma _ { 1}\cosh ( 2\gamma _ { 2}t)-\gamma _ { 2}\sinh ( 2\gamma _ { 2}t)-\gamma _ { 1}e^{-2\gamma _ { 1}t}}{\gamma _ { 1}^{2}-\gamma _ { 2}^{2 } } \notag \\ & & -\frac{\gamma _ { 1}\cos ( 2g_{2}t)+g_{2}\sin ( 2g_{2}t)-\gamma _ { 1}e^{-2\gamma _ { 1}t}}{\gamma _ { 1}^{2}+g_{2}^{2}}\big ] \notag \\ \rho _ { 68}(t ) & = & \rho _ { 37}^{\ast } ( t)\big|_{1\leftrightarrow 2},\rho _ { 77}(t)=\rho _ { 66}(t)\big|_{1\leftrightarrow 2 } , \notag \\ \rho _ { 88}(t ) & = & \rho _ { 33}(t)\big|_{1\leftrightarrow 2 } , \notag \\ \rho _ { 99}(t ) & = & 1-\rho _ { 33}(t)-\rho _ { 66}(t)-\rho _ { 77}(t)-\rho _ { 88}(t ) . \notag\end{aligned}\]]it may be noted that the initial state @xmath72 decays with a rate of the sum of the decays of both excited states but does not depend on the _ dd _ coupling terms @xmath47 and @xmath48 . however , the other population and cross terms strongly depend on the _ dd _ coupling . terms @xmath73 play the role of decays via the cosine and sine hyperbolic functions and the coefficients @xmath48 cause the _ dd _ coupling induced vacuum rabi oscillations . the time dependent solutions of the matrix elements show the oscillations with frequencies determined by the atom - atom coupling coefficients @xmath74 and @xmath75 . further , the _ dd _ terms are strongly dependent on the interatomic distance @xmath51 . hence the dynamics of the density matrix elements are also strongly affected by @xmath51 . we will present numerical plots and discussions for some of the important density matrix elements that help in evolving the sge in the following section . in this section , we calculate the time evolution of the entanglement between two - atoms . out of various different methods to calculate entanglement between the two atoms , we choose the negativity , defined by @xcite @xmath76as the measure of entanglement . here @xmath77 denotes the trace norm of @xmath78 @xcite ; @xmath78 is the partial transposition matrix of the atomic system density operator @xmath79 . the primed sum in the above equation represents the sum over only the negative eigenvalues @xmath80 of @xmath81 . for a high dimensional system , while a non - zero @xmath82 is a sufficient condition to prove that a system entangled , but a null @xmath82 does not necessarily qualify a system to become disentangled . from the definition , the negativity @xmath83 can also be greater than 1 . for different dimensions of the density matrix , the maximum value of @xmath83 is different . for a two - atom three - level system , such as ours , the state @xmath84 is maximally entangled one with the negativity @xmath85 . thus to obtain negativity in our two - atom system , we first calculate the eigenvalues of @xmath78 by using the density matrix @xmath79 . after a lengthy calculation , we obtain the exact eigenvalues as @xmath86 } , \\ \lambda _ { 9 } & = & \frac{\rho _ { 99}(t)}{2}-\frac{1}{2}\sqrt{\rho _ { 99}^{2}(t)+4[|\rho _ { 37}(t)|^{2}+|\rho _ { 68}(t)|^{2}]}. \notag\end{aligned}\]]it is clear that among all of the above eigenvalues , only @xmath87 can become negative . therefore , if we obtain a negative @xmath87 , it is sufficient to prove the occurence of the sge . clearly , @xmath87 can be negetive only if at least one of the matrix element @xmath88 or @xmath89 is non - zero , i.e. , if there is an exchange of at least one photon between two atoms . thus it is clearly established that radiative coupling leads to sge in the two - atom system . because both @xmath68 and @xmath90 contribute to the generation of entanglement . thus the three - level atoms offer us more channels to establish entanglement than two - level one . with different values of @xmath91 and @xmath92 . we set @xmath93,@xmath94 . the parameters ( @xmath95 , @xmath96 , and ( @xmath97 ) correspond to @xmath98 and @xmath99 that are represented in the figure as the solid , dashed and dotted line , respectively . ] before we proceed further , we first study the density matrix elements @xmath100 and @xmath101 that determine the entanglement . note that the two excited states are non - degenerate . assuming that @xmath102 , and say @xmath103 ; @xmath104 , @xmath105 , we have @xmath106 , @xmath107 and @xmath108 . for the numerical plots presented below , we use the parameters given in the table [ t1 ] determined from their definitions in eqs . ( [ gs ] , [ gam ] , gamma ) @xcite . note that as the interatomic distance reduces , @xmath109 oscillates @xcite . however , peak value of @xmath110 decreases with larger interatomic distances due to decreased dipole - dipole coupling between the two atoms . thus , @xmath47 ( @xmath48 ) can be same in two or more interatomic different distances . but any particular interatomic distance determines a particular value for the pair of @xmath111 . we will concentrate on the the photon exchange process with decreased trend of @xmath47 ( @xmath48 ) with the increasing interatomic separation . so , the parameters given in table is approximately monotonic . .the interatomic distance and the corresponding coupling parameters . all the frequency units are scaled with @xmath112 . [ cols="^,^,^,^,^",options="header " , ] in fig . 2 , we present the evolution of the density matrix element @xmath113 representing the single photon radiative coupling process , in which atom @xmath4 loses its excitation to excite atom @xmath5 from its ground state @xmath114 to the state @xmath115 . it is observed that , initially the process of exchange of photon increases . however , after reaching a maximum , re@xmath68 falls off quickly within one spontaneous emission cycle . the time needed to reach the maximum value for re@xmath68 is determined by @xmath116 . the maximum of im@xmath117 occurs at @xmath118 . in long time limit both real and imaginary part of @xmath68 vanish . similar conclusions can be derived for the matrix element @xmath69 which physically represents the simultaneous probability of two processes @xmath119 . corresponding to different pairs of ( @xmath120 @xmath121 . the curves and also corresponding legends are same as in fig.2 . ] in fig . 3 we present the evolution of the population in the state latexmath:[$% this plot also supports the physical process we described above . we can see that again large values of @xmath110 slows down @xmath101 to reach at its asymptotic value . in other words , the radiative coupling process survives longer . the steady state value is @xmath123 , i.e. , both the atoms reach their ground states in the long time limit . corresponding to different pairs of ( @xmath120 @xmath121 . all the parameters correspond to fig.2 , respectively . ] next , we discuss the property of the entanglement generated this atomic system . we present the plot of @xmath124 that describes the time evolution of the sge for different values of @xmath125 and @xmath126 in fig . it is shown that at @xmath127 , there is no entanglement because initially the atomic system is in the state @xmath52 . for @xmath128 the entanglement evolves to reach its maximum value , and then undergoes a process of disentanglement . finally , steady state of negativity becomes identically zero . but the relaxation time becomes longer when the atoms are nearer ( seen solid line in fig . 2a and fig . 4 ) . from the solution eq.(11 ) , we know that relaxation time of re ( @xmath129 is determined by @xmath130 which means larger the value of @xmath131 , longer the relaxation time for disentanglement . this is the competition between _ dd _ coupling and the all - direction spontaneous emission . the evolution of sge presented here can be understood as due to the following multiple radiative exchange processes : spontaneous emission of atom a via @xmath132 ( atom b via @xmath133 ) transition is followed by an absorption of the spontaneously emitted radiation by atom b via @xmath134 ( atom a via @xmath135 ) , as it is expressed by @xmath136 ( @xmath137 ) causing the two - atom entanglement . from the previous section , we have seen that the disadvantage of sge is the temporal evolution and the quickly diminishing of sge due to the decays in the system . however , for any useful application , for example , to use the two - atom system as a coupled qubit , sustaining the generated sge is essential . in order to achieve a steady state entanglement , we introduce an incoherent pump to continually repump population to the excited states . steady state entanglement using a classical coherent pumping is discussed in @xcite where the coherent pumping with single frequency drive the atoms . coherent field assisted entanglement is rather intutive . on the contrary , the usual notion associated with an incoherent pumping with a decoherence process and hence a source of disentanglement . however , in what follows below , we show that an appropriate strength of incoherent pump can lead to a steady entanglement between the two atoms . we consider a broadband incoherent pump acting on the two atoms which incoherently drive the population from @xmath138 to @xmath139 ( @xmath140 ) levels . incoherent pumping can be modeled as an inverse process of spontaneous emission @xcite . thus we add a third liouvillian @xmath141 to the the master equation eq.(4 ) to get @xmath36+(\mathcal{l}_{s}+\mathcal{l}_{dd}+% \mathcal{l}_{\mathrm{inc}})\rho , \label{incoh}\]]where @xmath142 \notag \\ & & + \lambda _ { 2}[(2\sigma _ { \mu g}^{a}\rho \sigma _ { g\mu } ^{a}-\sigma _ { \mu \mu } ^{a}\rho -\rho \sigma _ { \mu \mu } ^{a})+a\rightarrow b ] . \notag \\ & & \end{aligned}\]]where @xmath143 and @xmath144 denote incoherent pumping rates for @xmath145 transitions respectively . we explicitly write the density matrix equations involved in presence of the incoherent pump as @xmath146where @xmath147 ( @xmath148 ) . note that in presence of the incoherent pumping @xmath149 , the non - zero additional terms are the populations @xmath150 . hence we have a total of 13 non - vanishing density matrix elements in presence of @xmath149 . since we are looking for a steady state sge , we calculate the steady state values of the matrix elements by setting the differentials in the left - hand sides as zero and solving the coupled equations . the analytical solutions that we obtain are @xmath151with @xmath152 , \notag \\ a_{2 } & = & \lambda _ { 1}[\gamma _ { 2}+2\beta _ { 2}(\gamma _ { 1}+\gamma _ { 2 } ) ] , \notag \\ \beta _ { j } & = & \frac{s_{\alpha } \gamma _ { \alpha } ^{2}+\gamma _ { \alpha } ^{2}(\lambda _ { \alpha } -\gamma _ { \alpha } ) } { 2s_{\alpha } \gamma _ { \alpha } ( \lambda _ { 1}+\lambda _ { 2})},~j=1,2 , \notag \\ b & = & 2\gamma _ { 1}\gamma _ { 2}(\gamma _ { 1}+\gamma _ { 2})[(\beta _ { 1}+1)a_{2}+(\beta _ { 2}+1)a_{1 } ] \notag \\ & & + ( \gamma _ { 1}+\gamma _ { 2})(a_{2}\gamma _ { 2}\lambda _ { 1}+a_{1}\gamma _ { 1}\lambda _ { 2 } ) \notag \\ & & + \gamma _ { 1}\gamma _ { 2}(2a_{2}\lambda _ { 2}+2a_{1}\lambda _ { 1})\end{aligned}\]]it is interesting to note that the steady state of the density matrix elements do not depend on @xmath74 and @xmath75 . the level shift parameters @xmath153 and @xmath154 typically contribute to oscillation of population and coherence terms . hence , in the long time limit , such fast oscillation terms vanish . thus steady state solutions in eq . ( 17 ) are independent of @xmath74 and @xmath75 . once again , as in the previous section , we calculate the eigenvalues of @xmath155 to measure the entanglement . we obtain equation for the non - zero eigen values as @xmath156we obtain the numerical values of @xmath157 solving the above equation and substitute in eq . ( 12 ) to obtain the steady state negativity as a function of @xmath149 , as shown in fig . we have scaled the incoherent pumping rate @xmath149 with the spontaneous decay rate @xmath103 and also for simplicity we have assumed @xmath158 . clearly , a non - zero steady state entanglement is obtained by incoherently repumping the excited state . smaller the interatomic distance , larger is the steady state entanglement . further , as the incoherent pumping rate is increased , the sge increases but after reaching a certain optimal value at around @xmath159 , the atomic entanglement starts to reduce . for smaller the interatomic distances , even stronger incoherent pumping can be used to get entangled atoms . without any incoherent pumping the steady state sge is identically zero . physically , the increase in entanglement with the incoherent pumping can be understood as follows : the spontaneous emission in either of the two atoms followed by exchange of photon between them generates sge . but that does not survive longer because the spontaneously emitted photon can escape in any arbitrary direction . once both atoms loose their excitation , sge vanishes . an incoherent pump assists the atoms to bring back to the desirable excitation so that more spontaneous emissions and hence photon exchanges can take place between the two atoms . thus , increasing the repumping via incoherent pumping helps increasing the sge . however , incoherent repumping also competes with the photon exchange process to re - excite the atoms . while an excitation due to the photon - exchange process enhances the entanglement , an excitation by incoherent process has no direct contribution to the entanglement . in fact , for a larger @xmath160 , the incoherent excitation dominates the photon exchange process and hence causes a decrease in sge . for @xmath161 , sge becomes identically zero . where we set @xmath162 @xmath163 , @xmath94 , @xmath164 . from bottom to top , the values of @xmath165 and @xmath166 , corresponding to @xmath167 , @xmath168 and @xmath169 , respectively . ] we have investigated the spontaneously generated entanglement in a system of two three - level atoms are coupled to the common vacuum field . we have presented the time evolution of sge due to the photon exchange between the two atoms . we have shown that both the magnitude of entanglement and the survival period of sge are enhanced by reducing the interatomic distance . from our analytical calculations , we have shown the strong dependence of the sge on the radiative coupling parameters . we have explicitly demonstrated that the multilevel atoms are preferable compared to their two - level counterparts for sge , because each channel adds to enhance the magnitude of the entanglement . in the long time limit , however , sge vanishes . further , to reinforce the above short term evolution of sge in the radiatively - coupled two - atom system , we have proposed to use an incoherent pump that assists in repumping the deexcited atoms and sustain the sge . we have demonstrated that for a certain range of incoherent pumping , the steady state value of sge increases as it prevents atoms from loosing their excited state population . however , since incoherent pumping competes with the two - atom photon exchange process to reexcite the atoms , a stronger incoherent pumping is shown to be undesirable . we have shown that an appropriate rate of incoherent pump can help producing optimal sge . the above entanglement can further increase ( not discussed here ) if one considers atoms having degenerate or near degenerate excited states in their excited state that has additional coherences @xcite , which will be discussed elsewhere . the radiative coupling discussed above can be realized in any a tight ion trap . however , this work can be generalized to realizing sge in a chain of quantum dots or even in a typical dense multi - atom system . we believe this work will open up a new way to utilize the naturally occurring sge to realize an efficient entanglement source . this work was supported by nsfc under grant no.10774020 , and also supported by srf for rocs , sem . akp is indebted to prof . g. s. agarwal , dr . p. anisomov , and prof . m. o. scully for discussions on various aspects of the two - atom multilevel systems . s. haroche and j .- m . raimond , _ exploring the quantum _ , oxford univ . press , ny ( 2006 ) ; m. b. plenio and s. f. huelga , phys . rev . lett . * 88 * , 197901 ( 2002 ) ; m. karja , n. m. bornik , m. lffler , and h. walther , phys . rev . a * 60 * , 3229 ( 1999 ) . j. i. cirac and p. zoller , phys . a * 50 * , r2799 ( 1994 ) ; e. hagley , x. ma@xmath170tre , g. nogues , c. wunderlich , m. brune , j. m. raimond , and s. haroche , phys . lett . * 79 * , 1 ( 1997 ) ; m. b. plenio , s. f. huelga , a. beige and p. l. knight , phys . a * 59 * , 2468 ( 1999 ) ; a. beige , s.bose , d.braun , s. f. huelga , p. l. knight , m. b. plenio and v. vedral , j. of mod . opt . * 47 * , 2583 ( 2000 ) . duan , m. d. lukin , j. i. cirac , and p. zoller , nature ( london ) * 414 * , 513 ( 2001 ) ; c. w. chou , h. de riedmatten , d. felinto , s. v. polyakov , s. j. van enk , and h. j. kimble1 , nature ( london ) * 438 * , 828 ( 2005 ) .

we study spontaneously generated entanglement ( sge ) between two identical multilevel atoms in free space via vacuum - induced radiative coupling . we show that the sge in two - atom systems may initially increase with time but eventually vanishes in the time scale determined by the excited state lifetime and radiative coupling strength between the two atoms . we demonstrate that a steady - state sge can be established by incoherently pumping the excited states of the two - atom system . we have shown that an appropriate rate of incoherent pump can help producing optimal sge . the multilevel systems offer us more chanel to establish entanglement . the system under consideration could be realized in a tight trap or atoms / ions doped in a solid substrate .

the spectra of seyfert ( sey ) 2 galaxies detected in x - rays show absorption by neutral matter significantly in excess of the galactic one along the line of sight ( smith and done 1996 , turner et al . 1997a ) . on the contrary sey1s do not exhibit evidence for intrinsic absorption by cold material . this difference is interpreted as a further evidence in favour of the unification model , which states that the discriminating parameter between the two sey types is the observer s orientation with respect to an obscured molecular torus . it follows that the intrinsic spectra of sey1s and 2s should be the same once the effects of the torus absorbing material are properly accounted for . we have tested this expectation against a sample of 5 sey2s observed by bepposax during the ao1 : ngc2110 , ngc7172 , ngc4507 , mkn 3 and ngc7674 . in this contribution preliminary results are presented with emphasis on the role of the various spectral components . the 2 - 10 kev band is the one most effected by the torus material both in terms of absorption and reprocessing . in sources having n@xmath0 @xmath110@xmath2 @xmath3 , the matter is optically thin and the intrinsic emission should be visible above a given energy ( generally a few kev ) ; when n@xmath0 is around a few 10@xmath2 @xmath3 only x - rays in the 10 - 100 kev region can pass through the torus . beside absorbing the primary emission , the torus is also responsible for reflecting the continuum ( ghisellini et al . 1994 ) ; thus a bump in the 10 - 50 kev region similar to what observed in sey1 is expected . an iron line produced either via transmission through ( leahy and creighton 1993 ) and/or scattering- reflection ( ghisellini et al . 1994 ) by the absorbing material should also be observable : expected values of the iron line equivalent widths ( ew ) range from 100 ev up to @xmath4 1kev for high enough columns , i.e n@xmath0 @xmath5 10@xmath6 @xmath3 . for column densities in excess of 10@xmath7 @xmath3 , the absorbing matter is compton thick and the intrinsic continuum is not directly visible ; in this case only the ( unabsorbed ) emission reflected by the torus ( but also scattered in warm material above the nucleus ) should be detected by the observer and the iron line being measured against a depressed continuum is expected to have an ew @xmath5 1kev ( maiolino et al . moreover , a ( absorbed ) reflection component and associated iron fluorescence line due to an accretion disk ( as observed in sey1s , see perola et al . this proceeding ) should be present in all sey2s . however , at this stage of the analysis , this component has been neglected for the sake of simplicity and also in view of the fact that in sey2s it should be a second order effect because of the edge - on geometry and of the high n@xmath0 involved . table 1 lists for the observed sample of sey2s the spectral parameters deduced by fitting their broad band x - ray spectra with a baseline model which includes an absorbed power law , a reflection component due the torus and a narrow fe k gaussian line ; to account for the low energy data another power law having the photon index thight to the first one is also included in the fit . the uncertainties quoted correspond to 90@xmath8 confidence for two interesting parameters . one striking result of table 1 is the wide range of values observed for the parameter r , i.e the relative amount of reflection compared to the directly viewed primary power law . we range from sources having no or little reflection like ngc2110 and ngc4507 to objects reflection dominated like mkn 3 or even more ngc7674 . in this latter source the primary emission is totally absorbed and only radiation reprocessed by the torus is seen making the object a likely compton thick candidate ( see malaguti et al . 1998 for details ) . while broadly speaking the wide range in r is expected in the unified model , as both compton thin and thick sources are predicted , the observation of low reflection in some sources requires either that the torus is intrinsically optically thin or that it covers a small angle at the source . in this case , the small reflection observed maybe compatible with an origin in the accretion disk viewed edge - on ; at least for the case of ngc2110 this interpretation would be in agreement with the observation of a broad relativistic component in the iron line ( weaver @xmath9 reynolds 1998 ) . as expected , an iron line at 6.4 kev is clearly detected in each source and consistent with theoretical expectations . in compton thin cases , the line is compatible with transmission in the torus ( ngc2110 and ngc4507 ) possibly coupled with a reflection line component ( ngc7172 ) . in mkn 3 , the absorption is high enough to depress the continuum significantly leading to a line with ew @xmath4 1 kev which is the result of both transmission and reflection in the torus ( cappi et al . 1998 ) . in ngc7674 , as the source is compton thick , the line is simply the result of reflection in the torus ( malaguti et al . 1998 ) . * table 1 : seyfert 2 galaxies in the sample * + [ cols="<,^,^,^,^,^,^",options="header " , ] + @xmath10 in units of 10@xmath11 @xmath3 , @xmath12 in units of ev , @xmath13 observed flux in units of 10@xmath14 erg cm @xmath15 s@xmath16 + @xmath17 preliminary results to take with care . + in all our sources , the values of the intrinsic power law photon index are similar and well constrained in the range 1.7 - 2.0 ; therefore the primary component of the emission bears no differences from what observed in sey1s ( see perola et al . this proceedings ) . this is also true for those sources previously reported as flat , i.e ngc2110 and ngc7172 ( smith and done 1996 and guainazzi et al . 1998 ) highlighting the crucial role of the pds in estimating the primary power law component . to put a more stringent constrain on the intrinsic slope , a mean sey2 spectrum has been obtained by summing all data in the 20 - 100 kev range . note that the absorption affecting mkn 3 is negligible above 20 kev thus allowing this source to be added too ; viceversa ngc7674 has not been considered for its different spectral shape in the pds range.the resulting spectrum is shown in figure 1 ; a simple power law fit to the data gives a photon index of 1.81 @xmath18 0.05 . we have also tested individual source spectra for a high energy cut - off . in the case of sey2s this is not straightforward due to the complexity involved in the spectral fitting . nevertheless , our data suggest that also in type 2 objects the typical cut - off energy is above 100 kev as observed in sey1s ( perola et al . this proceedings ) ; for example in mkn 3 the lower limit on the cutoff energy is 150 kev at @xmath19 99% confidence ( cappi et al . preliminary bepposax results on a small sample of bright sey2 galaxies , while confirming the basic expectations of the unified theory , i.e. a primary shape similar to sey1s but distorted by absorption and reprocessing in the torus cold material , also highlights the need for a better understanding of the role of the torus in these sources . hopefully this will be possible by enlarging the sample with data from more sources covering a broader range of the space parameters

we report broad band ( 0.1 - 200 kev ) x - ray observations , made by bepposax , of a sample of bright seyfert 2 galaxies : ngc7172 , ngc2110 , ngc4507 , mkn 3 and ngc7674 . these spectra provide a better understanding of the effects of x - ray reprocessing by cold material in the source and allow to put tighter constraints on the various spectral parameters involved . in particular , the data are used to determine , with less ambiguities than in the past , the shape of the intrinsic continuum emission by means of the high energy data . within the small sample both compton thin and compton thick sources are found according to the expectations of the unified theory . # 1 # 2 _ mem . soc . astron . it . _ * # 1 * , # 2 # 1 # 2 _ the messenger _ * # 1 * , # 2 # 1 # 2 _ astron . nach . _ * # 1 * , # 2 # 1 # 2 _ astron . astrophys . _ * # 1 * , # 2 # 1 # 2 _ astron . astrophys . lett . _ * # 1 * , l#2 # 1 # 2 _ astron . astrophys . rev . _ * # 1 * , # 2 # 1 # 2 _ astron . astrophys . suppl . ser . _ * # 1 * , # 2 # 1 # 2 _ astron . j. _ * # 1 * , # 2 # 1 # 2 _ ann . rev . astron . astrophys . _ * # 1 * , # 2 # 1 # 2 _ astrophys . j. _ * # 1 * , # 2 # 1 # 2 _ astrophys . j. lett . _ * # 1 * , l#2 # 1 # 2 _ astrophys . j. suppl . _ * # 1 * , # 2 # 1 # 2 _ astrophys . space sci . _ * # 1 * , # 2 # 1 # 2 _ adv . space res . _ * # 1 * , # 2 # 1 # 2 _ bull . astron . inst . czechosl . _ * # 1 * , # 2 # 1 # 2 _ j. quant . spectrosc . . transfer _ * # 1 * , # 2 # 1 # 2 _ mon . not . r. astr . soc . _ * # 1 * , # 2 # 1 # 2 _ mem . r. astr . soc . _ * # 1 * , # 2 # 1 # 2 _ phys . lett . rev . _ * # 1 * , # 2 # 1 # 2 _ publ . astron . soc . japan _ * # 1 * , # 2 # 1 # 2 _ publ . astr . soc . pacific _ * # 1 * , # 2 # 1 # 2 _ nature _ * # 1 * , # 2

SECTION 1. CENTERS OF EXCELLENCE FOR RURAL HEALTH RESEARCH, EDUCATION, AND CLINICAL ACTIVITIES. (a) In General.--Subchapter II of chapter 73 of title 38, United States Code, is amended by adding at the end the following new section: ``Sec. 7330B. Centers of excellence for rural health research, education, and clinical activities ``(a) Establishment of Centers.--The Secretary, through the Director of the Office of Rural Health, shall establish and operate not less than one and not more than five centers of excellence for rural health research, education, and clinical activities, which shall-- ``(1) conduct research on the provision of health services in rural areas; ``(2) develop specific models to be used by the Department in furnishing health services to veterans in rural areas; ``(3) provide education and training for health care professionals of the Department on the furnishing of health services to veterans in rural areas; and ``(4) develop and implement innovative clinical activities and systems of care for the Department for the furnishing of health services to veterans in rural areas. ``(b) Geographic Dispersion.--The Secretary shall ensure that the centers established under this section are located at health care facilities that are geographically dispersed throughout the United States. ``(c) Selection Criteria.--The Secretary may not designate a health care facility as a location for a center under this section unless-- ``(1) the peer review panel established under subsection (d) determines that the proposal submitted by such facility meets the highest competitive standards of scientific and clinical merit; and ``(2) the Secretary determines that such facility has, or may reasonably be anticipated to develop, the following: ``(A) An arrangement with an accredited medical school to provide residents with education and training in health services for veterans in rural areas. ``(B) The ability to attract the participation of scientists who are capable of ingenuity and creativity in health care research efforts. ``(C) A policymaking advisory committee, composed of appropriate health care and research representatives of the facility and of the affiliated school or schools, to advise the directors of such facility and such center on policy matters pertaining to the activities of such center during the period of the operation of such center. ``(D) The capability to conduct effectively evaluations of the activities of such center. ``(d) Panel To Evaluate Proposals.--(1) The Director of the Office of Rural Health shall establish a panel-- ``(A) to evaluate the scientific and clinical merit of proposals submitted to establish centers under this section; and ``(B) to provide advice to the Director regarding the implementation of this section. ``(2) The panel shall review each proposal received from the Secretary and shall submit its views on the relative scientific and clinical merit of each such proposal to the Secretary. ``(3) The panel established under paragraph (1) shall be comprised of experts in the fields of public health research, education, and clinical care. ``(4) Members of the panel shall serve as consultants to the Department for a period not to exceed two years. ``(5) The panel shall not be subject to the Federal Advisory Committee Act (5 U.S.C. App.). ``(e) Reports.--Not later than April 1 of each year, the Secretary shall submit to Congress a report on the centers established under this section. Such report shall include-- ``(1) the results of research conducted under subsection (a)(1); ``(2) an evaluation of models related to furnishing health services to veterans in rural areas developed under subsection (a)(2); ``(3) an evaluation of the education and training provided under subsection (a)(3); and ``(4) an evaluation of clinical activities or systems of care related to furnishing health services to veterans in rural areas developed under subsection (a)(4). ``(f) Funding.--(1) There are authorized to be appropriated to the Medical Care Account and the Medical and Prosthetics Research Account of the Department of Veterans Affairs such sums as may be necessary for the support of the research and education activities of the centers operated under this section. ``(2) There shall be allocated to the centers operated under this section, from amounts authorized to be appropriated to the Medical Care Account and the Medical and Prosthetics Research Account by paragraph (1), such amounts as the Under Secretary of health considers appropriate for such centers. Such amounts shall be allocated through the Director of the Office of Rural Health. ``(3) Activities of clinical and scientific investigation at each center operated under this section-- ``(A) shall be eligible to compete for the award of funding from funds appropriated for the Medical and Prosthetics Research Account; and ``(B) shall receive priority in the award of funding from such account to the extent that funds are awarded to projects for research in the care of rural veterans.''. (b) Clerical Amendment.--The table of sections at the beginning of chapter 73 of such title is amended by inserting after the item relating to section 7330A the following new item: ``7330B. Centers of excellence for rural health research, education, and clinical activities.''.

Directs the Secretary of Veterans Affairs (VA) to establish and operate at least one, and up to five, centers of excellence for rural health research, education, and clinical activities. Requires the submission of annual reports on those centers.

twenty - four obese adolescents with ngt , 13 with ifg , 29 with igt , 11 with combined ifg / igt , and 30 with type 2 diabetes ( african american n = 45 and american white n = 62 ) adolescents were studied . ifg was defined according to the 2003 american diabetes association ( ada ) guidelines as fasting plasma glucose ( fpg ) of 100125 mg / dl ( 13 ) , based on the average of two fasting glucose measurements at the time of the ogtt ( at 15 and 0 min ) or the average of seven fasting glucose measurements obtained during the two clamp procedures ( three samples every 15 min at the baseline of the hyperglycemic clamp and four samples every 10 min at the baseline of the euglycemic clamp ) and ngt with 2-h post - ogtt glucose of < 140 mg / dl . igt was defined as normal fpg < 100 mg / dl and 2-h post - ogtt glucose of 140199 mg / dl according to ada criteria ( 13 ) . those with combined ifg / igt had fpg 100125 mg / dl and 2-h glucose between 140 and 199 mg / dl ( 13 ) . all subjects were pubertal and had exogenous obesity with no clinical evidence of endocrinopathy associated with obesity . type 2 diabetes in the adolescents was clinically diagnosed according to ada and world health organization criteria ( 14 ) . they were being treated with lifestyle alone ( n = 7 ) , metformin ( n = 11 ) , metformin + insulin ( n = 10 ) , or insulin alone ( n = 2 ) . all other participants were not taking any medications that affect glucose metabolism . in type 2 diabetic subjects , metformin and long - acting insulin were discontinued 48 h before the clamp studies . some of the participants ( 12 with ngt , 19 with igt , and 17 with type 2 diabetes ) have been reported before ( 12 ) . phenotypic and metabolic characteristics of obese adolescents with ngt , ifg , igt , ifg / igt , and type 2 diabetes data are means sd or medians ( 25th percentile75th percentile ) . body composition data was missing for 2 subjects with ngt , 2 with igt , and 5 with type 2 diabetes who exceeded the weight limit of 250 pounds of the dual - energy x - ray absorptiometry machine . * p value from anova for continuous variables with means presented and kruskal - wallis test with medians presented . superscript letters are significant post hoc analysis ( bonferroni correction , p < 0.05 ) : type 2 diabetes vs. ngt ; type 2 diabetes vs. ifg ; type 2 diabetes vs. igt ; type 2 diabetes vs. ifg / igt . participants were admitted twice within a 1- to 3-week period to the pediatric clinical and translational research center on the day before the clamp studies , once for a hyperinsulinemic - euglycemic clamp and the other time for a hyperglycemic clamp in random order . the 2-h ogtt ( 1.75 g / kg glucola [ maximum 75 g ] ) was performed on the day before the first pediatric clinical and translational research center admission . a fasting blood sample was obtained for determination of cholesterol , ldl , hdl , vldl , triglycerides , a1c , proinsulin , and c - peptide . fasting endogenous glucose production was measured with a primed constant rate infusion of [ 6,6-h2 ] glucose ( 0.306 0.009 mol / kg / min ; isotech , miamisburg , oh ) ( 12 ) . insulin - mediated glucose metabolism ( rd ) and insulin sensitivity were evaluated during a 3-h hyperinsulinemic - euglycemic clamp ( 12 ) . continuous indirect calorimetry by a ventilated hood ( deltatrac metabolic monitor , sensormedics , anaheim , ca ) was used to measure co2 production , o2 consumption , and respiratory quotient . measurements were made for 30 min at baseline and at the end of the euglycemic clamp ( 12 ) . first- and second - phase insulin and c - peptide secretion were evaluated during a 2-h hyperglycemic clamp ( 12.5 mmol / l ) as before ( 12 ) . body composition was determined by dual - energy x - ray absorptiometry and subcutaneous abdominal adipose tissue and visceral adipose tissue by a single - slice computed tomography scan at l4l5 ( 12 ) . plasma glucose was measured with a glucose analyzer ( ysi , yellow springs , oh ) ; insulin and c - peptide were measured by radioimmunoassay as before ( 12 ) . a1c was measured by high - performance liquid chromatography ( tosoh medics ) , and lipids were measured using the standards of the centers for disease control and prevention ( 12 ) . deuterium enrichment of glucose in the plasma was determined on a hewlett - packard ( palo alto , ca ) 5973 mass spectrometer coupled to a 6890 gas chromatograph ( 12 ) . pancreatic autoantibodies were determined in the northwest lipid metabolism and diabetes research laboratories , university of washington ( seattle , wa ) using the national institute of diabetes and digestive and kidney diseases sponsored standardization assay . fasting hepatic glucose production ( hgp ) was calculated during the last 30 min of the 2-h isotope infusion according to steady - state tracer dilution equations ( 12 ) . in the fasting state , an index of hepatic insulin resistance was calculated as the product of hgp and fasting insulin levels ( 14 ) . insulin - stimulated glucose disposal rate ( rd ) was calculated during the last 30 min of the euglycemic clamp to be equal to the rate of exogenous glucose infusion and expressed per fat free mass ( ffm ) ( milligrams per minute per kilogram ffm ) . peripheral insulin sensitivity was calculated by dividing the rd by the steady - state clamp insulin level and expressed per ffm ( milligrams per minute per ffm per microunits per milliliter ) ( 12 ) . insulin - stimulated carbohydrate oxidation rates were calculated according to the formulas of frayn ( 12 ) . during the hyperglycemic clamp , the first- and second - phase insulin and c - peptide concentrations were calculated as described previously ( 12 ) . the gdi was calculated as the product of insulin sensitivity first - phase insulin and expressed as milligrams per minute per kilogram ffm . statistical analyses were performed using anova followed by a post hoc bonferroni correction for five group comparisons . a kruskal - wallis test was used for multiple group comparison of nonparametric variables and a test to evaluate categorical variables . spearman 's correlation and multiple regression analyses were used to evaluate bivariate and multivariate relationships , respectively . participants were admitted twice within a 1- to 3-week period to the pediatric clinical and translational research center on the day before the clamp studies , once for a hyperinsulinemic - euglycemic clamp and the other time for a hyperglycemic clamp in random order . the 2-h ogtt ( 1.75 g / kg glucola [ maximum 75 g ] ) was performed on the day before the first pediatric clinical and translational research center admission . a fasting blood sample was obtained for determination of cholesterol , ldl , hdl , vldl , triglycerides , a1c , proinsulin , and c - peptide . fasting endogenous glucose production was measured with a primed constant rate infusion of [ 6,6-h2 ] glucose ( 0.306 0.009 mol / kg / min ; isotech , miamisburg , oh ) ( 12 ) . insulin - mediated glucose metabolism ( rd ) and insulin sensitivity were evaluated during a 3-h hyperinsulinemic - euglycemic clamp ( 12 ) . continuous indirect calorimetry by a ventilated hood ( deltatrac metabolic monitor , sensormedics , anaheim , ca ) was used to measure co2 production , o2 consumption , and respiratory quotient . measurements were made for 30 min at baseline and at the end of the euglycemic clamp ( 12 ) . first- and second - phase insulin and c - peptide secretion were evaluated during a 2-h hyperglycemic clamp ( 12.5 mmol / l ) as before ( 12 ) . body composition was determined by dual - energy x - ray absorptiometry and subcutaneous abdominal adipose tissue and visceral adipose tissue by a single - slice computed tomography scan at l4l5 ( 12 ) . plasma glucose was measured with a glucose analyzer ( ysi , yellow springs , oh ) ; insulin and c - peptide were measured by radioimmunoassay as before ( 12 ) . a1c was measured by high - performance liquid chromatography ( tosoh medics ) , and lipids were measured using the standards of the centers for disease control and prevention ( 12 ) . deuterium enrichment of glucose in the plasma was determined on a hewlett - packard ( palo alto , ca ) 5973 mass spectrometer coupled to a 6890 gas chromatograph ( 12 ) . pancreatic autoantibodies were determined in the northwest lipid metabolism and diabetes research laboratories , university of washington ( seattle , wa ) using the national institute of diabetes and digestive and kidney diseases sponsored standardization assay . fasting hepatic glucose production ( hgp ) was calculated during the last 30 min of the 2-h isotope infusion according to steady - state tracer dilution equations ( 12 ) . in the fasting state , an index of hepatic insulin resistance was calculated as the product of hgp and fasting insulin levels ( 14 ) . insulin - stimulated glucose disposal rate ( rd ) was calculated during the last 30 min of the euglycemic clamp to be equal to the rate of exogenous glucose infusion and expressed per fat free mass ( ffm ) ( milligrams per minute per kilogram ffm ) . peripheral insulin sensitivity was calculated by dividing the rd by the steady - state clamp insulin level and expressed per ffm ( milligrams per minute per ffm per microunits per milliliter ) ( 12 ) . insulin - stimulated carbohydrate oxidation rates were calculated according to the formulas of frayn ( 12 ) . during the hyperglycemic clamp , the first- and second - phase insulin and c - peptide concentrations were calculated as described previously ( 12 ) . the gdi was calculated as the product of insulin sensitivity first - phase insulin and expressed as milligrams per minute per kilogram ffm . statistical analyses were performed using anova followed by a post hoc bonferroni correction for five group comparisons . a kruskal - wallis test was used for multiple group comparison of nonparametric variables and a test to evaluate categorical variables . spearman 's correlation and multiple regression analyses were used to evaluate bivariate and multivariate relationships , respectively . table 1 depicts characteristics of the five groups of obese adolescents with ngt , ifg , igt , combined ifg / igt , and type 2 diabetes . there were no significant differences in age , sex , tanner stage , or ethnic distribution among the five groups . there were no significant differences in bmi , percent body fat , or abdominal visceral or subcutaneous fat among the five groups . fasting glucose was different among the groups as expected on the basis of predefined categorization . fasting endogenous glucose production ( hgp ) was significantly higher in the type 2 diabetic group compared with the ngt group ( post hoc p = 0.004 ) with no difference among the pre - diabetic groups . postabsorptive hepatic insulin resistance tended to be higher in the type 2 diabetic group versus the ngt group ( post hoc p = 0.07 ) with no difference among the other pre - diabetic groups . the proinsulin - to - insulin ratio was higher in the type 2 diabetic group but not significantly higher in the pre - diabetic groups compared with the ngt group . total , oxidative , and nonoxidative glucose disposal were lower in the type 2 diabetic group compared with the ngt group . oxidative glucose disposal was lower in the type 2 diabetic group compared with the ngt ( p = 0.016 ) , ifg ( p = 0.003 ) , and igt ( p = 0.023 ) groups in post hoc analysis but was not different from that in the ifg / igt group ( fig . first - phase insulin levels were significantly lower in the ifg ( post hoc p = 0.02 ) , igt ( p = 0.009 ) , and ifg / igt ( p = 0.011 ) groups and lowest in the type 2 diabetic group ( p < 0.001 ) compared with the ngt group ( fig . similarly , first - phase c - peptide levels were lowest in the type 2 diabetic group and significantly different between the type 2 diabetic and ngt groups ( p < 0.001 ) . 1b ) levels were significantly reduced in the type 2 diabetic group compared with the ngt ( p < 0.001 ) and igt ( p = 0.001 ) but not the ifg ( p = 0.3 ) or ifg / igt groups . gdi , which represents insulin secretion relative to insulin sensitivity , was significantly impaired in all categories of pre - diabetes , was lowest in type 2 diabetes , and was significantly different from ifg and igt but not ifg / igt ( fig . youth with type 2 diabetes receiving different treatment modalities did not differ with respect to their peripheral glucose disposal , insulin secretion , or gdi ( data not shown ) . a : insulin - stimulated total , oxidative , and nonoxidative glucose disposal in subjects with ngt ( open bars ) , ifg ( dotted bars ) , igt ( striped bar ) , ifg / igt ( diamond bars ) , and type 2 diabetes ( t2 dm ) ( filled bars ) . b : first- and second - phase insulin levels during the hyperglycemic clamp in ngt ( ) , ifg ( ) , igt ( ) , ifg / igt ( * ) , and type 2 diabetes ( ) . c : gdi in subjects with ngt ( open bar ) , ifg ( dotted bar ) , igt ( striped bar ) , ifg / igt ( diamond bar ) , and type 2 diabetes ( filled bar ) . in a and c , letters are significant post hoc analysis ( bonferroni correction ) : p < 0.05 ( a , type 2 diabetes versus ngt ; b , type 2 diabetes versus ifg ; c , type 2 diabetes versus igt ; e , ngt versus ifg / igt ; f , ngt versus igt ) . fasting glucose correlated with hepatic insulin resistance ( r = 0.30 , p = 0.004 ) , with first - phase ( r = 0.58 , p < 0.001 ) and second - phase ( r = 0.47 , p < 0.001 ) insulin , and with gdi ( r = 0.57 , p < 0.001 ) but not with peripheral insulin sensitivity . similarly , 2-h ogtt glucose correlated with first - phase ( r = 0.48 , p < 0.001 ) and second - phase ( r = 0.40 , p < 0.001 ) insulin and with gdi ( r = 0.63 , p < 0.001 ) but not with insulin sensitivity . in a multiple regression analysis with age , sex , ethnicity , bmi , hepatic insulin resistance , and gdi as independent variables and 2-h ogtt glucose or fasting glucose as the dependent variable , gdi was the significant determinant of the variance in the 2-h glucose ( = 0.47 , p < 0.001 ) and the fasting glucose ( = 0.32 , p = 0.009 ) . with visceral adipose tissue or fat mass instead of bmi in the regression model , gdi remains the significant determinant of the variance in mean fasting glucose ( = 0.4 , p < 0.001 ) and in 2-h glucose ( = 0.5 , p < 0.001 ) . the relationship between gdi and 2-h ogtt glucose or fasting glucose is depicted in fig . 2 . relationship of gdi to fpg ( a ) and 2-h ogtt glucose level ( b ) in ngt ( ) , ifg ( ) , igt ( ) , ifg / igt ( ) , and type 2 diabetes ( ) . table 1 depicts characteristics of the five groups of obese adolescents with ngt , ifg , igt , combined ifg / igt , and type 2 diabetes . there were no significant differences in age , sex , tanner stage , or ethnic distribution among the five groups . there were no significant differences in bmi , percent body fat , or abdominal visceral or subcutaneous fat among the five groups . fasting glucose was different among the groups as expected on the basis of predefined categorization . fasting endogenous glucose production ( hgp ) was significantly higher in the type 2 diabetic group compared with the ngt group ( post hoc p = 0.004 ) with no difference among the pre - diabetic groups . postabsorptive hepatic insulin resistance tended to be higher in the type 2 diabetic group versus the ngt group ( post hoc p = 0.07 ) with no difference among the other pre - diabetic groups . the proinsulin - to - insulin ratio was higher in the type 2 diabetic group but not significantly higher in the pre - diabetic groups compared with the ngt group . total , oxidative , and nonoxidative glucose disposal were lower in the type 2 diabetic group compared with the ngt group . oxidative glucose disposal was lower in the type 2 diabetic group compared with the ngt ( p = 0.016 ) , ifg ( p = 0.003 ) , and igt ( p = 0.023 ) groups in post hoc analysis but was not different from that in the ifg / igt group ( fig . first - phase insulin levels were significantly lower in the ifg ( post hoc p = 0.02 ) , igt ( p = 0.009 ) , and ifg / igt ( p = 0.011 ) groups and lowest in the type 2 diabetic group ( p < 0.001 ) compared with the ngt group ( fig . 1b ) . similarly , first - phase c - peptide levels were lowest in the type 2 diabetic group and significantly different between the type 2 diabetic and ngt groups ( p < 0.001 ) . 1b ) levels were significantly reduced in the type 2 diabetic group compared with the ngt ( p < 0.001 ) and igt ( p = 0.001 ) but not the ifg ( p = 0.3 ) or ifg / igt groups . gdi , which represents insulin secretion relative to insulin sensitivity , was significantly impaired in all categories of pre - diabetes , was lowest in type 2 diabetes , and was significantly different from ifg and igt but not ifg / igt ( fig . youth with type 2 diabetes receiving different treatment modalities did not differ with respect to their peripheral glucose disposal , insulin secretion , or gdi ( data not shown ) . a : insulin - stimulated total , oxidative , and nonoxidative glucose disposal in subjects with ngt ( open bars ) , ifg ( dotted bars ) , igt ( striped bar ) , ifg / igt ( diamond bars ) , and type 2 diabetes ( t2 dm ) ( filled bars ) . b : first- and second - phase insulin levels during the hyperglycemic clamp in ngt ( ) , ifg ( ) , igt ( ) , ifg / igt ( * ) , and type 2 diabetes ( ) . c : gdi in subjects with ngt ( open bar ) , ifg ( dotted bar ) , igt ( striped bar ) , ifg / igt ( diamond bar ) , and type 2 diabetes ( filled bar ) . in a and c , letters are significant post hoc analysis ( bonferroni correction ) : p < 0.05 ( a , type 2 diabetes versus ngt ; b , type 2 diabetes versus ifg ; c , type 2 diabetes versus igt ; e , ngt versus ifg / igt ; f , ngt versus igt ) . fasting glucose correlated with hepatic insulin resistance ( r = 0.30 , p = 0.004 ) , with first - phase ( r = 0.58 , p < 0.001 ) and second - phase ( r = 0.47 , p < 0.001 ) insulin , and with gdi ( r = 0.57 , p < 0.001 ) but not with peripheral insulin sensitivity . similarly , 2-h ogtt glucose correlated with first - phase ( r = 0.48 , p < 0.001 ) and second - phase ( r = 0.40 , p < 0.001 ) insulin and with gdi ( r = 0.63 , p < 0.001 ) but not with insulin sensitivity . in a multiple regression analysis with age , sex , ethnicity , bmi , hepatic insulin resistance , and gdi as independent variables and 2-h ogtt glucose or fasting glucose as the dependent variable , gdi was the significant determinant of the variance in the 2-h glucose ( = 0.47 , p < 0.001 ) and the fasting glucose ( = 0.32 , p = 0.009 ) . with visceral adipose tissue or fat mass instead of bmi in the regression model , gdi remains the significant determinant of the variance in mean fasting glucose ( = 0.4 , p < 0.001 ) and in 2-h glucose ( = 0.5 , p < 0.001 ) . the relationship between gdi and 2-h ogtt glucose or fasting glucose is depicted in fig . 2 . relationship of gdi to fpg ( a ) and 2-h ogtt glucose level ( b ) in ngt ( ) , ifg ( ) , igt ( ) , ifg / igt ( ) , and type 2 diabetes ( ) . in this study , we hypothesized that for similar degrees of adiposity insulin sensitivity will not differ among the different pre - diabetic groups compared with youth with ngt but will be lower in youth with type 2 diabetes , whereas insulin secretion will be impaired in all categories of glucose dysregulation . consistent with our hypothesis , the current findings demonstrate that all pre - diabetes states in obese youth of similar bmi , percent body fat , and abdominal adiposity are characterized by reductions in -cell function relative to insulin sensitivity , with no difference in insulin sensitivity . in youth with ifg , insulin - stimulated glucose disposal is preserved compared with that in those with ngt , whereas first- and second - phase insulin secretion is 50 and 30% impaired . in youth with igt , first - phase insulin is 40% lower compared with that in those with ngt with preservation of second - phase insulin . when both defects , ifg and igt , coexist , the impairment in insulin secretion is a mixture of both with 55% lower first - phase insulin and 30% lower second - phase insulin . in the full - blown diabetic state , insulin - stimulated glucose disposal is impaired by 30% , first - phase insulin is impaired by 75% , and second - phase insulin is impaired by 65% compared with those in youth with ngt . such cross - sectional observations are consistent with longitudinal studies showing a higher risk of progression to type 2 diabetes in the subjects with combined ifg / igt compared with those with isolated ifg or igt ( 15 ) . the present study confirms the results in some of the existing adult literature but contradicts others . our findings are consistent with observations in adults demonstrating greater impairment in insulin secretion in individuals with ifg ( 9,14,16,17 ) compared with those with igt , in that the defect in insulin secretion involves both first - phase and second - phase insulin in ifg , whereas second - phase insulin is preserved in igt . moreover , adult studies indicate that the loss of -cell function may start at levels of fpg on the higher end of the conventional normal range ( 18 ) . a recent longitudinal study suggests that a defect in insulin secretion ( evaluated by an ogtt - derived index ) is present in subjects with ifg and apparent 5 years before the development of fasting hyperglycemia ( 19 ) . on the other hand , other investigations in adults show greater insulin resistance in igt groups compared with ifg or ngt groups unlike our findings ( 17,18 ) . however , a major difference between our study and the adult studies , besides the age factor , is that almost invariably , the reported adults with igt ( 9,15,17,18,20 ) or ifg ( 9,15,18,20 ) have higher bmi and/or abdominal fat compared with the ngt groups , which could contribute to the observed differences in insulin action between igt , ifg , and ngt categories . this observation is supported by the fact that when subjects have similar anthropometric measures ( 21 ) , investigators did not find significant differences in peripheral glucose uptake in the ifg or ifg / igt groups compared with the ngt group ( 21 ) . in addition , controlling for body composition ( bmi and waist - to - hip ratio ) eliminated differences in insulin sensitivity among ngt , ifg , and igt subgroups in one study ( 22 ) and between igt and ngt in another study ( 23 ) . in that same study , lower insulin sensitivity is evident in the type 2 diabetic group compared with that in the ngt group and with that in the pre - diabetic groups after controlling for overweight ( 23 ) , consistent with our current and previous findings ( 12 ) . in this study , use of the hyperglycemic clamp allowed us to examine second - phase insulin secretion , information on which is not widely available in the published literature . the defect in first - phase insulin secretion in our pre - diabetic groups is consistent with the findings of cali ' et al . ( 11 ) of decreased glucose sensitivity of first - phase insulin secretion in the pre - diabetic state . in their study , absolute values of first- and second - phase insulin levels were not significantly different in the pre - diabetic groups compared with those in the ngt group , and glucose sensitivity of second - phase insulin was not affected except in the combined ifg / igt group . their study , however , did not include subjects with type 2 diabetes to allow them to evaluate the magnitude of impairment across the spectrum of glucose tolerance . in our study , inclusion of adolescents with type 2 diabetes allowed us to assess not only deviations from normal but also differences from the extreme abnormal . although absolute levels of second - phase insulin were significantly lower in the type 2 diabetic versus igt group , there was no difference between the type 2 diabetic and ifg or coexisting ifg / igt groups . such an observation suggests that in ifg the impairment in insulin secretion may play a more critical role in the progression to type 2 diabetes than is the case with igt . although our participants were limited to a balanced representation of african americans and whites , their study included subjects of multiple ethnicities with a significant number of hispanics who may differ in their metabolic response to perturbations in glucose homeostasis . in studies limited to latino adolescents , investigators did not find significant differences in the acute insulin response between those with ifg and ngt ( 10 ) or between those with igt and ngt ( 24 ) , although gdi was reduced in the ifg and igt groups compared with that in the ngt group , indicating an impairment in -cell function relative to insulin sensitivity . several adult studies suggested that the ifg state is characterized by hepatic insulin resistance measured during the euglycemic clamp ( 9,15,25 ) . however , the population in those studies consisted of mexican american adults in one ( 15 ) and native americans ( 9 ) in another . in addition , the pre - diabetic subjects had higher bmi and waist circumference ( 15 ) compared with those in the ngt group , which could have contributed to their hepatic insulin resistance . in a study by bock et al . ( 25 ) , mild hepatic insulin resistance was found in white subjects with ifg compared with those with ngt , which was attributed to increased gluconeogenesis . however , again the subjects with ifg were significantly more obese and had higher visceral fat ( 25 ) . our study participants in the five different groups had comparable degrees of total and abdominal adiposity , and thus it is possible that with similar degrees of obesity , the earliest detected abnormality is in -cell function and insulin secretion , and hepatic insulin resistance develops later and becomes more marked in individuals of certain ethnic backgrounds . therefore , we propose that the defect in insulin secretion in the ifg group in combination with hepatic insulin resistance ( which we did not measure during the clamp ) may be responsible for the mild fasting hyperglycemia . on the other hand , the interplay between impaired insulin secretion and peripheral insulin resistance in subjects with coexisting ifg / igt may prevent maintenance of plasma glucose within a normal range after a glucose load . one limitation in our study is the relatively smaller sample size of the ifg and combined ifg / igt groups . however , the use of the clamp , a sensitive method for assessing insulin sensitivity and secretion , allowed us to demonstrate significant differences in a five - group comparison . in summary , all pre - diabetic states in obese youth have impaired insulin secretion relative to insulin sensitivity , although the magnitude of impairment in -cell function may be variable . such differences potentially translate to a differential in the risk of progression to type 2 diabetes . the ultimate objective from such scientific advances is to individualize the therapeutic / preventive approach to the specific underlying metabolic dysfunction , leading to type 2 diabetes at a young age .

objectiveimpaired fasting glucose ( ifg ) and impaired glucose tolerance ( igt ) are considered pre - diabetes states . there are limited data in pediatrics in regard to their pathophysiology . we investigated differences in insulin sensitivity and secretion among youth with ifg , igt , and coexistent ifg / igt compared with those with normal glucose tolerance ( ngt ) and type 2 diabetes.research design and methodsa total of 24 obese adolescents with ngt , 13 with ifg , 29 with igt , 11 with combined ifg / igt , and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ( [ 6,6 - 2h2]glucose ) , insulin - stimulated glucose disposal ( rd , euglycemic clamp ) , first- and second - phase insulin secretion ( hyperglycemic clamp ) , body composition ( dual - energy x - ray absorptiometry ) , abdominal adiposity ( computed tomography ) , and substrate oxidation ( indirect calorimetry).resultsadolescents with ngt , pre - diabetes , and type 2 diabetes had similar body composition and abdominal fat distribution . rd was lower ( p = 0.009 ) in adolescents with type 2 diabetes than in those with ngt . compared with adolescents with ngt , first - phase insulin was lower in those with ifg , igt , and ifg / igt with further deterioration in those with type 2 diabetes ( p < 0.001 ) , and -cell function relative to insulin sensitivity ( glucose disposition index [ gdi ] ) was also lower in those with ifg , igt , and ifg / igt ( 40 , 47 , and 47% , respectively ) , with a further decrease ( 80% ) in those with type 2 diabetes ( p < 0.001 ) . gdi was the major determinant of fasting and 2-h glucose levels.conclusionsobese adolescents who show signs of glucose dysregulation , including abnormal fasting glucose , glucose intolerance or both , are more likely to have impaired insulin secretion rather than reduced insulin sensitivity . given the impairment in insulin secretion , they are at high risk for progression to type 2 diabetes . further deterioration in insulin sensitivity or secretion may enhance the risk for this progression .

skeletal dysplasias are a diverse group of diseases primarily affecting the development of the osseous skeleton . they manifest with disproportionate short stature , malformations , and/or deformations and range from relatively mild to severe and lethal conditions . to date there are over 250 unique and well - characterised skeletal dysplasias , many of which can be grouped into different diagnostic groups and/or bone dysplasia families based on clinical similarities . it is important to note that skeletal dysplasia mutations may also influence other nonskeletal organs , often mechanically by tightening the tracts in the body due to skeletal defects . for example , children with skeletal dysplasias often have respiratory problems and mental problems sometimes occur due to craniofacial defects . early diagnosis of skeletal dysplasias is therefore crucial for patient management and may enable relatively normal growing up and life span . skeletal muscle , tendon and ligament , and the bones themselves form a complicated biomechanical system of levers and forces ; therefore , abnormalities in one tissue may potentially affect the others . it is known that bones react and remodel according to the forces exerted by muscles . tendons and ligaments also repair and remodel according to the biomechanical forces exerted upon them . therefore , for the wellbeing of the patient , it is important to recognise all the tissues that the disease may be affecting . in this paper we summarise the relationships between different tissues in the musculoskeletal system and discuss several skeletal dysplasias in which muscle and/or tendon weakness has been recognised and described . this detailed paper will provide better understanding of the musculoskeletal biology and may enable better diagnosis and management of the patients in future . bone is a hard connective tissue consisting of osteocytes embedded in an abundant extracellular matrix ( ecm ) . bones act as a scaffold , attachment points , leverage , and protection for soft tissues . during life , and to enable growth , repair and mineralisation , the bone is constantly being remodelled by osteoblasts and osteoclasts . furthermore , bone is a dynamic tissue which is able to remodel in response to the mechanical load . for example , an increase in loading bone formation increases and resorption decreases whilst unloading of the bone has an opposite effect ( figure 1(a ) ) . the human skeleton consists of 206 bones of differing shapes and functions and distributed throughout the entire body . surprisingly , however , this complicated scaffolding is formed by only two distinct and very conserved processes . bones of the craniofacial skeleton evolve from migrating neural crest cells in a process called intramembranous ossification . the rest of the skeleton is formed by mesenchymal cells forming a cartilage anlagen , which is later replaced by bone in endochondral ( i.e. , in cartilage ) ossification . both ossification pathways are also implicated in bone repair at later stages of life , with intramembranous ossification being the method of repair for stabilised fractures , whilst unstable fractures heal via endochondral ossification . these separate pathways share many common regulatory genes and proteins , local paracrine regulators , blood stream hormones , and transcription factors . mechanical forces are also extremely important for proper development of the skeleton , influencing the shape of the bones , their repair processes , and signalling pathways [ 11 , 12 ] . limb development begins with the condensation of mesenchyme after which the cells differentiate into chondrocytes , which form the cartilaginous template . as the cartilage grows , the cells are forced apart by the extracellular matrix and become encapsulated in the thickening matrix . meanwhile , within the cartilage anlagen , the encapsulated cells die due to their intensive growth and calcium salt deposition , and the ecm eventually erodes . the blood vessels invade the cartilage , bringing bone - forming cells , which differentiate into osteoblasts and secrete additional extracellular matrix . this matrix is subsequently calcified forming trabeculae , some of which are later reabsorbed by the osteoclasts thus forming a bone marrow cavity . as the bones continue to grow , a secondary ossification centre is established in the epiphyses and between the shaft of the bone and the epiphysis a cartilage growth plate is formed ( figure 2 ) , allowing longitudinal bone growth . the thickening of bone is achieved by depositing further layers on the periosteum side by osteoblasts , and widening of the bone marrow cavity by osteoclasts . eventually , the epiphysis and metaphysis in the bone fuse , usually around puberty , forming a diaphyseal mature bone . growth plate cartilage extracellular matrix is composed of type ii collagen fibers and is abundant in proteoglycans , specifically aggrecan . this makes it a relatively compliant tissue and so it is able to respond to mechanical and gravity forces . to a certain extent , growing bones are able to align themselves according to the gravity forces exerted upon them , as can be seen in the correction of a mild genu varum in toddlers . however , strong compression inhibits bone growth and tension has an opposite effect by increasing growth in bone length [ 4 , 18 ] . this is known as the hueter - volkman law ( figure 1(b ) ) , which was further defined by frost in the twentieth century and is often used by clinicians in surgical correction of certain limb deformities [ 4 , 17 ] . lack of mechanical loading also results in decreased bone formation , as shown by weightlessness and suspension experiments ( figure 1(a ) ) [ 1921 ] . gravity induced mechanosensing in the growth plate cartilage is achieved by a microtubule - based organelle called the primary cilium [ 2224 ] . primary cilia are cytoplasmatic protrusions that are associated with many proteins implicated in signal transduction , specifically integrins and extracellular matrix receptors , and enable the cells to respond to mechanical stimuli . they exist on almost every cell in the human body and are very important for mechanosensing and biomechanics of many different tissues . its mechanical properties allow it to withstand compressive forces and also to a smaller extent resist shearing and torsional forces . cartilage consists mostly of an extracellular matrix and its structure varies according to species , location , and age of the tissue . it is a precursor to the growth plate ( physis ) , and it is also found at the articular surface of bones , where it acts as a shock absorber and protection for the underlying subchondral bone . chondrocytes in the hyaline cartilage are ovoid , ranging in shape from round to flat . lacuna ) encapsulated by the extracellular matrix , which is important for cartilage biomechanical properties . it has been shown that pericellular matrix of articular cartilage has a precise macromolecular architecture , with a high content of proteoglycans , such as aggrecan , embedded in the collagen matrix . the shape of individual chondrons is also important and they respond to the gravitational forces by producing a compact matrix cap pointing towards the surface of the tissue and a looser tail extending into the ecm below . chondrons have often been referred to as fluid bladders and indeed they seem to function in a similar manner . when cartilage is subjected to compression , the liquid is pushed out of the proteoglycan complex and the collagen rich matrix deforms , thus increasing the pressure within the chondron . this change in osmotic pressure due to escaping water protects the chondrocyte and enables its full recovery at unloading . chondrocytes also have a primary cilium which helps them sense these changes in forces [ 22 , 23 , 26 ] . this seems to be especially important in the aetiology and management of osteoarthritis where even a ligamentous instability or a weakness of periarticular muscles , and therefore an abnormal biomechanical environment , may result in joint degeneration [ 30 , 31 ] . fibrocartilage is an intermediate tissue between the hyaline cartilage and dense fibrous tissues [ 5 , 32 ] . it only has a few chondrocytes in the lacunae , and its matrix contains many thick collagen fibres arranged in an ordered fashion . it can be found in invertebral discs , symphysis pubis , articular disc of the sternoclavicular and temperomandibular joints , the menisci of the knee joints , and places where ligaments or tendons attach to bones and is formed as tendon 's reaction to compressive load . fibrocartilage is associated with epiphyseal tendons and ligaments and is important in force transduction as it dissipates the stress on the tendon fibers near the bone [ 32 , 34 , 35 ] . its molecular composition is similar to that of tendon , but several cartilage specific molecules , such as type ii and type ix collagen and aggrecan , are also present in the matrix . tendon ( figures 3(a ) and 3(b ) ) and ligament are soft collagenous tissues , linking muscle to bone and bone to bone , respectively . they consists of densely packed bundles of fibrous collagen and are characterised by high tensile strength and elasticity . tendon and ligament both have similar hierarchical structure , consisting of fascicles , which are built of smaller basic fibrils and fibroblasts . both ligaments and tendons are surrounded by a sheath of transparent material called the synovial membrane , a delicate connective tissue layer secreting synovium , a viscous lubricating fluid . they can remodel according to the forces exerted upon them [ 34 , 38 ] . it has been shown that the immobilisation of limbs leads to a decrease in collagen turnover in the tendon and a decrease in tendon diameters , and conversely , exercise leads to an increase in tendon diameter and collagen turnover . increase in tendon diameters correlates with an increase in the stiffness of the tissue , which means thicker tendons can withstand higher tensile forces exerted upon them by stronger muscles . tendons also become thicker and less compliant with age , which together with age - associated muscle wasting helps explain the weakness and difficulties in walking experienced by the elderly . another structure that is biomechanically important for conveying forces from muscle to tendon is the myotendinous junction ( mtj ; figure 4 ) . this is the site where tendon meets , and merges , with the skeletal muscle and the point where muscle contractile forces are transmitted to the tendon . this means that the tensile stress exerted by the contracting muscle fibers becomes shear stress instead , thus increasing the strength of the junction and protecting the tissues from injury . the myotendinous junction is also connected to the collagenous perimysium surrounding the skeletal muscle fascicles . the perimysium forms a lattice structure within the skeletal muscle and is involved in transmission of lateral forces in the muscle . mtj and perimysium are together responsible for conveying the forces from muscle to tendon [ 43 , 44 ] . skeletal muscle acts as the motor of the body and is essential for locomotion . as such it has a very complex hierarchical structure ( figure 4 ) . each myofiber is a one multinuclear cell ( with nuclei located to the periphery ) that often spans the length of the entire muscle . most of the myofiber is filled with contractile myofibrils consisting of actin and myosin and responsible for muscle contraction . the discovery of costameres by pardo et al . in 1983 showed the first direct link between the surrounding extracellular matrix and the myofibers . costameres are regularly spaced around the z - lines of the skeletal muscle and play a role in lateral force transmission , as shown by single myofiber studies performed by street et al . groups of muscle fibers are covered by another connective tissue sheath called the perimysium , which transmits the lateral forces between the muscle bundles . not every myofiber spans the entire muscle length and connects to the myotendinous junction ; however , all the fibrous extracellular matrices are interconnected and eventually lead to the myotendinous junction and to the tendon itself . muscle can also remodel and adapt to the mechanical load , and muscle hypertrophy is often seen as a result of exercise . skeletal dysplasias are a group of skeletal and musculoskeletal diseases that affect the development of the osseous skeleton . there are over 250 well - characterised phenotypes known to date , which affect the development of both flat and long bones . the many different genes that are mutated in skeletal dysplasias span a wide range of cellular and metabolic processes and include those involved in the extracellular matrix , metabolic pathways , folding and degradation of macromolecules , hormones and signal transduction mechanisms , nuclear proteins and transcription factors , oncogenes and tumour suppressor genes and rna , and dna processing and metabolism . many skeletal dysplasia phenotypes are characterised by severe deformations and/or malformations of numerous skeletal elements and with such conditions it is sometimes easy to overlook other clinical aspects , such as the effect these skeletal abnormalities may have on the soft tissues of the body . skeletal dysplasias may result in tightening of the tracts in the body thus affecting breathing and patient 's well - being . shorter limbs may result in a different distribution of biomechanical forces exerted by the muscles and thus may contribute to difficulties in walking . furthermore , many of the extracellular matrix genes expressed in bone and cartilage and involved in skeletal dysplasias are also present in other musculoskeletal tissues , such as muscle and tendon , and may affect patients ' well - being and quality of life . there are several skeletal dysplasia phenotypes in which myopathy is a recognised neuromuscular complication of the disease . in some of the cases , the muscle pathology stems directly from the fact that the mutant protein is expressed in the muscle as well as in cartilage and bone , but in others the effect appears to be more indirect . a detailed analysis of the muscular symptoms in these phenotypes is very important since the neuromuscular complications often manifest prior to the skeletal deformations , which may arise during pre - pubertal growth , and therefore might allow quicker diagnosis and better management of the patient . multiple epiphyseal dysplasia ( med ) is a skeletal dysplasia in which an associated myopathy has only recently been recognised and reported in patients [ 5355 ] . bone dysplasia family that also includes the related and more severe disease known as pseudoachondroplasia ( psach ) [ 51 , 56 ] . together these phenotypes form a distinct spectrum of disease severity ranging from a mild med through to severe psach at the other end of the spectrum . the psach - med phenotype is characterised by disproportionate short stature , lower limb deformations ( genu varum and genu valgum ) , joint laxity , and early onset degenerative joint disease . radiographic features of psach manifest in the epiphyses and the metaphyses of the long bones and in med are restricted to the epiphyses . psach and the more severe forms of med result from mutations in the gene encoding cartilage oligomeric matrix protein ( comp ) , a pentameric ecm bridging molecule found in cartilage , tendon , ligament , and skeletal muscle . psach - med mutations in comp cluster in the exons encoding the calcium - binding thrombospondin type 3 repeats ( t3 ) and the c - terminal domain ( ctd ) of comp . in chondrocytes the expression of these mutations results in various levels of endoplasmic reticulum ( er ) stress and cell death [ 59 , 60 ] . a role for comp in collagen fibrillogenesis has been proposed and it is thought to be one of the catalysts of this process . furthermore , in the cartilage extracellular matrix comp plays a bridging role and is able to interact with other ecm molecules such as matrilin-3 , type ix collagen , aggrecan , fibronectin , and integrins [ 6265 ] . it is therefore not surprising that other med - causing mutations were found in genes encoding proteins known to interact with comp such as matrilin-3 and type ix collagen , although the precise rationale for this genetic heterogeneity of med has yet to be determined . until recently , psach - med has primarily been described as a disease affecting bone growth , joint stability , and ligamentous laxity . in 2000 however , a form of med resulting from a mutation in one of the type ix collagen genes ( col9a3 ) was as associated with a mild myopathy . this initial observation was followed by the recognition that some forms of psach - med resulting from ctd - comp mutations may also present with mild myopathy [ 53 , 55 ] ( tables 1 and 2 ) . in an med family with a col9a3 mutation patients presented with proximal muscle weakness ( despite predominantly distal skeletal changes ) and mildly elevated levels of creatine kinase ( ck ; an indicator of muscle degeneration and myopathy ) . these individuals tired easily and a muscle biopsy from one affected family member showed mild myopathic changes characterised by a mild variability in fiber size . interestingly , there is no evidence that type ix collagen is expressed in skeletal muscle as a fully functioning trimer [ 66 , 67 ] . therefore , it is tempting to speculate that the pathology in this case arises from an abnormal enthesis ( the tendon to bone attachment site where type ix collagen is expressed ) . this may also explain why no gross myopathic changes were seen in the muscle biopsy from the patient , which would be the case if a muscle specific structural protein was mutated . our recent analysis of a ctd - comp mutant mouse model provided evidence in support of this hypothesis . med - comp patients with a ctd - comp mutation and an associated myopathy were described in 2003 by jakkula et al . . they suffered from muscle weakness from 3 years of age and had mildly elevated ck levels ; however a muscle biopsy was not performed at the time . in 2005 , the onset of the disease was early and included muscle weakness , fatigue , and difficulty rising from the floor , in comparison to the patient reported by jakkula ; the ck levels were also with normal limits . a biopsy of the patients ' muscle showed no variability in fiber size , however , scattered basophilic and small atrophic fibers were noted , indicating a mild myopathy . inconclusive data exists with respect to the expression of comp in skeletal muscle and tendon [ 69 , 70 ] ; therefore we analysed a knock - in mouse model carrying a ctd - comp mutation to determine the pathomolecular mechanisms of psach - med related myopathy . we have recently reported the clinical phenotype and investigated the pathology of psach - med associated myopathy using a transgenic mouse model with a t585 m comp mutation in the c - terminal domain of comp . we detected comp protein in skeletal muscle and in the tendons and ligaments of wild type and mutant mice , confirming that it is expressed in all of these tissues . mice carrying the t585 m ctd - comp mutation experienced a progressive muscle weakness even though histological evidence of myopathy was found only at the myotendinous and perimysial junctions . the collagen fibril organisation was abnormal in mutant tendons and characterised by an overall increase in fiber diameter with a corresponding increase in the number of branching or bifurcating fibrils . comp was expressed throughout skeletal muscle and tendon , yet the mutation resulted in a localised myopathy and a generalised tendinopathy . therefore , we concluded that the given myotendinous and perimysial junctions are responsible for transmitting the forces between the tendon and muscle fibers ; the myopathy was perhaps the result of an underlying tendon problem . this finding is very important as it may help explain the myopathy seen in med patients with type ix collagen gene mutations , and more recently , with matrilin-3 mutations ( table 2 ) . both of these molecules are not expressed in skeletal muscle ; however , they are present in the fibrocartilage attachment point ( enthesis ) between the tendon and bone . a disruption to mechanical forces transmitted to the muscle and an altered ability of those tissues to remodel following stress may explain some of the musculoskeletal complications of the med phenotype . to test the hypothesis that myopathy is specifically associated with ctd - comp mutations localised near the potential collagen and integrin binding sites , we have investigated a second mouse model , comp d469 knock - in mice ( t3-comp mutation ) , for muscle weakness using the experimental set - up as previously described in . at 3 weeks of age we found no evidence of muscle weakness in d469 mutant mice ( figure 5 ) ; however , by 9 weeks of age the mutant mice were weaker than their wild type littermates and tired easier , similar to the comp - ctd mutant mice . this indicates that psach - med comp related myopathy may be a mutation specific phenomenon and be related directly to the proximity of the mutation to the potential binding sites on comp rather than the specific domain of the molecule . recently , several psach and med patients with comp , type ix collagen , and also matrilin-3 mutations have been reported with muscular complications , and these patients were originally referred to neuromuscular clinics prior to the diagnosis of skeletal dysplasia . this seems to support our hypothesis that mutations in t3 domain of comp and in other structural molecules of tendon and cartilaginous enthesis may also result in a mild myopathy . blood samples from the patients showed normal or mildly increased ck levels and their muscle biopsy showed increased number of basophilic fibers , fiber necrosis , and/or variability in fiber diameters . we now present an updated summary of novel psach - med mutations associated with myopathic changes ( table 2 ) . interestingly , some of the newly found comp mutations associated with a myopathy cluster in the t3 repeats of the comp protein . the t3 and ctd domains of comp can form intramolecular interactions as demonstrated by the recent crystal structure model [ 72 , 73 ] . therefore , the mutations that associate specifically with a myopathy may do so due to their specific locations , possibly near a potential collagen or integrin binding sites and/or the intramolecular binding sites within comp , and myopathic phenotype may not segregate directly with the domain , but rather with a specific location of the mutation . type ix collagen and matrilin-3 mutations ' association with a myopathic phenotype may potentially be explained by the expression of these molecules in the fibrocartilaginous enthesis [ 33 , 74 ] ; however the pathomolecular mechanism of the muscle complications in these cases requires further investigation . an autosomal recessive disorder , schwartz - jampel syndrome ( sjs1 ) , results form mutations in the extracellular matrix molecule perlecan . it is expressed in cartilage , the endomysium of skeletal muscle , the nervous system , and in basement membranes throughout the body . it can interact with both fibroblast growth factor 2 ( fgf2 ) and transforming growth factor beta ( tgf ) and is believed to play a role in tissue growth . schwartz - jampel syndrome is characterised skeletally by short stature , irregular epiphyses , bowed diaphyses , general joint deformities , and coxa valga . in skeletal muscle the onset of the disease is quite early , from around 3 years of age , and the muscular phenotype often precedes the skeletal abnormalities . another affected tissue is the eye with patients often suffering from myopia and a dysplasia of the eyelids . interestingly , the skeletal symptoms of sjs1 are at least in part due to a defect in sodium and potassium gradients in the muscle and these may be pharmacologically corrected . what is extremely interesting is that perlecan is not a part of a voltage channel per se , rather it is expressed in the endomysial extracellular matrix , thus suggesting a link ( perhaps mechanical ) exists between voltage channels and signalling and the surrounding ecm . marfan syndrome is an autosomal dominant musculoskeletal and ocular syndrome resulting from mutations in the extracellular matrix protein , fibrilin-1 . fibrilin-1 is a component of extracellular microfibrils that are present in many connective tissues such as lung , skin , kidney , blood vessels , cartilage , muscle , cornea , and tendon . marfan syndrome patients are characterised by abnormally high stature , scoliosis , and highly arched palate with a crowding of the teeth . the muscular component ( skeletal muscle ) of marfan syndrome has been largely ignored until relatively recently . muscular abnormalities can include muscle hypoplasia , hypotonia , and weakness , and some patients also have problems with increasing the muscle mass upon exercise . the hypoplasia and hypotonia possibly result from the increased availability of tgf1 , which is known to bind to fibrilin associated latent tgf1 binding protein ( ltbp ) . recently losartan , an antagonist of tgf1 , has been shown to alleviate aortic aneurysm in a mouse model of marfan syndrome , and it may also help to reverse the muscular symptoms of marfan syndrome . since the onset of muscular symptoms can precede the bone pathology and the muscular symptoms may soon be treatable , an early diagnosis based on muscular phenomena may lead to better management and better quality of life for these patients . camurati - engelmann disease ( ced ) , also known as progressive diaphyseal dysplasia , is an early onset autosomal dominant skeletal dysplasia resulting in the thickening of the diaphyseal bones , sclerosis of the skull base , and bone pain . the first symptoms usually manifest in early childhood and always before 30 years of age . ced is caused by mutations in transforming growth factor 1 ( tgf1 ) , a molecule very important in proliferation and differentiation of many different cell types , including those of cartilage and bone . interestingly , ced patients are often initially referred to neuromuscular clinics with a suspicion of muscular dystrophy . they present with an increasing muscle weakness , easy fatigue , and a characteristic waddling gait . however , their plasma creatine kinase ( ck ) level ( an indicator of muscle degeneration ) is usually normal or only mildly elevated . muscle biopsies are often normal or show nonspecific changes , with some atrophic fibers ( but no group atrophy ) and thickened basement membrane around the small vessels . some degree of perimysial fibrosis ( but no endomysial fibrosis ) is also observed in a proportion of patients . electromyographs ( emg ) show small action potentials indicative of a myopathy in some muscles , especially around the pelvic girdle whereas other muscles are normal . these observations are extremely important as muscular complications often manifest themselves prior to the severe skeletal symptoms and some of the radiographic features of ced may be prevented or are treatable with corticosteroids . therefore , a muscle biopsy / assessment at the right site combined with radiological evidence could potentially enable better and earlier diagnosis and treatment of these patients . together these tissues enable locomotion , protect soft organs from damage , and act as a scaffold for our bodies . we sometimes forget however that all these tissues often develop together , are in fact interconnected , and can interact with each other , and that affecting one may have an effect on the others . understanding these intertissue relationships may also dramatically improve the therapies and management of certain diseases , such as the ones described in this paper . early detection of an asymptomatic or a mild myopathy may lead to an earlier diagnosis of an underlying skeletal dysplasia . identification of the tissues affected by the disease , and a better understanding of the disease aetiology may also lead to the alleviation of some of the disease symptoms , better corrective surgery , and better management of the patients . understanding the biomechanics of the interconnected musculoskeletal system may lead to better physiotherapies for osteoarthritis and many other bone / muscle related diseases . therefore , a thorough and interdisciplinary investigation of musculoskeletal diseases and tissues is required to further our understanding of these systems and to enable better management and a better quality of life for patients in the future .

musculoskeletal system is a complex assembly of tissues which acts as scaffold for the body and enables locomotion . it is often overlooked that different components of this system may biomechanically interact and affect each other . skeletal dysplasias are diseases predominantly affecting the development of the osseous skeleton . however , in some cases skeletal dysplasia patients are referred to neuromuscular clinics prior to the correct skeletal diagnosis . the muscular complications seen in these cases are usually mild and may stem directly from the muscle defect and/or from the altered interactions between the individual components of the musculoskeletal system . a correct early diagnosis may enable better management of the patients and a better quality of life . this paper attempts to summarise the different components of the musculoskeletal system which are affected in skeletal dysplasias and lists several interesting examples of such diseases in order to enable better understanding of the complexity of human musculoskeletal system .

A judge sentenced a Pico Rivera man to nearly 40 years in state prison for extorting 21 underage girls in eight states into sending him nude pictures online, authorities said. Cesar Mauricio Estrada-Davila, also known as Cesar Estrada, 20, pleaded “no contest” on Wednesday to 38 felony charges, including 21 counts of distributing or showing child pornography to a minor, 16 counts of possession of child pornography and one count of committing a lewd act on a child, Los Angeles County District Attorney’s Office spokesman Ricardo Santiago said in a written statement. At his sentencing on Friday in the Antelope Valley branch of Los Angeles County Superior Court, Estrada received a prison term of 39 years and 8 months. He will also be required to register as a sex offender for the rest of his life. “According to testimony at the preliminary hearing, Estrada reached out to young girls and befriended them on social media websites between January and April, 2015,” Santiago said. “The defendant told the victims he was a modeling agent who could make them famous online. “Estrada then asked the victims to send him pictures of themselves in their underwear,” according to Santiago. “Once the defendant received the images, he would tell the girls he was going to send the photos to their friends and family if they did not send nude photos.” Prosecutors filed charges in connection with 21 victims between the ages of 12 and 17 in the states of California, Nevada, Utah, Texas, Michigan, Washington, Colorado and Florida. The investigation began after a 14-year-old Antelope Valley girl who reported the online extortion to her father, who in turn contacted police, sheriff’s Lt. Andrew Meyer said shortly after Estrada’a arrest. Detectives searched Estrada’s home in the 8300 block of Rosemead Boulevard in Pico Rivera, where they found more than 26,000 pages of online and text conversations between Estrada and his victims, Meyer added. All of the victims were Latina girls, and many told investigators they had been living in fear of Estrada. Estrada was initially charged with more than 150 crimes and could have received multiple life sentences if convicted at trial, prosecutors said. The case was investigated by detectives from the Los Angeles County Sheriff’s Department’s Special Victims Bureau. ||||| LOS ANGELES -- Authorities said a 20-year-old Rosemead man has been sentenced to nearly 40 years behind bars for distributing revenge porn and extorting young girls for nude photos, CBS Los Angeles reports. Cesar Mauricio Estrada-Davila, AKA Cesar Estrada, pleaded no contest on Feb. 15 to a total of 38 felony counts: one count of lewd act upon a child; 21 counts of distributing or showing child or youth pornography to a minor and 16 counts of possession of child or youth pornography, according to the LA County District Attorney’s Office. Estrada-Davila was sentenced Friday to 39 years and 8 months in prison. As a result of the plea, Estrada also must register as a sex offender for the remainder of his life. Deputy DA’s Scott Yang and Steven Mac of the Antelope Valley Branch prosecuted the case. According to testimony at his preliminary hearing, Estrada-Davila found his victims on social media between January and April 2015. The defendant told the victims he was a modeling agent who could make them famous. Estrada then asked the victims to send him pictures of themselves in their underwear, prosecutors said. Once Estrada-Davila received the images, he threatened to send the photos to their friends and family if they did not send him nude photos, according to court testimony. Prosecutors said there were 21 female victims between the ages of 12 and 17 years old from California, Utah, Texas, Michigan, Washington, Colorado, Nevada and Florida. The case was investigated by the Los Angeles County Sheriff’s Department Special Victims Bureau.

– A California man who posed as a modeling agent to extort nude photos from young girls across America has been sentenced to almost 40 years in prison—twice as long as he has been alive. Cesar Mauricio Estrada-Davila, 20, pleaded no contest this week to 38 felony counts, including 16 counts of possessing child or youth pornography, and was sentenced to 39 years and 8 months, CBS reports. Prosecutors say that for several months in early 2015, Estrada-Davila reached out to young girls he found on social media websites. He told them he could make them famous and asked for photos of them in their underwear, then threatened to show the underwear photos to their families and friends if they didn't send him nude photos. Estrada-Davila was charged in connection with 21 victims between the ages of 12 and 17 in eight states. Police say he was arrested after a 14-year-old California girl told her father about his demands, the San Gabriel Valley Tribune reports. Cops searched his Los Angeles County home and found more than 26,000 pages of text and online conversations between him and his victims. Before a plea deal was worked out, Estrada-Davila faced more than 150 charges, enough to send him to prison for life several times over. (Oregon recently handed down its first sentence for revenge porn.)

This collection documents the Tea Party movement and right-leaning political populism in the United States. The Hoover Institution Library and Archives seeks to collect historically valuable and at-risk web content created by Tea Party organizations and groups, individual bloggers, and supporters of the movement to complement its holdings on this topic. Please contact the curator, Danielle Scott Taylor, at [email protected] with any content suggestions or questions. ||||| The conservative group ForAmerica is pushing to oust GOP leaders in both the House and Senate with a new campaign called "Dump the Leadership." The organization, long a critic of both House Speaker John Boehner (R-Ohio) and Senate Minority Leader Mitch McConnell (R-Ky.), calls on both leaders to step down in its new online advertising campaign. ADVERTISEMENT ForAmerica Chairman Brent Bozell tells The Hill that the group is likely to spend at least $675,000 on the web campaign between now and the November election, and could increase the sum to more than a million dollars in the future. "We need new leadership," Bozell said. "People are tired of supporting the Republican PArty because of the lack of leadership. These leaders have broken their word too many times and they need to be replaced. These men are simply not up to the task." Bozell ripped both Boehner and McConnell, and said the 4.5 million Facebook fans the group has will likely jump into action to support the group's efforts. "We know how to flex our muscles," he said. "Until there is new leadership, across the board Republicans are going to suffer. Good luck winning elections in November if the same people have the same formula as in 2012 — 'do nothing and we'll get the majority,' they're at it again. "I'm sick and tired of picking up the paper and finding these preemptive surrenders, like Boehner today on the debt ceiling. If they did anything that had a taste of fiscal conservatism I'd be shocked," Bozell continued. "They need a new generation of leadership. There's no question that these leaders have failed, they've not helped." Bozell has long a thorn in the side of GOP leaders, most recently calling for Boehner's ouster if he didn't acquiesce to conservatives' demands last fall as the GOP headed into negotiations which led to the government shutdown. This post was updated at 1:55 p.m. ||||| 3 years ago Washington (CNN) - A conservative group is launching a new campaign which calls on "the GOP leadership in both the House and the Senate to step aside." ForAmerica told CNN that it's putting six figures behind its "Dump the Leadership" campaign between now and November's leadership elections. Follow @politicaltickerFollow @psteinhausercnn The group says that its digital ads will target House Speaker John Boehner, Majority Leader Eric Cantor and Majority Whip Kevin McCarthy, as well as Senate Minority Leader Mitch McConnell and Minority Whip John Cornyn, and the group adds that the first paid spots are now up online. "Time and again, year after year, the Republican leadership in the House and Senate has come to grassroots conservatives, and Tea Party supporters pleading for our money, our volunteers, our time, our energy and our votes," said ForAmerica Chairman Brent Bozell in a statement to CNN. "In return they have repeatedly promised not just to stop the liberal assault on our freedoms and our national treasury, but to advance our conservative agenda. It's been years. There is not a single conservative accomplishment this so-called 'leadership' can point to." ForAmerica, which describes itself as "an online army of over 4.5 million people," is a conservative non-profit group which has often criticized congressional GOP leaders. ||||| During a speech in Lexington, KY, ForAmerica chairman Brent Bozell and Tea Party Patriots co-founder Jenny Beth Martin challenged Senate Minority Leader Mitch McConnell for his failure to stand up for conservatives in the Obamacare defunding debate. “Mitch McConnell must join Senator Mike Lee, Senator Ted Cruz and Senator Marco Rubio and speak up for the people – by passing a one year budget that funds the government but NOT ObamaCare,” Bozell said in his speech, according to prepared remarks provided to Breitbart News. “Senator McConnell, just say NO to funding ObamaCare. Senator McConnell, just say NO to President Obama and his cronies in Washington. Senator McConnell, we need you to keep your promise to the people of Kentucky. Senator McConnell, we need you to lead the fight to defund ObamaCare before it’s too late. Senator McConnell our message today is very simple: If you fund it, you own it.” advertisement Tea Party Patriots’ Martin echoed that message. “If Obamacare is not ready for Big Business, Big Labor, or Big Government, it’s not ready for the American people,” she said, according to prepared remarks provided to Breitbart News. “It is time for the President, Congress, and Sen. McConnell do the fair thing and exempt America from the Obamacare. The only way to do this is to stop spending our hard-earned tax money on Obamacare, which can be done while still funding the rest of the entire government in the fiscal year 2014.” McConnell has been decidedly quiet on this fight and has not stood up to fight Obamacare to defund it in the upcoming Continuing Resolution (CR) that funds the government. Bozell said in his Kentucky speech that while McConnell says publicly he is opposed to Obamacare, his unwillingness to defund it in the CR is a sign he is not serious about fighting the president’s signature legislative achievement. “Unfortunately, many Republicans, including Senator Mitch McConnell, come home and promise you that they are doing all they can to fight and stop ObamaCare,” Bozell said. “I am here to tell you they are not! We are here today to call on Senator McConnell to keep his promise to you and the rest of the nation. He can keep his promise of doing everything he can to stop ObamaCare by pledging today that he will fight to defund this monstrosity.” Martin said McConnell has a chance now to stop the law he said recently was a “disaster” and if he does not, it is a sign McConnell is standing up for special interests and big government instead of the needs of the American people. “Sen. McConnell just last week here in KY, said that the ‘law is a disaster’ and the solution to Obamacare is to pull it out ‘root and branch,'” Martin said. “Now Sen. McConnell has the opportunity to begin pulling the law out ‘root and branch.’ Sen. McConnell has a choice to make: stand up for the American People and do what is right for all Americans by funding the entire government and stop spending our hard earned tax money on Obamacare or stand up for the special interests in DC: big business, big labor, and big government while sticking this disastrous law on the American People. With the problems, delays, and exemptions in this law, the choice should be simple: stand with Americans and Exempt America.” ||||| The U.S. Senate is a clubby place, so it shouldn’t be all that surprising when some members break ranks to support the other side based on personal relationships they’ve forged over the years. Republicans John Warner and Richard Lugar, two of the senate’s most admired alums, back the candidacy of Michelle Nunn, the daughter of Sam Nunn, a Democratic former colleague with whom they worked closely. She’s running for her father’s old seat in Georgia, where an upset victory in a red state could salvage the Democrats’ majority in a tough year. A colleague’s daughter is one thing, but Warner announced last week that he is backing his fellow Virginian and former colleague, Democrat Mark Warner (no blood relationship) in his race against former Republican Party Chairman Ed Gillespie. “There are times you must, I think, recognize that certain individuals are superior in their talents and in what they have done and can potentially do for your state,” Warner told the Associated Press. It wasn’t the first time Warner crossed the aisle to buck his party. As a proud member of what he calls “the old school,” there was a time and place for such displays of independence. They made the difference between politicians and statesmen. A third senior Republican figure and storied name caught my attention: Barry Goldwater, Jr., a former member of Congress from California, now living in Arizona, son of Barry Goldwater, presidential candidate in 1964 and the father of modern conservatism. Goldwater co-chairs a campaign to “stand up to utility monopolies to ensure solar energy remains strong in America.” The group’s web site features an elephant TUSK, acronym for “Tell Utilities Solar Won’t Be Killed.” In Washington, where Republicans mock solar energy as a liberal fantasy, I was intrigued by Goldwater’s advocacy, and what it means when the son of such a legendary figure in American conservatism picks up the banner for a cause generally championed by his political opposites. I reached Goldwater by phone in Hawaii where he is lecturing at the university to ask him about his apparent apostasy. He made it clear in the first few minutes of our conversation that he is very much his father’s son, an outspoken conservative at home with the slings and arrows of politics. He publicly battled Arizona’s largest utility last fall when it threatened to impose a hefty surcharge on people who installed solar panels on their roofs. Conservative business interests rallied behind the utility, supporting the surcharge as a way to offset the rebate, or subsidy, that solar-energy users get when they generate excess energy that returns to the grid. The rebate and the “solar tax” became the centerpiece of a heated campaign with Goldwater in the forefront defending the subsidy. After first explaining that Republicans tend to oppose any government support or subsidies used for “social engineering,” calling it “the federal government’s devious way of manipulating the economy,” Goldwater said what conservative Republicans are not supposed to say, “I happen to think that subsidies used judiciously and intelligently can be used to better mankind. Renewable energy at some time has got to stand on its own—and oil and gas shouldn’t continue to feed at this trough. It’s ridiculous, and it should be stopped.” Goldwater’s intervention blunted the push by the utility, and a modest fee of about $5 was added to the electric bill of solar customers. Asked about the role he played, and the impact of his famous name, Goldwater bristled a bit. “I use it, but I don’t abuse it,” he said, adding, “It’s my name too.” Recalling his father’s views, he said they were firmly cemented in freedom. “He’s a libertarian—government has no business being in our lives. If you want to smoke pot, go ahead. If you want an abortion, that’s your choice. He was way ahead of his time on those issues.” Asked if he, the son, is ahead of his time on solar energy, Goldwater replied, “That makes for an interesting story.” But it’s not true, he says, citing polls taken during last fall’s campaign that found 75 percent of Republicans support solar energy. “It’s a misnomer that they don’t,” he says. Still, the Goldwater Institute, a non-profit organization founded in his father’s name, did not join the fight to preserve the subsidies though they are behind breaking up utility company monopolies. “We try to maintain the purity that Barry Goldwater’s name stands for,” says Nick Dranias, Constitutional Policy Director. The energy industry is where cell phones and fiber optic cables were in 1989, Dranias says, likening its potential to the explosive growth we’ve seen since then in technology. “Five years ago, I would have been railing against solar because it looked completely propped up and unfeasible, but in two to three years, it could actually be competitive cost-wise with coal,” he says. The co-chair of TUSK is Tom Morrissey, former Arizona Republican state party chairman, who resigned under pressure in 2012 after questioning the authenticity of President Obama’s birth certificate released by the White House. There’s nothing left-leaning about him. These alliances that may seem odd today reflect the growing divide within the Republican Party between its ascendant libertarian wing and business interests that find themselves newly challenged. What’s happening in Arizona with the fight between old and new energy sources adds another layer of complexity to the civil war within the GOP as some of its biggest names try to divine the future.

– The so-called GOP civil war may be going from cold to hot. The conservative group ForAmerica tells CNN that it intends to spend six figures on a campaign it's calling "Dump the Leadership," aimed at deposing all the GOP's leaders in both the House and Senate. "Time and again, year after year, the Republican leadership in the House and Senate has come to grassroots conservatives … pleading for our money, our volunteers, our time," the group's chairman says. "It's been years. There is not a single conservative accomplishment this so-called 'leadership' can point to." The group is vowing "significantly" more spending than the $200,000 it dropped to promote defunding ObamaCare, notes the Hill. The group says it's got digital ads online now, but it's unclear if those ads will attempt to convince voters to oust John Boehner, Mitch McConnell, and Co., or attempt to convince other GOP lawmakers to depose them. It's not the group's first swipe at leadership, either; it has repeatedly attacked McConnell for striking deals with Democrats, once dubbing him a "chicken" for not fighting hard enough to defund ObamaCare.

frequently encountered fbs include coins , batteries , and magnets , but there is a distinct group of cases of muslim children who wear headscarves inappropriately placing the safety pin in their mouth prior to securing the veil , leading to an accidental fb aspiration . we report a classic case to highlight the presentation and management of such a fb . an 11-year - old muslim girl was admitted to our hospital due to accidental aspiration of a headscarf pin . she aspirated the pin while securing her scarf and holding the pin in the mouth . initial chest x - ray showed a sharp radiopaque object in the left bronchus piercing the lung parenchyma . computed tomography ( ct ) chest was performed as requested by the thoracic surgeon for possible thoracotomy in case the bronchoscopy failed to remove the pin . ct chest showing sharp pin in left bronchus piercing the lung parenchyma an ear , nose , and throat ( ent ) surgeon failed to remove the pin by rigid bronchoscopy . a pediatric pulmonologist successfully removed the pin using flexible bronchoscopy , by bending the pin with forceps [ figures 2 and 3 ] . endoscopic view of sharp pin piercing the lung parenchyma sharp pin was bent to remove it endoscopically the nature of the fb varies according to region , age , food habits , and even clothing habits , but there is a common classification of organic and inorganic fb aspiration . organic materials such as nuts and seeds are the most commonly aspirated , while inorganic materials include a wide range of objects such as coins , plastic pieces , and toy parts . the younger age group is more vulnerable because of the lack of adequate dentition and immature swallowing coordination . in addition , among children of this age , introducing objects into their mouths is their way of exploring the world . muslim girls wearing headscarves because of sociocultural and religious tradition sometimes accidentally aspirate a headscarf pin while holding the pin between their lips in order to secure the veil . any maneuver then , such as laughter , talking , or coughing , predisposes them to aspiration , especially in the young teenage groups where they lack experience with such maneuvers . in contrast to other forms of fb aspiration , headscarf pin aspirations tend to be easily diagnosed by x - ray chest as all of these inhaled fbs are radiopaque . complications of intrabronchial fb are obstructive emphysema , recurrent pneumopathy , bronchiectasis , pulmonary abscess , pleural effusion , and even pneumomediastinum . rigid bronchoscopy is not successful , especially if the fb is distally located , hence flexible bronchoscopy is required in such cases . however , rigid bronchoscopy is preferred in children as it allows very efficient airway suctioning in case of massive bleed and is not time - consuming . cases have been reported where distally located fbs were removed by fluoroscopically guided catheters in a cardiac catheterization lab . the aspiration hazard can be minimized by using adhesive bands or snap fasteners instead of pins when wearing a scarf . headscarf pin aspiration is common in muslim girls , and the pins can usually be removed by flexible bronchoscopy . however , when the pin pierces the lung parenchyma , which is rare , it is necessary for a highly skilled pulmonologist to remove it endoscopically .

foreign body ( fb ) aspiration is commonly seen in children but less commonly in adolescents . headscarf pin aspiration is common in muslim girls , who inappropriately place the pins between their lips while securing the scarf on the head . bronchoscopy is the treatment modality of choice , and surgery is rarely required . an 11-year - old girl was admitted as a case of accidental aspiration of headscarf pin . x - ray chest showed a radiopaque object in the left bronchus piercing the lung parenchyma . computed tomography ( ct ) chest confirmed the diagnosis . the headscarf pin was removed by flexible bronchoscopy as the ear , nose , and throat ( ent ) surgeon failed to remove it by rigid bronchoscopy . the fb was removed successfully and the patient was discharged home . removal of a sharp pin by bronchoscopy is difficult , especially if it pierces the lung parenchyma . in our case , the pin was bent by forceps and then removed by a flexible bronchoscope , which requires a highly skilled professional .

An anonymous caller warned authorities Monday that his roommate was on his way to Yale University to shoot people, leading officials to lock the Ivy League campus down as police searched for a gunman. At least two witnesses reported seeing someone on or near campus with a long gun. An emergency call was received around 9:30 a.m. local time from a man at a pay phone about a mile (two kilometers) from the campus, said Officer David Hartman, a New Haven Police spokesman. "All he really said was that his roommate was on his way to the university, to Yale University, to shoot people," he said. Police later received reports from witnesses who reported seeing someone with a gun, Hartman said. He said that there was nothing specific about the threat and that the call lasted just several seconds. There were no reports of shots fired or anyone injured. Police blocked off several streets near the Ivy League university, located in the heart of New Haven. Several local schools also were placed in lockdown. Yale advised students and staff to shelter in place. The school also issued an advisory asking people off campus to stay away from the area. The school is on November break, with undergraduate classes to resume Dec. 2. Many students and staff had left campus for the American holiday of Thanksgiving. Pedestrian traffic in the normally bustling area also was sparse, with cold and windy weather keeping many people inside. Police in tactical gear entered several buildings, and a helicopter hovered over the area. Yale has been the target of violence in the past. In May 2003, a bomb damaged an empty classroom and adjacent reading room at the law school. A Yale professor, David J. Gelernter, was seriously injured in 1993, when a mail bomb mailed by Theodore Kaczynski, the man known as the Unabomber, exploded in his campus office. Friday's search came about two weeks after a scare on another Connecticut campus. Central Connecticut State University was in lockdown for several hours Nov. 4 after reports by witnesses of a masked man carrying a gun or sword. Police arrested a student, David Kyem, who said he had been wearing a ninja-like Halloween costume and meant no harm. He faces charges including breach of peace. ||||| A day-long lockdown of the Yale University campus was lifted this evening after authorities determined that a call warning of a gunman intent on shooting people was likely a hoax. Yale's New Haven, Conn., campus was put on lockdown after an anonymous male called 911 this morning to say his roommate was on his way to the campus with the intention of shooting people, according to officials. New Haven Police Chief Dean Esserman said there was "malicious intent" behind the call. However, after a search of the campus did not reveal any threats, he said authorities are "leaning toward this being a hoax." Esserman said once police identify the caller, that person "will face every charge possibly imaginable." The anonymous call was placed from a phone booth and the university sent out an alert at 10:17 a.m. ET. At a news conference earlier today, New Haven Police Officer David Hartman said authorities interviewed several witnesses who said they saw someone with a "long gun." After speaking with some of the witnesses, Hartman said, "Some of those witnesses in all probability saw police officers with long guns instead of a suspect." Yale Police Chief Ronell Higgins said this incident showed that the school's emergency preparedness plan worked well. "You have to exchange business cards with local law enforcement and schools before incidents like this one," he said. "We are always in constant communication." An email was also sent by Yale's dean to notify parents of undergraduate students of the threat. The school is on its November break, meaning there are fewer people on campus than usual. An alert send by the university this morning instructed people to shelter in place. "Confirmed report of person with a gun on/near Old Campus. SHELTER IN PLACE. This is NOT a test," the alert said. A search of the campus dorms was hampered because some students refused to open their doors to police, fearing that the person knocking was not really a police officer. The university has over 11,000 students.

– Yale University has lifted its lockdown after police said an anonymous call about a gunman headed to campus was probably a hoax, reports the AP. "New Haven is safe. The Yale campus is safe," said New Haven's police chief. "Though it is starting to tilt in the direction of an innocent mistake, it started with a purposeful and malicious call." A New Haven police officer said earlier that the caller claimed "that his roommate was on his way to the university, to Yale University, to shoot people." Several witnesses reported seeing someone with a "long gun," but there were no reports of shots fired or injuries, ABC News reports. During the lockdown, police blocked off several streets near the school and advised students and faculty to either stay off campus, or stay where they were on campus.

although the standard model ( sm ) has withstood all possible experimental challenges and has been tested to an unprecedented degree of accuracy , so far there has been no direct experimental verification of the phenomenon of spontaneous symmetry breaking . with the latter being considered a central pillar of this theory and its various extensions , the search for a higgs boson is one of the main aims for many current and future colliders @xcite . within the sm , the only fundamental spin-@xmath4 object is the ( @xmath0-even ) higgs boson and remains the only particle in the sm spectrum to be found yet . rather , a lower bound on the mass of the sm higgs boson , ( about 114.5 gev ) is provided by the direct searches at the lep collider @xcite . electroweak precision measurements , on the other hand , provide an upper bound on its mass of about 204 gev at 95% c.l . it should be realized that both these limits are model dependent and may be relaxed in extensions of the sm . for example , the lower limit can be relaxed in generic 2-higgs doublet models @xcite or in models with @xmath0 violation @xcite . in the latter case , direct searches at lep and elsewhere still allow the lightest higgs boson to be as light as 10 gev @xcite . similarly , the upper bound on the mass of the ( lightest ) higgs in some extensions may be substantially higher @xcite . the large hadron collider ( lhc ) is expected to be capable @xcite of searching for the higgs boson in the entire mass range allowed . it is then quite obvious that just the discovery of the higgs boson at the lhc will not be sufficient to validate the minimal sm . for one , the only neutral scalar in the sm is a @xmath5 state arising from a @xmath6 doublet with hypercharge 1 , while its various extensions can have several higgs bosons with different @xmath0 properties and @xmath7 quantum numbers . the minimal supersymmetric standard model ( mssm ) , for example , has two @xmath0-even states and a single @xmath0-odd one @xcite . thus , should a neutral spin-0 state be observed at the lhc , a study of its @xmath0-property would be essential to establish it as _ the _ sm higgs boson @xcite . since , at an @xmath8 collider , the dominant production modes of a neutral higgs boson proceed via its coupling with a pair of gauge bosons ( @xmath9 ) , any change in the @xmath10 couplings from their sm values can be probed via such production processes . within the sm / mssm , the only ( renormalizable ) interaction term involving the higgs boson and a pair of gauge bosons is the one arising from the higgs kinetic term . however , once we accept the sm to be only an effective low - energy description , higher - dimensional ( and hence non - renormalizable ) terms are allowed . if we only demand lorentz invariance and gauge invariance , the most general coupling structure may be expressed as @xmath11 \label{eq : coup}\end{aligned}\ ] ] where @xmath12 denote the momenta of the two @xmath13 s ( @xmath14 s ) , @xmath15 and @xmath16 . in the context of the sm , at the tree level , @xmath17 while the other couplings vanish identically . at the one - loop level or in a different theory , effective or otherwise , these may assume significantly different values . we study this most general set of anomalous couplings of the higgs boson to a pair of @xmath13s and @xmath14 at a linear collider ( lc ) in the processes @xmath18 , with @xmath19 being a light fermion . the various kinematical distributions for the process @xmath18 , proceeding via vector boson fusion and higgsstrahlung , with unpolarized beams has been studied in the context of the sm @xcite . the effect of beam polarization has also been investigated for the sm @xcite . the anomalous @xmath2 couplings have been studied in refs.@xcite for the lc and in refs.@xcite for the lhc in terms of higher dimensional operators . @xcite investigates the possibility to probe the anomalous @xmath20 couplings , @xmath21 , using the optimal observable technique @xcite for both polarized and un - polarized beams . @xcite , on the other hand , probes the @xmath0-violating coupling @xmath22 by means of asymmetries in kinematical distributions and beam polarization . in ref . @xcite , the @xmath10 vertex is studied in the process of @xmath23 using angular distributions of the decay products . the rest of the paper is organized as follows . in section [ sec : vvh ] we discuss the possible sources and symmetries of the anomalous @xmath10 couplings and the rates of various processes involving these couplings . in section [ sec : zzh ] we construct several observables with appropriate @xmath0 and @xmath24 property to probe various @xmath2 anomalous couplings . in section [ sec : wwh ] we construct similar observables to probe anomalous @xmath3 couplings , which we then use along with the ones constructed for the @xmath2 case . section [ sec : res ] contains a discussion and summary of our findings . the anomalous @xmath10 couplings in eq.([eq : coup ] ) can appear from various sources such as via higher order corrections to the vertex in a renormalizable theory @xcite or from higher dimensional operators in an effective theory @xcite . for example , in the mssm , the non - zero phases of the trilinear susy breaking parameter @xmath25 and the gaugino / higgsino mass parameters can induce @xmath0-violating terms in the scalar potential at one loop level even though the tree level potential is @xmath0-conserving . as a consequence , the higgs - boson mass eigenstates can turn out to be linear combinations of @xmath0-even and -odd states . this modifies the effective coupling of the higgs boson to the known particles from what is predicted in the sm ( or even from that within a version of mssm with no @xmath0-violation accruing from the scalar sector ) . in a generic multi - doublet model , whether supersymmetric @xcite or otherwise @xcite , the couplings of the neutral higgs bosons to a pair of gauge bosons satisfy the sum rule @xmath26 thus , while @xmath27 for a given higgs boson can be significantly smaller than the sm value , any violation of the above sum rule would indicate either the presence of higher @xmath6 multiplets or more complicated symmetry breaking structures ( such as those within higher - dimensional theories ) @xcite . the couplings @xmath28 or @xmath29 can arise only at a higher order in a renormalizable theory @xcite . furthermore , within models such as the sm / mssm where the tree - level scalar potential is @xmath0-conserving , @xmath29 may be generated only at an order of perturbation theory higher than that in which the higgs sector acquires @xmath0-violating terms . however , in an effective theory , which satisfies @xmath30 symmetry , the couplings @xmath28 and @xmath29 can arise , at the lowest order , from terms such as @xmath31 or @xmath32 @xcite where @xmath33 is the usual higgs doublet , @xmath34 is a field strength tensor and @xmath35 its dual . it can be easily ascertained that the effects of the higher dimensional terms in the trilinear vertices of interest can be absorbed into @xmath28 ( @xmath29 ) by ascribing them with non - trivial momentum - dependences ( form factor behavior ) . clearly , if the cut - off scale @xmath36 of this theory is much larger than the typical energy at which a scattering experiment is to be performed , the said dependence would be weak . in all processes that we shall be considering , this turns out to be the case . in particular , the bjorken process ( fig . [ fig : feyn](b ) ) essentially proceeds at a fixed center - of - mass energy , hence both @xmath37 and @xmath22 are constant for this process . even for the other processes of interest , namely gauge boson fusion ( fig . [ fig : feyn](a ) ) , the momentum dependence of the form - factors have a rather minor role to play , especially for @xmath38 . this suggests that we can treat @xmath39 as phenomenological and energy - independent parameters . a consequence of imposing an @xmath30 symmetry would be to relate the anomalous couplings , @xmath40 and @xmath41 , for the @xmath3 vertex with those for the @xmath2 vertex . however , rather than attempting to calculate these couplings within a given model , we shall treat them as purely phenomenological inputs , whose effect on the kinematics of various final states in collider processes can be analyzed . in general , each of these couplings can be complex , reflecting possible absorptive parts of the loops , either from the sm or from some new high scale physics beyond the sm . it is easy to see that a non - vanishing value for either @xmath42 or @xmath43 destroys the hermiticity of the effective theory . such couplings can be envisaged when one goes beyond the born approximation , whence they arise from final state interactions , or , in other words , out of the absorptive part(s ) of higher order diagrams , presumably mediated by new physics . a fallout of non - hermitian transition matrices is non - zero expectation values of observables which are odd under @xmath44 , where @xmath45 stands for the pseudo - time reversal transformation , one which reverses particle momenta and spins but does not interchange initial and final states . of course , such non - zero expectation values will be indicative of final state interaction only when kinematic cuts are such that the phase space integration respects @xmath44 . note that @xmath46 too can be complex in general and can give an additional @xmath24-odd contribution . however , for the processes that we will consider , the phase of at least one of @xmath47 and @xmath48 can always be rotated away , and we make this choice for @xmath48 . henceforth , we shall assume that @xmath47 and @xmath48 are _ close to their sm value _ , i.e. @xmath49 , the rationale being that any departure from @xmath50 and @xmath51 respectively would be the easiest to measure unfortunately , this still leaves us with many free parameters making an analysis cumbersome . one might argue that @xmath30 gauge invariance would predict @xmath52 . however , once symmetry breaking effects are considered , this does not necessarily follow @xcite . nevertheless , we will make this simplifying assumption that @xmath53 is real and equal to @xmath54 , i.e. @xmath55 , since the equality is found to hold true in some specific cases @xcite ( and would be dictated if @xmath30 were to be an exact symmetry of the effective theory ) . with this assumption , we list , in table [ tab : coup ] , the @xmath0 and @xmath45 properties of such operators . .[tab : coup]transformation properties of various anomalous couplings under discrete transformations . [ cols="^,^,^,^,^,^",options="header " , ] note that , unlike in the case of the @xmath2 couplings , we have largely been unable to construct observables that are primarily dependent only on a given anomalous coupling . in other words , the constraints are correlated . thus , it is of interest to obtain the maximal size that these couplings may assume with the aid of such correlations . such an analysis may be performed by examining the 9-dimensional parameter space ( i.e. , both @xmath2 and @xmath3 couplings ) and delineating the part that would be consistent with _ all _ the observables to a given level of confidence . clearly , the lack of correlations for the @xmath2 couplings renders the _ blind region _ to be trivial in five of the nine dimensions and the extent of these remain the same as in table [ tab : ind - lim ] . the most general simultaneous limits on the anomalous @xmath3 couplings obtained using this method are presented in table [ tab : com - wwh ] for both @xmath56 and @xmath57 . for the @xmath24-even couplings , such limits are comparable to the corresponding individual limits ( table [ tab : lim - wwh ] ) with only a small dilution due to contamination from @xmath2 vertex . for the @xmath24-odd couplings , however , the lack of any @xmath24-odd observable results in a possibly large contamination from @xmath2 vertex . consequently , the limits on @xmath58 and @xmath59 are only `` indirect '' and hence poor . finally , the effect of a non - zero @xmath60 is seen only in @xmath61 due to the large correlation between them ( see fig . [ fig : rebw - k2 ] ) . we have constructed observables which , due to their @xmath0 and @xmath62 transformation properties , receive contributions only from specific anomalous couplings with matching @xmath0 and @xmath24 properties . thus , most of the observables we construct are sensitive only to a single anomalous coupling . this one - to - one correspondence between the observable and the anomalous coupling allows us to obtain a robust constraint on the latter , _ independent _ of the values of all the other anomalous couplings . thus we see from tables [ tab : ind - lim ] [ tab : com - wwh ] that the individual and simultaneous limits are the same ( or very similar ) in most cases . the observables we construct are also very simple from the point of view of experimental measurements . in other words , they are both very physical and easily implementable in actual experiments . it should also be noted that the limits that we quote on the anomalous couplings , other than those on @xmath63 , are obtained using only asymmetries . in general , asymmetries are more robust with respect to the effects of radiative corrections , except in situations where the tree level contributions are accidentally small . this also means that we have a clear indication as to which observables bear a tighter scrutiny while assessing the effect of radiative corrections . available calculations of higher order corrections , in the sm @xcite , to the processes under consideration show that the total rates receive a correction less than 3% for a higgs with mass about 120 gev , thus validating our choice of @xmath64 . since radiative corrections to the processes we consider have been computed not only in the sm @xcite but also for the mssm @xcite , assessing the effects of these on the rates and asymmetries and hence on the sensitivity for the anomalous couplings will be the next logical step of this analysis which has shown efficacy of these variables to probe these couplings . furthermore , in our analysis , we have imposed simple cuts on the kinematic variables which virtually eliminate the non - higgs backgrounds to the particular final states under consideration . since the latter involve @xmath65 jets , we fold our results with realistic @xmath65-tagging efficiencies . in addition , certain cuts also serve to enhance / suppress particular contributions to the signal . for example , the additional cuts @xmath66 and @xmath67 were introduced to enhance the contribution from @xmath68channel and @xmath69channel diagrams respectively . if we look at the observables pertaining to the @xmath2 vertex , then all the couplings , except for @xmath70 , are best constrained with @xmath66 cut , i.e , via the bjorken diagram when @xmath14 boson is produced on - shell . the contributions from @xmath71 and @xmath72 are proportional to @xmath73 , and hence are small away from the @xmath14-pole . for @xmath70 , however , the contribution from the @xmath74-channel is roughly proportional to @xmath75 hence an analysis with the @xmath67 cut provides a better limit . the situation is more complicated for the @xmath3 couplings . while the relevant final state , namely @xmath76 , receives large contributions from @xmath24-odd coupling , the impracticality of measuring the momentum of an individual neutrino prevents us from isolating such contributions . consequently , we are left with just two observables , which , coupled with @xmath77 and @xmath78 cuts , provide probes of the @xmath24-even couplings . the bounds on the @xmath24-odd couplings are indirect and hence suffer from reduced sensitivity . furthermore , the contributions from non - zero anomalous @xmath2 couplings can not be eliminated in their entirety and are treated as contaminations in the determination of the @xmath3 couplings . together , these two factors result in the bounds on the two @xmath24-odd @xmath3 couplings to be as weak as order unity . note though that our entire formalism presupposes that the anomalous couplings are small and thus these limits on @xmath59 and @xmath58 are of little value . it is instructive to compare the results of our analysis with those of earlier investigations . @xcite had analyzed the case of @xmath2 couplings with ( out ) initial beam polarization . we find that the effect of realistic cuts on kinematic variables required to isolate the signal with the dominant final state with @xmath79 as well as the finite @xmath65-tagging efficiency , reduces the possible limits on @xmath22 by about a factor of 2 , compared to the ones quoted in ref . @xcite with unpolarized beams . needless to say , if the reduction in rates implied by these cuts is neglected , our analysis does reproduce the results of ref . @xcite . in ref . @xcite , an optimal observable analysis @xcite is performed , including along with an additional anomalous @xmath80 coupling . while such optimal variable analyses generally indicate the maximum achievable sensitivity , the observables constructed very often remain a little opaque with respect to the physics they probe . the parameterization of ref . @xcite is quite different from ours . still , making use of the correlation matrices given by them , and putting the @xmath80 coupling to zero , one may extract the limits their analysis will imply for our parameterization . doing this , we find that , for the @xmath24-even couplings , our limits compare quite well with those obtained in the analysis of ref . @xcite , implying thereby that our simple @xmath24 observables indeed catch the physics content of their optimal observables in this case . for the @xmath24-odd couplings , our use of simple observable like the expectation value of sign of @xmath81 rather than the expectation value of the momentum correlator , @xmath82 causes a loss in sensitivity only by a factor 4 . given the fact that some of this is attributable to our use of realistic kinematic cuts , @xmath65-tagging efficiencies etc , this is a very modest price to pay for the simplicity of the observable . the optimal observable analysis shows that the use of @xmath83 and @xmath84 final states and polarization of the beams can improve the sensitivity significantly . this is a very good motivation for constructing analogous simple observables similar to the ones constructed here . to summarize , we have looked at the higgs production processes at an @xmath8 collider involving @xmath10 coupling . we constructed several observables with appropriate @xmath0 and @xmath24 properties to probe various anomalous couplings incorporating realistic cuts and detection efficiencies . using these observables in the context of @xmath85 fusion and higgstrahlung processes , we obtain stringent but realistic bounds on the various anomalous @xmath2 couplings , even while allowing for maximal cancellations between the various individual contributions . as for the @xmath3 couplings , their effects can not be fully isolated from those of the @xmath2 couplings . nonetheless , we are able to derive quite stringent bounds for the @xmath24-even subset even while accounting for maximal contamination from the@xmath2 sector . on the other hand , the lack of suitable @xmath24-odd observables render the limits on the @xmath24-odd @xmath3 couplings to be only indirect and thus poor . we reemphasize that all our asymmetries are simple to construct , have specific @xmath0 and @xmath24 properties to probe specific anomalous coupling , and are robust against both the radiative correction to the rates as well as systematic errors . we thank b. mukhopadhyaya for collaboration in the initial phase of this project and s. d. rindani , m. schumacher and k. moenig for useful discussions and s. k. rai for reading the manuscript . we would like to acknowledge support from the department of science and technology under project number sr / fist / psi-022/200 , to the center for high energy physics , iisc , for the cluster which was used for computations . the work was also partially supported under the dst project sp / s2/k-01/2000-ii and the indo - french project ifc/3004-b/2004 . rks wishes to thank harish - chandra research institute for hospitality where this work was started and council for scientific and industrial research for the financial support . dc thanks the dst , india for financial assistance under the swarnajayanti grant . as mentioned in section iib , the total cross - section for @xmath86 receives contributions only from @xmath0-even and @xmath24-even couplings @xmath87 and @xmath88 , while the other couplings contribute to partial cross - section in such a way that their net contribution to the total rate is zero . in our analysis so far , we considered appropriately chosen partial cross - sections and combined them to construct asymmetries . in its stead , we could , in principle , have considered just the partial cross sections themselves and investigated their resolving power . this , we attempt now . to start with , we look at @xmath89 and constrain the higgs boson to be in the forward direction ( @xmath90 ) and @xmath91 to be above the higgs production plane ( @xmath92 ) . this partial cross - section , called `` forward - up '' and denoted by @xmath93 in section iii f , is plotted as a function of @xmath94 in fig . [ fig : fu - s ] for the sm . also shown are the corresponding cross - sections when only one anomalous coupling is non - zero . the large values of the anomalous couplings have been chosen to highlight the differences . we see that all four anomalous couplings contribute to the @xmath93 partial cross - section , which can now be parametrized as @xmath95 if only one anomalous coupling @xmath96 were to be non - zero , then the measurement of this partial cross - section would be sensitive to @xmath97 here @xmath98 is the degree of statistical significance , @xmath99 is the integrated luminosity of the @xmath8 collider and @xmath100 is the fractional systematic error . in fig . [ fig : lim - s ] , we show a simple ( @xmath101 ) limit on anomalous couplings , obtained using fig . [ fig : fu - s ] , for an integrated luminosity of 500 fb@xmath1 . a measurement of @xmath102 will thus be sensitive to values of @xmath96 lying above the corresponding curve . a similar exercise can be done for @xmath103 , and in fig . [ fig : hnn](a ) we display the @xmath93 partial cross - section for the same as a function of the center - of - mass energy . the presence of an additional @xmath74-channel diagram changes the @xmath94 behaviour of the partial cross - section and hence that of the limits that could be inferred in a fashion analogous to fig . [ fig : fu - s ] . for @xmath70 and @xmath104 , the @xmath105 bounds of table [ tab : ind - lim ] are much better than the @xmath106 limits shown in fig . [ fig : lim - s ] . this indicates that asymmetries with appropriate symmetry properties and combinations of various final states can be used efficiently to obtain stringent constraints on anomalous couplings . for @xmath104 , on the other hand , the limit obtained using @xmath107 is only comparable to the one obtained using just the partial rate @xmath108 after accounting for degrees of significance . however , the limit from @xmath108 is subject to the assumption that all other anomalous couplings are zero , while the one obtained using @xmath107 is independent of any other anomalous coupling . once again this underscores the importance of specific observables , such as @xmath109 , which receive a contribution from only one of the anomalous coupling , thus allowing us to obtain a robust constraint . and finally , we look at the @xmath110 channel , where both @xmath3 and @xmath2 vertices contribute thus doubling the number of anomalous couplings involved . since the final state fermions , the neutrinos , are not detectable , it is meaningless to construct the partial cross - section @xmath93 . instead we add @xmath93 and @xmath111 to form the `` forward '' cross - section , _ i.e. _ the higgs boson is constrained to be in the forward direction , and the @xmath94 dependence is displayed in fig . [ fig : hnn](b ) . the size of the anomalous contribution in these figures gives an idea about the sensitivity to that particular coupling . in this appendix , we list the square of invariant matrix element for the various processes considered in the text . to begin with , we define the fermion-@xmath14 vertices by @xmath113 in considering a process such as @xmath114 , it is further convenient to devise a notation for scalar products such as @xmath115 and similarly for the multitude of propagators that one encounters , namely @xmath116 we have , for where @xmath117 is any massless fermion , @xmath118 & & \displaystyle - \frac{\reazbzconj}{m_z^2}\ , \bigg ( ( \lesq \ , \lqsq + \resq \ , \rqsq ) \ , ( \pdot14 + \pdot23 ) \ , \left\ { \pdot13 \ , \pdot24 - \pdot12 \ , \pdot34 \ , - \pdot14 \ , \pdot23 \ , \right\}\\ & & \displaystyle \hspace*{6em } + ( \lesq \ , \rqsq + \resq \ , \lqsq ) \ , ( \pdot13 + \pdot24 ) \ , \left\ { \pdot14 \ , \pdot23 - \pdot12 \ , \pdot34 - \pdot13 \ , \pdot24 \right\ } \bigg)\\[3ex ] & & \displaystyle - \ , \frac{\imazbzconj}{m_z^2}\ , \ , { \cal a } \bigg((\lesq \ , \lqsq - \resq \ , \rqsq ) \ , ( \pdot14 - \pdot23 ) + ( \resq \ , \lqsq - \lesq \ , \rqsq)\ , ( \pdot13 - \pdot24 ) \bigg ) \\[3ex ] & & \displaystyle + \frac{\reazbtilzconj}{m_z^2 } \ , { \cal a } \ , \bigg ( ( \lesq \ , \lqsq + \resq \ , \rqsq ) \ , ( \pdot14 + \pdot23 ) - ( \lesq \ , \rqsq + \resq \ , \lqsq ) \ , ( \pdot13 + \pdot24 ) \bigg ) \\[3ex ] & & \displaystyle - \ ; \frac{\imazbtilzconj}{m_z^2 } \ , \bigg ( ( \lesq \ , \lqsq -\resq \ , \rqsq ) \ , ( \pdot23 - \pdot14 ) \left\ { \pdot12 \ , \pdot34 - \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \right\ } \\ & & \displaystyle \hspace*{6em } + ( \resq \ , \lqsq - \lesq \ , \rqsq ) ( \pdot13 - \pdot24 ) \ , \left\ { \pdot12 \,\pdot34 - \pdot14 \ , \pdot23 + \pdot13 \ , \pdot24 \right\ } \bigg)\bigg ] \end{array } \label{mesq_quark}\ ] ] for @xmath119 , the expressions are a bit more complicated , and @xmath120 \end{aligned}\ ] ] where , @xmath121 - \ , \frac{\imazbzconj}{m_z^2 } \ , ( \lefour - \refour ) \ , { \cal a } ( \pdot14 - \ , \pdot23 ) \\ & + & \displaystyle \frac{\reazbzconj}{m_z^2 } \ ; \bigg[(\lefour + \refour ) \ , ( \pdot14 + \pdot23 ) \ \left\ { \pdot12 \ , \pdot34 - \ , \pdot13 \ , \pdot24 \ + \ , \pdot14 \ , \pdot23 \right\ } \\ & & \displaystyle \hspace*{3em } + 2 \ , \lesq \resq \ , ( \pdot13 + \pdot24 ) \ , \left\ { \pdot12 \ , \pdot34 + \pdot13 \ , \pdot24 - \pdot14 \ , \pdot23 \right\ } \bigg ] \\[2ex ] & + & \displaystyle \frac{\imazbtilzconj}{m_z^2 } \ , ( \lefour - \refour ) \ , ( \pdot14 - \pdot23 ) \ , \left\ { \pdot12 \ , \pdot34 - \ , \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \right\ } \\[2ex ] & + & \displaystyle \frac{\reazbtilzconj}{m_z^2 } \ , { \cal a } \ , \left[(\lefour + \refour ) \ , ( \pdot14 + \ , \pdot23 ) - 2 \ , \lesq \resq ( \pdot13 + \pdot24 ) \right ] , \end{array}\ ] ] @xmath122 - \ ; \frac{\imazbzconj}{m_z^2 } \ ; ( \refour - \lefour ) \ , { \cal a } \ , ( \pdot14 - \pdot23 ) \\[2ex ] & + & \displaystyle \frac{\reazbzconj}{m_z^2 } \ ; \bigg [ ( \lefour + \refour ) \ , ( \pdot14 + \pdot23 ) \ , \left\ { - \ , \pdot12 \ , \pdot34 + \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \right\ } \nonumber \\ & & + 2 \ , \lesq \resq \ , ( \pdot12 \ , + \pdot34 ) \ ; \left\ { - \pdot13 \ , \pdot24 - \pdot12 \ , \pdot34 + \pdot14 \ , \pdot23 \right\ } \bigg ] \nonumber\\ & + & \displaystyle\frac{\imazbtilzconj}{m_z^2 } \ ; ( \refour - \lefour ) \ ; ( \pdot23 - \pdot14 ) \ ; \left\ { - \pdot12 \ , \pdot34 + \ , \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \ , \right\}\nonumber\\ & - & \displaystyle\frac{\reazbtilzconj}{m_z^2 } \ ; { \cal a } \ ; \left [ ( \lefour + \refour ) ( \pdot14 + \pdot23 ) + 2 \ , \lesq \ , \resq \ , ( \pdot12 + \pdot34 ) \right ] , \end{array}\ ] ] @xmath123 & + & \displaystyle \frac{(\lefour - \refour)}{m_z^2 } \ ; ( \pdot23 - \pdot14 ) \ ; \left [ i \ , \reazbzconj \ ; { \cal a } + i \ , \reazbtilzconj \ , ( \pdot13 \ , \pdot24 - \pdot12 \ , \pdot34 ) + \imazbtilzconj \ , \pdot14 \ , \pdot23 \right ] \\[3ex ] & - & \displaystyle \frac{(\lefour + \refour)}{m_z^2 } \ ; ( \pdot14 + \pdot23 ) \ ; \left [ i \ , \imazbzconj \ ; ( \pdot12 \ , \pdot34 - \pdot13 \ , \pdot24 ) + i \ , \imazbtilzconj \ , { \cal a } + \reazbzconj \ , \pdot14 \ , \pdot23 \right ] \end{array}\ ] ] and finally , for @xmath124 , @xmath125 \end{aligned}\ ] ] where , @xmath126 + \frac{\imazbzconj}{m_z^2 } \ ; { \cal a } \ ; \bigg[\lesq \ , ( \pdot23 - \pdot14 ) + \resq \ , ( \pdot24 - \pdot13 ) \bigg ] \nonumber\\ & + & \frac{\reazbzconj}{m_z^2 } \ , \bigg [ \lesq \ , ( \pdot14 + \pdot23 ) \ , \left\ { \pdot12 \ , \pdot34 - \ , \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \right\ } + \resq \,(\pdot13 + \pdot24 ) \ , \left\ { \pdot12 \ , \pdot34 + \pdot13 \ , \pdot24 - \pdot14 \ , \pdot23 \right\ } \bigg ] \nonumber\\ & + & \frac{\imazbtilzconj}{m_z^2 } \ , \bigg[\lesq \ , ( \pdot14 - \pdot23 ) \ , \left\ { \pdot12 \ , \pdot34 - \ , \pdot13 \ , \pdot24 \ , + \pdot14 \ , \pdot23 \right\ } + \resq \ , ( \pdot24 - \pdot13 ) \ , \left\ { \pdot12 \ , \pdot34 + \pdot13 \ , \pdot24 - \pdot14 \ , \pdot23 \right\ } \bigg ] \nonumber\\ & - & \frac{\reazbtilzconj}{m_z^2 } \ ; { \cal a } \ ; \bigg[\resq \,(\pdot13 + \pdot24 ) - \lesq \ , ( \pdot14 + \ , \pdot23 ) \bigg],\end{aligned}\ ] ] @xmath127 @xmath128 \nonumber\\ & - & i \ ; \frac{a_w \ , \btilz^*}{m_z^2 } \ , \bigg [ ( \pdot23 - \pdot14 ) \ , \left\ { \pdot12 \ , \pdot34 - \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \right\ } - i \ ; { \cal a } \ ; ( \pdot14 + \pdot23 ) \bigg]\nonumber\\ & + & \frac{a_z^ * \ , b_w}{m_w^2 } \ , \bigg [ ( \pdot14 + \pdot23 ) \ , \left\ { \pdot12 \ , \pdot34 - \ , \pdot13 \ , \pdot24 - \ , \pdot14 \ , \pdot23 \right\ } - i \ ; { \cal a } \ ; ( \pdot14 - \pdot23 ) \bigg]\nonumber\\ & + & i \ ; \frac{a_z^ * \ , \btilw}{m_w^2 } \ , \bigg [ ( \pdot23 - \pdot14 ) \ , \left\ { - \pdot12 \ , \pdot34 + \pdot13 \ , \pdot24 + \pdot14 \ , \pdot23 \right\ } - i \ ; { \cal a } \ ; ( \pdot14 + \pdot23 ) \bigg]\end{aligned}\ ] ] in the propagators , we ignore the contribution proportional to @xmath129 except for @xmath130 , which goes on - shell , and can not be ignored , in general . r. akers _ et al . _ [ opal collaboration ] , z. phys . c * 61 * , 19 ( 1994 ) ; d. buskulic _ et al . _ [ aleph collaboration ] , z. phys . c * 62 * , 539 ( 1994 ) ; m. acciarri _ et al . _ [ l3 collaboration ] , z. phys . c * 62 * , 551 ( 1994 ) ; p. abreu _ et al . _ [ delphi collaboration ] , z. phys . c * 67 * , 69 ( 1995 ) ; d. antreasyan _ et al . _ [ crystal ball collaboration ] , phys . b * 251 * , 204 ( 1990 ) ; p. franzini _ et al . _ , phys . d * 35 * , 2883 ( 1987 ) ; j. kalinowski and m. krawczyk , phys . b * 361 * , 66 ( 1995 ) [ arxiv : hep - ph/9506291 ] ; d. choudhury and m. krawczyk , phys . d * 55 * , 2774 ( 1997 ) [ arxiv : hep - ph/9607271 ] . m. carena , j. r. ellis , a. pilaftsis and c. e. m. wagner , nucl . * b586 * , 92 ( 2000 ) ; a. mendez and a. pomarol , phys . b * 279 * , 98 ( 1992 ) ; j. f. gunion , h. e. haber and j. wudka , phys . d * 43 * , 904 ( 1991 ) ; j. f. gunion , b. grzadkowski , h. e. haber and j. kalinowski , phys . lett . * 79 * , 982 ( 1997 ) [ hep - ph/9704410 ] ; i. f. ginzburg , m. krawczyk and p. osland , hep - ph/0211371 . r. l. kelly and t. shimada , phys . d * 23 * , 1940 ( 1981 ) ; p. kalyniak , j. n. ng , p. zakarauskas , phys . d * 29 * , 502 ( 1984 ) . w. kilian , m. kramer and p. m. zerwas , phys . b * 373 * , 135 ( 1996 ) [ arxiv : hep - ph/9512355 ] . j. c. romao and a. barroso , phys . b * 185 * , 195 ( 1987 ) . k. hagiwara and m. l. stong , z. phys . c * 62 * , 99 ( 1994 ) . h. j. he , y. p. kuang , c. p. yuan and b. zhang , phys . b * 554 * , 64 ( 2003 ) [ arxiv : hep - ph/0211229 ] . k. hagiwara , s. ishihara , r. szalapski and d. zeppenfeld , phys . d * 48 * , 2182 ( 1993 ) ; k. hagiwara , r. szalapski and d. zeppenfeld , phys . b * 318 * , 155 ( 1993 ) [ arxiv : hep - ph/9308347 ] . g. j. gounaris , f. m. renard and n. d. vlachos , nucl . b * 459 * , 51 ( 1996 ) [ arxiv : hep - ph/9509316 ] . b. zhang , y. p. kuang , h. j. he and c. p. yuan , phys . d * 67 * , 114024 ( 2003 ) [ arxiv : hep - ph/0303048 ] . t. plehn , d. rainwater and d. zeppenfeld , phys . lett . * 88 * 051801 ( 2002 ) k. hagiwara , s. ishihara , j. kamoshita and b. a. kniehl , eur . j. c * 14 * , 457 ( 2000 ) [ arxiv : hep - ph/0002043 ] . d. atwood and a. soni , phys . d * 45 * , 2405 ( 1992 ) . t. han and j. jiang , phys . d * 63 * , 096007 ( 2001 ) m. c. gonzalez - garcia , int . j. mod . a * 14 * , 3121 ( 1999 ) [ arxiv : hep - ph/9902321 ] . v. barger , t. han , p. langacker , b. mcelrath and p. zerwas , phys . d * 67 * , 115001 ( 2003 ) [ arxiv : hep - ph/0301097 ] . a. mendez and a. pomarol , phys . b * 272 * , 313 ( 1991 ) . d. choudhury , a. datta and k. huitu , nucl . b * 673 * , 385 ( 2003 ) [ arxiv : hep - ph/0302141 ] . a. pilaftsis and c. e. m. wagner , nucl . b * 553 * , 3 ( 1999 ) ; m. carena , h. e. haber , h. e. logan and s. mrenna , phys . d * 65 * , 055005 ( 2002 ) v. d. barger , k .- cheung , a. djouadi , b. a. kniehl and p. m. zerwas , phys . d * 49 * , 79 ( 1994 ) [ arxiv : hep - ph/9306270 ] . d. choudhury , t. m. p. tait and c. e. m. wagner , phys . d * 65 * , 115007 ( 2002 ) [ arxiv : hep - ph/0202162 ] . for a recent review , see a. djouadi , arxiv : hep - ph/0503172 . m. acciarri _ et al . _ [ l3 collaboration ] , phys . b * 439 * , 225 ( 1998 ) ; p. abreu _ et al . _ [ delphi collaboration ] , eur . phys . j. c * 9 * , 367 ( 1999 ) ; s. m. xella - hansen , m. wing , d. j. jackson , n. de groot and c. j. s. damerell , lc - phsm-2003 - 061 ; a. denner , s. dittmaier , m. roth and m. m. weber , nucl . b * 660 * , 289 ( 2003 ) [ arxiv : hep - ph/0302198 ] ; a. denner , s. dittmaier , m. roth and m. m. weber , nucl . suppl . * 135 * , 88 ( 2004 ) [ arxiv : hep - ph/0406335 ] ; f. boudjema _ et al . _ , phys . b * 600 * , 65 ( 2004 ) [ arxiv : hep - ph/0407065 ] ; g. belanger et al , phys . b * 559 * , 252 ( 2003 ) [ arxiv : hep - ph/0212261 ] ; nucl . suppl . * 116 * , 353 ( 2003 ) [ arxiv : hep - ph/0211268 ] . t. hahn , s. heinemeyer and g. weiglein , nucl . b * 652 * , 229 ( 2003 ) [ arxiv : hep - ph/0211204 ] ; s. heinemeyer and g. weiglein , nucl . suppl . * 89 * , 210 ( 2000 ) ; h. eberl , w. majerotto and v. c. spanos , nucl . b * 657 * , 378 ( 2003 ) [ arxiv : hep - ph/0210038 ] .

we examine , in a model independent way , the sensitivity of a linear collider to the couplings of a light higgs boson to gauge bosons . including the possibility of @xmath0 violation , we construct several observables that probe the different anomalous couplings possible . for an intermediate mass higgs , a collider operating at a center of mass energy of 500 gev and with an integrated luminosity of 500 fb@xmath1 is shown to be able to constrain the @xmath2 vertex at the few per cent level , and with even higher sensitivity in certain directions . however , the lack of sufficient number of observables as well as contamination from the @xmath2 vertex limits the precision with which the @xmath3 coupling can be measured .

topological defects have played a key role in understanding the physics of scalar and spinor superfluids . the first topological defect observed in a gaseous bose - einstein condensate ( bec ) was a quantized vortex created using the phase imprinting method @xcite . vortices have also been created using rotating potential @xcite and by means of adiabatic spin rotation accompanied by a topological berry phase @xcite . in these methods , topological defect formation is enforced by an external laser or magnetic field . on the other hand , topological defects can also be created spontaneously . the mermin - ho texture @xcite of superfluid @xmath0 in a cylindrical container involves a coreless vortex . the kibble - zurek mechanism @xcite in a quenched superfluid or in the early universe affords another intriguing example of spontaneous topological defect formation . thermally nucleated vortices have recently been observed in a gaseous bec , presenting yet another topological phase transition known as the berezinskii - kosterlitz - thouless transition @xcite . recently , the berkeley group @xcite observed the spontaneous topological defect formation of spin in a spin-1 @xmath1 bec . the atoms were prepared in the @xmath2 state ( polar phase in fig . [ f : phase ] ) in a strong magnetic field , where @xmath3 is the magnetic quantum number . . in the ferromagnetic phase , the ground state is the @xmath4 state for @xmath5 and the @xmath6 state for @xmath7 , while in the polar phase , the ground state is the @xmath2 state . the ground - state wave function in the broken - axisymmetry phase possesses three nonzero components given in eq . ( [ baxi ] ) , and the spin vector tilts against the applied magnetic field . the arrow indicates the direction of the quench of the magnetic field . , width=317 ] the magnetic field is then lowered below a certain critical value ( broken - axisymmetry phase in fig . [ f : phase ] ) , where the @xmath2 state becomes dynamically unstable and magnetization grows in a direction perpendicular to the magnetic field , and , consequently , the axisymmetry in the spin space is spontaneously broken @xcite . in the experiment , the magnetic field was rapidly decreased across the critical value ( as shown by the arrow in fig . [ f : phase ] ) a process we refer to as `` quench '' and the ensuing magnetization dynamics was observed by the spin - sensitive _ in situ _ measurement @xcite . after the quench , it was observed that magnetization grew to form complicated ferromagnetic domains , and that , remarkably , some snapshots of the spatial spin distribution revealed topological spin textures , known as polar - core spin vortices @xcite . it has been predicted that a variety of spin textures , such as the staggered domain and helical textures , are created by the quench of the magnetic field @xcite . the spontaneous nucleation of the polar - core vortex has also been predicted in ref . the underlying physics in the spontaneous spin - texture formation is spin conservation , which prohibits uniform magnetization . motivated by the berkeley experiment @xcite , in the present paper we study the dynamics of a spin-1 bec caused by the quench of the magnetic field from the polar to the broken - axisymmetry phase , and investigate the formation dynamics of the topological spin texture . we show that the spin vortices observed in ref . @xcite are formed in two steps . first , spin domains separated by domain walls develop , breaking the axisymmetry in the spin space . secondly , the domains transform into spin vortex - antivortex pairs . we find that the details of the dynamics depend on the initial seed in the @xmath8 states , which represents residual atoms , quantum fluctuations , and thermal noises , and identify an initial seed that reproduces the experimental results . we also study the quench - time dependence of the number of created spin vortices . this paper is organized as follows . section [ s : meanfield ] reviews the mean - field theory of the spin-1 bec and some of its key properties relevant to later discussions . we also point out an analogy between defects in a spinor bec and those in a scalar bec in sec . [ s : topological ] . section [ s : dynamics ] studies the magnetization dynamics of the trapped system . sections [ s : uniform ] , [ s : noise ] , and [ s : cutoff ] examine three different kinds of initial noise conditions and identify an appropriate one that captures the main features of the berkeley experiment . section [ s : quench ] investigates the dependence of the dynamics on the speed of the quench and on the final value of the magnetic field . section [ s : transverse ] studies the behavior of the growth of the total magnetization , and sec . [ s : conclusion ] concludes the paper . the zero - temperature mean - field energy of a spinor bec confined in an optical trapping potential @xmath9 is given by @xmath10 + e_{\rm int } + e_b,\ ] ] where @xmath11 is the mass of the atom and @xmath12 is the condensate wave function for atoms in magnetic sublevel @xmath3 , satisfying @xmath13 with @xmath14 being the total number of atoms . we define the atomic number density @xmath15 and the spin density @xmath16 where @xmath17 is the vector of the spin-1 matrices . the interaction energy @xmath18 for the spin-1 atom has the form @xcite @xmath19 where @xmath20 with @xmath21 being the @xmath22-wave scattering length for two colliding atoms with total spin @xmath23 . in the present paper , we consider the case of spin-1 @xmath1 atoms , and take @xmath24 and @xmath25 @xcite , where @xmath26 is the bohr radius . the linear and quadratic zeeman energy @xmath27 under magnetic field @xmath28 is given by @xmath29_{m m ' } \psi_{m'},\ ] ] where @xmath30 is the bohr magneton , @xmath31 is the hyperfine splitting energy , and @xmath32 in the first term is the land g - factor . the mean - field dynamics of the system is thus described by the multicomponent gross - pitaevskii ( gp ) equation , [ gp ] @xmath33 where @xmath34 , @xmath35 , and the magnetic field is assumed to be in the @xmath36 direction . the linear zeeman terms @xmath37 in eq . ( [ gp1 ] ) only rotate the spin around the @xmath36 axis at the larmor frequency . going onto the rotating frame of reference by setting @xmath38 and @xmath39 , we find that the linear zeeman terms can be eliminated . we briefly review the ground state and excitation spectrum for the homogeneous case @xcite . for spin-1 @xmath1 atoms , @xmath40 is negative , and the ground - state phase diagram is given as fig . [ f : phase ] , where @xmath41 with @xmath42 being the lagrange multiplier @xcite . here , @xmath42 is introduced to set @xmath43 at a prescribed value , since the total magnetization in the @xmath36 direction is conserved . when the quadratic zeeman energy @xmath44 is larger than @xmath45 , the polar phase , @xmath46 , is the ground state . between the polar and ferromagnetic phases , there is a broken - axisymmetry phase shown as the shaded region in fig . [ f : phase ] . the order parameter in this phase is given by @xcite [ baxi ] @xmath47 where @xmath48 are arbitrary phases of the @xmath8 states . we note that spin vector @xmath49 in this phase tilts against the direction of the magnetic field , breaking the axisymmetry spontaneously @xcite . the phase boundaries are given by @xmath50 and @xmath51 , across which the system undergoes the second - order phase transition . in sec . [ s : dynamics ] , in an attempt to study the berkeley experiment we will examine the magnetization dynamics from the initial @xmath2 state . in order to understand the dynamics qualitatively , we consider the bogoliubov excitations from the @xmath2 state for the homogeneous case . solving the bogoliubov - de genne equation , we obtain the excitation spectrum as @xcite @xmath52 where @xmath53 with @xmath54 being the wave number . the mode given in eq . ( [ e0 ] ) involves only the @xmath2 state , and can be regarded as a phonon mode , whose excitation energy is always real and positive . the two modes given in eq . ( [ e1 ] ) are magnon modes , which transfer the atoms from the @xmath2 state to the @xmath8 states . the excitation energies @xmath55 are complex for @xmath56 . therefore , when @xmath40 is negative and @xmath57 , the @xmath2 state is dynamically unstable against long - wavelength excitations of the magnon modes . for @xmath58 , the most unstable wavelength is @xmath59 and the corresponding imaginary part of @xmath55 is @xmath60 , giving a characteristic time scale for the dynamical instability as @xmath61 for a larger magnetic field satisfying @xmath62 , the most unstable wave number is @xmath63 , and therefore the system tends to magnetize uniformly . the corresponding time scale is given by @xmath64^{1/2}$ ] . the above bogoliubov analysis is valid only when the system is homogeneous and deviations from the initial state are small . to investigate regions beyond such restrictions , we will solve full gp equation ( [ gp ] ) numerically in sec . [ s : dynamics ] , and analyze the detailed magnetization dynamics of the trapped system . quantized vortices and dark solitons in scalar becs are topological defects , in which the density vanishes due to the topological constraint on the phase of the wave function . we relate these topological defects in scalar becs to spin vortices and domain walls in spinor becs , in which local magnetization vanishes . we first note that throughout the spin - exchange dynamics the total density @xmath65 remains almost constant because @xmath66 . since the transverse magnetization develops from the @xmath2 state , we also assume that @xmath67 = @xmath68 and phases @xmath69 of @xmath12 are related to each other by @xmath70 , where @xmath71 is an arbitrary function . substituting these relations in the gp equation ( [ gp ] ) , we can eliminate @xmath72 and @xmath73 , obtaining @xmath74 where we drop the trapping potential and the linear zeeman term for simplicity . equation ( [ singlegp ] ) is the single - component gp equation with a repulsive interaction ( @xmath75 ) . the general form of a spin - vortex state is given by @xmath76 where @xmath77 is the azimuthal angle , @xmath78 s are global phases , @xmath79 s are integers , and @xmath80 s are real functions of @xmath81 . in eq . ( [ gensv ] ) , we assume that the system is uniform in the @xmath36 direction and that the vortex core is located on the @xmath36 axis . for example , the mermin - ho texture has topological charges @xmath82 , @xmath83 , and @xmath84 . the solution to eq . ( [ singlegp ] ) with a singly - quantized vortex is given by @xmath85 where @xmath86 is an arbitrary phase and @xmath87 . since the @xmath8 states have topological defects , @xmath88 vanishes at @xmath89 , and the core is then occupied by the @xmath2 ( polar ) state . the state given by eq . ( [ pcv ] ) is therefore referred to as a polar - core vortex . equation ( [ singlegp ] ) indicates that @xmath90 is proportional to @xmath91 near @xmath89 , where @xmath92 and hence the size of the vortex core is characterized by @xmath93 . the spin density of eq . ( [ pcv ] ) is given by @xmath94 @xmath95 . equation ( [ fp ] ) shows that the spin vector circulates around the @xmath36 axis with phase winding @xmath96 and vanishes at @xmath89 . in fact , the spin current @xmath97\ ] ] for eq . ( [ pcv ] ) is calculated to be @xmath98 and @xmath99 where @xmath100 is a unit vector in the azimuthal direction . on the other hand , state ( [ pcv ] ) has no mass current , @xmath101,\ ] ] and has no orbital angular momentum . equation ( [ singlegp ] ) has a dark - soliton solution as @xmath102 where @xmath103 and we assume that the planar dark soliton is located at @xmath104 . this solution describes a domain wall at @xmath104 , since the spin vector @xmath49 vanishes at @xmath104 and asymptotically approaches a constant vector with opposite directions for @xmath105 . the magnitude of transverse magnetization @xmath106 is proportional to @xmath107 thus , the width of the domain wall is of the same order as the size of the spin vortex . the planar dark soliton is known to be dynamically unstable against `` snake instability '' @xcite . this instability arises for the wavelength longer than the critical wavelength , @xmath108 after the distortion by the snake instability , the dark soliton transforms into vortex - antivortex pairs @xcite . this phenomenon has been observed in a nonlinear optical medium @xcite and in a two - component bec @xcite . in the spinor bec , an analogous instability causes formation of polar - core vortex - antivortex pairs . we will show in the next section that spin vortices are generated from domain walls by this mechanism . in this section , we will numerically simulate the magnetization dynamics in a situation corresponding to the berkeley experiment @xcite and compare the results . we first briefly review the experiment . the trapping frequencies of the optical potential used in the experiment are given by @xmath109 hz , and the system is effectively quasi - two dimensional ( 2d ) in the @xmath110-@xmath36 plane . the atoms prepared in the @xmath6 state are transferred to the @xmath2 state by rf field , and the magnetic field of @xmath111 g is applied in the @xmath36 direction . the number of spin-1 @xmath1 atoms in the bec is @xmath112 with a peak density of @xmath113 @xmath114 . these conditions give @xmath115 , and therefore the prepared state is stable ( see fig . [ f : phase ] ) . the residual component in each of the @xmath8 states is less than 0.3% . the strength of the magnetic field is then suddenly decreased to 50 mg , which corresponds to @xmath116 . it follows from fig . [ f : phase ] that the @xmath2 state is no longer the ground state and spontaneous magnetization emerges . from @xmath117 ms to 100 ms , the transverse ( @xmath110-@xmath118 direction ) magnetization grows exponentially with the time constant of 15 ms . the spin vector varies in space and points in various random directions , and complicated spin textures can be observed . the polar - core vortices are identified in about one - third of the snapshots of the spin distribution , and sometimes several vortices coexist in a single sample . the correlation function for the transverse magnetization , @xmath119,\ ] ] oscillates in both @xmath110 and @xmath36 directions . the wavelength of the oscillation in the @xmath110 direction is @xmath120 @xmath121 and that in the @xmath36 direction is @xmath122 @xmath123 . the longitudinal magnetization @xmath124 shows no significant change within @xmath125 ms , where @xmath126 the quantities discussed in sec . [ s : meanfield ] and observed in the experiment are summarized in tab . [ tab ] . .length and time scales obtained by the mean - field theory and those observed in the berkeley experiment @xcite . the last row of the right column is blank , since it has not yet been observed . [ cols="^,^",options="header " , ] we perform full 3d numerical calculations of the gp equation ( [ gp ] ) using the crank - nicolson scheme with a typical grid size of @xmath127 @xmath123 . in the numerical calculations , we ignore the linear zeeman terms in the gp equation for the reason mentioned below eq . ( [ gp ] ) . we first prepare the ground state in the @xmath2 state , @xmath128 , by the imaginary - time propagation of the gp equation ( [ gp ] ) with @xmath129 . if the initial populations of the @xmath8 states are exactly zero , no spin - exchange dynamics follow within the gp equation . we therefore add small initial seeds to the @xmath8 states to trigger the spin - exchange dynamics . possible physical origins of the initial seed include ( i ) residual atoms due to imperfections in the rf transfer , ( ii ) quantum fluctuations , and ( iii ) thermal components . in the experiment , although the residual fraction in each of the @xmath130 states is suppressed below 0.3% @xcite , this upper limit corresponds to 6300 atoms , which is still large enough to significantly affect the subsequent dynamics . the spatial distribution of the residual atoms should reflect that of the condensate @xmath131 , while its phase and magnitude can fluctuate spatially due to experimental noise . quantum fluctuations trigger the spin - exchange dynamics even if the initial populations in the @xmath8 states are exactly zero , since the @xmath132 term in the second quantized hamiltonian transfers the @xmath2 population to the @xmath133 states . the quantum fluctuations can be taken into account by random noises in the initial state @xcite . the thermal component also triggers the growth of the @xmath8 states having phase fluctuations . in order to find an appropriate initial seed to reproduce the experimental results and capture the essential mechanism that triggers the magnetization , we will examine three kinds of initial seeds which reflect the shape of the condensate and various types of noise . we will see that the dynamics crucially depend on the nature of the initial seed . in the berkeley experiment the atoms are first prepared in the @xmath6 state and then transferred to the @xmath2 state . we suppose that the transfer is imperfect and a small fraction is left in the @xmath6 state . thus we assume the initial state to be @xmath134 where @xmath135 is a small constant . we take @xmath136 and hence the initial population in the @xmath137 state is 0.25% , which is consistent with the experimental condition ( @xmath138 0.3% ) . figure [ f : uniform ] shows snapshots of the transverse spin density @xmath106 and its direction @xmath139 . for the initial condition in eq . ( [ uniform ] ) with @xmath136 . the upper panels show transverse spin density @xmath106 and the lower panels show its phase @xmath139 . the gray scale represents the density from 0 to the peak value @xmath140 for the upper panels , and the phase from @xmath141 to @xmath142 for the lower panels . the field of view of each panel is 400 @xmath143 25 @xmath144 . , width=317 ] the spin - density profile at @xmath145 ms exhibits three magnetic domains , where the middle one magnetizes in the @xmath110 direction and the two side ones in the @xmath146 direction . the width of each domain @xmath147 @xmath144 roughly equals half of the most unstable wavelength ( [ lambda ] ) . as time proceeds , new domains are formed at both ends of the cigar - shaped trap , whose alignment is perpendicular to the central domains ( see the snapshot at @xmath148 ms in fig . [ f : uniform ] ) . some of them become unstable and spin vortex - antivortex pairs are produced ( enclosed by the square at @xmath148 ms in fig . [ f : uniform ] ) . afterward , the two central domain walls become wavy ( @xmath149 ms ) , which is followed by the formation of spin vortex - antivortex pairs ( enclosed by the square at @xmath150 ms in fig . [ f : uniform ] ) . around the spin vortex the direction of the spin vector rotates by @xmath151 in the @xmath110-@xmath118 plane , and the core is occupied by the @xmath2 component . this topological defect is therefore the polar - core vortex discussed in sec . [ s : pcv ] . thus , the domain walls are first formed and the polar - core vortices then develop from the domain walls . we show that the dark - soliton picture discussed in sec . [ s : darksoliton ] describes the dynamics shown in fig . [ f : uniform ] very well . the domain walls generated in fig . [ f : uniform ] can be regarded as dark solitons according to eqs . ( [ singlegp ] ) and ( [ dark ] ) . fitting @xmath106 with eq . ( [ darkf ] ) , we find the width of the domain walls along the @xmath36 axis at @xmath145 ms is @xmath152 @xmath144 , and @xmath153 @xmath144 for those along the @xmath110 axis at @xmath154 ms . the latter is in good agreement with @xmath155 @xmath156 and the former is somewhat smaller probably due to the influence of the trapping potential . the snake instability manifests itself as the wavy domain walls at @xmath157 ms with a wavelength @xmath158 @xmath144 , which is roughly equal to eq . ( [ lamcr ] ) . figure [ f : uniform2 ] ( a ) shows time evolution of @xmath159 and @xmath124 , which indicate the degrees of magnetization in the @xmath110-@xmath118 and @xmath36 directions , respectively . ( solid curve ) and @xmath124 ( dashed curve ) and ( b ) @xmath160 for the initial condition given in eq . ( [ uniform ] ) with @xmath136 . , width=317 ] the transverse magnetization @xmath159 exponentially grows in @xmath161 ms with a time constant @xmath162 ms , which is in good agreement with the experimental observation of 15 ms . the oscillation of @xmath159 at the frequency of @xmath163 hz is seen from 100 ms to 600 ms , which was not observed in the experiment . the longitudinal magnetization @xmath124 remains small for @xmath164 ms . the transverse correlation function @xmath165 is shown in fig . [ f : uniform2 ] ( b ) . the stripe pattern in the @xmath110 direction emerges at @xmath166 ms , which becomes unstable ( @xmath167 ms ) , transforming into the stripe in the @xmath36 direction . the initial growth of the magnetic domains staggered in the @xmath110 direction is due to the anisotropy in the momentum distribution in the initial seed ( [ uniform ] ) . the fourier component of the most unstable wavelength ( [ lambda ] ) contained in the initial seed has the largest weight in the @xmath110 direction . since the domain walls staggered in the @xmath110 direction in fig . [ f : uniform ] ( b ) were not observed in the experiment , the initial seed in eq . ( [ uniform ] ) does not correspond to that in the experiment . next we examine the case of white noise as an initial seed in the @xmath130 states as @xmath168 where @xmath169 is a normalization constant , @xmath170 s are random numbers obeying the normal distribution @xmath171 , and @xmath172 is an envelope function . the random number is chosen independently on each grid . we take @xmath173 , and the initial population in each of the @xmath8 states is @xmath174% . the envelope function @xmath172 is taken to be @xmath175 . figure [ f : noise ] shows the distributions of the magnitude and direction of the spin for initial state ( [ noise ] ) . ) . , width=317 ] in contrast to fig . [ f : uniform ] , the domain structure staggered in the @xmath36 direction first emerges at @xmath176 ms . the size of the single domain is @xmath177 @xmath144 , which is roughly the same as the domain width in fig . [ f : uniform ] at @xmath145 ms , reflecting the fact that the domain size is set by the most unstable length scale of the system . some of the domain walls then develop into the polar - core vortices as shown in the squares in fig . [ f : noise ] , and the system exhibits complicated spin dynamics similar to the experimental results described in ref . @xcite . time evolution of the transverse @xmath159 and longitudinal @xmath124 squared magnetization is shown in fig . [ f : noise2 ] ( a ) . ( solid curve ) and @xmath124 ( dashed curve ) and ( b ) @xmath160 for the initial condition given in eq . ( [ noise ] ) . , width=317 ] the time at which @xmath159 rises in fig . [ f : noise2 ] ( a ) is later than that in fig . [ f : uniform2 ] . this is because the most unstable fourier component in the initial seed is smaller in the present case due to the broad momentum distribution of the white noise . figure [ f : noise2 ] ( b ) shows the transverse correlation function @xmath178 . the clear stripe pattern at @xmath179 ms indicates the establishment of the long - range correlation over @xmath180 @xmath144 . the stripe pattern is then distorted and its width becomes broader for @xmath181 ms . we note that the qualitative behaviors in figs . [ f : noise ] and [ f : noise2 ] are relatively insensitive to the envelope function @xmath182 of the initial seed in eq . ( [ noise ] ) . we have used @xmath183 based on the assumption that the noise reflects the shape of the condensate . however , we find that the results remain qualitatively the same even when the envelope function is not multiplied . we have also confirmed that the results shown above are insensitive to grid size , despite the fact that a random number is initially assigned to each grid and the momentum distribution of the initial noise depends on the grid size . the initial states ( [ uniform ] ) and ( [ noise ] ) examined in secs . [ s : uniform ] and [ s : noise ] have been inadequate to reproduce the experimental results . in the experiments , the transverse correlation function @xmath184 oscillates both in the @xmath110 and @xmath36 directions and the wavelength of the oscillation is larger in the @xmath36 direction than that in the @xmath110 direction . for the initial seed proportional to @xmath175 given in eq . ( [ uniform ] ) , the domains staggered in the short axis first grow , and for the white noise in eq . ( [ noise ] ) , the domains are staggered in the long axis . therefore , we expect that the experimental result can be reproduced using the initial seed that combines eqs . ( [ uniform ] ) and ( [ noise ] ) , i.e. , anisotropy and randomness . since the white noise in eq . ( [ noise ] ) induces the growth of the domains along the @xmath110 direction ( fig . [ f : noise ] , @xmath185 ms ) and the wavelength of the oscillation of @xmath178 , @xmath186 @xmath121 ( fig . [ f : noise2 ] , @xmath179 ms ) , is shorter than that in the experiment , @xmath187 @xmath123 , we cut off the short - wavelength components from the white noise . the initial state is thus given by @xmath188 where we produce the noise function @xmath189 from the white noise by eliminating the fourier components whose wavelengths are shorter than @xmath190 . the envelope function @xmath172 is taken to be @xmath175 . the results for @xmath191 @xmath123 are shown in figs . [ f : cutoff ] and [ f : cutoff2 ] . ) with @xmath191 @xmath123 . , width=317 ] ( solid curve ) and @xmath124 ( dashed curve ) and ( b ) @xmath160 for the initial condition given in eq . ( [ cutoff ] ) with @xmath191 @xmath123 . , width=317 ] the behavior of @xmath178 shown in fig . [ f : cutoff2 ] ( b ) is similar to that observed in the experiment @xcite in that the wavelength of the oscillation in the @xmath36 direction is larger than that in the @xmath110 direction . this anisotropy originates from the envelope function @xmath192 of the initial seed in eq . ( [ cutoff ] ) . the momentum distribution in the @xmath110 direction of @xmath172 is broad and the most unstable wavelength ( [ lambda ] ) grows in this direction , while in the @xmath36 direction the typical wavelength in @xmath178 is determined by the cutoff wavelength @xmath190 of the noise . we note that the qualitative behaviors shown in fig . [ f : cutoff2 ] ( b ) are independent of the details of the envelope function @xmath172 in the initial seed . the similar behaviors can be obtained as long as the size of the envelope function is much larger than the unstable wavelength @xmath193 in the @xmath36 direction and is comparable to @xmath193 in the @xmath110 direction . in fact , when we use @xmath194 , qualitatively similar results are obtained . the behavior of the local transverse magnetization @xmath159 in fig . [ f : cutoff2 ] ( a ) is also in good agreement with the experimental result . it exponentially increases from @xmath117 ms to @xmath195 ms with a time constant @xmath196 ms . after @xmath197 ms , @xmath159 gradually increases from 0.4 to 0.6 until @xmath198 ms , which also captures the basic characteristics of the experimental result . as in figs . [ f : uniform ] and [ f : noise ] , fig . [ f : cutoff ] shows that the magnetic domains are first formed ( @xmath199 ms ) followed by the development of some of the domain walls into the polar - core vortices . thus , this process of spin - vortex formation appears rather universal . we also found that the polar - core vortices drift in and out of the condensate in the dynamics . we have so far considered the case of sudden quench , i.e. , the magnetic field being suddenly reduced to 50 mg at @xmath200 . if the time scale of the quench is longer than @xmath161 ms ( time scale in which @xmath159 rises in fig . [ f : cutoff2 ] ) , the excitations are expected to be suppressed because of the adiabatic theorem . figure [ f : slowquench ] shows the time evolution for the slow quench , where the initial magnetic field of 530 mg is reduced to 50 mg during 300 ms so that @xmath44 linearly decreases . linearly decreases . the initial condition is the same as in figs . [ f : cutoff ] and [ f : cutoff2 ] . , width=317 ] we find from fig . [ f : slowquench ] ( a ) that the spin state has nearly a single - domain structure and no spin vortices are created . the transverse @xmath159 and longitudinal @xmath124 components of the squared magnetization are shown in fig . [ f : slowquench ] ( b ) . a large value of @xmath201 is due to the absence of the spatial spin structure . figure [ f : vortexnum ] shows the dependence of the number of spin vortices at @xmath202 ms on ramp time . the initial state is given in eq . ( [ cutoff ] ) with @xmath203 @xmath123 and the magnetic field is decreased from 530 mg to 50 mg so that @xmath44 is linearly ramped down during @xmath204 . the plots and error bars represent the average and standard deviation with respect to ten runs of simulations for different random numbers to generate the noise . , width=317 ] the number of spin vortices decreases with an increase in the ramp time , and the time scale beyond which the spin vortices no longer emerge is given by @xmath161 ms . we note that this time scale coincides with @xmath205 , indicating that the energy scale for the creation of a spin vortex is given by @xmath206 reminds us of the kibble - zurek mechanism @xcite of the vortex creation in the quenched system , which also depends on the quench time . however , the relationship between the present phenomenon and the kibble - zurek mechanism is not straightforward . in the kibble - zurek mechanism , each domain is assumed to be created with an independent phase . in the present system , however , the magnetization at each position can not be independent of that of other positions , since there is the restriction on the change in the total spin , which is clearly seen in the long - range correlation in @xmath178 . gaining a deeper understanding of the relationship between the spin - vortex formation and the kibble - zurek mechanism constitutes an interesting and challenging problem which merits further investigation . the spin - vortex formation is also suppressed if the quench of the magnetic field is made just below the critical strength of the magnetic field , which is given by @xmath207 ( see fig . [ f : phase ] ) and corresponds to @xmath208 mg for the peak density . figure [ f : largem ] shows the spin dynamics for @xmath209 mg . . the initial condition is the same as in figs . [ f : cutoff ] and [ f : cutoff2 ] . , width=317 ] from eq . ( [ e1 ] ) , the most unstable wavelength for this magnetic field is @xmath210 , and the system is more unstable against excitations with larger wavelengths . in fig . [ f : largem ] ( a ) , therefore , only the long - wavelength modes are excited and no spin vortex is formed . in fig . [ f : largem ] ( b ) , the transverse squared magnetization @xmath159 saturates around 0.2 , since @xmath106 of the ground state is small near the phase boundary between the broken - axisymmetry and polar phases . we define the total magnetization as @xmath211 where @xmath49 is the spin density defined in eq . ( [ f ] ) . if the quadratic zeeman effect is absent , the @xmath36 component @xmath212 and the transverse component @xmath213 are conserved , and the vector @xmath214 rotates in the @xmath110-@xmath118 plane at the larmor frequency determined by the linear zeeman energy . in the presence of the quadratic zeeman effect , not only @xmath215 rotates in the @xmath110-@xmath118 plane but also @xmath213 changes with time . figure [ f : transverse ] shows time evolution of @xmath213 for the initial conditions given by eqs . ( [ uniform ] ) , ( [ noise ] ) , and ( [ cutoff ] ) , where the system is quenched by a decrease in the magnetic field to 50 mg at @xmath200 as in figs . [ f : uniform]-[f : cutoff2 ] . ( dashed curve ) , and fig . [ f : cutoff ] ( dotted curve ) . , width=317 ] for the initial condition ( [ uniform ] ) , @xmath213 has a large initial value @xmath216 , and reaches a maximum value @xmath217 . for the initial condition ( [ cutoff ] ) , @xmath213 monotonically increases to twice the initial value during 600 ms . thus the quadratic zeeman effect generates the transverse component in the total magnetization . the transverse magnetization @xmath213 may also be changed by the dipole - dipole interaction , since it couples the spin angular momentum with the orbital angular momentum @xcite . the effect of the dipole - dipole interaction on the transverse magnetization merits further study . we have studied the spontaneous magnetization and spin - texture formation of a spin-1 @xmath1 bec , where the initial state is the @xmath2 stationary state @xmath175 plus a small seed in the @xmath8 states . we have reproduced the polar - core spin - vortex formation observed in the experiment , as shown in figs . [ f : uniform ] , [ f : noise ] , and [ f : cutoff ] . typically , the spin vortex is formed in two steps . the magnetic domains are first formed , and then the domain walls transform into the spin vortex - antivortex pairs . this process of vortex formation appears to be universal regardless of various initial conditions . we have examined three kinds of initial seeds : the one proportional to @xmath175 , white noise , and colored noise . the first two seeds produce the domain structures staggered in the short and long axes , respectively ( figs . [ f : uniform]-[f : noise2 ] ) . the magnetization developed from the third seed has both characteristics of the first two seeds , and the correlation function oscillates in both the long and the short axes ( fig . [ f : cutoff2 ] ( a ) ) , in qualitative agreement with the berkeley experiment @xcite . this is due to the fact that the third seed has a broad momentum distribution in the short axis , originating from the shape of @xmath218 , and long - wavelength fluctuations in the long axis . from these results , we can conclude that the anisotropy and colored noise in the initial seed are important to account for the experiment . the time evolution of the transverse magnetization @xmath159 is also in close agreement with the experimental result ( fig . [ f : cutoff2 ] ( b ) ) . the number of spin vortices created in the magnetization depends on how fast the magnetic field is quenched . when the magnetic field is decreased slowly , the number of nucleated spin vortices decreases ( figs . [ f : slowquench ] and [ f : vortexnum ] ) . we have also shown that the number of spin vortices decreases for the magnetic field close to the critical value ( fig . [ f : largem ] ) . we have pointed out a close analogy between the topological defects in the present system and those in a scalar bec , and that the creation of spin vortex - antivortex pairs from the domain walls is related to the instability in the planar dark solitons . it is of interest to investigate if the counterparts of vortex lattices , multiply - quantized vortices , and gray solitons are generated in a ferromagnetic spinor bec . this work was supported by grants - in - aid for scientific research ( grant nos . 17740263 and 17071005 ) and by the 21st century coe programs on `` coherent optical science '' and `` nanometer - scale quantum physics '' from the ministry of education , culture , sports , science and technology of japan . yk acknowledges support by the japan society for promotion of science ( project no . mu acknowledges support by a crest program of the jst .

we study the dynamics of the quantum phase transition of a ferromagnetic spin-1 bose - einstein condensate from the polar phase to the broken - axisymmetry phase by changing magnetic field , and find the spontaneous formation of spinor domain walls followed by the creation of polar - core spin vortices . we also find that the spin textures depend very sensitively on the initial noise distribution , and that an anisotropic and colored initial noise is needed to reproduce the berkeley experiment [ sadler _ et al . _ , nature * 443 * , 312 ( 2006 ) ] . the dynamics of vortex nucleation and the number of created vortices depend also on the manner in which the magnetic field is changed . we point out an analogy between the formation of spin vortices from domain walls in a spinor bec and that of vortex - antivortex pairs from dark solitons in a scalar bec .

SECTION 1. AMENDMENT TO DEFINITION OF INDIAN TRIBE. Section 8(a)(13) of the Small Business Act (15 U.S.C. 637(a)(13)) is amended-- (1) by redesignating subparagraphs (A) and (B) as clauses (i) and (ii), respectively, and adjusting the margins accordingly; (2) by striking ``the term `Indian tribe' means'' and inserting the following: ``the term `Indian tribe'-- ``(A) means''; (3) by striking ``, including any Alaska Native village or regional or village corporation (within the meaning of the Alaska Native Claims Settlement Act)''; (4) in subparagraph (A)(i), as so designated, by striking ``, or'' and inserting ``; or''; (5) by striking the period at the end and inserting ``; and''; and (6) by adding at the end the following: ``(B) does not include an Alaska Native Corporation or Alaska Native Village.''. SEC. 2. SOCIAL AND ECONOMIC DISADVANTAGE. (a) In General.--Section 29(e) of the Alaska Native Claims Settlement Act (43 U.S.C. 1626(e)) is amended-- (1) in paragraph (1), by striking ``For all purposes of'' and inserting ``Except as provided in paragraph (5), for all purposes of''; (2) in paragraph (2), by striking ``For all purposes of'' and inserting ``Except as provided in paragraph (5), for all purposes of''; and (3) by adding at the end the following: ``(5) For purposes of sections 7(j)(10) and 8(a) of the Small Business Act (15 U.S.C. 636(j)(10) and 637(a)), whether a Native Corporation or Native village or a direct and indirect subsidiary corporation, joint venture, or partnership of a Native Corporation or Native village is socially or economically disadvantaged shall be determined in accordance with paragraph (5) or (6), respectively, of section 8(a) of the Small Business Act.''. (b) Standards.--Section 8(a) of the Small Business Act (15 U.S.C. 637(a)) is amended-- (1) in paragraph (4)-- (A) in subparagraph (A)-- (i) in clause (i)-- (I) in subclause (II), by striking ``or'' at the end; and (II) by adding at the end the following: ``(IV) a socially and economically disadvantaged Alaska Native Corporation or Alaska Native Village, or''; and (ii) in clause (ii)-- (I) in subclause (II), by striking ``or'' at the end; (II) in subclause (III), by striking the period at the end and inserting ``, or''; and (III) by adding at the end the following: ``(IV) a socially and economically disadvantaged Alaska Native Corporation or Alaska Native Village.''; (B) in subparagraph (B)-- (i) in clause (ii), by striking ``or'' at the end; (ii) in clause (iii), by striking the period at the end and inserting ``, or''; and (iii) by adding at the end the following: ``(iv) members of a socially and economically disadvantaged Alaska Native Corporation or Alaska Native Village described in subparagraph (A)(i)(IV) or subparagraph (A)(ii)(IV).''; and (C) by adding at the end the following: ``(D) The Administrator may not waive the requirement under this paragraph that the management and daily business operations of a business concern participating in the program under this subsection are controlled by one or more socially and economically disadvantaged individuals for a business concern owned by an Alaska Native Corporation or Alaska Native Village.''; (2) in paragraph (5)-- (A) by inserting ``(A)'' after ``(5)''; and (B) by adding at the end the following: ``(B) For purposes of this subsection and section 7(j)(10), the Administrator shall determine whether an Alaska Native Corporation or Alaska Native Village is, as an entity, socially disadvantaged in accordance with the factors described in subparagraph (A).''; and (3) in paragraph (6), by adding at the end the following: ``(F) For purposes of this subsection and section 7(j)(10), the Administrator shall annually determine whether an Alaska Native Corporation or Alaska Native Village is economically disadvantaged in the same manner as for an applicant for or participant in the program under this subsection that is a Native Hawaiian organization.''. SEC. 3. AFFILIATION. Section 7(j)(10)(J)(ii)(II) of the Small Business Act (15 U.S.C. 636(j)(10)(J)(ii)(II)) is amended by inserting ``, as defined in section 8(a)(13)'' after ``Indian tribe''. SEC. 4. SOLE SOURCE CONTRACTING DOLLAR LIMITS. (a) Competitive Thresholds.--Not later than 270 days after the date of enactment of this Act, the Administrator shall amend the regulations issued under sections 7(j)(10) and 8(a) of the Small Business Act (15 U.S.C. 636(j)(10) and 637(a)) in accordance with this Act and the amendments made by this Act to apply to small business concerns owned by an Alaska Native Corporation or Alaska Native Village the competitive thresholds for awarding sole source contracts under section 8(a)(1)(D) of the Small Business Act (15 U.S.C. 637(a)(1)(D)) that are applicable to small business concerns that are owned by a socially and economically disadvantaged individual. (b) Maximum Total Dollar Amount.--Section 8(a)(1)(D) of the Small Business Act (15 U.S.C. 637(a)(1)(D)) is amended by adding at the end the following: ``(iii) For purposes of eligibility for the award of a contract on the basis of restricted competition under this subparagraph, the Administrator may not establish a maximum total dollar amount of such awards during the period of Program Participation for participants that are owned by an Alaska Native Corporation or Alaska Native Village that is different from the amount for Program Participants that are owned by a socially and economically disadvantaged individual.''. SEC. 5. ONE TIME ELIGIBILITY. Section 7(j)(11)(B)(iii) of the Small Business Act (15 U.S.C. 636(j)(11)(B)(iii)) is amended in the matter preceding subclause (I) by inserting ``(as defined in section 8(a)(13))'' after ``Indian tribe''. SEC. 6. GRADUATION. (a) In General.--Section 7(j)(15) of the Small Business Act (15 U.S.C. 636(j)(15)) is amended-- (1) by redesignating subparagraphs (A) and (B) as clauses (i) and (ii), respectively; (2) by inserting ``(A)'' after ``(15)''; and (3) by adding at the end the following: ``(B) The Administrator may not extend or waive the time limitations under this paragraph for a business concern owned by an Alaska Native Corporation or Alaska Native Village.''. (b) Technical and Conforming Amendments.--The Small Business Act (15 U.S.C. 631 et seq.) is amended-- (1) in section 7(j) (15 U.S.C. 636(j))-- (A) in paragraph (10)(E)(ii), by striking ``paragraph (15)'' and inserting ``paragraph (15)(A)''; and (B) in paragraph (11)(D), by striking ``paragraph (15)'' and inserting ``paragraph (15)(A)''; and (2) in section 8(a)(1)(C) (15 U.S.C. 637(a)(1)(C)), in the matter preceding clause (i), by striking ``section 7(j)(15)'' and inserting ``section 7(j)(15)(A)''. SEC. 7. REPORTING. Section 8(a)(6)(B) of the Small Business Act (15 U.S.C. 637(a)(6)(B)) is amended-- (1) by redesignating clauses (i), (ii), and (iii) as subclauses (I), (II), and (III), respectively; (2) by inserting ``(i)'' after ``(B)''; and (3) by adding at the end the following: ``(ii) The annual report submitted under clause (i) by a Program Participant that is an Alaska Native Corporation or Alaska Native Village shall include, for the period addressed by the report-- ``(I) the total revenue of the Alaska Native Corporation or Alaska Native Village; ``(II) the revenue of the Alaska Native Corporation or Alaska Native Village attributable to the participation of the Alaska Native Corporation or Alaska Native Village in the program under this subsection; and ``(III) the total amount of benefits paid to shareholders of the Alaska Native Corporation or Alaska Native Village.''. SEC. 8. REGULATIONS. Not later than 270 days after the date of enactment of this Act, the Administrator shall amend the regulations issued under sections 7(j)(10) and 8(a) of the Small Business Act (15 U.S.C. 636(j)(10) and 637(a)) in accordance with this section and the amendments made by this section, which shall include-- (1) establishing criteria for determining whether an Alaska Native Corporation or Alaska Native Village is, as a group, socially disadvantaged, in accordance with the factors described in section 8(a)(5)(A) of the Small Business Act, as so designated by this Act; (2) establishing criteria for determining whether an Alaska Native Corporation, Alaska Native Village, or Native Hawaiian Organization is economically disadvantaged; (3) repealing the provision that excludes certain affiliates of an Alaska Native Corporation or Alaska Native Village in determining whether a business is a small business concern; (4) repealing the waiver for Alaska Native Corporations and Alaska Native Villages of the requirement that the management and daily business operations of a business concern participating in the program under section 8(a) of the Small Business Act (15 U.S.C. 637(a)) are controlled by one or more socially and economically disadvantaged individuals; (5) applying to small business concerns owned by an Alaska Native Corporation or Alaska Native Village the limitation on eligibility for a sole source award under section 8(a)(1)(D) of the Small Business Act (15 U.S.C. 637(a)(1)(D)) based on the maximum total amount of competitive and sole source awards under such section 8(a) that are applicable to small business concerns that are owned by a socially and economically disadvantaged individual; (6) prohibiting a single Alaska Native Corporation or Alaska Native Village from conferring eligibility to participate in the program under section 8(a) of the Small Business Act (15 U.S.C. 637(a)) on more than 1 small business concern at any one time; and (7) applying to small business concerns owned by an Alaska Native Corporation or Alaska Native Village the limitation on ownership of other firms participating in the program under section 8(a) of the Small Business Act (15 U.S.C. 637(a)) that is applicable to small business concerns that are owned by a socially and economically disadvantaged individual. SEC. 9. DEFINITIONS. In this Act-- (1) the term ``Administrator'' means the Administrator of the Small Business Administration; (2) the terms ``Alaska Native Corporation'' and ``Alaska Native Village'' have the meanings given those terms in section 3(p)(6) of the Small Business Act (15 U.S.C. 632(p)(6)); (3) the term ``Native Hawaiian Organization'' has the meaning given that term in section 8(a)(15) of the Small Business Act (15 U.S.C. 637(a)(15)); and (4) the term ``small business concern'' has the meaning given that term under section 3 of the Small Business Act (15 U.S.C. 632).

Amends the Small Business Act to exclude from the definition of "Indian tribe" any Alaska Native Corporation (ANC) or Alaska Native Village (ANV). Amends the Alaska Native Claims Settlement Act to provide that, for purposes of eligibility for procurement contracts provided through the Small Business Administration (SBA), whether an ANC or ANV is socially or economically disadvantaged shall be determined by the SBA Administrator according to eligibility standards for SBA 8(a) general small business loans. Makes members of socially and economically disadvantaged ANCs or ANVs eligible for such loans. Directs the Administrator to apply to small businesses owned by an ANC or ANV the competitive thresholds for awarding SBA sole source contracts that are applicable to small businesses owned and controlled by socially and economically disadvantaged individuals. Prohibits the Administrator from extending or waiving, for small businesses owned by an ANC or ANV, the time limitations applicable to participants in the small business capital ownership development program. Outlines annual report requirements for program participants who are ANCs or ANVs. Requires the Administrator to amend SBA regulations to incorporate amendments made by this Act.

the transition between grain filling and maturation in cereal seed development involves the cessation of starch and storage protein synthesis as well as the expression of genes that initiate processes that prepare the seed for dormancy , and dramatic changes in gene expression in the endosperm have been described ( wan et al . , 2008 ) . the hormone abscisic acid ( aba ) is one of the major players in this process and the recent elucidation of the aba signal transduction pathway ( cutler et al . , 2010 ) means that there is now the opportunity to advance our understanding of the mechanisms by which aba influences seed development . integral to aba signalling is sucrose nonfermenting-1-related protein kinase-2 ( snrk2 ) . in the absence of aba , snrk2 is kept in an inactive state through the action of protein phosphatase 2c ( pp2c ) . in the presence of aba , aba receptors pyr / pyl / rcar bind to and inhibit pp2c , allowing the accumulation of active snrk2 and subsequent phosphorylation of aba - response element binding proteins ( arebps ) ( cutler et al . , 2010 ) . arebps ( also known as abfs ) are a family of basic leucine zipper ( bzip ) transcription factors that recognize the aba response elements ( abres ) present in some aba - regulated genes ( cutler et al . , 2010 ) . snrk2s phosphorylate arebps at serine ( preferentially ) or threonine residues with a basic residue at 3 with respect to the serine / threonine residue ( fujii et al . , 2007 ; two of the snrk2 target sites in arebps are potential targets for phosphorylation by a related protein kinase , snrk1 , which also phosphorylates serine residues with a basic residue at 3 , but has an additional requirement for hydrophobic residues at 5 and + 4 . these snrk1 target sites are conserved throughout the arabidopsis arebp family and in all of the arebps that have been identified so far in other species ( zhang et al . , 2008 ) . peptides with amino acid sequences based on these sites have been shown to be phosphorylated by both snrk1 and 2 ( zhang et al . , snrk1 is functionally as well as structurally related to snf1 of fungi and adenosine monophosphate ( amp)-activated protein kinase ( ampk ) of animals , both of which are major regulators of metabolism and a range of cellular processes in their respective systems ( reviewed by hey et al . , 2010 ) . snrk2-type protein kinases , on the other hand , do not have any direct functional counterpart in fungal or animal cells . they are encoded by a medium - sized gene family with , for example , 10 members in arabidopsis ( arabidopsis thaliana ) and are involved with or implicated in responses to abiotic stresses such as drought , salinity , cold and osmotic stress ( hey et al . , ( 2004 ) divided arabidopsis snrk2s into three classes , based on phylogeny and their response to aba : class 1 , which are not activated in response to aba , class 2 , which are activated weakly by aba and class 3 , which are strongly activated by aba . in a recent study , we investigated the interactions between aba , snrk1 and snrk2 in wheat and showed contrasting effects of aba on snrk1 and snrk2 protein levels and phosphorylation state ( coello et al . , 2012 ) . application of aba to wheat roots brought about a dramatic decrease in snrk1 protein , and phosphorylation / activation of a 42 kda snrk2 . unusually for snrk2 , this member of the family was calcium - dependent . these results imply differential roles for snrk1 and snrk2 in aba signalling and antagonistic effects of snrk1 and snrk2 on gene expression . consistent with this , transient repression of snrk1 has been shown to repress the activity of an -amylase gene ( -amy2 ) promoter in cultured wheat embryos ( laurie et al . , 2003 ) , while a snrk2 , pkaba1 , has been shown to down - regulate -amylase genes in response to aba ( gomez - cadenas et al . , 1999 ) . recently , aba - responsive cis - elements have been identified in the promoters of key genes of starch biosynthesis in barley : hvsus1 , encoding sucrose synthase , and hvagp - l1 , encoding the large subunit of adp - glucose pyrophosphorylase ( agpase ) ( seiler et al . , homologous genes are up - regulated in response to snrk1 over - expression in potato tubers ( mckibbin et al . , 2006 ) , with a concomitant increase in starch content . in this study , we have investigated the expression of genes encoding components of the aba sensing and signalling pathway in developing barley endosperm and embryo , compared expression patterns of different snrk1 and snrk2 family members , and identified cereal arebp and other bzip transcription factors with snrk target sites . the aim was to provide new knowledge of the interactions between snrk1 , snrk2 , pp2c , aba and transcription factors in the control of cereal seed development . blast searches of the non - redundant ( nr ) protein sequence database were performed using the national center for biotechnology information ( ncbi ) portal ( www.ncbi.nlm.nih.gov/ ) . barley1 22k microarray data ( dash et al . , 2012 ) was accessed via the plexdb portal ( www.plexdb.org/modules/tools/plexdb_blast.php ) . plants of the two - rowed barley ( hordeum vulgare ) cultivar triumph were grown in 15 cm diameter pots in a glasshouse with a 16 h day - length ( supplemental lighting was used as necessary ) and a minimum temperature of 14 c by night and 18 c by day . there was 1 plant per pot and pots were laid out in a randomised design . ears were tagged at anthesis , grain sampled at 15 , 20 , 25 and 30 days post - anthesis ( dpa ) , and caryopses dissected under a dissecting microscope . dissected samples were immediately frozen in liquid nitrogen and stored at 80 c . images of the dissected grain were obtained with a leica m205 fa stereomicroscope ( leica microsystems , milton keynes , uk ) . total rna was isolated using trizol reagent ( ambion , usa ) according to the manufacturer 's instructions . the quality and the concentration of rna were measured by spectrophotometry using a nanodrop nd-100 ( thermo fisher , wilmington , de , usa ; supplied by labtech international ltd , uckfield , uk ) and confirmed by electrophoresis through an agarose gel . the rna was treated with rq1 rnase - free dnase ( promega , usa ) ; cdna was then synthesised using superscript iii reverse transcriptase ( invitrogen , usa ) . the cdna was checked for purity by polymerase chain reaction ( pcr ) amplification using primers catcaagctcaaggacgaca and gccttgtccttgtcagtgaa , which anneal to sites flanking an intron within the hvgapdh gene . primers were designed using either primer express software version 3.0 ( applied biosystems , usa ) or primer 3 ( http://primer3.wi.mit.edu/ ) . pcr reactions were performed in 96-well plates on a 7500 real time pcr system ( applied biosystems , usa ) using sybr select master mix ( applied biosystems , usa ) . the reactions for biological replicates were separated across three plates , thus forming statistical blocks for subsequent data analysis . reactions contained 10 l 2 mix , 0.6 l of each primer ( 10 m ) and 100 ng cdna template in a final volume of 20 l . the same thermal profile was used for all pcr reactions : 50 c for 2 min , 95 c for 10 min , 45 cycles of 95 c for 15 s and 60 c for 1 min ; data collection was carried out during the 60 c step . the efficiency of the pcr was estimated using the linreg pcr programme ( ramakers et al . , 2003 ) . a ct value was obtained by 7500 software v2.0.5 ( applied biosystems , usa ) and the ct and efficiency values were then used to calculate the relative quantity ( rq ) , and the normalised relative quantity ( nrq ) of a target gene 's expression with respect to three reference genes , hvactin , hvcyclophilin and hvgapdh . nrq was calculated using the following formula : nrq = etargetct , targetehvactinct , hvactinehvcyclophilinct , hvcyclophilinehvgapdhct , hvgapdhwhere etarget , ehvactin , ehvcyclophilin and ehvgapdh are the estimated pcr efficiencies for a particular target gene and the two reference genes and where ct , target , ct , hvactin , ct , hvcyclophilin and ct , hvgapdh are the corresponding ct values . the ct values of each reference gene were found to be stable across the time points , prior to using the geometric mean of the rq values as shown in the formula . statistical analysis of the nrq data was performed using the genstat statistical package ( 2011 , 14th edition , vsn international ltd , hemel hempstead , uk ) . taking account of the three plates as statistical blocks , anova was applied to the log ( to base 2)-transformed inverse of the nrq data ( rieu and powers , 2009 ) . this transformation ensured homogeneity of variance and effectively provided values back on the ct - scale . therefore , as for ct values ( ct = log2(1/nrq ) ) , a low log2(1/nrq ) indicated a high gene expression , whereas a high log2(1/nrq ) indicated low gene expression . following a significant ( p < 0.05 , f - test ) result from anova , the analysis assessed the statistical significance of differences in gene expression between time points using the least significant difference ( lsd ) at the 5% ( p < 0.05 ) level of significance . the aim of the project was to analyse expression of genes encoding proteins potentially involved in the abscisic acid ( aba ) signalling pathway during barley grain development , including the aba receptor protein , rcar , protein phosphatase 2c ( pp2c ) , sucrose nonfermenting-1-related protein kinase 2 ( snrk2 ) and related protein kinase snrk1 , and aba response element binding proteins ( arebps ) , as well as additional transcription factors that could be substrates for snrk1 or snrk2 . two genes encoding aba receptors were studied ; these were hvrcar35_47387 and hvrcar35_2538 ( seiler et al . , 2011 ) . the protein phosphatase 2c gene was hvabi1d ( seiler et al . , 2011 ) . the abi1 name derives from the fact that this gene was first identified in arabidopsis in a screen of mutants that were aba insensitive ( finkelstein , 1994 ) . two snrk2 genes from barley have been described previously : hvsnrk2.6 ( mangelsen et al . , 2011 ; 2011 ) and hvpkaba1 ( yamauchi et al . , 2002 ) , and these were both included in the study . a third snrk2 gene was identified from barley1 22k microarray data ( dash et al . , 2012 ) and also included . it has been annotated as hvsnrk2.4 but there is no experimental evidence that the snrk2 that it encodes is a functional equivalent of arabidopsis snrk2.4 , which is aba - independent . two snrk1 genes have been characterised previously in barley : hvsnrk1a ( also known as bkin2 ) and hvsnrk1b ( also known as bkin12 and related bkin9 ) ( halford et al . , 1992 ) . hvsnrk1a has been shown to be expressed in all tissues that have been analysed to date , whereas hvsnrk1b is expressed at high levels in the seed but at relatively low levels elsewhere ( hannappel et al . , 1995 ) . despite its relatively low levels of expression in non - seed tissues , antisense inhibition of hvsnrk1b gene expression in anthers has been shown to result in impaired pollen development , a failure of pollen grains to accumulate starch , and pollen inviability ( zhang et al . , 2001 ) . southern analysis of the gene family has suggested that it comprises 1020 members ( halford et al . , 1992 ) . a blast search of the non - redundant ( nr ) protein sequence database was performed with the hvsnrk1a amino acid sequence using the national center for biotechnology information ( ncbi ) portal . this identified one barley snrk1a entry , accession number caa57898.1 , and seven barley snrk1b entries , accession numbers baj95249.1 , bak03923.1 , caa46555.1 , caa46556.1 , bak05223.1 , caa07813.1 and caa46554.1 . primers with which to amplify hvsnrk1a and hvsnrk1b products were designed to reveal any of these homologues with the aim being to distinguish between the two types . snrk1 interacts with two non - catalytic subunits to form a heterotrimeric complex and the expression of a barley gene , hvsnrk1 , encoding one of these was identified from barley1 22k microarray data ( dash et al . , 2012 ) and this gene was also included in the study . the screen of aba - insensitive arabidopsis mutants that identified abi1 ( finkelstein , 1994 ) also identified genes encoding transcription factors of the aba response element binding protein ( arebp ) class . arabidopsis contains 14 genes encoding arebp - type transcription factors ( zhang et al . , 2008 ) ; of these , abi5 has been the most intensively studied because of its role in germination ( abi5 mutant seeds germinate in the presence of aba at levels that prevent germination of wild - type seeds ) . however , it is important to note that other arebps may have different but equally important roles in controlling plant development . unfortunately , the prominence of abi5 in the literature has led to arebps from other species being annotated as abi5 analogues , in some cases without any evidence that they have the same function as abi5 . snrk2 phosphorylates arebps at multiple sites , requiring only a serine or threonine residue with a basic residue at 3 for substrate recognition ( furihata et al . , 2006 ) . two of the sites in arebps that can be phosphorylated by snrk2 have also been shown to be phosphorylated by snrk1 ( zhang et al . , 2008 ) . snrk1 phosphorylates target proteins at serine residues with a hydrophobic residue at 5 and + 4 with respect to the serine as well as the basic residue ( preferably arginine ) at 3 or ( sub - optimally ) at 4 . in order to identify cereal arebps , blast searches were performed of the non - redundant protein sequence database using a barley arebp amino acid sequence identified previously ( zhang et al . , 2008 ) . this identified members of the arebp family from barley , wheat , brachypodium , rice , maize and sorghum . the n - terminal regions of one arebp from each species are shown in fig . 1 , with snrk1 target sites highlighted in red . two such sites are present in all six of the arebps shown and also in all but one ( abi5 itself ) of the arebps in arabidopsis ( zhang et al . , 2008 ) . synthetic peptides based on both sites have been shown to be phosphorylated by partially - purified snrk1 and snrk2 from wheat roots ( coello et al . , 2012 ) . for the present study , primers for analysis of arebp gene expression were based on the barley gene annotated as hvabi5 ( casaretto and ho , 2003 ) . the tolerance of multiple similar amino acids within the snrk1 target site makes computational identification of putative snrk1-regulated proteins and protein families difficult . a pipeline has therefore been developed consisting of a basic motif search , prosite family searches ( falquet et al . , 2002 ) and multiple alignments within each prosite family . arebps were identified as potential substrates for snrk1 using this pipeline ( zhang et al . , 2008 ) . for the present study , the database that was compiled using this pipeline was mined for additional bzip transcription factors that could also be phosphorylated by snrks . this process identified another class of cereal bzips with n - terminal snrk1 target sites , comprising opaque2 dimerising protein ( ohp1 ) from maize ( np_001105687 ; 542704_ohp1 ) and sorghum , blz1 from barley ( hvblz1 ; caa56374 ) and multiple uncharacterised bzips from rice ( np_001051558 ; aap44683 ; abf99347 ; baf13472 ; os03g0796900 ; baa11431 ; eay92182 ; baa36492 ) . recognizes the so - called n motif of the prolamin box of wheat , barley and rye storage protein gene promoters and was therefore included in the analysis of gene expression . plants of barley ( hordeum vulgare ) cultivar triumph were grown in a glasshouse and grain sampled at 15 , 20 , 25 and 30 days post - anthesis ( dpa ) ( fig . 2 ) . caryopses were dissected to separate the embryo ( including the scutellum ) and endosperm . for the endosperm analysis , only material from the central , starchy endosperm was analysed ( fig . 2 ) . rna was purified from the samples and used as a template for quantitative , real - time polymerase chain reaction ( qrt - pcr ) analysis of gene expression for the hvrcar35_47387 , hvrcar35_2538 , hvabi1d , hvsnrk2.4 , hvsnrk2.6 , hvpkaba1 , hvabi5 , hvsnrk1a , hvsnrk1b , hvsnrk1 , and hvblz1 genes described above . the primers used for the pcr reactions , mean log2(1/nrq ) values and results of anova to consider significance of differences in gene expression between time points for the genes of interest are given in supplementary information . for comparison , expression of a gene encoding a late embryogenesis abundant protein , hvlea3 , was also included . each analysis included three biological replicates from different pots and the expression level of a gene was calculated as the normalised relative quantity ( nrq ) with respect to three reference genes , hvactin , hvcyclophilin and hvgapdh . the results for expression in the endosperm are shown in fig . 3 and the embryo in fig . 4 . the differences in scales on the graphs within and between figs . 3 and 4 should be considered when comparing the expression levels of different genes or the same gene in different tissues . the expression of the hvlea3 gene was as expected , rising through mid - development to its highest level in the endosperm at 30 dpa and the embryo at 2530 dpa . gene expression , in contrast , was readily detectable in the endosperm , with expression peaking at 20 dpa ( fig . 3 ) , but almost undetectable in the embryo ( not shown ) , while hvrcar35_2538 was expressed at low but detectable levels in the embryo , with expression declining through seed development ( fig . 4 ) , but not in the endosperm ( not shown ) . the expression of the pp2c - encoding gene , hvabi1d , showed a similar pattern to hvrcar35_47387 in the endosperm , with a peak at 20 dpa . however , it was also expressed in the embryo , with expression increasing through development to its highest point at 30 dpa . at 20 dpa ( the peak of its expression in the endosperm ) , the level of expression in the endosperm was approximately six times that in the embryo , but by 30 dpa , with expression declining in the endosperm but increasing in the embryo , there was only a two - fold difference . analysis of expression of the three snrk2 genes , hvsnrk2.6 ( mangelsen et al . , 2011 ; sreenivasulu et al . , 2006 ; seiler et al . , 2011 ) , hvpkaba1 ( yamauchi et al . , 2002 ) and hvsnrk2.4 ( barley1 22k microarray data ; dash et al . , 2012 ) , revealed clear differences . hvsnrk2.4 was expressed at the highest levels of the three in the endosperm , with expression peaking at 20 dpa . it was also detectable in the embryo but at levels 20 times or more lower than in the endosperm , with expression showing no change through development . hvsnrk2.6 showed a similar pattern of expression in the endosperm , peaking at 20 dpa , but its expression levels were ten times lower than hvsnrk2.4 . it showed comparable levels of expression in the embryo , but in contrast to hvsnrk2.4 , its expression increased from 15 dpa through to 30 dpa , so that by 30 dpa it was expressed more highly than hvsnrk2.4 . snrk2.4 is considered to be aba - independent in arabidopsis , but the similar expression pattern of hvsnrk2.4 to other genes encoding components of the aba signalling pathway suggests that this is not the case in barley . hvpkaba1 was not expressed at detectable levels in the endosperm , but was expressed in the embryo , with expression increasing from low levels at 15 dpa to its highest at 30 dpa . in other words , expression of this snrk2 was associated with mid- to late - development in the embryo . previous studies in wheat and barley have implicated this snrk2 with a role in controlling the onset of seed dormancy , aba - induction of gene expression and the suppression of genes that are induced by ga , as well as responses to cold and drought ( gmez - cadenas et al . , 1999 ; yamauchi et al . , 1995 ) increased ( p < 0.05 , lsd ) between 15 and 20 days post - anthesis , then did not change significantly ( fig . 3 ) . this gene was also expressed in the embryo ( fig . 4 ) , but levels increased steadily after 15 dpa and were at their highest at 30 dpa . at this point , transcription in the endosperm was still approximately four times higher than in the embryo . hvsnrk1b ( also known as bkin12 ) showed a similar pattern of expression in the endosperm , although its level was about half that of hvsnrk1a . however , its expression in the embryo , while detectable , was approximately 100 times lower ( fig . 4 ) . ( 1995 ) , although that study suggested that hvsnrk1b was expressed more highly in the endosperm than hvsnrk1a . currently there is insufficient knowledge of the different roles of snrk1a and snrk1b to assess the significance of their different expression patterns . however , specific down - regulation of hvsnrk1b in anthers has been shown to have profound effects on pollen development , including a failure to accumulate starch , arrested development and inviability ( zhang et al . , 2001 ) . snrk1bhomologues have also been implicated in controlling starch accumulation in sorghum and rice grain ( jain et al . the gene encoding the snrk1 non - catalytic subunit , hvsnrk1 , had a similar pattern of expression in the endosperm to hvsnrk1a and hvsnrk1b , with the peak at 20 dpa . in contrast , its expression in the embryo , while similar to that of hvsnrk1a at 15 dpa , did not rise in the way that hvsnrk1a gene expression did , resulting in it being substantially lower than hvsnrk1a by 30 dpa . the arebp - encoding gene , annotated as hvabi5 , showed a similar expression pattern to hvrcar35_47387 , hvsnrk2.4 and hvsnrk2.6 in the endosperm , with expression peaking at 20 dpa . expression was also detectable in the embryo but at much lower levels that remained constant throughout development . the expression of hvblz1 was also more than ten times higher in the endosperm than the embryo , with expression in the endosperm rising significantly ( p < 0.05 , lsd ) from 15 to 20 dpa and then remaining relatively high . the different events that occur in the endosperm and embryo during the onset of seed dormancy have been reviewed by sreenivasulu et al . ( 2006 ) , who considered the cells of the endosperm to undergo a form of programmed cell death , while those of the embryo enter true dormancy , from which they emerge at germination . aba is implicated in bringing about both of these very different developmental programmes and an important conclusion of the present study is that different aba receptors and snrk2s are involved in the different tissues . hvrcar35_47387 ( encoding an aba receptor ) , hvabi1d ( pp2c ) , hvsnrk2.4 and the arebp - encoding gene annotated as hvabi5 were expressed highly in the endosperm but at much lower levels in the embryo . conversely , a second aba receptor - encoding gene , hvrcar35_2538 , and the snrk2-encoding gene , hvpkaba1 , were expressed at higher levels in the embryo than the endosperm , while hvsnrk2.6 was expressed at similar levels in both ( although hvsnrk2.4 was the predominant snrk2 transcript in endosperm ) . this adds a level of complexity to what otherwise might be regarded as a relatively simple aba signalling pathway . it should be noted here that while differential regulation of gene expression is the most likely explanation of these results , post - transcriptional effects , such as alternative splicing resulting in the loss of regions spanning primer - binding sites , could explain why a transcript was detected in one tissue but not the other . it should also be noted that there is no contradiction in the high expression of hvabi1 ( pp2c ) in the endosperm , or the fact that its expression pattern closely matches that of hvsnrk2.4 and hvrcar35_47387 . the presence of pp2c would ensure that snrk2 would only be activated in the presence of aba . hvrcar35_47387 , hvabi1d , hvsnrk2.4 and the arebp - encoding gene annotated as hvabi5 all peaked in expression in the endosperm at 20 dpa . aba is required for both storage compound accumulation and the transition from filling to maturation , and we hypothesise that high levels of the signalling components are present at this time to enable these processes to be initiated . snrk1 on the other hand , has been implicated in the initiation and control of starch biosynthesis in seeds , tubers and pollen ( jain et al . , 2008 ; , 2005 ; mckibbin et al . , 2006 ; zhang et al . , , we found snrk1 to be expressed in both endosperm and embryo throughout development , with sub - type snrk1b showing much higher levels of expression in the endosperm than the embryo , while snrk1a was expressed at more similar levels in both tissues . however , snrk1 has been shown to be broken down in wheat roots in the presence of aba , while at least one snrk2 is activated ( coello et al . , 2012 ) . we propose a possible model for the interaction between aba and the two snrk families in which the hormone brings about a transition from a snrk1-dominated state in early grain filling to a snrk2-dominated state during maturation ( fig . 5 ) .

the expression of genes encoding components of aba and metabolic signalling pathways in developing barley endosperm and embryo was investigated . the genes included hvrcar35_47387 and hvrcar35_2538 ( encoding aba receptors ) , hvabi1d ( protein phosphatase 2c ) , hvsnrk2.4 , hvsnrk2.6 and hvpkaba1 ( snrk2-type protein kinases ) and hvabi5 ( aba response element binding protein ; arebp ) , as well as two genes encoding snrk1-type protein kinases . both snrk1 and snrk2 phosphorylate arebps , but snrk2 is activated by aba whereas snrk1 may be broken down . multiple cereal arebps with two conserved snrk1/2 target sites and another class of bzip transcription factors with snrk1/2 binding sites , including hvblz1 , were identified . barley grain ( cv . triumph ) was sampled at 15 , 20 , 25 and 30 days post - anthesis ( dpa ) . hvrcar35_47387 , hvabi1d , hvsnrk2.4 and hvabi5 were expressed highly in the endosperm but at much lower levels in the embryo . conversely , hvpkaba1 and hvrcar35_2538 were expressed at higher levels in the embryo than the endosperm , while hvsnrk2.6 was expressed at similar levels in both . hvrcar35_47387 , hvabi1d , hvsnrk2.4 and hvabi5 all peaked in expression in the endosperm at 20 dpa . a model is proposed in which aba brings about a transition from a snrk1-dominated state in the endosperm during grain filling to a snrk2-dominated state during maturation .

complex systems consisting of large number of highly interconnected dynamic units , whose structure is usually irregular have been the subject of intense research efforts in the past few years @xcite . the complexity of such systems is reflected not only in their structure but also in their dynamics . the usual representation of a wide range of systems of this kind in nature and society uses networks as the concept appropriate for the study of both the topology and dynamics of complex systems . the usual approach to study networks is via graph theory which was well developed for regular and random graphs both of which have been found to be exceptional cases of limited use in real world realizations and applications . recently , along with the discovery of new types of network structures such as the small - world @xcite and scale - free networks @xcite , the tools of statistical mechanics have been successfully implemented offering explanations and insights into the the newly recognized properties of these systems . in spite of many advances based on statistical mechanics approaches to various issues involving networks , from biology to social sciences , it is our opinion that there is a need for more versatile approach which would rely on new topological methods either separately or in combination with the techniques of statistical mechanics . in particular , the program is to encode the network into a simplicial complex which may be considered as a combinatorial version of a topological space whose properties may now be studied from combinatorial , topological or algebraic aspects . the motivation stems from the q - analysis introduced by r. atkin @xcite , @xcite who advocated its use in various areas of physics and social systems analysis in the 70 s . the methods of q - analysis were extended further into a combinatorial homotopy theory , called a - theory @xcite . consequently , the invariants of simplicial complexes may be defined from three different points of view ( combinatorial , topological or algebraic ) and each one of them provides completely different measures of the complex and , by extension , of the graph ( network ) from which the complex was constructed . in @xcite , for several standard types of networks we constructed vector valued quantities representing topological and algebraic invariants and showed , among other issues , that their statistical properties perfectly match their corresponding degree distributions . such an approach provided a link between topological properties of simplicial complexes and statistical mechanics of networks from which simplicial complexes were constructed . in the present exposition we focus on simplicial complexes ( obtained from random , scale- free networks and networks with exponential conectivity distributions ) and their homological properties . in most general terms , algebraic topology offers two methods for gauging the global properties of a particular topological space @xmath0 by associating with it a collection of algebraic objects . the first set of invariants are the _ homotopy groups _ @xmath1 @xmath2 the first one ( i.e. for @xmath3 ) , known as the fundamental homotopy group being well known . homotopy groups contain information on the number and kind of ways one can map a @xmath4-dimensional sphere @xmath5 into @xmath0 , with two spheres in @xmath0 considered equivalent if they are homotopic ( belonging to a same path equivalence class ) relative to some fixed basepoint . computational demands of such an approach are in general extremely high and for that reason the second set of invariants , the _ homology groups , _ is of more practical interest . homology groups of dimension @xmath4 , @xmath6 , provide information about properties of chains formed from simple oriented units known as simplices . the elements of homology groups are cycles ( chains with vanishing boundary ) and two @xmath4-cycles are considered homologous if their difference is the boundary of @xmath7-chain . in more general terms @xmath6 determines the number of @xmath4-dimensional subspaces of @xmath0 which have no boundary in @xmath0 and themselves are not boundary of any @xmath8-dimensional subspace . in contrast to homotopy groups , homology groups can be computed using the methods of linear algebra and the ease of these methods are counterbalanced by obtained topological resolution . it should be remarked that these computations can be quite time consuming in spite of recent advances in computational techniques mishaikow . although homology groups are computable and provide insight into topological spaces and maps between them , our interest is in discerning which topological features are essential and which can be safely ignored , similar to signal processing procedure when signal is removed from noise . one of the important informations about the topological space is the number and type of holes it contains and going beyond standard homological approaches one could be interested in finding out which holes are essential and which are unimportant . this is the subject of persistence and persistent homology , as introduced by edelsbrunner , letscher and zomorodian @xcite , whose aim is to extract long - lived topological features ( topological signal ) which persist over a certain parameter range and which are contrasted with short - lived features ( topological noise ) . with networks encoded into simplicial complexes we are interested in topological features which persist over a sequence of simplicial complexes of different sizes . this sequence reflects the formation of the network or the change of the existing network when new node or nodes are introduced or removed . here we focus on recognizing persistent and non persistent features of random , modular and non modular scale - free networks and networks with exponential connectivity distribution . in the following exposition our main topic will be homology and although it is self contained an elementary knowledge of homology would be helpfull , as may be found for example in chapter 2 of @xcite . our main motivation is to show that each of these different types of networks have different persistent homological properties although here we do not attempt to present these features as generic . moreover , long - lived topological attributes reveal new and important information related to connectivity of the network which could not be inferred using any other conventional methods . the outline of the exposition is as follows : in section 2 we review concepts from algebra and simplicial homology while in section 3 we present the methods of constructing simplicial complexes from graphs . in section 4 we introduce the concept of persistent homology and discuss computational aspects . section 5 contains description of graphical representation of persistent homology groups . in section 6 we present the results of persistent homology calculations for random networks while in section 7 and 8 persistent homologies are determined for networks with exponential degree distribution and three types of scale - free networks respectively . concluding remarks are given in section 9 . any subset of @xmath9 @xmath10 determines an @xmath11-@xmath12 denoted by @xmath13 the elements @xmath14 of @xmath15 are the vertices of the simplex denoted by @xmath16 and @xmath17 is the dimension of the simplex . any set of simplices with vertices in @xmath15 is called a simplicial family and its dimension is the largest dimension of its simplices . a @xmath18-simplex @xmath19 is a @xmath18-face of an @xmath17-simplex @xmath20 , denoted by @xmath21 , if every vertex of @xmath22 is also a vertex of @xmath23 a simplicial complex represents a collection of simplices . more formally , a simplicial complex @xmath24 on a finite set @xmath25 of vertices is a nonempty subset of the power set of @xmath15 , so that the simplicial complex @xmath24 is closed under the formation of subsets . hence , if @xmath26 and @xmath27.@xmath28 @xmath29 then @xmath30.@xmath31 two simplices @xmath32 and @xmath27 are @xmath33 if there is a sequence of simplices @xmath34 such that any two consecutive ones share a @xmath18-face,.implying that they have at least @xmath35 vertices in common . such a chain is called a @xmath18-chain . the complex @xmath24 is @xmath18-connected if any two simplices in @xmath24 of dimensionality greater or equal to @xmath18 are @xmath18-connected . the dimension of a simplex @xmath36 is equal to the number of vertices defining it minus one . the dimension of the simplicial complex @xmath24 is the maximum of the dimensions of the simplices comprising @xmath24 . in fig . 1 we show an example of a simplicial complex and its matrix representation . in this example @xmath37 } , and the simplicial complex @xmath24 consists of the subsets @xmath38 and @xmath39 . its dimension is @xmath40 , as there is a @xmath40-dimensional simplex , in addition to two @xmath41-dimensional ones , two @xmath42-dimensional and one @xmath43-dimensional simplex . a convenient way to represent a simplicial complex is via a so called incidence matrix , whose columns are labeled by its vertices and whose rows are labeled by its simplices , as shown also in fig . 1 . the multifaceted property ( algebraic , topological and combinatorial ) of simplicial complexes makes them particularly convenient for modelling complex structures and connectedness between different substructures . chains and cycles are simplicial analogs of paths and loops in the continuous domain . the set of all @xmath4-chains together with the operation of addition forms a group @xmath44 . a collection of @xmath45-dimensional faces of a @xmath4-simplex @xmath29 itself a @xmath45-chain , is the boundary @xmath46 of @xmath47 the boundary of @xmath4-chain is the sum of the boundaries of the simplices in the chain . the boundary operator @xmath48 is a homomorphism @xmath49 and @xmath50 s for @xmath51 connect the chain groups into a chain complex,@xmath52 with @xmath53 for all @xmath4 . the kernel of @xmath50 is the set of @xmath4-chains with empty boundary while a @xmath4-cycle , denoted by @xmath54 , is a @xmath4-chain in the kernel of @xmath55 the image of @xmath56 is the set of @xmath45-chains which are boundaries of @xmath4-chains with a @xmath4-boundary , denoted by @xmath57 , being a @xmath4-chain in the image of @xmath58@xmath59the collection of @xmath54 s and @xmath57 s together with addition form subgroups of @xmath44 while the property @xmath60 shows that @xmath61 i.e. these groups are nested as illustrated in figure 2 . the @xmath4-th homology group is@xmath62 if @xmath63 , @xmath64 then the difference between @xmath65 and @xmath66 is the boundary and @xmath65 and @xmath66 are homologous . the @xmath4-th betti number of a simplicial complex @xmath24 is @xmath67 the rank of the @xmath4-th homology group , @xmath68 @xmath69 or @xmath70 @xmath71 from expression ( [ h ] ) , @xmath72due to an alexander duality property @xcite , there is an intuitive depiction of the first three betti numbers nicely explained in @xcite . since a non - bounding @xmath73-cycle represents the set of components of complex @xmath74 , there is one basis element per component so that consequently @xmath75 represents the number of components of @xmath24 . hence , @xmath76 @xmath77 for connected complex @xmath24 so that the notion of connectivity is reflected in @xmath78 . a non - bounding @xmath43-cycle represents a collection of non - contractible closed curves in @xmath24 , or based on duality property , a set of tunnels formed by @xmath24 . each tunnel can be represented as a sum of tunnels from the basis so that @xmath79 represents the dimension of the basis for the tunnels . these tunnels may be perceived as forming graph with cycles @xcite . a @xmath80-cycle which itself is not a boundary represents the set of non - contractable closed surfaces in @xmath24 , or based on duality principle , a set of voids which exist in the complement of the simplicial complex , i.e. @xmath81 the dimension of the basis for voids , equal to the number of voids is represented by @xmath82 simplicial complexes may be constructed from undirected or directed graphs ( digraphs ) in several different ways . here we only consider two of them : the neighborhood complex and the clique complex . the neighborhood complex _ _ n__@xmath83 is constructed from the graph @xmath84 , with vertices @xmath85 in such a way that for each vertex @xmath86 of @xmath84 there is a simplex containing the vertex @xmath86 , along with all vertices @xmath87 corresponding to directed edges @xmath88 the neighborhood complex is obtained by including all faces of those simplices and in terms of matrix representation , the incidence matrix is obtained from the adjacency matrix of @xmath84 by increasing all diagonal entries by @xmath43 . an example of the construction of a neighborhood complex is represented in fig . @xmath41 . the clique complex @xmath89 has the complete subgraphs as simplices and the vertices of @xmath84 as its vertices so that it is essentially the complete subgraph complex . the maximal simplices are given by the collection of vertices that make up the cliques of @xmath84 . in literature , a clique complex is also referred to as flag complex . an example of a clique complex is presented in fig . 4 . these two methods are not the only ones that may be used for constructing simplicial complexes from graphs . actually , any property of the graph @xmath84 that is preserved under deletion of vertices or edges may be used for construction purposes . a detailed account of the methods for obtaining simplicial complexes from graphs , among many other issues related to the relationship between graphs and simplicial complexes , may be found in johnss . the basic aim of persistent homology @xcite is to measure life - time of certain topological properties of a simplicial complex when simplices are added to the complex or removed from it . usually the evolution of the complex considers its creation starting from the empty set , hence the assumption is that simplices are added to the complex ( corresponding to the growing network ) . the sequence of subcomplexes constructed in the process is known as filtration . in more formal terms the filtration of the simplicial complex @xmath24 is a sequence of complexes @xmath90 , such that:@xmath91the simplices in @xmath24 are indexed by their rank in a filtration sequence and each prefix of the sequence is a subcomplex . two filtration constructions are usually considered when the history of the complex is studied . the first one is formed when at each stage of the filtration only one simplex is added ( i.e. @xmath92 consists of one simplex @xmath93 for each @xmath94 ) . in the second case a simplex @xmath93 is added to the sequence , say to subcomplex @xmath95 , when all its faces are already parts of some @xmath90 @xmath96 hence , the second case does not require only one simplex to be added at each stage of filtration . these two filtrations contain complete orderings of its simplices and figure 5 illustrates the two progressive sequences . naturally , other filtrations may also be applied in practice including `` irregular '' ones when simplices are removed or disappear in the sequence . for these filtrations the main aspect of change is not only growth but decrease as well . following the expositions in the pioneering paper on persistent homology @xcite and in reference @xcite we give here some basic notions and concepts . persistence is defined in conjunction with cycle and boundary groups of complexes in filtration i.e. with respect to homology groups and associated betti numbers . since homology captures equivalent classes of cycles by factoring out the boundary cycles , the focus is on the count of non - bounding cycles whose life - span lasts beyond a chosen threshold ( say represented by number @xmath97 of next complexes in the filtration sequence ) and which determine persistent or long lasting topological properties of the complex . these cycles persist through @xmath97 phases of the sequence , hence they are important . in a complementary manner our interest also lies in cycles with short life - spans which convert to boundaries during filtration . algebraically , it is relatively simple to perform the count of persistent non - bounding cycles . let @xmath98 and @xmath99 represent the @xmath4-th cycle group and the @xmath4-th boundary group , respectively , of the @xmath100-th complex @xmath101 in filtration sequence . in order to obtain the long - lasting non - bounding cycles , the @xmath4-th cycle group is factored by the @xmath4-th boundary group of the @xmath102 complex , @xmath97 complexes later in the filtration sequence . formally , the @xmath97-persistent @xmath4-th homology group of @xmath103 is @xmath104clearly @xmath105 is a group itself being an intersection of two subgroups of @xmath106 the @xmath97-persistent @xmath4-th betti number , @xmath107 of the @xmath100-th complex @xmath101 in filtration is the rank of @xmath108@xmath109hence , @xmath110 counts homological classes in the complex @xmath111 which were created during filtration in the complex @xmath101 or earlier . there is a betti number for each dimension @xmath97 and for every pair of indices @xmath112 @xmath113 to get a more intuitive illustration of persistence concept let us consider a non - bounding @xmath4-cycle created at time ( step ) @xmath94 as a consequence of the appearance of the simplex @xmath32 in the complex so that the homology class of @xmath114 is an element of @xmath115 , i.e. @xmath116\in h_{k}^{i}.$ ] the simplex @xmath32 will be labelled as a @xmath117 simplex , or @xmath118positive simplex ) . consider the appearance of another simplex @xmath119 at time @xmath120 which turns a cycle @xmath121 in @xmath116 $ ] into a boundary , so that @xmath122 this causes the decrease of the rank of the homology group since the class @xmath116 $ ] is joined with the older class of cycles . the simplex @xmath119 will be labelled as an @xmath123 simplex , @xmath124(negative simplex ) since it annihilates both @xmath121 and @xmath116 $ ] . the persistence of @xmath114 and its homology class @xmath116 $ ] is then @xmath125 . as @xmath97 increases by one step ( assuming full ordering of simplices ) , persistence of all non - bounding cycles is decreased by one so that while @xmath97 increases , negative simplices cancel positive ones which appeared earlier in the filtration . for @xmath97 large ( long enough ) , the topological noise may be removed from pertinent information about homology groups and betti numbers . high quality algorithms exists for the computation of homology groups with respect to various applications . a comprehensive introduction to the subject of computational homology is @xcite ( and the associated computational homology project chomp @xcite ) while the algorithms for persistent homology are given in @xcite and @xcite . various practical issues related to these algorithms and computational methods for evaluating betti numbers are covered in @xcite . the matlab - based program `` plex '' @xcite , designed for the homology analysis of point cloud data set converted into a global simplicial complex ( rips , ech or other ) offers a wealth of possibilities for various operations with simplicial complexes and simplicial homology calculations . also , a package `` simplicial homology '' @xcite , requiring `` gap '' @xcite , a system for computational discrete algebra with special emphasis on computational group theory , provides numerous functionalities related to simplicial homology . both plex and simplicial homology have been extensively used in our calculations presented here . since persistent homology represents an algebraic invariant that detects the birth and death of each topological feature as the complex evolves in time , it is advantageous to encode the persistent homology in the form of a parametrized version of the rank of homology group i.e. its betti number @xcite . one possible choice for the parameter is time as it encompasses both the case of simplex growth ( addition of simplex or simplices ) and of its decrease ( removal of simplex or simplices ) . the other choice is to use intervals whose endpoints are filtration complexes essentially representing the filtered simplicial complex at times when the addition ( or removal ) of simplices takes place . during its temporal existence , each topological attribute plays a part in the formation of some betti number and our interest lies in those properties with long lifetimes ( persistent properties ) . the parameter intervals represent lifetimes of various stages of filtration and they may be represented on the horizontal axis while arbitrary ordered homology generators @xmath71 may be represented on the vertical axis . figure 6 shows an example of filtration and the barcode for @xmath126 . the rank of persistent homology group @xmath127 equals the number of intervals in the barcode of homology group @xmath71 within the limits of the corresponding parameter range or lifetime @xmath128 $ ] . here @xmath94 and @xmath129 may denote filtration times @xmath130 and @xmath131 or filtration complexes @xmath132 and @xmath133 . clearly , barcodes do not provide information on delicate structure of the homology however the information about persistent parametrized rank ( since @xmath134 @xmath71 a barcode reflects the persistent properties of betti numbers ) enables clear distinction between topological noise and topological `` signal '' . for the purpose of illustrating persistent homology we first consider random ( erds - rnyi ) networks @xmath135 for which the number of nodes , @xmath136 is fixed and with each link inserted with the same probability @xmath137 as is well known , a random network has a characteristic scale in its node connectivity reflected by the peak of the distribution which corresponds to the number of nodes with the average number of links . we have constructed the clique complex @xmath89 of a random network so that the obtained complex is a random simplicial complex @xmath138 the filtration @xmath139 of the complex is @xmath140then the @xmath94-th complex in the filtration is given by@xmath141where @xmath142 is the @xmath129-th skeleton of the clique complex ( the set of simplices of dimension less or equal to @xmath129 ) . the random network considered consists of @xmath143 nodes with the probability of two nodes having a link equal to @xmath144 . the corresponding barcode is presented in fig . 7 . due to sparsity of the network the filtration steps are limited to complexes of dimension @xmath41 . it is evident that persistent @xmath78 has betti number @xmath145 @xmath146 corresponding to one line that persists through all stages of filtration . since the zero dimensional homology measures the connectivity of the underlying graph the graph is always connected and this property remains for arbitrary choice of @xmath97 @xmath147 or @xmath17 , as one would expect . in addition @xmath148 @xmath149 while @xmath150 @xmath151 the maximal rank of persistent homology of this random network is @xmath43 . however , due to the short lifetime of @xmath152 through only two filtrations , it may be inferred that the content of topological noise dominates the network for this choice of parameters @xmath97 and @xmath17 . the same results , from the aspect of persistence , are obtained for the neighborhood complex @xmath153 @xmath154 @xmath155 @xmath156 increasing the probability @xmath97 or the number of nodes @xmath17 leads to occurrence of higher dimensional homology groups which though appear only as noise as illustrated in fig . 8 for the case of @xmath157 and @xmath158 . there is an interval outside which homology vanishes , and inside which only lowest ranked homologies persist , i.e. @xmath78 and @xmath152 . this conlcusion is in agreement with recent theoretical studies on clique and neighborhood complexes of random graphs @xcite , @xcite . in order to analyze the emergence of self - similar properties in a complex network , an e - mail network was studied in @xcite . each e - mail address in this network represents a node and links between nodes indicate e - mail communication between them . after removal of bulk e - mails , the connectivity distribution of this network is exponential , @xmath159 for @xmath160 and with @xmath161 the number of nodes ( e - mail users ) is 1700 . calculations were performed using both the clique and the neighborhood complex and both showed consistent persistency property . the corresponding persistency barcode is presented in fig . 9 in which the rank of the homology group equals the number of intervals in the barcode intersecting the dashed line which corresponds to the filtration stage . the first three homology groups , i.e. @xmath78 , @xmath152 and @xmath162 have long lived generators while higher dimensional homology groups appear only as topological noise . although random networks analyzed earlier and the e - mail network have comparable number of nodes , the number of higher dimensional homology groups is considerably larger in the latter case . this is the consequence of an internal organization of an e - mail network into a number of communities arenas which is an essential prerequisite for emergence of higher dimensional complete graphs . clearly , no such organizational principle exists in random networks ( random simplicial complexes ) and @xmath43-cycles dominate the complex . the fact that homology groups of dimension higher than @xmath42 have short lifetimes indicates that communications among certain groups of e - mail users may not exist for a certain time during the growth of the network however these communication channels are reestablished at later stages of the network evolution . among scale - free networks we consider scale - free models with modular structure developed recently @xcite . the model including preferential - attachement and preferential - rewiring during the graph growth is generalized so that new modules are allowed to start growing with finite probability . the structural properties of modular networks are controlled by three parameters : the average connectivity @xmath163 , the probability of the emergence of a new modul @xmath164 and the attractiveness of the node @xmath165 by varying these parameters the internal structure of modules and the network connecting various modules is kept under control . detailed explanation of the role of each of these parameters in the control process are discussed in @xcite . here we consider the persistent homology of three scale - free networks developed using three diferent sets of parameters @xmath166 @xmath167 @xmath168 chosen as paradigmatic for the type of network considered . the results for both clique and neighborhood complexes were constructed and since the results do not differ for the two cases the presented ones are obtained from the clique complex filtration [ f1 ] and [ f2 ] . all networks were generated with 1000 nodes . the average connectivity ( number of links per node ) is @xmath169 . the network has @xmath170 nodes and @xmath171 modules so that @xmath172 the attractiveness of the node is @xmath173 which enables stronger clustering effect , hence the label `` clustered modular network '' . the corresponding barcodes are presented in fig . 10 . there are unique persistent generators for @xmath78 and @xmath152 while for @xmath174 there are @xmath42 persistent generators . @xmath175 also has a persistent generator which starts at stage @xmath42 of filtration . it is interesting that once the homology is generated at later stages of filtration it remains persistent for all @xmath176 @xmath177 as indicated by arrows . one aspect of existence of persistent homology groups is robustness of the complex ( network ) with respect to addition or reduction of simplices ( nodes ) . the fact that four homology groups show persistence is a clear sign of robustness . moreover , practically there is no topological noise in this case . the parameters for this type of network are @xmath178 @xmath179 ( no modules ) and @xmath173 ( strong clustering ) . the persistence barcodes for this network are presented in fig . the most striking feature of these topological persistency representations is the existence of @xmath180 another striking feature is that @xmath175 does not exist for this particular value of clustering parameter @xmath181 showing that higher ranked persistency generators may not be distributed continuously across dimensions . there are four generators for @xmath182 however they persist through five stages of filtration and there are several more generators with shorter lifetime some of which may be considered as topological noise , such as the ones whose lifetime is one or two filtration phases . the fact that @xmath175 generators do not exist shows that for this choice of parameters there are no @xmath41-dimensional non - bounding cycles in the complex . the average connectivity is @xmath169 . modular probability is @xmath183 and clustering coefficient @xmath184 so that there is only one link between each of the modules and effectively there is non clustering . the corresponding barcodes are shown in fig . there is only one generator for @xmath185 for @xmath152 there is a unique generator persistent from the beginning of filtration however there are several generators which persist while occurring with the slight delay in filtration sequence . the maximal persistent homology rank is @xmath42 and @xmath174 has relatively long lived generators with a slight noise . of the three cases considered this one has the smallest number of persistent homology groups , namely three ( @xmath78 , @xmath186 and @xmath174 ) , and also the smallest number of generators for the homology group @xmath174 . since both clustered modular and clustered non - modular networks have higher ranked persistent homology ( @xmath175 and @xmath182 respectively ) then the non - clustered modular network ( @xmath174 ) , it is clear that clustered networks are more robust with respect to addition ( removal ) of nodes ( simplices ) . moreover , clustering property is more important for robustness then modularity as may be also inferred by comparison with the e - mail network discussed in sec . 7 which also shows modular structure . the fact that only @xmath187-dimensional and @xmath42-dimensional cycles ( voids ) are persistently missing in non - clustered simplices with respect to additional lack of @xmath41 and @xmath40-dimensional cycles in modular simplices may convey important information depending upon the context of the analysis and types of networks under study . in general the persistence of @xmath17-th homology generators ( @xmath17-th betti numbers ) means that somewhere in the complex @xmath17-th dimensional subcomplex is missing through all stages of complex growth or reduction . in other words an @xmath17-dimensional object formed by simplices of dimension at most @xmath17 is absent from the complex . this property may be translated to the `` network language '' in terms of connectivity relations which depend on the context . in simplified terms , for example for @xmath188 the network lacks in dyadic ( binary ) relations ; for @xmath188 there are no triadic ( ternary ) relations and so on where @xmath17-adic relations should be regarded not only as the set of its node - to - node relations but in their relational entirety . as an example , a face of a triangle represents a relational entirety ( essentially a relationship of higher order ) of a three node relation . construction of simplicial complexes from graphs ( networks ) creates a topological setting which offers flexible tools for gauging various topological attributes . here our interest lies in detection of long lived homology groups of a simplicial complex ( network ) during the course of its history which includes both addition and removal of simplices ( nodes ) . the method relies on visual approach of recognizing persistent features in the form of a barcode which may be regarded as the persistence analogue of a betti number . the results show distinct persistency attributes for random networks , networks with exponential degree distributions and for scale - free networks . persistency includes the two lowest dimensional homology groups @xmath189 and @xmath152 for random networks . for the case of neworks with exponential degree distribution persistency includes @xmath190 @xmath191 and @xmath192 while for scale - free networks persistent homology groups are @xmath190 @xmath191 @xmath174 , @xmath175 and even @xmath182 . an obvious consequence of persistency is that it gives important information about robust quality of the network so that scale - free networks , especially the ones with clustering properties , exhibit the highest topological resilience to change in the form of addition or removal of the nodes . however persistence of certain topological attributes assumes also long lived defficiency in certain topological forms in simplicial complexes corresponding to defficiency of certain relations in networks . in order to reveal more about the sense of balance between these two properties we will use more subtle topological methods in our future work . 99 boccaletti s , latora v , moreno y , chavez m and hwang d - u 2006 _ phys . rep . _ * 424 * 175

long lived topological features are distinguished from short lived ones ( considered as topological noise ) in simplicial complexes constructed from complex networks . a new topological invariant , persistent homology , is determined and presented as a parametrized version of a betti number . complex networks with distinct degree distributions exhibit distinct persistent topological features . persistent topological attributes , shown to be related to robust quality of networks , also reflect defficiency in certain connectivity properites of networks . random networks , networks with exponential conectivity distribution and scale - free networks were considered for homological persistency analysis .

Workplace A new survey by Citrix (CTXS), the Fort Lauderdale (Fla.) company that designs technology for employees to work remotely, shows that many people sneak in other activities while working from home. Based on a survey of 1,013 American office workers, conducted in June by Wakefield Research, 43 percent watch TV or a movie and 20 percent play video games while officially working from home. Parents are more likely than those without children to partake in these two activities, which aren’t work-related. Employees might not even be sober: 24 percent admit to having a drink. Twenty-six percent say they take naps. Others are distracted by housekeeping: 35 percent do household chores; 28 percent cook dinner. Yet despite all the distractions, telecommuters are actually more productive than their peers in the office, according to preliminary findings from Stanford University’s study of a Chinese travel agency. Jack M. Nilles, founder of management consulting firm, JALA International, says in an e-mail, “If an employee is doing the work and producing the desired results, what difference does it make if he/she includes a nap or cooking or a school play in the so-called work day?” He adds: “The whole point of teleworking, from the employee’s point of view, is the ability to fit one’s work into the rest of one’s life, not the other way around, as is the case in the ‘traditional’ office. The point of teleworking, from the employer’s point of view, is that its bottom-line benefits (productivity gains, space savings, employee retention, etc.) far exceed any feared risks of losses.” Sharon Davis, who runs the website 2work-at-home.com and does other work from her home in Fort Bragg, Calif., says, “Whether it’s expected or O.K. [to do other things during work hours] depends on the arrangement you have with your employer and what their expectations are. If they give you complete autonomy to get your work done and don’t care if you hold certain hours, go knock yourself out.” Davis, who did a phone interview with me in her pajamas while watching morning television, says she takes advantage of the flexibility that working from home provides, especially when it comes to caring for her children. Still, she warns that turning on the TV can easily become a big time waster. Half of survey takers say their bosses oppose the practice of working from home. Kim DeCarlis, Citrix’s vice president for corporate marketing, says in an e-mail that it’s not surprising that workers allow themselves to get distracted at home. “It speaks to the fluidity with which people are moving between work and life today,” she says. “Work no longer happens just between 9 a.m. and 5 p.m. from Monday through Friday. Life is no longer squeezed in on the weekends and evenings. These days, it’s more a question of who hasn’t checked and responded to a work e-mail on a weekend or while attending a child’s sport activity.” Citrix’s survey revealed other workplace habits. For example, the top reason employees sneak out in the middle of the day is to exercise, followed by “changing clothes,” “getting hair done,” and “taking a nap.” ||||| I work at home, which I much prefer to going into an office every day, for a whole host of reasons. There's the lack of a commute, which means that the hour and a half I used to spend every day in transit is now devoted to sleep, time with family, and even sometimes more work. There's money saved by not commuting. There's the ability to bathe at a time of your choosing. Most importantly, there's the feeling of autonomy you get from knowing that there isn't someone looking over your shoulder at all times, monitoring your movements. But what are people who work at home actually doing with our time? The short answer is, goofing off. But that's only part of the story: Based on a survey of 1,013 American office workers, conducted in June by Wakefield Research, 43 percent watch TV or a movie and 20 percent play video games while officially working from home. Parents are more likely than those without children to partake in these two activities, which aren’t work-related. Employees might not even be sober: 24 percent admit to having a drink. Twenty-six percent say they take naps. Others are distracted by housekeeping: 35 percent do household chores; 28 percent cook dinner. Yet despite all the distractions, telecommuters are actually more productive than their peers in the office, according to preliminary findings from Stanford University’s study of a Chinese travel agency. I wouldn't necessarily take the results of a study of a Chinese travel agency to be easily extrapolated to the entire American economy, but it makes sense to me. The reason is that people who work in offices spend a great deal of their time doing things other than work. They just happen to be different non-work things than the people who work at home do. If you work in an office, there's a good chance you spend a good deal of time surfing the web, which looks a lot like working to an outside observer, because you're staring at your computer. You also may do things like take hour-long lunch breaks. But more than anything else, you probably spend a lot of time chatting with your co-workers, which is something you don't do if you work at home. There's nothing wrong with that. It builds camaraderie and team spirit! But it's really just hanging out, and the fact that you do it in an office while wearing a tie doesn't mean it more closely resembles real work than watching last night's Colbert at noon. But you know who doesn't get to do that? People who work on assembly lines. And cashiers. And almost anyone who works for an hourly wage. One of the privileges of being a 21st century knowledge worker is that even in an office your time has a certain flexibility to it, which can make an otherwise unpleasant job tolerable. And now, I'm off to take a nap. Which I used to do by accident pretty often when I worked in an office. The only difference is that after 20 minutes I don't have to jerk up and pretend that I was awake the whole time.

– If you work at home, you may have just been caught red-handed: Business Week reports on a new survey finding that, while on the clock: 43% of telecommuters watch TV or a movie 35% do chores around the house 28% make dinner 26% take naps 24% have a drink 20% play video games But another recent survey found that people who work from home are actually more productive than those who work in an office. OK, so that study was focused on a Chinese travel agency, but it makes sense that telecommuters would be more productive—despite the distractions, writes Paul Waldman on Prospect.org. Why? Because there are just as many distractions for office workers, who frequently surf the web, take long lunches, and chat with co-workers. "The fact that you do it in an office while wearing a tie doesn't mean it more closely resembles real work than watching last night's Colbert at noon," he points out.

recent studies have observed the reduced blood flow in both ocular and peripheral districts in patients suffering from retinitis pigmentosa ( rp ) . the drop of the blood flow has been detected not only in retinal and choroidal vessels but also in retroocular vessels [ 24 ] . also , a reduced baseline peak flow in the cutaneous capillary of fingers has been measured and a significantly longer recovery time has been found after cold provocation . in the early stages of rp before detecting any ophthalmoscopic fundus modification , an increase of the arteriovenous passage time has been observed in the retina . using colour doppler imaging , cellini and coworkers demonstrated reduced peak systolic velocities in both ophthalmic arteries and posterior ciliary arteries [ 3 , 4 ] . they also observed a certain augmentation of endothelin-1 ( et-1 ) plasma levels in patients with early - stage rp , even though some investigators took issue with this observation [ 68 ] . a sort of dysregulation of both blood supply and vessel caliber seems to occur often in rp patients . konieczka has suggested that the primary vascular dysregulation syndrome , mainly characterized by an impaired vascular tone , might describe a wide range of local and systemic signs , such as ocular blood flow reduction with subsequent augmentation of et-1 plasma levels in the eye and peripheral vasospasm in response to cold , emotional stress , or low blood pressure [ 1 , 913 ] . disturbed autoregulation of ocular perfusion provokes an irregular blood flow , which means an unstable retinal blood supply , and a sort of attenuation of retinal vessels with reduced neurovascular coupling [ 14 , 15 ] . therefore , a large number of rp patients show a high prevalence of primary vascular dysregulation syndrome as the primary manifestation of ocular blood flow dysfunction . even if the exact pathophysiological mechanism is still unknown , the dysfunction of both autonomic nervous system and endothelial cells is currently investigated . it is characterized by alterations of photoreceptors ( prs ) and retinal pigment epithelium ( rpe ) resulting in progressive retinal degeneration . the most frequent symptoms are night - blindness and the growing impairment of visual field , perceived as tunnel vision , that may lead to legal blindness . clinical signs found at ophthalmic fundus examination are characteristic : bone - spicule pigment deposits in the mid periphery along with rpe atrophy , attenuation of retinal vessels , waxy pallor of the optic disc , and relatively spared macula surrounded by a perimacular ring of depigmentation [ 16 , 17 ] . the age of onset , the rate of progression , and the severity of rp are extremely variable depending not only on the genetic background but also on some influencing factors . symptoms may start in childhood as well as in the early or mid - adulthood . even though the progression of the disease is unpredictable , severe visual impairment typically occurs by the age of about 4050 years . the prevalence of all different forms of rp is reported to be about 1 : 35005000 individuals and , nowadays , it is estimated that there are almost two million affected people around the world [ 18 , 19 ] . the group of rp is characterized by a complex association between tremendous genotypic multiplicity and great phenotypic heterogeneity . the severity of the clinical manifestation depends on the penetrance of the disease gene , but also interactions between the gene expression and the environmental factors are of great importance . specific biochemical and molecular signaling pathways keep monitoring the perfusion pressure , originally controlled by the heart pump , and the local resistances , depending on the vessel caliber . vasospasm stands for inappropriate constriction of an artery . in the presence of excessive vasoconstriction and/or altered vasodilation , the overall condition is described as vascular dysregulation and it is often accompanied by a barrier dysfunction . if this condition is associated with symptoms or signs , it is referred to as vascular dysregulation syndrome . the diameter of the vessels is regulated by contraction ( vasoconstriction ) or relaxation ( vasodilation ) of both smooth muscle cells , forming the arterial or venous wall , and pericytes , encircling the capillaries . the smooth muscle cells are very sensitive to modifications of tension ( myogenic regulation ) , numerous metabolic factors originating from surrounding tissues , and biochemical signals coming from the autonomic nervous system ( neurohumoral regulation ) . the local perfusion pressure , depending on the cardiac output , and the local resistance to flow , depending on the rate of local autoregulation , are the two main aspects of the tissue blood flow . the endothelium is a very thin layer of cells lining vessels inwards . beyond its function as mechanical barrier , it plays crucial roles in immune and inflammatory responses , in haemostasis , and in vascular tone regulation . also it has autocrine , paracrine , and endocrine functions [ 24 , 25 ] . the first supplies the iris , the ciliary body , the choroid , and also , by diffusion , the outer retina , including the photoreceptors . the retinal vascular network is characterized by low perfusion rate , high vascular resistance , and high oxygen extraction . conversely , the choroidal network shows a high perfusion rate , a low vascular resistance , and a low oxygen extraction . autoregulation , actually effective within certain limits of perfusion pressure , is the intrinsic capacity to maintain constant flow despite changes in perfusion pressure . the neurovascular coupling is the tight link between the caliber of retinal vessels and the neuroretinal activity . a signal from the central nervous system , closely connected to the retina , is able to evoke small changes in the retinal blood flow through complex pathways involving neurons , glia , and endothelial cells . furthermore , the retinal vascular system features the blood retinal barrier which regulates the flux of ions , proteins , hormones , and water , even monitoring the infiltration of immune competent cells . it provides oxygen and other metabolites , controls eye temperature , and mostly contributes to the fine - tuning of accommodation by regulating choroidal thickness . the endothelin ( et ) system encompasses three active peptides ( et-1 , et-2 , and et-3 ) , two g protein - coupled receptors ( eta and etb ) , and activating peptidases including the et - converting enzymes ( ece-1 and ece-2 ) , . knock - out mice have been used as models to study pathophysiological role of the et system . some et components are essential for the development of both tissues , such as cardiac or craniofacial tissue , and systems , such as enteric and nervous system [ 2931 ] . endothelin-1 ( et-1 ) , widely distributed in human tissues , is produced by vascular endothelial cells and also by many other cells . endothelin-2 ( et-2 ) , with equally high affinities for both eta and etb , is largely expressed in the gastrointestinal tract and it serves as local and paracrine / autocrine mediator . very little is known about the function of endothelin-3 ( et-3 ) , except for the fact that it seems to be secreted somewhere near the relevant target cells , such as enteric neuroblasts expressing the etb . first identified in 1988 , et-1 is the most powerful endogenous vasoconstrictor of both small and large vessels [ 34 , 35 ] . it is a peptide with 21 amino acid residues and it is mostly released by endothelial cells of arteries , veins , and lymphatic vessels . et-1 acts as a modulator of the secretion of renin , vasopressin , and aldosterone , but at the same time it inhibits platelet aggregation . indeed , it has been observed in patients suffering with high blood pressure , arteriosclerosis , acute myocardial infarction , and diabetes mellitus [ 3841 ] . also hypoxic or oxidative stress , systemically and locally , has been identified as strong stimulus to raise primarily the levels of hypoxia - inducible factor 1 ( hif-1 ) and subsequently the levels of et-1 . in the eye , local synthesis and secretion of et-1 are performed by many tissues , such as cornea , uveal tissue , retinal microvascular pericytes , rpe cells , and optic nerve , suggesting that the et system could have an important role in the pathophysiology of some eye diseases [ 4246 ] . glaucoma , diabetic retinopathy , retinal vein / artery occlusion , proliferative vitreoretinopathy , and inherited retinal dystrophies are featured by impaired ocular blood circulation and they all present abnormal et-1 plasma levels [ 4751 ] . et-2 is a protein encoded by the endothelin-2 gene ( edn2 ) and is a member of the et system . it is referred to as macrophage chemoattractant and it is strongly induced in prs in the course of retinal diseases and injury , being involved as stress signal to mller cells through etb [ 52 , 53 ] . supposedly , a wide range of retinal disorders , including the inherited retinal dystrophies such as rp , converge on a relatively small number of molecular pathways going towards the cellular repair or death . mller cells , the most abundant glial cells in the retina , seem to monitor the status of retinal neurons , being generally activated after prs ' degeneration or death [ 55 , 56 ] . there is evidence that injured or degenerated prs start to release et-2 stimulating the activation of the mller cells fitted with etb . these glial cells increase both the production of glial fibrillary acidic protein and the sensitivity to et-2 by upregulating the etb as part of their repairing response [ 53 , 57 ] . et-1 can be used as biochemical marker to assess ocular hemodynamics . to measure intraocular et-1 blood concentration , investigations showed the significant correlation between et-1 plasma choroidal and plasma systemic concentrations . in cases of rp , cellini and coworkers have reported that a general increase in plasma levels of et-1 elicits vasoconstriction both systemically and locally in the eye , causing retinal and choroidal hemodynamic impairment involving both ophthalmic artery and posterior ciliary arteries [ 2 , 5 , 6 , 58 , 59 ] . the role of the et system in the pathogenesis of several ocular diseases , including the rp , is unquestionably important . however , at present there are some discordant studies about et-1 plasma levels in people suffering from inherited retinal dystrophies . cellini and colleagues have repeatedly observed high concentrations of et-1 in these patients , whereas ohguro and colleagues reported low levels of et-1 [ 3 , 8 , 51 , 60 ] . regardless of their opposite experimental observations , common evidence is the decreased intraocular blood flow , initially in both choroid and optic nerve head and later in retina , due to abnormal plasma levels of et-1 [ 61 , 62 ] . a proper biochemical pathway responsible for the reduced intraocular blood flow is still not ascertained ; however , there are some hypotheses under investigation . the first is about the migration of rpe cells to the inner layers of the retina after prs ' death . local secretion of et-1 from the proliferated and migrated rpe cells may stimulate repairing processes by deposition of extracellular matrix just underneath the retinal vessels . as a consequence , thinning and fenestration of retinal vascular endothelial cells the second assumption considers the fact that the more the prs die the less the ocular blood supply is required . another aspect to take into consideration is the low oxygen consumption by the degenerated and dying prs . the subsequent vasoconstriction , mediated by increased levels of et-1 , is referred to as mechanism for limiting higher oxygen levels locally [ 65 , 66 ] . table 1 supplies a brief and clear summary of the crucial role of et-1 in rp . on the basis of recent investigations , in subjects with rp there is a statistically significant correlation between the augmentation of et-1 plasma levels and the drop of the peak systolic velocity in both the ophthalmic artery and the posterior ciliary arteries . the genetics are definitely remarkable , but the impaired retinochoroidal blood supply might be considered as an important modifier of the progressive loss of prs . furthermore , a sort of systemic dysfunction of the microcirculation seems to be in people with rp . in fact , cellini and coworkers have measured , by means of laser doppler flowmetry , a lower baseline cutaneous capillary blood flow and a longer warm recovery time in rp patients with respect to healthy subjects . it has been observed that biochemical and metabolic alterations of the endothelial cells of retinal vessels and the augmentation of the intraocular oxygen concentration are triggering factors for the retinal production of et-1 . this molecule provokes high levels of intracellular ca in glial and neuronal cells and increases both neuronal activities and neuronal responses to glutamate . also , through eta receptors et-1 may have a synergistic effect on the glutamate - induced neurotoxicity in the retina . other studies have also highlighted the pivotal role of et-1 in relation to the apoptosis of the retinal ganglion cells through etb receptors . to date , big efforts are still to be made to assess a fine correlation between genetic mutations and clinical manifestations in the rp . the most of mutations occur in genes coding for proteins involved in the cycle of vision , at the level of rods , cones , and rpe cells . in the course of the disease , the prs go towards apoptosis , so that the outer retinal nuclear layer flattens . the pigment deposits , described as bone - spicule pigmentation , result from both rpe cell degeneration and migration into the neural retina after prs ' death . there is evidence that oxidative stress and related conditions play an important role in the inherited retinal dystrophies . another important aspect of rp is the reduced blood flow in both ocular and peripheral districts along with a substantial increase in levels of inflammation [ 1 , 22 ] . strobbe and coworkers demonstrated a statistically significant correlation between ocular inflammation , detected by measuring aqueous flare with the noninvasive laser flare - cell meter , and high et-1 plasma levels in patients suffering from rp . this condition features alterations in choroidal thickness and blood flow leading to a boost in free radicals and oxidative stress . several general conditions , such as hypoxia , chronic oxidative stress , vascular dysregulation , or systemic inflammation , provoke the increase of et-1 plasma levels . this aspect is well - recognized in patients with rp who have low and impaired ocular blood flow , also characterized by progressive choroidal thinning and attenuation of retinal vessels . some authors have observed that rp subjects feature an imbalance of the antioxidant - oxidant status in the peripheral blood . thus , the subclinical general inflammation and the substantial oxidative stress trigger the production of high levels of et-1 , which in turn bring about vascular dysregulation and diffuse hypoxic stress . this vicious circle contributes to activating and amplifying the inflammatory response . in the eye , vasospasm and altered intraocular perfusion bring about relative ischemia and , as a consequence , degeneration of the prs . further investigations are needed to confirm the link between vascular dysregulation and subclinical inflammation in rp . however , in the next future research probably focuses on the development of novel drugs as antagonists of et-1 and new antioxidants in order to better improve the vascular function systemically as well as locally .

retinitis pigmentosa is a clinical and genetic group of inherited retinal disorders characterized by alterations of photoreceptors and retinal pigment epithelium leading to a progressive concentric visual field restriction , which may bring about severe central vision impairment . haemodynamic studies in patients with retinitis pigmentosa have demonstrated ocular blood flow abnormalities both in retina - choroidal and in retroocular vascular system . moreover , several investigations have studied the augmentation of endothelin-1 plasma levels systemically in the body and locally in the eye . this might account for vasoconstriction and ischemia , typical in vascular dysregulation syndrome , which can be considered an important factor of reduction of the ocular blood flow in subjects affected by retinitis pigmentosa .

in washington , all clinical laboratories and healthcare providers are required to submit salmonella isolates to the washington state department of health public health laboratory ( phl ) for serotyping and surveillance ( washington administrative code 246101201 ) . the phl is a participant in pulsenet , a national surveillance system established in 1996 that allows state and local public health epidemiologists to compare pfge profiles of salmonella strains from all us regions ( 7 ) . all human isolates are compared at the phl by using a standard pfge pulsenet protocol ( 8) . beginning in january 2004 , all human - origin isolates were obtained from the phl by the washington state university zoonosis research unit in pullman . animal - origin isolates were obtained from the washington animal disease diagnostic laboratory in pullman , the washington avian health laboratory in puyallup , and a private veterinary diagnostic laboratory . in addition to isolates originating from clinical veterinary submissions , we obtained isolates from a research study targeting salmonella occurrence on dairy farms in washington ( d. hancock et al . all isolates were tested for resistance to a panel of antimicrobial drugs with a standard disk - diffusion method ( 9 ) according to clinical and laboratory standards institute guidelines ( 10 ) ( table 1 ) . isolates collected from january 1 , 2000 , through april 2005 were tested for susceptibility to a panel of antimicrobial drugs ( table 1 ) . animal - origin isolates that matched human - origin isolates by serotype and resistance pattern were further compared by using a standard pfge protocol ( 8) . cluster analysis using the unweighted pair group method with arithmetic mean analysis ( upgma ) of dice similarity coefficients based on pfge banding patterns was computed in bionumerics ( applied maths , sint - martens - latem , belgium ) . to limit the effect of nonindependence among isolates , only the first in each serotype and resistance pattern group within each herd and calendar year was included in the analysis . statistical significance testing of the change in proportions was conducted in epiinfo version 6.0 with for linear trend ( 11 ) . * pfge , pulsed - field gel electrophoresis . a , ampicillin ; su , triple - sulfa ; caz , ceftazidime ; k , kanamycin ; t , tetracycline ; s , streptomycin ; c , chloramphenicol ; sxt , trimethoprim - sulfamethoxazole ; g , gentamicin . in april 2005 nitrofurantoin , trimethoprim , and ciprofloxacin were dropped from the panel , and amoxicillin - clavulanic acid , nalidixic acid , and ceftazidime - clavulanic acid were added . we observed an increase in bovine - origin s. typhimurium isolates that were represented by 2 highly similar pfge patterns , identified as washington state pulsenet types typ035 and typ187 ( table 2 ) . they were clearly distinguishable from phage type dt104 strains isolated during the same time frame ( appendix figure ) . to determine whether these xbai pfge types were clonal , we characterized 60 s. typhimurium isolates , including 32 typ035-typ187 isolates from bovines and 19 typ035-typ187 isolates from humans , by pfge following digestion of dna by spei . thirteen isolates that were xbai - typ035 had spei patterns indistinguishable from those of xbai - typ187 isolates . in the cluster analysis of spei patterns , the typ035 and typ187 isolates xbai patterns were at least 90.1% similar compared to an overall 83.7% similarity for all s. typhimurium isolates in the analysis . characterization of isolates within the xbai pfge type typ035 also included plasmid profiles of 38 isolates with published plasmid - profiling methods ( 12 ) . isolates were selected for plasmid profiling to maximize the diversity of resistance patterns , geographic origin , and year of isolation . plasmid sizes were estimated relative to a bac - tracker supercoiled dna ladder ( epicentre biotechnologies , madison , wi , usa ) . the remainder had variable plasmid profiles , but the plasmid profiling data did not correlate with resistance phenotype or spei - banding variations ( data not shown ) . similar results were obtained with phage typing of a convenience sample of 31 isolates by rafiq ahmed at the national microbiology laboratory , winnipeg , manitoba , canada . all 31 typ35 isolates were phage - type untypable with the standard colindale panel of phages , although an additional set of phages were able to discriminate among some of them ( r. ahmed , pers . the resulting categories of untypable phages ( ut2 , ut5 , ut7 , and ut8 ) were also not consistent with either plasmid profile or resistance phenotypes ( data not shown ) . * for human isolates only a single isolate per individual was included , and for bovine isolates only independent isolates were included . the proportion of all bovine independent s. typhimurium isolates in the typ035typ187 clade increased significantly from 2000 to 2006 in washington ( for linear trend , p<0.01 ) . the proportion also increased significantly among human s. typhimurium isolates during the same period ( for linear trend , p<0.01 ) ( table 2 ) . expansion of typ035 apparently occurred in the bovine population of the pacific northwest before its increase among human isolates because in 2000 it represented over one quarter of all bovine s. typhimurium , but it was uncommon among human - source s. typhimurium before 2002 to 2003 ( table 1 ) . similarly , typ187 was detected in bovine isolates 2 years before its detection in human isolates . resistance characteristics varied among typ035 and typ187 isolates . before 2003 , the predominant resistance pattern among typ035 isolates was the akssut phenotype ; after 2002 , isolates were distributed more widely among several resistance patterns ( table 1 ) . the strain type reported here may be an emerging epidemic clone of mdr salmonella with the potential to expand further . since 2001 , typ035 has been infrequently reported in the national pulsenet database , and most sporadic cases were from washington . comparison of pfge patterns between northwest and new york state s. typhimurium isolates at the cornell university zoonosis research unit showed no occurrences of typ035 or typ187 among 23 bovine and 29 human s. typhimurium isolates from the same period . these comparisons with isolates from other parts of the united states suggest that the emergence of the typ035/ typ187 clade is currently focused in the pacific northwest region but has the potential to become more widespread . in 2006 , the massachusetts department of public health investigated an outbreak of salmonellosis associated with owl pellets among elementary school students ( 46 primary cases , 12 secondary cases ) ( 13 ) . this outbreak was caused by typ035 s. typhimurium , and the supplier of the owl pellets was located in a rural county in south - central washington . this outbreak illustrates that epidemic clones may disseminate widely by means of unpredictable vehicles and that nonfoodborne transmission can have a major public health impact . the typ035/typ187 clade first increased in the animal reservoir , followed by spillover into the human population , consistent with its being an emergent clone . whether or not this strain will continue to expand , further characterization of this pfge type and continued surveillance will be important steps for improving our understanding of epidemic salmonella clones ( 3,5 ) dendogram of cluster analysis of pulsed - field gel electrophoresis ( pfge ) banding patterns of xbai - digested salmonella enterica serotype typhimurium dna . a , ampicillin ; c , chloramphenicol ; k , kanamycin ; sxt , trimethoprim - sulfa ; s , streptomycin ; t , tetracycline ; su , sulfonamine ; caz , ceftazidime . each isolate represented here is a unique bovine - origin isolates ( each is from a different herd , year , and resistance type ) .

we compared human and bovine isolates of salmonella enterica using antimicrobial - drug resistance profiles and pulsed - field gel electrophoresis . from 2000 through 2006 , we observed an increase in a novel multidrug - resistant clone of s. typhimurium with no recognized phage type . this clone may represent an emerging epidemic strain in the pacific northwest .

haemoglobinopathies are genetic defect that results in abnormal structure of one of the globin chains of the haemoglobin molecule abnormal haemoglobin appears in one of three basic conditions ; structural defects in the haemoglobin molecule , diminished production of one of the two subunits of the haemoglobin molecule ( thalassemias ) , and abnormal association of otherwise normal subunits . the patients suffering from beta - thalassemia major and hbe / beta - thalassemia do not survive for more than 5 years without blood transfusion . more than 700 haemoglobin variants have been described that involve genes both from alpha and beta gene clusters . occasionally , someone inherit two different variants from the alpha - globin gene cluster or two different variants from beta - globin gene cluster . the nature of two genes inherited determines whether a clinically significant disease state develops . among these the thalassemias comprise a diverse group of disorders and are broadly classified into , , - and -- thalassemias , depending on the globin chain(s ) , which are insufficiently synthesized . since humans have 4-globin genes on chromosome 16 and 2-globin genes on chromosome 11 , symptomatic -thalassemia is rarer than -thalassemia . in addition to the transfusion - dependent form of -thalassemia , -thalassemia major , there are milder conditions that may escape detection until adulthood . because of their high frequency and severity , the -thalassemias pose the most important public health problem . inherited disorders of haemoglobin synthesis are , therefore , an important cause of morbidity and mortality worldwide . they place a large burden to the patients , their families , and even their communities . they are generally not curable but can be prevented by population screening , genetic counseling , and prenatal diagnosis . the present study was undertaken to evaluate the spectrum and pattern haemoglobinopathies in a selected population of bangladesh . the samples were collected from different hospitals located at dhaka city during april to june 2011 . they were suspected of suffering from anaemia and referred to these hospitals from peripheral regions . the samples were analyzed at the department of biochemistry and molecular biology , dhaka university . written informed consent was obtained from the study participants and local ethical review committee approved the design of the study . about 2 - 3 ml intravenous blood samples were collected after obtaining informed consent using edta ( ethylene diamine tetra acetic acid ) as anticoagulants by disposable syringes and needles from each individual free of blood transfusions . the sysmex xe-2100 system haematology analyzer ( sysmex corporation , kobe , japan ) was used to determine peripheral cell count and red blood cell indices ( rbc , hb% , hct , mcv , mch , and mchc ) using standard procedure that employed rf / dc detection method , hydrodynamic focusing , flow cytometry method and sls - haemoglobin method . haemoglobin electrophoresis was carried out on agarose gel using the hydragel k20 system ( sebia , issy - les - moulineaux , france ) . analysis of variance ( anova ) of the data was used to detect overall difference in group means . out of 600 cases , 253 ( 42.2% ) cases were found normal and 347 ( 57.8% ) had one or the other form of haemoglobinopathies . out of 347 abnormal cases , 174 ( 50.1% ) were males and 173 ( 49.8% ) were females , which gives an equal incidence in both males and females . table 1 represents the spectrum of haemoglobinopathies encountered during three months of time and figure 1 depicted the electropherograms of different types of haemoglobinopathies . it is important to note here that -thalassemia minor is the most common form of haemoglobinopathy ( 21.3% ) , followed by e- -thalassemia ( 13.5% ) , hbe trait ( 12.1% ) , hbe disease ( 9.2% ) , hb d / s trait ( 0.7% ) , -thalassemia major ( 0.5% ) , and --thalassemia ( 0.5% ) , respectively . though the study was conducted in dhaka city , this data represent an overall picture of the country , because most of the patients were referred from peripheral regions , where such investigation facility is not available . table 2 represents an age- and sex - wise distribution of cases of different haemoglobinopathies . it is apparent from the table that majority of the cases of haemoglobinopathy belong to neonatal to childhood period ( 015 years ) followed by reproductive age group ( 1645 years ) and only a few cases of old age ( 46 + years ) who were detected when they face clinical complications . as shown in table 3 , patients of -thalassemia minor had milder anemia with decreased total hb ( p < 0.001 ) and hba ( p < 0.001 ) and a slight increase in hba2 , e , and f compared to normal subjects . e- -thalassemia patients suffered severe anaemia with significant decrease in total hb ( p < 0.001 ) and hba ( p < 0.001 ) . there was significant increase in hbe ( p < 0.001 ) and f ( p < the elevation of hbe and f was higher in this group than -thalassemia minor group but lower than that of e--thalassemia group . in hbe - trait there was no sign of anaemia , still there was a significant increase in hbe ( p < 0.001 ) level as found in hbe disease compared to -thalassemia minor group . -thalassemia major patients had severe anaemia with significant decrease in total hb and rbc count and showed highest increase in hbf levels among all the groups studied . --thalassemia and d / s trait groups showed milder anaemia with slight increase in hba2 and hbf levels . however , --thalassemia group did not show an increase in hbe levels as it was evident in d / s trait group . haemoglobinopathies are monogenic disorders of erythrocyte formation that has a widespread prevalence extending from mediterranean zone , middle east , indian subcontinent , and parts of southeast asia . though the exact data regarding the prevalence and spectrum of haemoglobinopathies in bangladesh is not known , it seems to be increasing . if the disease continues to pass vertically , it may take the form of epidemic . since there is no effective treatment of the disease , the only way to prevent the disease is carrier detection and awareness among the people about this emerging epidemic . this study , therefore , provides a comprehensive data on the pattern of spectrum of haemoglobinopathies in bangladesh . present study was conducted on 600 individuals referred to different hospitals at dhaka city between april to june 2011 . among the 600 cases studied , 42.2% were found to be normal and 57.8% had one or the other forms of anaemia ( table 1 ) . out of 347 abnormal cases equal incidence in males ( 50.1% ) and females ( 49.8% ) was observed ( table 2 ) . most common haemoglobinopathies observed were -thalassemia minor ( 21.3% ) , e--thalassemia ( 13.5% ) , haemoglobin e disease ( 9.2% ) , and haemoglobin e trait ( 12.1% ) . several other studies also have documented such high frequency of these haemoglobin formation disorders in neighbouring and other southeast asian countries [ 69 ] . other less common haemoglobinopathies observed were --thalassemia ( 0.5% ) , -thalassemia ( 0.5% ) , and haemoglobin d / s trait ( 0.7% ) . the onset of the diseases was most prominent in neonatal to childhood period ( 015 years ) , followed by reproductive age group ( 1645 years ) . few cases of old age ( 46 + years ) were detected only when they faced clinical complications ( table 2 ) . this study found many variations in the clinical presentation of disease ( table 3 ) . patients belonging to -thalassemia minor group had mild anaemia with decreased total hb ( p = 0.001 ) and hb a ( p = 0.001 ) compared to normal . haemoglobin electrophoresis showed a slight increase in hba2 and f. since these patients inherit one gene of -thalassemia , they are either asymptomatic or develop mild - to - moderate anaemia . though sometimes the red blood cells may be hypochromic and microcytic , iron supplementation is not required except for pregnant woman . genetic counselling for couples at risk for offspring with homozygous -thalassemia may be done at this stage . patients belonging to this group were severely anaemic with a significant decrease in total hb ( p = 0.001 ) and hb a levels ( p = 0.001 ) . e--thalassemia patients inherit one gene for -thalassemia and one gene for hb e disease . as a result their clinical presentation is similar to those of -thalassemia major or hbe disease , except that they showed greater elevation in hbe and f among all the groups studied . many other studies also reported e--thalassemia as the commonest form of thalassemia in southeast asia [ 6 , 10 , 11 ] . hbe disease and e trait are homozygotic and heterozygotic conditions of a -chain variant , where a lysine residue is substituted by glutamic acid . this monogenic disease also has a broad distribution throughout the mediterranean , the middle east , and the indian subcontinent [ 12 , 13 ] . this study found 9.2% hb e disease and 12.1% hb e trait among the overall study subjects . the haematological parameters in hbe disease were similar with -thalassemia major with the exception that -thalassemic patients had a very high level of hb f and absence of hb e. hb e - trait patients had milder anaemia comparable to -thallasemia minor with significantly higher levels of hb e ( p = 0.001 ) . in -thalassemia major , as expected , there was severe anaemia with extremely low total hb with hypochromia and microcytosis . this study found only a slight increase in hb f level still , much less compared to -thalassemia major patients . the gene controlling delta chain production is located very close to beta gene on chromosome 11 . if one gene is deleted then the other may be affected . / s trait is a heterozygotic condition where either one hb d or s chain is combined with one normal chain . both d and s are variants of beta chain , in which a single amino acid is replaced . in hb s the beta subunit has the amino acid valine at position 6 instead of glutamic acid , whereas in hb d glutamine replaces glutamic acid at 121 positions on beta chain . sickle cell disease is most common in people of african ancestry and tribal people of india . the carrier frequency of sickle gene is cited 1 in 10 in the usa and may be higher in canada where the black population is composed largely of individuals of caribbean and african origin . hb d on the other hand occurs mainly in northwest india , pakistan , and iran . the frequency of hb d / s trait found in this study was 0.7% , higher than --thalassemia , or -thalassemia major . the electrophoretic mobility of hb d and hb s is identical at alkaline ph in cellulose acetate . -thalassemia minor ( 21.3% ) is the commonest encountered haemoglobin formation disorders followed by e--thalassemia ( 13.5% ) , hbe trait ( 12.1% ) , and hbe disease ( 9.2% ) in bangladesh . since these patients were referred from peripheral regions of the country where the diagnostic facility is not much available , this data is representative of an overall prevalence of haemoglobinopathies and thalassemias of the country . an effective strategy of preventing the progression of the disease in bangladesh might be a nation - wide screening program employing more sophisticated techniques like polymerase chain reaction ( pcr ) followed by direct sequencing , genetic counseling , and creating public awareness .

thalassemia and other structural haemoglobinopathies are the major erythrocyte formation disorder prevalent in certain parts of the world including bangladesh . we investigated 600 cases of anaemic patients referred from various parts of the country for diagnosis and counselling during 3 months ( april to june 2011 ) of time . the most common form of haemoglobin ( hb ) formation disorder observed in 600 subjects studied was -thalassemia minor ( 21.3% ) . two other conditions , such as e--thalassemia and hbe trait , were also fairly common ( 13.5 and 12.1% , resp . ) in the total subjects studied . other forms of haemoglobin formation disorders observed were hbe disease ( 9.2% ) , hb d / s trait ( 0.7% ) , -thalassemia major ( 0.5% ) , and --thalassemia ( 0.5% ) . the majority of the haemoglobinopathies belonged to neonatal to childhood period ( 015 years ) , followed by reproductive age group ( 1645 years ) . few old - age ( 46 + years ) cases were also detected in course of clinical complications .

this requires that homeostatic processes maintain blood glucose concentration at a minimum of 5 mm to ensure sufficient provision of glucose to the brain ( unger and orci , 1981 ) . specialized glucose sensing cells present in peripheral locations , such as the hepatoportal vein area , and in the cns are activated by hypoglycemia and initiate a counterregulatory response to normalize glycemia ( chan and sherwin , 2013 , frizzell et al . this response is mediated by activation of the autonomous nervous system and the hypothalamo - pituitary - adrenal axis , leading to the release in the bloodstream of glucagon secreted by pancreatic alpha cells , and of catecholamines and glucocorticoids secreted by the adrenal gland ( verberne et al . , 2014 ) . the combined action of these hormones promotes hepatic glucose production , lipolysis in the adipose tissue , suppression of insulin secretion , and inhibition of glucose uptake in muscle and fat . these actions restore normoglycemia and glucose flux to the brain ( verberne et al . , 2014 ) . the counterregulatory response to hypoglycemia is , thus , essential for survival . in type 1 and type 2 diabetic patients treated with insulin , the counterregulatory response to hypoglycemia is progressively blunted causing occasional hypoglycemia . antecedent hypoglycemic episodes then lead to a progressive loss of the hypoglycemia cognitive warning signals and to a reduced hormonal counterregulatory response . this condition , referred to as hypoglycemia associated autonomic failure ( haaf ) , augments the risks to develop hypoglycemic episodes of increased severity and is a major obstacle in the treatment of diabetes with insulin ( cryer , 2013 ) . hypoglycemia detection in the brain occurs within specialized brain areas , mainly the hypothalamus and the brainstem ( marty et al . these brain structures contain neuron subpopulations activated by an increase or a fall in extracellular glucose concentrations and which are referred to as glucose excited ( ge ) or glucose inhibited ( gi ) neurons , respectively ( routh , 2002 ) . identification of these neurons is based on electrophysiological recording of their firing activity assessed in acute brain sections or using dispersed neuron populations . the molecular mechanisms of glucose sensing by ge or gi neurons are diverse ( thorens , 2012 ) . glucose sensing by ge neurons involves proteins also controlling glucose - induced insulin secretion by pancreatic beta - cells such as glut2 ( lamy et al . , 2014 , glucokinase ( levin et al . , 2008 , stanley et al . , 2013 ) , and the katp channel ( evans et al . , 2004 , miki et al . the na / glucose co - transporters sglt1 and sglt3 may also contribute to glucose sensing by ge neurons ( omalley et al . on the other hand , amp - activated protein kinase ( ampk ) plays a key role in activation of gi neurons by hypoglycemia ( alquier et al . in contrast to ampk and the katp channel , which are present in all neurons , glut2 , glucokinase , and the sglts are present in specific , only partly overlapping neuronal subpopulations and may thus be used as markers of glucose - sensing neurons . identification of glucose sensing cells , in particular , those implicated in the adaptive response to hypoglycemia is of high importance to better understand the cause and possible management of haaf . so far , the mechanisms of central glucose sensing have been explored based on the targeted analysis of genes known to be involved in glucose metabolism or signaling . unbiased identification of genes controlling quantitative traits is , however , possible by screening genetic reference populations . the bxd recombinant inbred mice , which have been derived from the cross of dba/2j and c57bl6/j mice , form a particularly useful genetic reference population ( andreux et al . , 2012 , chesler et al . , 2004 , peirce et al . , 2007 , rosen et al . , 2007 ) . these mice have been successfully used to identify genes involved in various physiological processes such as sleep ( franken et al . , 2001 ) , aging ( houtkooper et al . , 2013 ) , blood pressure ( koutnikova et al . , 2009 ) , or beta - cell function ( wong et al . , 2013 ) . here , we aimed at identifying genes involved in the counterregulatory response by screening a bxd mouse panel for the glucagon response to 2-deoxy - d - glucose ( 2dg)-induced neuroglucopenia . this led to the identification of a significant qtl on the distal part of chromosome 7 . to identify the causal gene in the qtl , we hypothesized that this gene should be expressed in the hypothalamus , and that its expression should correlate with the glucagon trait . combining qtl analysis and rna - sequencing ( seq ) data , we identified hypothalamic fgf15 as the most likely candidate gene . the functional involvement of fgf15 was supported by showing that : ( 1 ) it is expressed in dorsomedial hypothalamus and perifornical neurons ; ( 2 ) intracerebroventricular ( i.c.v . ) delivery of fgf19 , the human ortholog of fgf15 , reduced 2dg - induced glucagon secretion through suppression of dorsal vagal complex neuron activation , and reduction of parasympathetic nervous activity ; and ( 3 ) silencing of fgf15 in the dmh increased 2dg - induced glucagon secretion . we searched for genomic intervals associated with glucagon secretion induced by 2dg - induced neuroglucopenia in a panel of 36 bxd mouse strains . groups of male mice were generated for each bxd strain and used when they reached 10 weeks of age . in a first experimental session , mice were injected intraperitoneally ( i.p . ) with a saline solution and blood was collected 30 min later for plasma preparation and storage . glucagon levels were measured by radioimmunoassay at the same time for all mice and the ratio between plasma glucagon after 2dg and nacl injections was calculated . this trait varies by 3-fold between bxd strains ( figure 1a ) with the lowest response ( 1.5-fold ) detected in bxd49 and the highest ( 4.7-fold ) in bxd50 . this trait was due to differences in stimulated plasma glucagon levels rather than to differences in basal glucagonemia ( figure 1b ) ; it was not correlated to differences in total pancreatic glucagon content across all the bxd strains ( figure 1c ) . this suggests that the variability in the secretion response results from differences in hypoglycemia detection and signaling to pancreatic alpha cells rather than from differences in pancreatic glucagon stores . quantitative trait analysis identified a whole genome significant qtl at the distal part of the chromosome 7 ( figure 1d ) . the likelihood ratio statistic ( lrs ) peak is centered on marker rs2304086585 ( lrs : 24.679 ; position : 151.6236 mb ) and flanked by markers c7.loc119 ( position : 147.5303 mb ) and rs31652431 ( position : 152.4411 mb ) ( figure 1e ) . this locus is 5 mb wide and it contains 128 genes ; it explains 49 percent of the variance of the glucagon trait . to narrow down the genes within the qtl , which could regulate glucagon secretion , we hypothesized , first , that these must be expressed in the hypothalamus where glucose sensitive neurons are located ( karnani and burdakov , 2011 , ritter et al . , 2011 , routh , 2010 ) and , second , that their level of expression must correlate with the glucagon phenotype , assuming that they are non - coding polymorphisms . we thus performed transcriptomic analysis of the hypothalamus from all the bxd strains using mice that had not undergone qtl screening to avoid a possible impact of 2dg treatment on gene expression . rna was extracted from the hypothalamus of 36 mice for each strain and equal amounts of rna from each mouse were pooled for transcript profiling by rna sequencing analysis . we found that 65 of the 128 genes present in the chr7 locus were expressed in the hypothalamus . the hypothalamic expression level of 11 genes was significantly correlated to the glucagon trait ( table 1 ) . fgf15 mrna was the most significantly , and negatively , correlated to the glucagon phenotype ( r = -0.571 ; p = 2.73 10 ) ( table 1 ) . the second gene in this table , which shows a similar high correlation with the trait as fgf15 is gm17685 ( r = 0562 ; p = 3.58 10 ) . this encodes a long non - coding rna transcribed in reverse orientation from exon 2 of fgf15 , and its expression is highly correlated with that of fgf15 ( r = 0.824 ; p = 6.68 10 ) . the correlation with the glucagon trait of the other nine genes ( table 1 ) showed at least 10-fold less significant p values . furthermore , the fgf15 gene of the dba/2j and c57bl/6 mice encodes the same amino acid sequence , supporting differential expression of this gene as a possible underlying cause of the glucagon trait . we thus selected to further investigate fgf15 expression in the hypothalamus and its role in the response to neuroglucopenia . quantitative analysis of fgf15 expression in different brain nuclei showed highest expression in the hypothalamus ( average cycle threshold [ ct ] of 28.7 ) and lower expression in the hippocampus , thalamus , and brainstem , with almost undetectable levels in the cerebellum and cortex ( average cts of 29.6 , 30.1 , 30.1 , 34.2 , and 34.5 , respectively ) ( figure 2a ) . brain expression of fgf15 was , however , much lower than its expression in the ileum , its major site of expression ( average ct of 21.1 ) ( figure 2a ) ( inagaki et al . , 2005 ) . expression of the fgf15 receptors fgfr1c , fgfr4 , and of the co - receptor klotho beta was found in all brain regions ( figures 2b2d ) . to determine the site of fgf15 expression , we performed in situ hybridization analysis on hypothalamic sections . as shown in figures 2e2i , fgf15 expression was found mainly in the perifornical area ( pef ; figure 2e ) and the dorsomedial hypothalamus ( dmh ; figure 2 g ) . in situ hybridization using a control probe derived from a bacterial gene , dapb , showed no staining ( figure 2h ) . no fgf15 transcripts were detected in the dorsal vagal complex of the brainstem ( figure 2i ) . detection of fgf15 in illeal villi is shown for comparison ( figure 2j ) . finally , double in situ hybridization of fgf15 and of the neuronal marker neun showed that fgf15 was expressed in neurons ( figures 2k and 2l ) . to verify that fgf15 could regulate glucagon secretion through a central mechanism of action , we injected c57bl/6 mice i.c.v . with fgf19 ( the human ortholog of fgf15 , which shows high stability in vivo and activates the same receptors ; owen et al . , 2015 ) or an artificial cerebrospinal fluid ( acsf ) . injections of acsf or fgf19 ( figure 3a ; t = 0 ) and was similarly increased 30 min after i.p . however , following 2dg - induced neuroglucopenia , the glucagon response was markedly lower in mice previously treated with i.c.v . next , we assessed hypothalamic fgf15 expression and 2dg - induced glucagon secretion in normal chow ( nc ) or high fat diet ( hfd ) fed mice , which show altered glucagon plasma levels ( burcelin et al . , 2002 ) . mice fed a hfd for 4 weeks showed increased hypothalamic expression of fgf15 compared to nc fed mice ( figure 3f ) . when injected with 2dg , nc and hfd mice showed the same hyperglycemic response ( figure 3 g ) . the basal glucagonemia of both groups of mice were the same , but the plasma glucagon response to 2dg was markedly reduced in hfd fed mice ( figure 3h ) . thus , hfd feeding increased hypothalamic fgf15 expression and is correlated with reduced neuroglucopenia - induced glucagon secretion in agreement with the results of the genetic screen . to more directly determine whether the level of expression of fgf15 in the hypothalamus regulates glucagon secretion , we developed recombinant lentiviruses to express a control or an fgf15-specific short hairpin ( sh)rna . three shrnas were designed to target the fgf15 sequence and were subcloned in lentiviral vectors . these were first tested in hek293 t cells co - transfected with an fgf15-gfp expression plasmid . one vector induced efficient silencing of fgf15 mrna and protein expression ( figures 4a4c ) . this was used to generate a recombinant lentivirus , which effectively silenced fgf15 expression in transduction experiments ( figure 4d ) . this or a control lentivirus was then injected bilaterally in the dmh ( figure 4e ) . no difference in basal glycemia or in glycemic response to 2dg injection was observed between the two groups of mice ( figure 4f ) . however , neuroglucopenia - induced glucagon secretion was significantly increased ( 22% ) in mice with correct bilateral dmh injection of the silencing lentivirus as compared to mice injected with the control lentivirus ( figure 4 g ) or mice injected with fgf15-specific shrna lentivirus outside of the dmh ( figure 4 g , missed ) . bilateral injection of the silencing lentivirus in the pef ( figure 4h ) did not impact glycemia before and 30 min after i.p . 2dg ( figure 4i ) , nor the neuroglucopenia - induced glucagon secretion ( figure 4h ) . taken together , these data show that fgf15 expression by dmh neurons has a negative impact on neuroglucopenia - induced glucagon secretion . glucagon secretion during hypoglycemia is triggered by the activation of both parasympathetic and sympathetic branches of the autonomic nervous system ( ans ) ( taborsky and mundinger , 2012 ) . fgf19 decreased the glucagon response to 2dg - induced neuroglucopenia , but had no effect in non - injected or i.p . saline injected mice , we measured sympathetic and parasympathetic nerve activities in response to i.p . parasympathetic nerve activity showed no differences between groups in the basal state ( figure 5a ) . after 2dg injection , its activity increased 2-fold in mice pre - treated with acsf , but remained unchanged in mice pre - treated with fgf19 ( figure 5a ) . sympathetic nerve activity showed no differences between the groups in the basal state or following 2dg injections ( figure 5b ) . the dorsal motor nucleus of the vagus ( dmnx ) is formed by the soma of the vagal neurons and is controlled by inputs from several brainstem and hypothalamic nuclei ( berthoud et al . , 1990 , 2015 ) . to investigate whether fgf19 influences these neurons directly or indirectly , we quantified the number of perk1/2 ( activated by fgf19 binding to its receptor ) positive cells in the hypothalamus and the brainstem 30 min after i.c.v . we observed an increased number of perk1/2 positive cells in the arcuate nucleus ( arc ) after i.c.v . no increase in perk1/2 positive cells was observed in other hypothalamic nuclei , in the dorsal vagal complex ( dvc , which comprises the dmnx , the nucleus tractus solitarius [ nts ] , and the area postrema [ ap ] ) , nor in other brainstem areas . these results are consistent with a previous study ( marcelin et al . , 2013 ) and suggest that the primary neurons involved in the effect of fgf19 are located within the arc . to determine whether fgf19 could control vagal neurons of the dvc in an indirect manner , we injected mice i.c.v . with acsf or fgf19 and 1 hr later i.p . with nacl or 2dg . thirty min later , the mice were killed and brain sections prepared for c - fos expression analysis by in situ hybridization . 2dg induced a strong increase in c - fos expression in the nts and the dmnx . however , in mice , which had previously received fgf19 , 2dg - induced c - fos expression was markedly lower in both structures . these data further support a role for central fgf15 in modulating the sensitivity of the dvc to 2dg - induced neuroglucopenia and in reducing the stimulation of vagal activity . they also support a role of fgf15 neurons in controlling the dvc through an indirect mechanism that first controls arcuate neurons activity . the present unbiased approach identified hypothalamic fgf15 as a negative regulator of glucagon secretion in response to neuroglucopenia . in situ hybridization revealed that fgf15 is expressed by a subgroup of neurons of the dmh and pef . injection of fgf19 reduced , whereas shrna mediated silencing of fgf15 in the dmh increased neuroglucopenia - induced glucagon secretion . delivery of fgf19 prevented the increase in vagal activity induced by neuroglucopenia , and this was associated with a reduced activation of dvc neurons . as i.c.v . fgf19 activates perk1/2 only in hypothalamic arc neurons , our data suggest that hypothalamic fgf15 modulates dvc activity in an indirect manner . fgf15/19 belongs to the endocrine fibroblast growth factor family , which also includes fgf21 and fgf23 ( owen et al . , 2015 ) . fgf15/19 expression in ileal cells is induced by the bile acids released in the intestinal lumen in the postprandial state through activation of the bile acid nuclear receptor fxr ( inagaki et al . , 2005 ) . fgf15/19 binds to receptors consisting of fgfr1c or fgfr4 and the co - receptor klotho - beta ( owen et al . , 2015 ) . in liver , ffg15/19 reduces bile acid synthesis through the inhibition of cyp7a1 ( jung et al . , 2007 , it also induces glycogen synthesis through the activation of the ras - erk - p90rsk and inhibits gluconeogenesis via the creb - pgc1 pathway ( kir et al . ffg15/19 has more recently been described to affect body weight , glucose tolerance , and insulin sensitivity through a central action ( marcelin et al . , 2013 , , we found that fgf15 is also expressed in the hypothalamus through an unbiased search for genetic intervals associated with neuroglucopenia - induced glucagon secretion in recombinant inbred mice . among the 128 genes present in the identified qtl of chromosome 7 , rna - seq analysis revealed that 11 of these genes were expressed in the hypothalamus and expression of fgf15 , and , of the large intergenic noncoding rna ( linc)rna - encoding as lincrnas are implicated in the control of gene expression through a variety of mechanisms ( zhao and lin , 2015 ) , it could be hypothesized that gm17685 plays a regulatory role in fgf15 expression . testing this will , however , require future investigations . to localize fgf15 expression in the brain , we used a highly sensitive and specific in situ hybridization technique . in the hypothalamus , expression of fgf15 was found in the pef and in the dmh , and co - in situ hybridization analysis with the neuronal marker neun revealed that it was expressed in neurons . no signal for fgf15 was identified in the dvc or in any other brainstem nuclei . to assess whether central fgf15 could impact neuroglucopenia - induced glucagon secretion , fgf19 decreased the glucagon response induced by 2dg , in agreement with the results of the genetic screen . we also observed in a model of high fat diet feeding an association between overexpression of hypothalamic fgf15 and a decrease in 2dg - induced glucagon secretion , lending further support to the negative correlation between hypothalamic fgf15 and glucagon secretion . however , the most convincing evidence for a direct link between hypothalamic fgf15 expression and glucagon secretion comes for the shrna - mediated silencing of fgf15 . this effect was observed when injection of the recombinant lentivirus was in the dmh , but not in the pef . because the pef is a rather large structure , it is possible that our injections were not sufficiently extensive over the entire pef structure to observe an effect . nevertheless , the critical observation is that injection of the recombinant lentivirus in the dmh was sufficient to increase 2dg - induced glucagon secretion , establishing a direct link between fgf15 in this structure and the control of glucagon secretion . fgf19 could improve glucose tolerance in hfd fed mice and ob / ob mice ( marcelin et al . , 2013 , morton et al . , 2013 ) . in ob / ob mice , the effect of fgf19 on glucose tolerance was associated with an increase in insulin - independent glucose disposal and insulin sensitivity without changes in insulin secretion . injection of fgf19 and was not modified by this treatment ( morton et al . , 2013 ) . neuroglucopenia - induced glucagon secretion involves activation of the parasympathetic and sympathetic branches of the autonomic nervous system . during graded hypoglycemia development , the parasympathetic nerve is activated immediately when the glycemia falls under the 5 mm and sympathetic activity is increased at lower glycemic levels ( taborsky and mundinger , 2012 ) . here , we found that i.c.v . fgf19 dampens parasympathetic , but not sympathetic nerve activity during 2dg - induced neuroglucopenia , an observation that provides an explanation for the reduced glucagon secretion . moreover , the observation that 2dg - induced - glucagon secretion was not completely blunted after i.c.v . fgf19 can be explained by the fact that the sympathetic activity was not affected by i.c.v . this suggests that fgf19 specifically impairs the parasympathetic activity to reduce glucagon secretion during neuroglucopenia . the primary neurons activated by i.c.v . fgf19 and identified by immunofluorescence detection of perk1/2 are , however , present in the arc and not found in other hypothalamic or brainstem nuclei . this is in agreement with previous observations showing that fgf19 activates perk1/2 in the arc ( marcelin et al . , 2013 ) . fgf19 blunted 2dg - induced neuronal activation in the nts and the dmnx as assessed by c - fos expression analysis . fgf19 can prevent activation of dvc neurons in response to neuroglucopenia , and our observations suggest that its action may be indirect through a first action on arc neurons . fgf19 induces perk1/2 in npy / agrp neurons , but fails to induce c - fos in pomc neurons ( marcelin et al . thus , npy / agrp neurons could be the primary target neurons of fgf15 neurons of pef and/or dmh , and these neurons may then negatively control dvc neurons in a perk1/2-dependent manner . a role for the arc and npy / agrp neurons in mediating the effects of fgf15/19 can be supported by the fact that the melanocortin pathway has been shown to be necessary for the central effects of fgf19 on glucose tolerance ( marcelin et al . whereas tracing approaches in mice expressing the cre recombinase under the control of fgf15 promoter should be used to confirm these observations , our data provide a first insight in a fgf15-dependent neural network , which involves an arc / dvc pathway to regulate glucagon secretion during neuroglucopenia . together , our genetic screen combined with gene expression analysis provides compelling evidence that hypothalamic fgf15 is negatively involved in the control by neuroglucopenia of glucagon secretion . fgf15 is expressed by discrete subpopulations of neurons in the pef and dmh and fgf15/19 blunts vagal firing activity and dampens the response of the dvc neurons to 2dg - induced neuroglucopenia , a response that involves activation of perk1/2 in arc neurons . collectively , these results , initiated by an unbiased search for novel genes involved in counterregulatory response to neuroglucopenia , reveal a new site of fgf15 expression and provide a mechanistic framework to elucidate fgf15 action in the control of parasympathetic nervous activity and glucagon secretion . they may provide new insight into the neuronal control of counterregulation and its deregulation in the etiology of haaf in type 1 and type 2 diabetic patients . bxd mouse strains were purchased from the center of phenogenomics of epfl ( lausanne ) . animals were housed on a 12 hr light / dark cycle and were fed a standard rodent chow diet ( diet 3436 , provimi kliba ) or a high - fat diet ( 235 hf , safe diets ) . number : 10 - 1247 - 10 , mercodia ) , and corticosterone ( cat . free plasma epinephrine was quantified as described ( dunand et al . , 2013 ) . on the first experiment day , glycemia was taken at 9:00 a.m. and , if stable for 1 hr , the mice received at 10:00 am an i.p . total rna extraction from hypothalamus and brainstem samples was performed using the peqgold trifast method ( peqlab ) . rna were obtained from mice sacrificed during the morning in random fed conditions as for the qtl screening . rna integrity was verified with a 2100 bioanalyser ( agilent ) . for each bxd strain , equal amounts of rnas from 3 to 6 hypothalami were pooled in a final volume of 50 l . rna - seq libraries were prepared using 1 g of pooled rnas and the illumina truseq stranded mrna reagents ( illumina ) on a sciclone liquid handling robot ( perkinelmer ) using a perkinelmer - developed automated script . cluster generation was performed with the resulting libraries using the illumina truseq sr cluster kit v3 reagents and sequenced on the illumina hiseq 2000 using truseq sbs kit v3 reagents . a sequencing depth of 40 millions of reads using 100 bp single - end reads was used . reads were mapped to the mm9 genome with tophat ( v. 2.0.8 ) using library - type = fr - firststrand . count data for exons were generated using htseq - count from the htseq package ( http://www.huber.embl.de/users/anders/htseq/ , version 0.5.4p3 ) using refseq annotation , with parameters stranded = reverse and mode = union . the normalized read counts per gene were log transformed , and then pearson correlation was used to calculate the correlation of gene expression with the physiological trait . genenetwork ( www.genenetwork.org ) variants data set comprising about 15,000 snps on the whole mouse genome was used to perform qtl mapping . calling snps on our rna - seq data have been used as a way to check for genetic drift in the bxd strains . snp calling was performed using the genome analysis toolkit from the broad institute ( v. 3.2 ) using the recommended workflow for rna - seq data . this allowed tagging the discrepant variants compared to our rnaseq experiments as unknown ( eight 0.05% genotypes per strain ) for qtl analysis . finally , variants similar to our snp calling data were merged to remove redundant information . for qtl analysis , we used the r / qtl packages with haley - knott ( hk ) regression method . qtl location was obtained with 1.5 lod ( 6.915 lrs ) support intervals as suggested previously ( broman and sen , 2009 ) . the significance and suggestive thresholds were computed with 2,000 permutations : the sequences of the various strains were shuffled 2,000 times and association recalculated at each permutation . this allowed calculating the probability to find these associations by chance . to test the efficiency of the fgf15 shrnas , an fgf15 cdna was subcloned in frame with gfp in the pcmv6-ac - gfp plasmid ( cat . number : mg202456 , origene ) and scrambled or fgf15-targeted shrnas were subloned in the pgfp - c - shlenti plasmid ( cat . the vectors were co - transfected into hek293 t cells using lipofectamine 3000 ( cat . number : l3000015 , thermo fisher scientific ) . at 48 hr later , total rna and proteins were extracted and fgf15 expression was determined by qrt - pcr and protein by western blot . the selected shrna sequence has the following sequence : 5-gtctgtgtcagatgaagatccactctttc-3. lentiviruses were produced as described ( salmon and trono , 2006 ) . the silencing efficacy of the fgf15-shrna lentivirus was tested in infected hek293 t cells that were transfected with fgf15 expression plasmid . cannulas were placed in the lateral ventricle ( 0.7 mm from the bregma ; 1.3 mm from the midline ; and 1.8 mm from the surface of the skull ) ( paxinos and watson , 1982 ) . lentiviruses ( 200 nl ; 4.10 tu / ml ) were injected in the dmh ( 1.7 mm from the bregma ; 0.35 mm from the midline ; and 5.0 mm from the surface of the skull ) and pef ( 1.7 mm from the bregma ; 0.75 mm from the midline ; and 5.15 mm from the surface of the skull ) ( paxinos and watson , 1982 ) . animals were allowed to recover for 1 week with daily handling and body weight monitoring after i.c.v . the placement of the cannula was checked by histological analysis after blue ink delivery , and the sites of injection ( gfp fluorescence ) were verified on 40 m brain sections . acsf ( 125 mm nacl , 2.5 mm kcl , 1.25 mm nah2po4 , 1 mm mgcl2 , 2 mm cacl2 , 26 mm nahco3 and 12.5 mm sucrose , 300 mosm , and ph = 7.4 ) or fgf19 ( 2.5 g ) ( cat . number : cyt-700-b , prospecbio ) . one hr later , mice were injected i.p . with nacl 0.9% or 2dg 600 mg / kg . blood and brains were collected 30 min later for quantification of glucagon secretion or for in situ hybridization detection of c - fos . for perk1/2 detection tissues preparation , rna extraction , and qrt - pcr were performed as described ( mounien et al . , 2010 ) . the following forward ( f ) and reverse ( r ) primers were used : fibroblast growth factor 15 ( fgf15 ) f5-gaggaccaaaacgaacgaaatt-3 and r5-acgtccttgatggcaatcg-3 ; fibroblast growth receptor 1 isoform c ( fgfr1c ) : f5-ggaggtgcttcatctacgga-3and r5-agagtgatgggagagtccga-3 ; fibroblast growth receptor 4 ( fgfr4 ) : f5-gcccgacagttctctttgga-3 and r5- ttcccaaagcggatcgagag-3 ; klotho beta ( klotho beta ) : f5-ccttcccactggcaatctgt-3and r5-gggtggtacaacgtcaccat-3 ; and beta - glucuronidase ( gusb ) : f5-gtgatggaggagctggttcg-3 and r5-agcagaggaaggctcattgg-3. gusb was used as a housekeeping gene to normalize gene expression in all experiments . for immunofluorescence detection of perk1/2 , mice were fixed by a transcardiac perfusion of 4% cold paraformaldehyde ( pfa ) in sodium phosphate buffer ( 0.1 m , ph 7.4 ) . brains were dissected and kept for 2 hr in pfa at 4c before overnight incubation in sucrose 30% at 4c and frozen at 80c . there were 20 m cryosections that were prepared , placed on glass slides , and incubated in a blocking buffer consisting of 0.1 m phosphate buffer ph 7.4 containing 3% of normal goat serum and 0.3% triton x-100 for 1 hr , then with a rabbit monoclonal antibody directed against perk1/2 ( cat . number : 4370 , 1/200 , cell signaling ) for 48 hr , and for 1.5 hr with an alexa fluor 488-conjugated goat anti - rabbit igg ( h+l ) antibody ( cat . for in situ hybridization analysis , the hypothalamus and brainstem were dissected using a mouse brain matrix with 1-mm section dividers ( cellpoint scientific ) ; all tissues were fixed for 28 hr in 10% formalin before embedding in paraffin . there were 5 m sections that were cut and in situ hybridization for fgf15 , c - fos , neun , and dihydrodipicolinate reductase ( dapb ) ( cat . number : 412811 , 316921 , 313311 , and 310043 ) was processed using the rnascope and rnascope 2.0 hd red detection kit assay ( advanced cell diagnostics ) . number : 363123s , vwr ) , and observed using an axio imager d1 ( zeiss ) microscope interfaced with axiovision software ( zeiss ) . quantification of c - fos expression was performed on sections cut at bregma 7.56 mm from three different mice . the firing rates of the thoracic branch of both vagal and sympathetic nerves along the carotid artery were recorded as previously described ( magnan et al . unipolar nerve activity was recorded continuously for 1 hr under isoflurane anesthesia ( 30 min during basal condition after i.c.v . 2dg and 30 min during 2dg - induced neuroglucopenia ) using the labchart 8 software ( ad instrument ) . statistical analysis were performed using graphpad prism 5.0c , either by a one - way anova followed by bonferroni post hoc test , a two - way anova followed by bonferroni post hoc test , or by an unpaired two - tailed student s t test when appropriate . , j.s . , and x.b . performed the phenotyping of glucagon secretion in bxd mice .

summarythe counterregulatory response to hypoglycemia , which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain , is critical for survival . to discover underlying brain regulatory systems , we performed a genetic screen in recombinant inbred mice for quantitative trait loci ( qtl ) controlling glucagon secretion in response to neuroglucopenia . we identified a qtl on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami . this revealed fgf15 as the strongest candidate to control the glucagon response . fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area . intracerebroventricular injection of fgf19 , the human ortholog of fgf15 , reduced activation by neuroglucopenia of dorsal vagal complex neurons , of the parasympathetic nerve , and lowered glucagon secretion . in contrast , silencing fgf15 in the dorsomedial hypothalamus increased neuroglucopenia - induced glucagon secretion . these data identify hypothalamic fgf15 as a regulator of glucagon secretion .

it is very important to identify the underlying cause of ear symptoms such as tinnitus and hearing loss . if these symptoms present unilaterally , a retocochlear lesion , vascular lesion or inner ear anomaly should be considered in the diagnostic process . many diagnostic tools have been suggested for use in the evaluation of retrocochlear lesions . however , there is no single novel method to easily evaluate all lesions causing unilateral ear symptoms . since selters first introduced auditory brainstem evoked response ( abr ) as a diagnostic method for retrocochlear lesions , the abr test has been commonly used as a screening test . however , the low sensitivity of the abr test has lowered its diagnostic value as a screening test , especially in small intracanalicular tumors.1,2 ) after the introduction of magnetic resonance image ( mri ) technology , mri testing was applied in the assessment of retrocochlear lesions with high sensitivity and high specificity.3 ) nevertheless , the high cost of conventional mri testing , the use of contrast media and the long image acquisition time might be limitations for using it as a screening tool . recently , three - dimensional fast imaging employing steady - state acquisition ( 3d - fiesta ) images have been introduced . 3d - fiesta imaging can give much higher spatial resolution with outstanding image contrast between the cranial nerves and cerebrospinal fluid . and it has a shorter image acquisition time than conventional mri scan and does not need contrast media.4,5 ) in this study , we aimed to evaluate the usability of 3d - fiesta imaging as a screening tool for inner ear lesions with applying 3d - fiesta image in the diagnostic pathway of the patients with unilateral ear symptoms . from january 2011 to december 2011 , 253 patients who presented with unilateral ear symptoms and underwent 3d - fiesta imaging as a screening were enrolled in this study . patients suspected to have meniere 's disease and complained of bilateral ear symptoms were excluded . all patients underwent 3d - fiesta imaging as a screening tool with a philips achieva ( best , the netherlands ) 3.0 tesla mri scanner . if an inner ear lesion or a brain lesion was suspected on the 3d - fiesta image , an additional diagnostic brain mri scan , a temporal mri scan , or temporal bone ct scans were performed to elucidate the final diagnosis . the images from the screening and diagnostic imaging investigations were reviewed to compare their ability to find various cochlear , retrocochlear or vascular lesions . patients were divided into three groups according to their chief complaint : tinnitus , unilateral hearing loss , and unilateral sudden idiopathic hearing loss , to compare their clinical presentations and radiological results . clinical data and 3d - fiesta results were analyzed to figure out the relationships between the clinical presentations of acoustic neuroma and tumor size . the kruskal - wallis test was applied for the statistical analysis of tumor size using commercially available software ( statistical package for the social sciences , version 17.0 ; spss inc . , chicago , il , usa ) . a p value of < 0.05 was considered as statistically significant . among two hundred and fifty - three patients with a unilateral ear symptom , 105 ( 41.5% ) patients were male and 148 ( 58.5% ) were female . tinnitus was the most common symptoms of patients ( 129 , 49.6% ) , sudden sensory neural hearing loss was the second most common ( 83 , 31.9 ) and unilateral hearing loss was the next most common ( 41 , 15.7% ) . in the 3d - fiesta imaging results , acoustic neuroma was the most common retrocochlear lesion in patients with unilateral ear symptoms in this study ( fig . twelve patients were diagnosed with acoustic neuroma ( figs . 2 - 4 ) , and four patients were confirmed as having enlarged vestibular aqueduct syndrome ( fig . other lesions such as a congenital anomaly , a vascular lesion , a mass and acute infarction could be detected with 3d - fiesta imaging ( figs . we also tried to figure out the association between clinical symptoms and the final diagnosis . six patients who initially presented with tinnitus were diagnosed with acoustic neuroma and two patients were diagnosed with posterior inferior cerebellar artery aneurysm . abnormal findings in 3d - fiesta images in patients with hearing loss were acoustic neuroma , enlarged vestibular aqueduct syndrome , inner ear anomaly and 8th nerve hypoplasia ( table 1 ) . the mean size of acoustic neuromas which were finally diagnosed was 1714 mm ( 43 - 6264 mm ) , the mean size of tumors in the tinnitus group , unilateral hearing loss group and sudden idiopathic sensorineural hearing loss group was 1310 mm , 5223 mm , and 119 mm respectively . table 2 shows the clinical characteristics of patients who were finally diagnosed with acoustic neuroma . the mean tumor size of the unilateral hearing loss group tended to be smaller than that of other groups . however , we could not find any significant correlation between the groups ( p=0.582 ) . in patients with unilateral ear symptoms , it is important to approach these patients with a high index of suspicion for cochlear or retrocochlear lesions such as an inner ear anomaly , tumor , vascular or inflammatory lesion . with conventional audiologic testing , retrocochlear lesions can be suspected by a relatively low speech discrimination score or low score in the short increment sensitivity index test . retrochoelar lesions were diagnosed more easily after computed tomography ( ct ) and the abr test were introduced.6,7 ) but the temporal bone ct scan is inadequate for screening tool due to the high false or negative positive rate for the diagnosis of retrocochlear lesions especially in the case of acoustic neuroma . abr test has been used as a favored screening tool for retrocochlear lesions ; this test compares the amplitude and latency of waves produced by the auditory pathway . however , barrs , et al.8 ) reported that even though abr demonstrated 97% of the tumors ruckenstein , et al.9 ) reported that the abr screening test for retrocochlear pathology had a sensitivity of 63% and a specificity of 64% . these findings imply that abr probably has a limited role in acoustic neuroma screening . after the application of mri for the diagnosis of retrocochlear lesions began in the 1980s , the specificity and sensitivity of mri was found to be up to 100% and it became to be considered the most accurate diagnostic tool.10,11 ) but mri is a very expensive test and it takes 40 - 60 minutes to get images with contrast . thus , mri has limitations as a screening test due to the low cost and time effectiveness . with the development of the image acquisition technique with mri , new protocols for 3d - fiesta sequences were introduced which provided much higher spatial resolution and clearer depiction of small structures such as cranial nerves especially within the cisternal spaces . the 3d - fiesta uses an ultrafast pulse sequence that produces 0.3 mm thin section high resolution images with outstanding image contrast between the cerebrospinal fluid , vessels and cranial nerves . it usually takes 5 to 7 minutes to get a proper image and does not need contrast media . the cost of 3d - fiesta is just 1/5 - 1/6 that of conventional mri . so it could be a very effective test protocol for the screening of retrocochlear lesions in patients with unilateral ear symptoms . in this study , variable lesions such as small tumors less than 5 mm , inner ear anomalies and vascular malformations could be identified using 3d - fiesta imaging . and there is one report which showed that with 3d - fiesta , there was decreased vestibular signal intensity on the affected side in patients with vestibular schwannoma , but that this was not present in those with cerebellopontine angle meningiomas or in normal subjects.12 ) recently , mri with high - dose contrast media has been introduced for detecting cochlear endolymphatic hydrops.13 ) 3d - fiesta images have a limitation in detecting inner ear lesions ; however , 3d - fiesta images can detect inner ear anomalies so it may be sufficient to use as a screening tool for retrocochlear lesions . acoustic neuroma , one of the most common retrocochlear lesions , is a benign tumor originating from the vestibular nerve sheath in the internal auditory canal . in the early stage of acoustic neuromas , symptoms can be nonspecific but as the tumor grows , progressive unilateral hearing loss and tinnitus are typical symptoms . it is well known that about 10 to 20% of acoustic neuroma patients can be present with sudden sensorineural hearing loss , and on the other hand only 1 to 3% of sudden seonsorineural hearing loss patients have acoustic neuroma.14 - 16 ) in this study , 9.7% of unilateral hearing loss patients , 4.6% of unilateral tinnitus and 2.4% of sudden sensorineural hearing loss patients were diagnosed with acoustic neuroma . the mean size of acoustic neuroma varied from a tiny tumor smaller than 5 mm to a large tumor up to 64 mm . the mean size of the tumor in the sudden hearing loss patients group was larger than the other two groups , but there was no statistically significant difference between the groups . in addition to acoustic neuroma , many retrocochlear lesions , intracranial masses and acute infarctions can be diagnosed with screening using 3d - fiesta imaging . with these findings , we suggest that 3d - fiesta imaging could be a reliable screening test for patients who complain of unilateral otologic symptoms . but considering that this study was a simple retrospective observational study , further comparative study investigating the sensitivity and specificity of 3d - fiesta imaging will be required . 3d - fiesta imaging is a cost - effective and sensitive method for the diagnosis of cochlear or retrocochlear lesions . 3d - fiesta imaging is a useful screening tool for patients with unilateral ear symptoms .

background and objectivesunilateral auditory dysfunction such as tinnitus and hearing loss could be a warning sign of a retrocochlear lesion . auditory brainstem response ( abr ) and internal auditory canal magnetic resonance image ( mri ) are suggested as novel diagnostic tools for retrocochlear lesions . however , the high cost of mri and the low sensitivity of the abr test could be an obstacle when assessing patients with unilateral ear symptoms . the purpose of this study was to introduce the clinical usefulness of three - dimensional fast imaging employing steady - state acquisition ( 3d - fiesta ) mri in patients with unilateral ear symptoms.subjects and methodstwo hundred and fifty - three patients with unilateral tinnitus or unilateral hearing loss who underwent 3d - fiesta temporal bone mri as a screening test were enrolled . we reviewed the abnormal findings in the 3d - fiesta images and ear symptoms using the medical records.resultsin patients with unilateral ear symptoms , 51.0% of the patients had tinnitus and 32.8% patients were assessed to have sudden sensory neural hearing loss . with 3d - fiesta imaging , twelve patients were diagnosed with acoustic neuroma , four with enlarged vestibular aqueduct syndrome , and two with posterior inferior cerebellar artery aneurysm . inner ear anomalies and vestibulocochlear nerve aplasia could be diagnosed with 3d - fiesta imaging.conclusions3d-fiesta imaging is a highly sensitive method for the diagnosis of cochlear or retrocochlear lesions . 3d - fiesta imaging is a useful screening tool for patients with unilateral ear symptoms .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Afghanistan Freedom Act of 2001''. SEC. 2. FINDINGS. Congress makes the following findings: (1) The rise to power of the Taliban in Afghanistan has caused a drastic decline in the human, political, and civil rights of the Afghan people, particularly among women, girls, and ethnic minorities. (2) In the year 2001, millions of Afghans are on the verge of starvation, the largest such group in the world. (3) The United States is the single largest donor of humanitarian assistance to Afghanistan, totaling more than $185,000,000 in fiscal year 2001. (4) There are approximately 2,000,000 Afghan refugees in Pakistan, 1,500,000 Afghan refugees in Iran, and 1,000,000 internally displaced persons in Afghanistan, most fleeing oppression, violence, and economic hardship. (5) During the period of Taliban rule, Afghanistan has become the world's largest source of illegal opium, and proceeds from the sale of raw opium to drug traffickers are used by the Taliban to finance its war on the Afghan people. (6) Under Taliban rule, Afghanistan has become a training ground, operational base, and safe haven for terrorists and international terrorist organizations, many of whom gain experience fighting alongside Taliban forces inside Afghanistan prior to conducting terrorist operations outside Afghanistan. (7) The Taliban have, since 1996, harbored and protected terrorist leader Osama bin Laden and members of his terrorist al Qaeda network. (8) Osama bin Laden and his al Qaeda associates were indicted for the August 7, 1998, bombings of the United States embassies in Nairobi, Kenya, and Dar-es-Salaam, Tanzania, as a result of which the United Nations Security Council adopted Resolution 1267 (1999), demanding that the Taliban surrender Osama bin Laden for trial and determining that the Taliban's continued provision of sanctuary to international terrorist organizations constitutes a threat to international peace and security. (9) In order to compel the Taliban to surrender Osama bin Laden and terminate support for international terrorist organizations, the United Nations Security Council has imposed progressively more comprehensive sanctions on the Taliban under Resolutions 1267 (1999), 1333 (2000), and 1363 (2001), which sanctions are binding on all members of the United Nations under Chapter VII of the Charter of the United Nations. (10) As a result of the Taliban's failure to comply with the demands of the United States and the United Nations Security Council, Osama bin Laden and his al Qaeda network were able to orchestrate from Afghanistan the September 11, 2001, terrorist attack on the United States in which approximately 6,000 Americans and foreign nationals were murdered. (11) The Taliban have, since the September 11th attack on the United States, rejected all entreaties by the United States and other governments to surrender Osama bin Laden, close down international terrorist operations in Afghanistan, and comply with the other demands that have been made by the United Nations Security Council. (12) Afghanistan is an ethnically diverse nation that can prosper only under a representative government that affords all citizens of that nation their basic human rights, restores peace and security, eradicates the drug trade, and brings all terrorists and terrorist organizations in Afghanistan to justice. SEC. 3. UNITED STATES POLICY TOWARD AFGHANISTAN. It shall be the policy of the United States to promote the removal from power of the Taliban regime in Afghanistan so as to diminish the risk of future terrorist attack on the United States and restore basic human freedoms to the people of Afghanistan. SEC. 4. MILITARY ASSISTANCE TO AFGHAN RESISTANCE ORGANIZATIONS. (a) Authority To Provide Military Assistance.-- (1) Types of assistance.--The President is authorized to direct the drawdown of defense articles from the stocks of the Department of Defense, defense services of the Department of Defense, and military education and training for eligible Afghan resistance organizations. (2) Amount of assistance.--The aggregate value (as defined in section 644(m) of the Foreign Assistance Act of 1961) of assistance provided under paragraph (1) may not exceed $300,000,000. (b) Eligible Afghan Resistance Organizations.--An Afghan resistance organization shall be eligible to receive assistance under subsection (a) if the President determines and reports to the appropriate congressional committees that such organization, or coalition of organizations, is committed to-- (1) the removal from power of the Taliban regime in Afghanistan; (2) preservation of the territorial integrity and political independence of Afghanistan; (3) respect for internationally recognized human rights; and (4) the suppression of terrorism in all of its forms and the surrender to justice of all international terrorists in Afghanistan, including perpetrators of the September 11, 2001, attack on the United States. (c) Reimbursement for Assistance.-- (1) In general.--Defense articles, defense services, and military education and training provided under subsection (a) shall be made available without reimbursement to the Department of Defense except to the extent that funds are appropriated pursuant to the authorization of appropriations under paragraph (2). (2) Authorization of appropriations.-- (A) In general.--There are authorized to be appropriated to the President for fiscal year 2002 such sums as may be necessary to reimburse the applicable appropriation, fund, or account for the value (as defined in section 644(m) of the Foreign Assistance Act of 1961) of defense articles, defense services, or military education and training provided under subsection (a). (B) Availability.--Amounts appropriated pursuant to the authorization of appropriations under subparagraph (A) are authorized to remain available until expended, and are in addition to amounts otherwise available for the purposes described in this section. (e) Authority To Provide Assistance.--Activities under this section may be undertaken notwithstanding any other provision of law. SEC. 5. DISASTER AND HUMANITARIAN ASSISTANCE FOR THE PEOPLE OF AFGHANISTAN. (a) Disaster and Humanitarian Assistance.--Chapter 9 of part I of the Foreign Assistance Act of 1961 (22 U.S.C. 2292 et seq.) is amended by adding at the end the following: ``SEC. 495L. AFGHAN RELIEF, REHABILITATION, AND RECONSTRUCTION. ``(a) Declaration of Policy.--Congress recognizes that prompt United States assistance is necessary to alleviate the human suffering of the people of Afghanistan from four years of extreme drought and 20 years of civil war and to restore the confidence of the people in that country. ``(b) Assistance.--The President is authorized to furnish assistance on such terms and conditions as the President may determine for the relief, rehabilitation and reconstruction needs of the people of Afghanistan, including displaced persons and other needy people. Assistance provided under this section shall be for humanitarian purposes with emphasis on providing food, medicine and medical care, clothing, temporary shelter, and transportation for emergency supplies and personnel. ``(c) Policies and Authorities To Be Applied.--(1) Assistance under this section shall be provided in accordance with the policies and general authorities of section 491. ``(2) Assistance under this section or any other provision of law to alleviate the human suffering caused by famine and disease in Afghanistan shall be provided, to the maximum extent practicable, through international agencies, private voluntary organizations, and any eligible Afghan resistance organization. ``(d) Authorization of Appropriations.--There are authorized to be appropriated to the President to carry out this section $100,000,000 for each of the fiscal years 2002 and 2003. Amounts appropriated pursuant to the authorization of appropriations under the preceding sentence are in addition to amounts otherwise available for such purposes and are authorized to remain available until expended.''. (b) Other Assistance for Afghanistan.-- (1) Assistance.--The President is authorized to provide assistance from funds made available to carry out chapter 4 of part II of the Foreign Assistance Act of 1961 (relating to the economic support fund) for the provision of food, medicine, or other assistance to the Afghan people, notwithstanding any other provision of law. (2) Amount of assistance.--In each of fiscal years 2002 and 2003, not less than $50,000,000 of the aggregate amount of funds made available to carry out chapter 4 of part II of the Foreign Assistance Act of 1961 is authorized to be made available for assistance to the Afghan people pursuant to paragraph (1). SEC. 6. ESTABLISHMENT OF RADIO FREE AFGHANISTAN. (a) Establishment.--The Broadcasting Board of Governors is authorized to make grants for surrogate radio broadcasting by RFE/RL, Incorporated (formerly known as Radio Free Europe/Radio Liberty) to the people of Afghanistan in languages spoken in Afghanistan, such broadcasts to be designated ``Radio Free Afghanistan''. (b) Submission of Plan to Broadcasting Board of Governors.--Not later than 15 days after the date of the enactment of this Act, RFE/RL, Incorporated, shall submit to the Broadcasting Board of Governors a detailed plan for the establishment of the surrogate radio broadcasting described in subsection (a). (c) Authorization of Appropriations.-- (1) Fiscal years 2002 and 2003.--In addition to such sums as are authorized to be appropriated for each of the fiscal years 2002 and 2003 for ``International Broadcasting Operations'', $8,000,000 is authorized to be appropriated for the fiscal year 2002 and $6,000,000 is authorized to be appropriated for the fiscal year 2003 for ``International Broadcasting Operations'' to be available only for the surrogate radio broadcasting described in subsection (a). (2) Transmitter.--Of the amounts authorized to be appropriated by paragraph (1) for the fiscal year 2002, $1,500,000 shall be available only for a new transmitter for the surrogate radio broadcasting described in subsection (a). SEC. 7. COMPLIANCE WITH MEASURES DIRECTED AGAINST THE TALIBAN BY THE UNITED NATIONS SECURITY COUNCIL. (a) Reports to Congress.--Not later than one month after the date of the enactment of this Act, and every three months thereafter until the President determines and reports to the appropriate congressional committees that the Taliban no longer exercises power in any part of Afghanistan, the President shall submit to the appropriate congressional committees a report that identifies the government of each foreign country with respect to which there is credible information that the government has, on or after the date of the enactment of this Act, violated, or permitted persons subject to its jurisdiction to violate, measures directed against the Taliban pursuant to United Nations Security Council Resolutions 1267 (1999), 1333 (2000), or 1363 (2001), or pursuant to any other United Nations Security Council resolution adopted under the authority of Chapter VII of the Charter of the United Nations. (b) Content of Reports.--Each report submitted under subsection (a) shall detail with respect to each government of a foreign country identified in such report the nature of the violation (other than violations detailed in previous reports submitted pursuant to this section), and shall evaluate-- (1) the importance of the violation to the efforts of the Taliban to remain in power in Afghanistan; (2) the importance of the violation to the efforts of terrorist groups to continue operating from Afghanistan; and (3) the risk posed by such violation to the safety of the United States Armed Forces and the armed forces of other countries acting in coalition with the United States. (c) Authority To Impose United States Sanctions.--The President is authorized to impose one or more of the United States sanctions provided in subsection (d) if the President determines and reports to the appropriate congressional committees that-- (1) a government of a foreign country identified in a report submitted under subsection (a) has knowingly violated, or knowingly permitted persons subject to its jurisdiction to violate, measures directed against the Taliban pursuant to United Nations Security Council Resolutions 1267 (1999), 1333 (2000), or 1363 (2001), or pursuant to any other United Nations Security Council resolution adopted under the authority of Chapter VII of the Charter of the United Nations; and (2) such violation has put at risk the lives of members of the United States Armed Forces, or other United States citizens. (d) United States Sanctions Authorized To Be Imposed.--The United States sanctions referred to in subsection (c) are the following: (1) No assistance may be provided to that government or nationals under the Foreign Assistance Act of 1961 or the Arms Export Control Act. (2) No license may be issued for any transfer to that government or nationals of any goods, services, or technology controlled under the Arms Export Control Act, the Export Administration Act of 1979, or the Export Administration Regulations. (3) The restrictions of subsections (a) and (b) of section 3 of the Trading With the Enemy Act (50 U.S.C. App. 3(a) and (b)) shall apply to relations between the United States and the government of a foreign country and all nationals of that country with respect to which the President makes a determination described in subsection (c). SEC. 8. SUBMISSION OF DETERMINATIONS AND REPORTS IN CLASSIFIED FORM. When the President considers it appropriate, determinations and reports to the appropriate congressional committees submitted under this Act, or appropriate parts thereof, may be submitted in classified form. SEC. 9. DEFINITIONS. In this Act: (1) Appropriate congressional committees.--The term ``appropriate congressional committees'' means the Committee on International Relations of the House of Representatives and the Committee on Foreign Relations of the Senate. (2) National.--The term ``national'' means, with respect to a foreign country, a national of the country, including a natural person, corporation, business association, partnership, or other entity operating as a business enterprise under the laws of the country.

Afghanistan Freedom Act of 2001- Declares it the policy of the United States to promote the removal from power of the Taliban regime in Afghanistan in order to diminish the risk of terrorist attack on the United States and to restore basic freedoms to the Afghan people.Authorizes the President to provide military assistance, including defense articles, services, and education and training, for eligible Afghan resistance organizations.Amends the Foreign Assistance Act of 1961 to authorize the President to provide humanitarian assistance to the Afghan people, with emphasis on food, medicine, medical care, clothing, temporary shelter, and transportation for emergency supplies and personnel. Requires that such assistance be provided, to the extent practicable, through international agencies, private voluntary organizations, and eligible Afghan resistance organizations.Authorizes the Broadcasting Board of Governors to make grants for, and requires submission of a plan for establishing, surrogate radio broadcasting by RFE/RL, Incorporated (formerly known as Radio Free Europe/Radio Liberty) to the people of Afghanistan (to be designated as Radio Free Afghanistan).Requires the President to submit quarterly reports to the appropriate congressional committees on violations by foreign countries or nationals of measures directed against the Taliban pursuant to specified United Nations Security Council resolutions. Requires such reports to evaluate the seriousness of any violations and authorizes the President to impose sanctions for violations that put at risk the lives of U.S. armed forces personnel or citizens, including: (1) denying assistance under the Foreign Assistance Act of 1961 or the Arms Export Control Act; (2) denying licenses for transfers of goods, services, or technology controlled under the Arms Export Control Act, the Export Administration Act of 1979, or the Export Administration Regulations; or (3) applying restrictions under the Trading With the Enemy Act.

coronal ( or x - ray ) jets are collimated , transient eruptions of hot plasma observed predominantly in coronal holes and at the periphery of active regions , driven by flux emergence or cancellation ( e.g. , * ? ? ? `` standard jets '' are launched by reconnection between open magnetic fields and expanding closed fields , while the more energetic `` blowout jets '' additionally involve an eruption of the closed fields @xcite . for detailed descriptions of coronal jets see the recent reviews by @xcite , @xcite , and @xcite . coronagraph and in - situ observations revealed that coronal jets can produce signatures in the outer corona , sometimes even at earth or beyond @xcite . it was therefore suggested that they contribute to powering the corona and solar wind ( e.g. , * ? ? ? * ; * ? ? ? quantifying this contribution from observations is difficult , and only few attempts have been made so far . @xcite obtained a `` crude estimate '' for the energy budget of coronal jets , which was @xmath1 times smaller than required for maintaining the sw . @xcite suggested a mass - contribution of coronal jets to the sw of @xmath210% , though @xcite remarked that this value should be 2.5 times smaller . using heliospheric images from smei @xcite , @xcite estimated mass and energy contributions of 3.2% and 1.6% , respectively . finally , estimated the energy provided by coronal jets to be less than 1% of what is required to heat a polar coronal hole . they emphasized , though , that many high - temperature jets may be missed by the observations @xcite . thus , while it appears that the contribution of coronal jets to the sw may be small compared to the potential contribution by the much more numerous jet - like events on smaller scales @xcite , its exact amount remains uncertain . numerical models provide a powerful tool to address this question . however , mhd simulations of coronal jets were so far restricted to a limited treatment of the energy transfer in the corona and to heights far below the sw - acceleration region . recently , @xcite presented mhd simulations of coronal jets that overcame both limitations . using these simulations , we evaluate here the mass and energy contribution of coronal jets to the sw , and compare our results to previous observational estimates . the simulations we use for our analysis are described in @xcite , and a more detailed account will be provided in a forthcoming publication ( trk _ et al . _ , in preparation ) . they were performed using the 3d , viscous , resistive mhd model in spherical coordinates developed at predictive science inc . @xcite . the model incorporates thermal conduction parallel to the magnetic field , radiation losses , and parametric coronal heating . the nonuniform grid covers 120@xmath3 , where @xmath3 is the solar radius , using @xmath4 points in @xmath5 . the smallest radial grid interval at @xmath6 is @xmath7 km ; the angular resolution is @xmath8 in the area containing the jet . a purely radial coronal magnetic field , produced by a magnetic monopole located at sun center is prescribed . starting from an initial thermodynamic sw - solution @xcite , we relax the system to a spherically symmetric , steady - state solar wind . afterwards , using the method of @xcite , we emerge a flux rope whose structure and evolution was previously computed with the model of @xcite . this is done by prescribing the values of the magnetic field and calculating the velocities using the characteristic equations at @xmath9 . ) . ( b ) magnitude of elssser variable in a plane intersecting the jet ; same time as in ( a ) . ( c ) same as ( a ) 1.66hrs later , showing coronal signatures of the blowout jet . ( d ) same as ( b ) at the time shown in ( c ) . the times correspond to peak energy fluxes at @xmath10 ( cf . figures[fig - poynting_wave ] and [ fig - f1_f2 ] ) . , scaledwidth=47.7% ] here we analyze three runs . in all cases , the system is in a steady - state at @xmath11 , when the flux emergence is started . in our main run , _ jet 1 _ , emergence is imposed for 4.5hrs , and the evolution is modeled for a total of 12hrs . the simulation produces a standard jet at @xmath12h , launched by the first strong occurrence of magnetic reconnection in the current layer that forms between the emerging flux and the open coronal field . several reconnection episodes follow , driven by the continuous expansion of the emerging flux rope . at @xmath13h a blowout jet is produced , associated with the eruption of the rope , which again is followed by several reconnection episodes , now occurring in the current layer that forms below the eruption . the blowout jet is much stronger than the standard jet , with a peak kinetic energy of @xmath14erg , compared to only @xmath15erg for the standard jet . plasma is ejected upwards by reconnection outflows during the jets , and additionally by the flux - rope eruption during the blowout jet . both jets produce alfvn waves , which travel much faster than the ejected plasma , due to the relatively large coronal alfvn speed in our model ( several 1000kms@xmath16 ) . in figure[fig - jet1 ] we show manifestations of the jets in the outer corona , using synthetic difference - images of the polarization brightness @xcite and the magnitude of the elssser variable , @xmath17 , which represents an outward propagating alfvn perturbation along a radial magnetic field line ( e.g. , * ? ? ? * ) . at @xmath18h an elongated brightness - enhancement and a clear wave - signature are visible in panels ( a ) and ( b ) , respectively . the former is associated with plasma ejected by the standard jet , while the latter is associated with the alfvn wave triggered by the blowout jet ( the significantly weaker alfvn wave triggered by the standard jet has already left the field - of - view at this time ) . at @xmath19h the plasma ejected by the blowout jet becomes visible , while there are no strong wave - signatures anymore . the brightness - image shows density - enhancements and rarefactions , reminiscent of narrow coronal mass ejections and `` streamer blobs '' ( e.g. , * ? ? ? * ) . our second run , _ jet 2 _ , has the same settings as _ jet 1 _ , but here we stop the flux emergence after 2hrs , so that only the standard jet occurs . this run is calculated for 6hrs . in both runs ohmic heating is included , so that magnetic energy dissipated through the resistivity ( corresponding to a resistive diffusion time @xmath20 hrs ) contributes to the energy equation . finally , in _ jet 3 _ , we again impose the emergence for4.5 hrs , but turn off ohmic heating . an inspection of this run reveals that it is essentially a lower - energy version of _ jet 1 _ , so we stopped the calculation shortly after the occurrence of the blowout jet , at @xmath21h . at @xmath22 , @xmath23 , @xmath24 , which contains the jet at all times . for our analysis we then select an area @xmath25 that corresponds to the jet s maximum transverse expansion . , scaledwidth=47.7% ] following @xcite and , we calculate the mass and energy fluxes associated with our jets , and integrate them in time and space to find the total mass and energy injected into the sw . different from these authors , we perform our analysis high in the corona , at @xmath10 , and use the poynting flux , rather than the wave - energy flux , for a more accurate calculation of the total energy flux ( [ ss : wave_vs_poynting ] ) . for the integration we use a spherical quadrangle @xmath26 at @xmath27 that contains the jet - signatures at all times ( figure[fig - flux ] ) . the area @xmath25 corresponds to the maximum lateral expansion of the blowout jet as it passes through @xmath26 at @xmath28h ( see figure [ fig - jet1](c ) ) . we define @xmath25 as the area within which the perturbation in the sum of the kinetic and magnetic energies is larger than @xmath29 at that time . as in the above - mentioned papers , we consider the kinetic , potential , enthalpy , and wave energy fluxes : @xmath30 and the radial component of the poynting flux , @xmath31 fluxes due to radiation and thermal conduction are neglected . for each flux @xmath32 we determine the constant background @xmath33 produced by the steady - state sw ( which is zero for @xmath34 and @xmath35 ) . then we calculate the net power through @xmath26 due to the fluxes by integrating @xmath36 and removing the background : @xmath37 dividing each @xmath38 by @xmath25 , we obtain the average , background - subtracted energy fluxes associated with the jets as functions of time : @xmath39 for _ jet 13_. the magenta line shows the respective fluxes of the background solar wind . ] first we compare in figure [ fig - poynting_wave ] the wave - energy flux with the radial poynting flux . for the former we use the transverse velocities and the magnetic field strength . we see that the wave - energy flux is always smaller than the poynting flux . in fact , the wave - energy flux formula assumes equipartition of ( perpendicular ) magnetic and kinetic energy , therefore missing some energy contribution when this condition does not fully apply . henceforth we use only the poynting flux to measure the wave energy injected into the sw . prior to the occurrence of the standard jet , no significant wave flux is transferred into the sw . as mentioned above , alfvn waves launched low in the corona require only a few minutes to arrive at @xmath26 in our model . consequently , we see for all runs the first clear signal shortly after the first strong reconnection associated with the onset of the standard jet at @xmath40h . _ jet 2 _ , for which the flux emergence is terminated at @xmath41h , does not produce any significant signal afterwards . for _ jet1 _ and _ jet3 _ , activity increases strongly shortly after @xmath42h , marking stronger reconnection episodes associated with the increasing expansion of the emerging flux rope prior to its eruption . the strongest peaks are around @xmath43h , when signals associated with the blowout jet arrive at @xmath26 . for _ jet1 _ , which was calculated for a longer time than _ jet3 _ , the following decay phase contains two secondary peaks . the first one results from small reconnection events in the current sheet that forms below the erupting flux rope , while the second one may be related to a third jet that grows out of the flaring current sheet ( trk _ et al . _ , in preparation ) . the overall evolution of the poynting flux is very similar for _ jet1 _ and _ jet3 _ , suggesting a negligible influence of ohmic heating on the strength of the alfvn waves generated by reconnection . a clear deviation can be seen only during the strongest peak , which is associated also with the flux - rope eruption . figure[fig - f1_f2 ] shows @xmath44 , @xmath45 , and @xmath46 together with the background sw flux . _ jet 2 _ shows relatively weak activity , associated with plasma accelerated during the standard jet , which needs about 2hrs to arrive at @xmath26 . very similar activity is visible for _ jet 1 _ but much less for _ jet 3 _ , which lacks ohmic heating and produces weaker plasma upflows . an additional increase , coinciding with the major peak in the poynting flux ( figure [ fig - poynting_wave](b ) ) , occurs in @xmath44 at @xmath47h for _ jet 1 _ and _ jet 3_. its absence in the other fluxes indicates that it is due to a ( transverse ) velocity increase rather than a density increase , as the alfvn wave associated with the blowout jet passes through @xmath26 . indeed , @xmath48 at this time , comparable to the background sw speed ( @xmath49 ) , while @xmath50 and @xmath51 increase by 10 and 30% at most , respectively . _ jet 1 _ then shows a strong increase of all fluxes for @xmath52h , when the blowout jet ( i.e. , the erupted flux rope ) passes through @xmath26 ( which at @xmath19 increases @xmath50 and @xmath51 by factors of up to 1.2 and 3.1 , respectively ) . the flux maxima ( @xmath19h ) are very similar and about one order of magnitude smaller than the peak poynting flux associated with the preceding alfvn wave ( cf . figure[fig - poynting_wave](b ) ) ; their ratios change if the analysis is performed at a different radius . ] . afterwards all fluxes show a strong oscillation and a final slow decay . the oscillation has similar amplitude for all fluxes , and is due to the density enhancements and rarefactions visible in figure[fig - jet1](c ) . all this activity is barely noticeable in the poynting flux ( @xmath53 = 28kms@xmath16 at @xmath19 , much smaller than at @xmath18 ) . for @xmath54h @xmath44 remains smaller than @xmath55 , since @xmath50 falls below the sw speed at @xmath56 once the ejecta has passed . in order to compare our results with observational estimates , we calculate the mass and total energy injected during _ jet 1 _ into the sw : @xmath57 where @xmath58 is the average mass flux calculated from @xmath59 according to eqs . ( [ eq - pt]-[eq - fbar ] ) . figure[fig - total ] shows the mass flux and the total energy flux as functions of time . to calculate @xmath60 and @xmath61 , we extrapolate after @xmath62h the integrands to infinity and obtain @xmath63 and @xmath64 , the latter corresponding to @xmath21% of the magnetic - energy release during the blowout jet . @xmath60 equals the order - of - magnitude estimate obtained from uvcs observations at @xmath65 by @xcite . in contrast , both @xmath60 and @xmath61 are about one order of magnitude smaller than the mass and kinetic energy estimated by @xcite . assuming that _ jet 1 _ represents an average coronal jet , a jet - occurrence frequency @xmath66 @xcite , and a fully open magnetic field at @xmath56 , we obtain a total energy flux @xmath67 and a proton - density flux @xmath68 , where @xmath69 is the proton mass and @xmath70 the spherical surface at @xmath56 . scaling these fluxes to 1 astronomical unit ( au ) , assuming spherical sw - expansion at constant speed , we get @xmath71 @xmath72 is significantly smaller than the 1au estimate @xmath73 by @xcite and @xcite and the correction by @xcite . ] . in order to compare with the energy - flux estimate by , which was obtained for the low corona , we calculate @xmath74 for a typical height extension of coronal jets , @xmath75 @xcite , and employ the same assumptions for jet frequency and coronal hole area as those authors . we get @xmath76 , in very good agreement with their value @xmath77 . finally , we compare our results with sw fluxes derived from in - situ spacecraft measurements . according to @xcite , the total energy flux of the sw at 1au is @xmath21.5erg@xmath78s@xmath16 , and very similar for the slow and fast solar wind . the proton - density flux varies by a factor of about 2 between the slow and fast wind , and falls into the range @xmath79 ( * ? ? ? * ; * ? ? ? * and references therein ) . comparing these values to our jet - produced fluxes scaled to 1au ( equation[eq:1au ] ) , we estimate that coronal jets provide @xmath80% and @xmath0% to the total energy and mass content of the sw , respectively . we used an mhd simulation with an advanced energy equation and a large spherical grid to estimate the mass and energy contributions of coronal jets to the sw . the simulation ( _ jet 1 _ ) produced both a standard and a blowout jet and included ohmic heating . we followed the previous , observational analysis by , except that we calculated mass and energy fluxes at @xmath27 rather than in the low corona , and used the poynting flux instead of the wave - energy flux to obtain the total energy flux . our results can be summarized as follows . \(1 ) the blowout jet produces a strong perturbation in the sw , the standard jet only to a minor one . this is not surprising , as the former is much more energetic than the latter in our simulation ( the peak kinetic energies differ by almost two orders of magnitude ) . such a large difference is in line with the results of @xcite , who estimated the magnetic energy released during a blowout jet to be about 2030 times larger than for a standard jet . \(2 ) the blowout jet ( and associated flux - rope eruption ) triggers a strong alfvn wave that arrives at @xmath56 more than one hour before the ejecta . this significant lag is due to the relatively large coronal alfvn speed in our model , and is expected to decrease if more realistic values for the alfvn speed in coronal holes are chosen . the wave yields the dominant contribution to the poynting flux , while the contributions of alfvn waves triggered by the standard jet and by interim reconnection events remain relatively small . \(3 ) the bulk kinetic energy , potential energy , and enthalpy fluxes are also dominated by the blowout jet . in contrast to the poynting flux , the evolution of these fluxes is characterized by a pronounced oscillation , which reflects plasma density enhancements and rarefactions associated with the eruption . ( 4 ) the mass and total energy contributions of the blowout jet ( the contributions by the standard jet are negligible ) at @xmath56 are @xmath81 and @xmath82 , respectively . these are only @xmath83 of the heliospheric mass and kinetic energy estimates by @xcite , but those authors considered three of the largest jets during a three - week _ hinode _ campaign @xcite . on the other hand , @xmath60 agrees with the order - of - magnitude estimate by @xcite obtained at @xmath84 . \(5 ) using observed occurrence - rates of coronal jets , we estimated ranges for the total energy and proton - density fluxes produced by these events in the low corona and at 1au . we found very good agreement with the low - corona energy - flux estimate by . our estimate for the proton - density flux at 1au is almost an order of magnitude smaller than the values given by @xcite , @xcite , but it must be kept in mind that their estimate was obtained merely from _ hinode_/xrt observations . ( 6 ) comparing our results with in - situ measurements of sw fluxes , we estimate that coronal jets provide @xmath80% and @xmath0% to the total energy and mass content of the sw , respectively . our results are largely consistent with existing observational estimates of the contribution of coronal jets to the mass and energy content of the sw , and thus support the present conjecture that the these contribution are relatively small . however , it must be kept in mind that ( i ) obtaining such estimates requires simplifying assumptions , ( ii ) the measurement uncertainties are large , and ( iii ) our simulation is relatively idealized and only one parameter - set of the model ( assumed to be representative ) was considered so far . more advanced observations ( for instance from the upcoming solar orbiter and solar probe plus missions ) and simulations are needed to finally pin down the contribution of coronal jets to the sw . we thank the referee for helpful comments and acknowledge support by nasa s h - sr and lws programs . m.g.l . and j.e.l . were is part supported by the chief of naval research . this work benefited from discussions within the issi international team 258 `` understanding solar jets and their role in atmospheric structure and dynamics '' . , j. w. , golub , l. , lundquist , l. , van ballegooijen , a. , savcheva , a. , shimojo , m. , deluca , e. , tsuneta , s. , sakao , t. , reeves , k. , weber , m. , kano , r. , narukage , n. , & shibasaki , k. 2007 , science , 318 , 1580 , b. v. , buffington , a. , hick , p. p. , altrock , r. c. , figueroa , s. , holladay , p. e. , johnston , j. c. , kahler , s. w. , mozer , j. b. , price , s. , radick , r. r. , sagalyn , r. , sinclair , d. , simnett , g. m. , eyles , c. j. , cooke , m. p. , tappin , s. j. , kuchar , t. , mizuno , d. , webb , d. f. , anderson , p. a. , keil , s. l. , gold , r. e. , & waltham , n. r. 2004 , , 225 , 177 , n .- e . 2011 , in astronomical society of the pacific conference series , vol . 437 , solar polarization 6 , ed . j. r. kuhn , d. m. harrington , h. lin , s. v. berdyugina , j. trujillo - bueno , s. l. keil , & t. rimmele , 99 raouafi , n. e. , patsourakos , s. , pariat , e. , young , p. r. , sterling , a. c. , savcheva , a. , shimojo , m. , moreno - insertis , f. , devore , c. r. , archontis , v. , trk , t. , mason , h. , curdt , w. , meyer , k. , dalmasse , k. , & matsui , y. 2016 , space science reviews , 1 , k. , ishido , y. , acton , l. w. , strong , k. t. , hirayama , t. , uchida , y. , mcallister , a. h. , matsumoto , r. , tsuneta , s. , shimizu , t. , hara , h. , sakurai , t. , ichimoto , k. , nishino , y. , & ogawara , y. 1992 , , 44 , l173 , k. , nakamura , t. , matsumoto , t. , otsuji , k. , okamoto , t. j. , nishizuka , n. , kawate , t. , watanabe , h. , nagata , s. , ueno , s. , kitai , r. , nozawa , s. , tsuneta , s. , suematsu , y. , ichimoto , k. , shimizu , t. , katsukawa , y. , tarbell , t. d. , berger , t. e. , lites , b. w. , shine , r. a. , & title , a. m. 2007 , science , 318 , 1591 , o. c. , howard , r. a. , simnett , g. m. , gurman , j. b. , plunkett , s. p. , sheeley , n. r. , schwenn , r. , koomen , m. j. , brueckner , g. e. , michels , d. j. , andrews , m. , biesecker , d. a. , cook , j. , dere , k. p. , duffin , r. , einfalt , e. , korendyke , c. m. , lamy , p. l. , lewis , d. , llebaria , a. , lyons , m. , moses , j. d. , moulton , n. e. , newmark , j. , paswaters , s. e. , podlipnik , b. , rich , n. , schenk , k. m. , socker , d. g. , stezelberger , s. t. , tappin , s. j. , thompson , b. , & wang , d. 1997 , in esa special publication , vol . 415 , correlated phenomena at the sun , in the heliosphere and in geospace , ed . a. wilson , 103 , t. , lionello , r. , titov , v. s. , leake , j. e. , mikic , z. , linker , j. a. , & linton , m. g. 2016 , in astronomical society of the pacific conference series , vol . 504 , coimbra solar physics meeting : ground - based solar observations in the space instrumentation era , ed . i. dorotovic , c. fischer , & m. temmer , 185

transient collimated plasma eruptions in the solar corona , commonly known as coronal ( or x - ray ) jets , are among the most interesting manifestations of solar activity . it has been suggested that these events contribute to the mass and energy content of the corona and solar wind , but the extent of these contributions remains uncertain . we have recently modeled the formation and evolution of coronal jets using a three - dimensional ( 3d ) magnetohydrodynamic ( mhd ) code with thermodynamics in a large spherical domain that includes the solar wind . our model is coupled to 3d mhd flux - emergence simulations , i.e , we use boundary conditions provided by such simulations to drive a time - dependent coronal evolution . the model includes parametric coronal heating , radiative losses , and thermal conduction , which enables us to simulate the dynamics and plasma properties of coronal jets in a more realistic manner than done so far . here we employ these simulations to calculate the amount of mass and energy transported by coronal jets into the outer corona and inner heliosphere . based on observed jet - occurrence rates , we then estimate the total contribution of coronal jets to the mass and energy content of the solar wind to @xmath0% and ( 0.3 - 1.0)% , respectively . our results are largely consistent with the few previous rough estimates obtained from observations , supporting the conjecture that coronal jets provide only a small amount of mass and energy to the solar wind . we emphasize , however , that more advanced observations and simulations are needed to substantiate this conjecture .

MIAMI (AP) — Chicago White Sox first baseman Jose Abreu told a Miami federal jury Wednesday that he ate a chunk of a fake passport while flying to the U.S. to cover up his illegal travel as part of a Cuban ballplayer smuggling operation. Abreu testified he ordered a beer on an Air France flight from Haiti to Miami and slowly consumed the page containing a false name and his photo. Abreu said he traveled illegally because he was worried he would miss an October 2013 deadline and lose the $68 million contract he later signed with Chicago. "If I had not been there on that particular day, the deadline, then the contract would not be executed and would no longer be valid," Abreu told jurors. "We had to be in Chicago to sign the contract." The testimony came in the trial of Florida-based sports agent Bartolo Hernandez and baseball trainer Julio Estrada, who are accused of alien smuggling and conspiracy. They allegedly operated a ring that took Cuban players from the communist-governed island to third countries where they could sign lucrative Major League Baseball contracts once they established residency. Abreu, who was American League Rookie of the Year in 2014, testified under a grant of limited immunity for his illegal conduct — meaning he won't be prosecuted if he tells the truth on the witness stand. Several other Cuban players have also testified, including Adeiny Hechavarria of the Miami Marlins and Leonys Martin of the Seattle Mariners. Abreu will return Thursday to complete his testimony. Abreu told jurors that he got the fake passport in Haiti, where he had been taken along with his family from Cuba by speedboat in August 2013. His main contact and fixer there was Amin Latouff, he said, a man who was indicted along with Hernandez and Estrada but who has not been arrested. It was Latouff, Abreu testified, who got him the passport and booked the Air France flight, telling the ballplayer to destroy the document on the plane. But instead of tearing it up and tossing it in the garbage, Abreu said he ordered a Heineken beer and chewed it up in his seat. "Little by little I swallowed that first page of the passport. I could not arrive in the United States with a false passport," he said. Once in Miami, under the Cuban immigration policy at the time Abreu was allowed to remain in the U.S. because he had reached American soil despite having no travel documents. That "wet-foot, dry-foot" policy was rescinded recently by former President Barack Obama. Abreu testified that Hernandez and his partners negotiated his deal with the White Sox and that Estrada oversaw his training, lodging and other needs while in Haiti and also in the Dominican Republic. Estrada's company, Total Baseball, was to be paid 20 percent of Abreu's contract and Hernandez was to receive 5 percent. Later Wednesday, Abreu testified that he has paid more than $7 million to Estrada's company under their agreement and began sending him $25,000 a month after Estrada's assets were frozen following his indictment in 2016. Abreu also said he bought a $500,000 house in the Florida Keys for Estrada to live in, although it remains in Abreu's name. Estrada was also best man at Abreu's wedding and became a close friend along with Estrada's wife, the player testified. "These were people who had helped me a lot in getting into this country, so I had a lot of trust in them," Abreu testified. "In my case, I had the ability to perform that charitable work, you might call it." But Abreu said it was his idea alone to get the illegal Haiti travel document and asked Latouff for help. "I trusted that he was someone who could help me and I confided in him that secret," Abreu testified. The trial, which has already lasted about a month, is expected to continue a few more weeks. Abreu, who hit 25 home runs and drove in 100 runs last season, was given time off from White Sox spring training in Arizona to testify in the Miami case. _____ Follow Curt Anderson on Twitter: http://twitter.com/Miamicurt ||||| Senior White House officials believe that resolution of the issue would represent an important symbolic moment in the thaw between the two nations, highlighting the potential for Americans and Cubans to bond over a common cultural obsession even as their governments remain divided over politics and policy. President Obama will travel to Havana on March 21, becoming the first sitting United States president to visit in 88 years. The Tampa Bay Rays will play the Cuban national baseball team in an exhibition game on March 22, and Mr. Obama is expected to attend. Cuban officials have also expressed interest in finding a safer path to the major leagues for their players. “To play in that type of baseball — in the United States — where the majority of the greatest players in the world want to be, you need to give up something big here, your dignity of being Cuban,” Higinio Velez, the president of the Cuban Baseball Federation, said in December. “We hope that, in the future, Cuban players can go anywhere in the world and play, representing their federation, and that there are not intermediaries that take advantage of them.” While the decision on drafting players from Cuba is pending, there is urgency for such an accord. Waves of Cuban ballplayers are leaving the island: According to OnCuba, a Miami-based magazine, 150 players left Cuba last year. Many are still seeking contracts with big league organizations. Often they travel in the hands of smugglers and under other dangerous circumstances. Bart Hernandez, a sports agent, was indicted last month on charges of human trafficking related to bringing Cuban players to the United States. Another agent recently cut ties with a player who defected; the agent said he had received a death threat from the player’s trainer in the Dominican Republic. Because of complex immigration and free-agency rules, Cuban players must establish residency in a third country to enter the market for American teams and cash in on a lucrative contract, as stars like Yasiel Puig of the Los Angeles Dodgers and Aroldis Chapman of the Yankees have done in recent years. ||||| When Chicago White Sox first baseman Jose Abreu finally boarded a plane to the U.S after being smuggled from Cuba to Haiti, he said he had one mission: Destroy the fake Haitian passport he was traveling on before his flight landed in Miami. He testified Wednesday that he went to the restroom as soon as possible after the flight took off from Haiti. But flight attendants quickly started knocking on the door. So he ripped out the first page, which bore his photo and a fake name, and dumped the rest of the passport in the restroom garbage. "I went back to my seat, I ordered a beer - a Heineken beer - and then, little by little, I swallowed that first page of the passport," Abreu testified, speaking Spanish translated by a courtroom interpreter. A Major League Baseball contract with the White Sox - worth $68 million over five years - was riding on Abreu's ability to enter the U.S. by a deadline in late October 2013, federal prosecutors say. They called Abreu, 30, of Kendall, to testify in federal court in Miami in the trial of baseball agent Bartolo Hernandez, of Weston, and trainer Julio Estrada, of Miami. Hernandez and Estrada have pleaded not guilty to allegations they were heavily involved in the shadowy world of illegally smuggling Cuban baseball players to the U.S. for lucrative contracts. The men also helped smuggle the players' family members and loved ones, according to the indictment. Hernandez and Estrada face long federal prison terms if convicted of conspiracy and alien-smuggling charges. Their defense lawyers deny they did anything criminal and say they just represented and helped some 20 Cuban-born players after they defected from the communist island. Abreu owed millions of dollars to the smugglers and their associates and paid at least $5.8 million to them in 2014, according to prosecutors Michael "Pat" Sullivan and H. Ron Davidson. Abreu has not been charged with any crime, though he acknowledged using fake documents and arranging to have "runners" from South Florida deliver payments to the people who helped him in Haiti. If he testifies truthfully, prosecutors have agreed he won't be prosecuted for his illegal conduct. Wearing a stylish black suit, black shirt and red-soled black shoes, Abreu answered prosecutors' questions quickly and in detail. He testified for about five hours on Wednesday and is due back Thursday for more questioning by both sides. In his testimony, Abreu spoke at some length about a third defendant, Amin Latouff, a Haitian resident, who is accused of being a "fixer" for Hernandez and Estrada in the smuggling operation. Latouff is considered a fugitive from justice, according to authorities. Abreu told the jurors that he was paid about $20 per month as a baseball player in his native Cuba. He left in August 2013 with his then-girlfriend, his parents, his sister and brother-in-law. He testified the blue boat was about 27-feet long and had two outboard engines, 150 horsepower each. The boat was crowded with Abreu and his five family members, three crew members and a few other people fleeing to Haiti. Abreu told the jury he spent a short time in Haiti, where the "fixer" helped him get Haitian residency papers and he then crossed the border to the Dominican Republic. While there, he signed contracts with Estrada, Hernandez and Hernandez's associates, he said. He trained and attended showcases with U.S. major league teams. After learning he had an oral agreement to sign with the White Sox, Abreu said he returned to Haiti. He tried and failed to get a Cuban passport but Latouff arranged to get him the fake Haitian passport under an assumed name, he said. Latouff told him he could not enter the U.S. using the fake passport and would have to destroy it while the plane was in flight, he said. Because of the immigration rules in effect at the time for Cubans, Abreu was granted permission to remain in the U.S. and was released from the airport hours after he landed. Shortly after he arrived in the U.S., before the deadline, the Sox announced their contract with him. His girlfriend, now his wife, and his other relatives all made it to the U.S., with help from the fixer, within the next nine months or so, he said. Prosecutors say that, because of free agent rules, Abreu needed to establish residency in another foreign country before signing with a major team, so he could make more money. Abreu testified he made millions of dollars in payments to Hernandez and Estrada since 2014, including about $7 million to Estrada. Abreu suggested that was under the terms of his contracts, which gave 20 percent of his earnings to Estrada and 5 percent to Hernandez. Estrada was best man at Abreu's wedding, Abreu told the 15-member jury panel, made up of 11 women and four men. He said he advanced money to Estrada, including paying for a $500,000 house in the Florida Keys, owned by Abreu but occupied by Estrada and his family. After Estrada was criminally charged last year, he asked Abreu for $15,000 a month because his assets were frozen. Abreu said he insisted on giving him $25,000 a month. Estrada's wife also works for him. "These were people who had helped me a lot in getting into this country, so I had a lot of trust in them," Abreu testified. "In my case, I had the ability to perform that charitable work, you might call it. Prosecutors said Abreu never directly paid the lower-level people who helped him in Haiti and the Dominican Republic. In her questioning of Abreu, Estrada's lawyer Sabrina Puglisi emphasized that Abreu had risked being placed in the draft because, she said, he shocked Estrada and Hernandez by illegally entering the U.S. without a visa. She said he had risked reducing his earnings and she suggested Estrada had no reason to encourage him to come without a visa because it would have reduced Estrada's 20 percent commission. Abreu said it worked out for him but he had just wanted to be free, play baseball and live in the U.S.

– Some people snack on the peanuts offered on airline flights; Jose Abreu scarfs down beer and pieces of his passport. That's what the first baseman for the Chicago White Sox testified Wednesday in Miami at a trial for a baseball agent and a trainer accused of smuggling Cuban baseball players, and their families, into the US, the Sun Sentinel reports. The 30-year-old Abreu—who isn't being charged with anything and won't be if he tells the truth in court, prosecutors say—revealed to jurors he was pulling in just $20 a month in 2013 playing baseball in his native Cuba when he hooked up with Bartolo Hernandez, the agent, and trainer Julio Estrada, who said they'd help him get to the US before a late October deadline that year to sign a White Sox contract worth $68 million. Abreu, who testified with the help of a Spanish translator, explains that before leaving Cuba for the US, he went to Haiti to receive fake residency documents and a phony passport under an alias. Prosecutors explain that under free-agent and immigration rules for Cuban players, Abreu had to prove he lived in a different foreign country other than Cuba to score the lucrative US contract. But once he was on the plane headed to America, a Haitian "fixer" told him, he'd have to somehow get rid of the fake Haitian passport. And so "I went back to my seat … ordered … a Heineken beer, and then, little by little, I swallowed that first page of the passport" that contained his photo and phony name, he told the court. The AP explains that under the now-rescinded "wet foot, dry foot" policy, Cuban immigrants back then were permitted to stay in the US even if they had no travel papers. Abreu said the same fixer helped his girlfriend (now wife), parents, and other family get to the US over the next few months—and that he paid millions to Hernandez and Estrada for their efforts.

the idea that star clusters evolve dynamically has been around for nearly as long as the very concept of star clusters itself . the first to discuss the general properties of clusters in some detail was william herschel , who attributed their various degrees of `` central concentration '' to an evolutionary sequence in which the globular clusters represented the final stage @xcite . at that time , however , a real theory of stellar dynamics was still far in the future and the subject of cluster evolution remained dormant for well over a century . in the early 20th century , the attention was mostly focussed on external perturbations . @xcite remarked that `` a cluster of stars will suffer continual disintegration from its encounters with other stars or clusters '' . in his monograph on `` star clusters '' , @xcite devoted only a brief statement to dynamical evolution , noting that `` some of the globular clusters may be affected in freedom , form , and eventual survival by contacts with galaxies or other clusters . '' the stability of `` moving clusters '' was investigated by jeans and later by @xcite . the important effect of internal two - body encounters was first studied by @xcite who noted that stars in the high - velocity tail of the maxwellian velocity distribution will gradually escape , leading to disruption of typical open clusters on time scales of a few gyrs , depending on cluster mass . with remarkable foresight , ambartsumian also realised that low - mass stars will escape preferentially , and suggested that more evolved clusters might be recognisable by their lack of low - mass stars . similar conclusions were reached ( in the context of old globular clusters ) by @xcite . these ideas have been continuously refined ever since and it would lead too far to review the relevant literature on models for the dynamical evolution of star clusters here . excellent reviews on the dynamical evolution of open and globular clusters are in @xcite , @xcite and @xcite and the field remains very active as illustrated by several contributions in this volume . the remainder of this review concentrates on observational constraints on cluster evolution . in order to address dynamical evolution in a meaningful way observationally , a method to age - date individual star clusters becomes a necessity . the catalogue of open clusters compiled by @xcite listed the spectral types of the brightest stars in 100 milky way open clusters , but the use of this information as a suitable chronometer had to await the emergence of the first detailed sets of stellar model calculations in the 1950s . once it became possible to derive cluster ages from colour - magnitude diagrams , it quickly became clear that the number of old open clusters is lower than one would naively predict from a continuous formation rate , even taken into account the fact that younger clusters are more easily detected than older ones because they contain brighter stars . the relative paucity of old open clusters was noted almost simultaneously in at least three papers @xcite , all of which based on trumpler s catalogue . it appears that they all arrived at the same conclusion quite independently ( van den bergh , priv . all three papers also singled out disruption as the most likely cause of the decline in number of clusters with ages greater than @xmath1 years . considering the effects of stellar mass loss , a tidal field and relaxation due to stellar encounters , @xcite estimated an average cluster lifetime of @xmath2 years , in reasonable agreement with his best observational estimate of 500 myrs . @xcite calculated cluster disruption times of @xmath3 years for typical open cluster densities , in fair agreement with the observational estimates , and also noted that encounters between clusters and interstellar clouds might play an important role for cluster disruption . thus , one might argue that theoretical and observational estimates of cluster disruption times were in agreement to within a factor of 2 already 50 years ago ! in the context of this meeting , it is also interesting to note that the connection between stellar mass loss and the evolution of star clusters was recognised early on . of course , many of the details still remained ( and remain ! ) to be worked out . using more recent compilations of open cluster data , @xcite estimated that about 50% of open clusters in the milky way disintegrate within about 200 myrs . he also noted a significant scatter in the disruption times , with 2% of the clusters surviving for longer than a gyr , and suggested that the disruption time probably depends on the size and mass of the cluster ( as anticipated by ambartsumian ) . observational support for the importance of giant molecular cloud ( gmc ) encounters was provided by @xcite who pointed out that the oldest open clusters ( @xmath4 gyr ) are strongly concentrated towards the galactic anti - centre direction , where the density of gmcs is lower . this observation , as well as the fact that old open clusters tend to be found further from the galactic plane than young ones , has since been confirmed by several studies ( * ? ? ? * and references therein ) . theoretically , further support for the importance of gmc encounters came from n - body simulations by @xcite . the first observational evidence that cluster disruption times depend on mass came from @xcite . however , it has also been clear for some time that the disruption times may not be the same in all galaxies . both the lmc and smc show a less pronounced lack of old clusters than the milky way @xcite , and already @xcite suggested that different gmc densities in the milky way , smc and lmc might play a role . however , a direct comparison with the milky way remained somewhat hampered by different detection limits and the bursty star formation history of the lmc . prior to the launch of the _ hubble space telescope _ in 1990 , little was known about the detailed properties of ( young ) cluster populations in other galaxies , and even in the local group spirals m33 and m31 the data were insufficient to strongly constrain cluster lifetimes . little has been said explicitly thus far about the _ clusters ( gcs ) , which present a number of interesting problems . in the milky way , they are associated with the spheroidal component(s ) and thus considered typical `` population ii '' objects @xcite . in fact , every major galaxy is surrounded by ancient gcs akin to those found in the milky way . the mass distribution of gcs is markedly different from that of milky way open clusters , with a relative deficit of low - mass gcs ( [ sec : gclf ] , * ? ? ? this difference has sometimes lead to the notion that gcs may be fundamentally different from star clusters forming today , and might have formed by quite different processes which were unique in the early universe @xcite . however , the young `` populous '' star clusters in the lmc , some of which have gc - like masses , have remained a puzzle since the early 20th century @xcite , and continue to serve as a reminder that the distinction between open and globular clusters is not necessarily as clear - cut in other galaxies as it may seem in our own . the idea that gc formation may not have been restricted to the early universe received renewed interest when @xcite suggested that new gcs form in galaxy mergers this might solve the `` specific frequency problem '' ( i.e. , the fact that elliptical galaxies contain many more gcs per unit host galaxy luminosity than do spirals ) , which had been raised as a major objection against the idea that elliptical galaxies form from spiral - spiral mergers @xcite as suggested by @xcite . the subsequent discovery by hst observations of young `` super '' star clusters in a number of interacting and merging galaxies in the 1990s ( as reviewed by * ? ? ? * ) further stimulated interest in this idea , but the problem remains that the `` cluster initial mass function '' ( the cimf ) seems very different from that of the ancient gcs . besides other objections to the major merger picture ( e.g. * ? ? ? * ) this still represents a major challenge , as i will discuss shortly . over the last 12 decades , it has become abundantly clear that the basic division into `` open '' and `` globular '' clusters as it applies in the milky way quickly becomes inadequate when a wider variety of host galaxy types are considered . young clusters with masses in the range @xmath5 @xmath6 or greater have now been found in many different types of external galaxies @xcite . furthermore , hst observations of some lenticular ( s0 ) galaxies have revealed populations of old ( @xmath7 gyrs ) star clusters with larger effective radii than normal open and globular clusters , and with a mass distribution that does not display the turn - over observed in classical old gc systems @xcite . these `` faint fuzzy '' clusters are clearly associated with the disks of their host galaxies , and do not easily fit the classical description of either open or globular clusters . ultimately , the dynamical evolution of all flavours of star clusters must be governed by the same basic laws of stellar dynamics . we must therefore demand from any successful theory of cluster evolution that it is able to account for the observed properties of _ all _ types of star clusters without too much tweaking . the fact that the luminosity function of old globular clusters is ( nearly ) universal may be an important clue to the mechanisms that shaped it , as will be discussed further below ( [ sec : gclf ] ) . however , before seeking to explain the _ evolution _ of clusters , we must make sure that we know their _ initial _ properties . was the difference between the mfs of young and old ( `` globular '' ) star clusters set up at formation , or is it a result of dynamical evolution ? that gcs formed with a mf that was different from that observed in young cluster systems today @xcite is perhaps not an entirely unreasonable idea , given that conditions in the early universe were likely quite different from those prevalent today . however , this is unattractive for several reasons : first , direct observations of the formation of individual gcs at cosmological distances to test this hypothesis ( over a mass range that allows useful constraints on the cimf ) will not be possible for a long time to come . second , it would be a return to the notion that gcs are `` special '' , and thus make them less attractive as general tracers of the star formation histories of galaxies . at the end it may of course turn out that this is how nature really works . but alternatively , we may seek to understand the present - day mf of gcs as a result of dynamical evolution from the mfs observed in young cluster systems . it is then worthwhile to ask whether there _ is _ a universal cimf , and what it might look like . even after more than a decade of hst observations , the number of galaxies where the mf of young star clusters is known well is still in the single digits . direct application of the virial theorem requires reliable measurements of both the size and velocity dispersion of each individual cluster , and is impractical for large samples of clusters . most determinations of the masses of extragalactic star clusters rely on assumptions about the mass - to - light ( m / l ) ratio , usually from simple stellar population ( ssp ) models which assume a `` standard '' stellar mass function ( e.g. * ? ? ? * ; * ? ? ? the major complication here is that the m / l ratios are strongly age - dependent , so that knowledge of individual cluster ages is required in order to convert the observed luminosities into a mf . ssp models provide predictions for the evolution of broad - band colours as a function of age , which can be used to infer the ages of star clusters for ( in principle ) arbitrary combinations of passbands . however , for clusters younger than about a gyr , optical colours are only weakly sensitive to age , and strongly degenerate with respect to reddening , making imaging in the @xmath8-band a necessity for reliable age ( and hence mass ) determinations . galaxies where the mf has been determined for young clusters include the milky way @xcite , the lmc and smc @xcite , the nearby interacting spiral m51 @xcite , the starburst galaxies ngc 3310 and ngc 6745 @xcite and the `` antennae '' @xcite . in all these cases , the mf is consistent with a power - law of the form @xmath9 with @xmath0 , although the mass ranges probed by the different studies differ substantially . in the antennae and in ngc 3310/ngc 6745 , the lower limits are at @xmath10 @xmath6 , but these are purely observational limits and there is no reason to suspect that lower - mass , `` open '' clusters are absent in these galaxies . this lower limit coincides roughly with the mass of the most massive young clusters known in the milky way ( with a couple of exceptions ) , but again this may be an observational selection effect due to the limited volume of the galactic disk probed by current open cluster catalogues . [ fig : mwclusters ] shows the spatial distribution of open and globular clusters in the milky way from the catalogues of @xcite and @xcite , projected onto the galactic plane . the median distance of the open clusters from the sun is 1.1 kpc , and more than 80% have distances @xmath11 kpc , a strong indication that the current sample is highly spatially incomplete beyond @xmath12 kpc . indeed , a few young clusters with masses of @xmath13 @xmath6 have recently been identified in the milky way , including westerlund 1 @xcite and an object detected in the 2mass survey @xcite . both are located at distances of several kpc ( but still closer than the galactic centre ) , and subject to large amounts of foreground extinction . the existence of these objects at distances of a few kpc is fully consistent with extrapolation from the mf of open clusters in the solar neighbourhood , and strongly suggests that several young clusters with masses of @xmath14 @xmath6 or greater remain undiscovered in the disk of our galaxy @xcite . the known globular clusters , on the other hand , are more or less symmetrically distributed with respect to the galactic centre , suggesting that the sample does not suffer from severe spatial incompleteness . luminosity functions ( lfs ) are more readily obtained for large samples of clusters than mfs . generally , these also show power - law behaviours although often with slightly steeper slopes than the mfs @xcite . one way such a difference could arise is if the mf is truncated at some upper limit @xmath15 . @xcite noted a `` bend '' in the lf of young clusters in the antennae at @xmath16 , with a slope of @xmath17 above the bend . for an age of 10 myr , the bend corresponds to a mass of @xmath13 @xmath6 , tantalisingly close to the turn - over of the globular cluster mf . however , @xcite found that the mf of young clusters in the antennae is , in fact , consistent with a power - law with @xmath18 over the range @xmath5 @xmath6 , and noted that the bend in the lf could be due to a truncation of the mf near @xmath19 @xmath6 . the relation between the presence of a bend in the lf and a truncation of the mf has been investigated in more detail by @xcite , who suggested that the mf in the spirals m51 and ngc 6946 is truncated at @xmath20 @xmath6 , and at about @xmath21 @xmath6 in the antennae . thus , while direct data for the mf are preferable , studies of the lf may still hold interesting clues to the underlying mf , albeit not without some assumptions . it must be mentioned that some dwarf galaxies host a few star clusters which appear too luminous ( and massive ) to simply form the high - mass tail of a power - law distribution . most conspicuous among these is ngc 1705 , in which there is a gap of 3 magnitudes between the two brightest clusters , but a similar effect is observed in other dwarfs @xcite . in an hst study of a sample including 36 dirr galaxies , @xcite noted a possible turn - over in the lf of young star clusters , and speculated that different cluster formation mechanisms might be at work in isolated dwarf galaxies . such differences would be particularly interesting in view of the idea that some gcs may have formed in dwarf - like fragments @xcite . inevitably , studies of star clusters in dwarf galaxies tend to be complicated by small number statistics , and a systematic study of an even larger sample of star - forming dwarfs would be desirable . in summary , the current ( limited ) evidence suggests that the cimf is consistent with a power - law @xmath22 _ over some mass range _ in most galaxies . so far , there is no indication for any significant difference in the shape of the cimf in the milky way and more actively star - forming galaxies . if an upper limit to the cimf exists in our galaxy it is probably at @xmath23 @xmath6 or greater , and the apparent lack of `` super star clusters '' in the milky way disk may be , at least to some extent , a size - of - sample effect due to the limited volume we are sampling . more generally , whether or not the cimf has an upper limit , and how it might depend on host galaxy properties , is only now starting to be explored . however , we must also remain open to the possibility that cluster populations do not _ everywhere _ form with a single power - law mf . although the basic mechanisms responsible for the disruption of star clusters were identified already half a century ago , a detailed framework to compare observations and theory has only recently become available . @xcite derived the `` disruption time '' , @xmath24 , for star clusters in m51 , m33 , the smc and the solar neighbourhood under the assumption that @xmath24 could be parameterised as a simple analytic function of cluster mass : @xmath25 , where @xmath26 is the disruption time of a @xmath27 @xmath6 cluster . by explicitly including the dependence on mass , they could compare disruption times in different galaxies more directly than had been done before . the longer cluster disruption time in the smc ( by about an order of magnitude ) was confirmed , and @xcite also found a significantly shorter disruption time in the central parts of m51 . interestingly , the parameter @xmath28 was found to have a value close to 0.60 . this is significantly shallower than expected from classical two - body relaxation , which predicts that a star cluster should lose mass at a roughly constant rate and thus @xmath29 @xcite . however , a value of @xmath30 is consistent with @xmath31-body simulations for clusters with a realistic stellar mass function ( albeit with concentrations typical of gcs ) , evolving in an external tidal field @xcite . the scaling factor @xmath26 appears to depend on the mean ambient density as expected from @xmath31-body simulations , although the disruption time derived for the central regions of m51 by @xcite remained too short by about an order of magnitude compared to the predictions . the shorter disruption time - scale near the centre of m51 might be caused by a high density of gmcs there @xcite . @xcite assumed that clusters disrupt instantaneously at @xmath24 , but in later papers a more realistic treatment of gradual mass loss has been included . @xcite showed that the present - day age- and mass distributions of milky way open clusters can both be very well fitted in a scenario where clusters form at a ( nearly ) constant rate and disrupt on a timescale proportional to @xmath32 . they derived a disruption time for a @xmath27 @xmath6 cluster in the solar neighbourhood of 1.3 gyr , based on the @xcite catalogue . for masses in the range @xmath33 , this corresponds to disruption times between 75 and 300 myrs , consistent with the earlier studies . a few words on the concept of a high degree of `` infant mortality '' for star clusters , which has become popular in recent years : this idea is inspired by the facts that 1 ) the formation rate of embedded star clusters in the milky way over - predicts the number of observed open clusters by a large factor @xcite and 2 ) many studies of extragalactic young star clusters find a disproportionately large number of objects with ages @xmath34 years @xcite . the objection has been raised that these young objects may not be gravitationally bound , and thus do not deserve the label `` star clusters '' to begin with @xcite . certainly , young clusters tend to be located in crowded regions , and the identification of individual clusters becomes challenging even with hst at distances greater than a few mpc @xcite . ultimately , whether or not the definition of a star cluster should include the requirement that it be gravitationally bound may depend on the context , and for very young , still embedded objects it may be impossible to apply this criterion . in any case , this initial round of destruction appears to be independent of mass , and should not strongly affect the shape of the mf . one of the more remarkable and puzzling facts about old gcs is the ( near ) universality of their luminosity function the gclf . assuming that gcs in most galaxies display at most a small age spread , the gclf is a good proxy for the mf . fig . [ fig : gclf ] compares the milky way gclf [ data from @xcite ] with data for the sombrero galaxy , based on hst / acs observations @xcite . in the left panel , the two gclfs are plotted in the traditional way , i.e. as a histogram of number of clusters per magnitude bin . the best student s @xmath35 function fit to the sombrero data from spitler et al . is overplotted . clearly , the gclfs in the two galaxies are very similar . that the gclf may have a universal shape was suggested early on by @xcite , and it is now clear that the variations , if any , are small over a large range of hubble type and luminosity ( e.g. * ? ? ? * ; * ? ? ? it should be noted that there _ are _ subtle radial trends in the gclf within the milky way gc system . in particular , the luminosity function of gcs with galactocentric distances @xmath36 kpc may be bimodal @xcite . these outer halo clusters have been omitted from fig . [ fig : gclf ] although they are relatively few in numbers and would not strongly affect the comparison . the impression of a characteristic gc mass is driven to some extent by the logarithmic binning of the data @xcite . when the gclf is plotted as number of clusters per luminosity bin it can be equally well fitted by a broken power - law as illustrated in the right - hand panel of fig . [ fig : gclf ] . the arrow marks the peak of the @xmath35 function fit and the two straight lines are power - law fits to the sombrero gclf on either side of the arrow . at the high - mass end , the slope is @xmath37 , very close to the `` canonical '' @xmath18 value for the mf in young cluster systems . similar results have been found for many other gc systems @xcite , although the exact slope evidently depends on the mass range over which the fit is carried out . the detailed behaviour of the gclf below the turn - over is less well constrained , which is unfortunate since this is where the mfs of young and old cluster systems differ . it probably can not yet be ruled out that some variations are present . in the case of the sombrero , the fit in fig . [ fig : gclf ] indicates an essentially flat distribution , but possibly slightly steeper for the milky way . [ fig : sombrero ] shows the sombrero gclf in three radial bins , corresponding roughly to ( projected ) galactocentric distances of @xmath38 kpc , @xmath39 kpc and @xmath40 kpc . it is clear that the gclf does not change much with radial distance , although a visual inspection of the histograms might suggest a slight shift of the peak towards fainter magnitudes in the outer bins . however , differences in the turn - over are not statistically significant @xcite although it has long been clear that dynamical evolution will lead to preferential survival of star clusters with certain combinations of mass and size ( e.g. * ? ? ? * ) , this invariance of the gclf with galactocentric radius is a challenge in most models for the dynamical evolution of the mf . qualitatively , most models develop a bend or turn - over as the low - mass clusters disrupt , but disruption should be more effective closer to the centre , invariably leading to a decrease in turn - over mass with galactocentric distance . @xcite found that the absence of a significant radial trend in the milky way gclf turn - over could be explained if the velocity distribution becomes more radially anisotropic with galactocentric distance . however , the required degree of radial anisotropy is inconsistent with the observed gc kinematics , although the authors argued that an initial population of gcs on highly radial orbits might have been disrupted by now . in their model the cluster disruption time scales linearly with mass ( i.e. @xmath41 ) , contrary to the empirical findings of @xcite and @xcite and the @xmath31-body simulations of @xcite . for the gc system of m87 , @xcite again found that the observed constancy of the gclf turn - over requires strongly radial orbits beyond a few kpc , at odds with kinematic data @xcite . one shortcoming of many models is the assumption of a single concentration parameter . in fact , for gcs in the milky way the concentration parameter displays a correlation with @xmath42 magnitude . [ fig : mv_w0 ] shows the @xcite concentration parameter @xmath43 versus @xmath42 for the galactic gcs . while there is a significant scatter in @xmath43 at any given @xmath42 , there is also a clear trend of decreasing concentration for fainter clusters . @xcite found that early stellar mass loss may lead to disruption of low - concentration clusters , causing a turn - over in the mf at about the right mass . since this early disruption is mainly driven by processes internal to the cluster , the lack of dependence on external parameters would be naturally explained . however , a detailed study of this effect on the time evolution of the mf is yet to be carried out . although the previous paragraphs have stressed the similarity of the gclf in different environments , there are some hints that the gclf may not be truly universal . as already noted , the gclf in the outer part of the milky way halo shows some differences with respect to the canonical shape illustrated in fig . [ fig : gclf ] and appears skewed towards fainter luminosities . a similar effect may be present in the sample of gcs in dwarf galaxies studied by @xcite . in a sample of five spiral galaxies , @xcite noted an excess of faint , red star clusters in m101 and , perhaps , ngc 6946 . in the case of m101 this excess was confirmed by @xcite , but these authors suggested that many of the fainter clusters might be reddened young objects masquerading as old gcs . further data will be needed before a clear picture emerges . other important clues to the role of disruption processes in shaping the gclf may come from the populations of faint extended star clusters recently discovered in several s0-type galaxies @xcite . these clusters have disk - like orbits ( at least in one case ; * ? ? ? * ) and spatial distributions and effective radii of 715 pc , much larger than the @xmath44 pc typical of gcs @xcite . interestingly , these objects are mostly _ fainter _ than the gclf turn - over , and their lf does not display a turn - over down to the detection limit of current studies ( @xmath45 ) . being more extended , the two - body relaxation time will be longer , and disk - like orbits would reduce the role of disk- and bulge shocks . however , gmc encounters and spiral arm shocks might still have been important at earlier stages in the history of the host galaxies . thus , these clusters might provide clues to both dynamical destruction processes and the evolution of s0-type galaxies . important insight into the dynamical evolution of the mf might be gained from populations of clusters with intermediate ages ( @xmath46several gyrs ) and a small age spread . among the best candidates for hosting such populations are remnants of major spiral - spiral mergers . these are known to produce rich populations of star clusters , although confusion with ancient gcs remains a difficulty . the nearest such system is ngc 1316 , a @xmath44 gyr old merger remnant , whose cluster population has been studied in detail by @xcite using deep hst / acs imaging . the metal - poor gcs have a normal gclf , while goudfrooij et al . found that the metal - rich clusters ( believed to have been formed in the merger ) displayed a lf more consistent with a power - law down to the 50% completeness limit at @xmath45 . only in the central regions did they see some evidence for a flattening of the gclf at the faint end for the metal - rich gcs . this would be consistent with the expectation that dynamical processes should first start to erode the mf near the centre , but also raises the problem that a radial gradient in the gclf in ngc 1316 would be contrary to observations of old gcs and the early disruption scenario of @xcite . so the implications for understanding the evolution of the gclf are unclear . another candidate for hosting an intermediate - age cluster population is m82 . based on hst @xmath47 imaging , @xcite derived ages of about 1 gyr for clusters in the `` fossil starburst '' region b. their derived mf displays a turn - over at @xmath48 which they could not explain as a result of dynamical evolution from a power - law cimf , thus suggesting that the cimf may have been approximately log - normal . however , since m82 is seen nearly edge - on the extinction correction remains a concern , and another question is whether a starburst would still remain observable as a coherent region after @xmath12 gyr . @xmath8-band observations are currently under way ( p.i . l. smith ) , and should help resolve the issue . in summary , studies of intermediate - age cluster systems , while potentially promising , have not yet solved the problem of whether or not a power - law cimf can evolve towards the mass function of old gcs . for several decades it has been clear that a star cluster , even if left in isolation , will gradually disrupt as the velocity distribution approaches a maxwellian form and stars in the high - velocity tail escape . this process can be greatly accelerated in the presence of external perturbations such as the tidal field of the host galaxy , or tidal shocks from encounters with bulges , disks , spiral arms and/or gmcs . in the context of this meeting , it is also worth emphasising that stellar mass loss may play an important part for the dynamical evolution of star clusters , especially in the earliest stages . there is now excellent agreement between the observed mass- and age distributions of open clusters in the milky way and theoretical predictions , assuming evolution from an initial power - law mass function . it also appears that we are well under way to understanding differences in disruption time - scales in different environments . however , explaining the mass distribution of ancient globular clusters remains an unsolved problem , and this is probably where most work lies in the future . once again , the effect of stellar mass loss may turn out to be important , possibly in combination with a more realistic treatment of the structural properties of star clusters . an additional complication is that ancient gcs are subject to destruction mechanisms which are unimportant for star clusters forming today and evolving in disk galaxies ( bulge , disk shocks ) , while in contrast the role of other mechanisms which may now be important ( spiral arm passages , gmc encounters ) is difficult to assess for gcs . ambartsumian , v. a. 1938 , sci . leningrade state univ . # 22 , ser . ( astronomy ) , 4 , 19 baade , w. 1944 , , 100 , 137 barmby , p. , kuntz , k. d. , huchra , j. p. , & brodie , j. p. 2006 , , 132 , 883 bastian , n. , gieles , m. , lamers , h. j. g. l. m. , et al . 2005 , , 431 , 905 baumgardt , h. , & makino , j. 2003 , , 340 , 227 bik , a. , lamers , h. j. g. l. m. , bastian , n. , et al . 2003 , , 397 , 473 billett , o. h. , hunter , d. a. , & elmegreen , b. g. 2002 , , 123 , 1454 bok , b. j. 1934 , harvard college observatory circular , 384 , 1 boutloukos , s. g. , & lamers , h. j. g. l. m. 2003 , , 338 , 717 brodie , j. p. , & larsen , s. s. 2002 , , 124 , 1410 chandar , r. , whitmore , b. , & lee , m. g. 2004 , , 611 , 220 clark , j. s. , negueruela , i. , crowther , p. a. , & goodwin , s. p. 2005 , , 434 , 949 ct , p. , mclaughlin , d. e. , hanes , d. a. , et al . 2001 , , 559 , 828 de grijs , r. , anders , p. , bastian , n. , et al . 2003 , , 343 , 1285 de grijs , r. , bastian , n. , & lamers , h. j. g. l. m. 2003 , , 583 , l17 elmegreen , b. g. , & efremov , y. n. 1997 , , 480 , 235 elson , r. a. w. , & fall , s. m. 1985 , , 299 , 211 fall , s. m. , & rees , m. j. 1977 , , 181 , 37 fall , s. m. , & zhang , q. 2001 , , 561 , 751 fall , s. m. , chandar , r. , & whitmore , b. c. 2005 , , 631 , 133 figer , d. f. , mackenty , j. w. , robberto , m. , et al . 2006 , , 643 , 1166 forbes , d. a. , brodie , j. p. , & grillmair , c. j. 1997 , , 113 , 1652 friel , e. d. 1995 , , 33 , 381 gieles , m. , bastian , n. , lamers , h. j. g. l. m. , & mout , j. n. 2005 , , 441 , 949 gieles , m. , larsen , s. s. , bastian , n. , & stein , i. t. 2006 , , 450 , 129 gieles , m. , larsen , s. s. , scheepmaker , r. , et al . 2006 , , 446 , l9 gieles , m. , portegies zwart , s. f. , baumgardt , h. , et al . 2006 , , in press ( preprint astro - ph/0606451 ) goudfrooij , p. , gilmore , d. , whitmore , b. c. , & schweizer , f. 2004 , , 613 , 121 harris , w. e. , & pudritz , r. e. 1994 , , 429 , 177 harris , w. e. 1996 , , 112 , 1487 harris , w. e. , & racine , r. 1979 , , 17 , 241 herschel , w. 1789 , phil . trans . of the r.a.s . , 79 , 212 hodge , p. w. 1987 , , 99 , 724 hunter , d. a. , elmegreen , b. g. , dupuy , t. j. , & mortonson , m. 2003 , , 126 , 1836 janes , k. , & adler , d. 1982 , , 49 , 425 jeans , j. h. 1916 , , 76 , 552 johnson , k. e. 2005 , in massive star birth : a crossroads of astrophysics , iau symp . 227 , eds . r. cesaroni , m. felli , e. churchwell & m. walmsley jordn , a. , ct , p. , blakeslee , j. p. , et al . 2005 , , 634 , 1002 kharchenko , n. v. , piskunov , a. e. , rser , s. , et al . 2005 , , 438 , 1163 king , i. r. 1966 , , 71 , 64 king , i. r. 1980 , in star clusters , iau symp . 85 , 139 , d. reidel publishing co. , dordrecht , ed . j. e. hesser kroupa , p. 2001 , , 322 , 231 lada , c. j. , & lada , e. a. 2003 , , 41 , 57 lamers , h. j. g. l. m. , gieles , m. , & portegies zwart , s. f. 2005 , , 429 , 173 lamers , h. j. g. l. m. , gieles , m. , bastian , n. , et al . 2005 , , 441 , 117 larsen , s. s. 2002 , , 124 , 1393 larsen , s. s. 2004 , , 416 , 537 larsen , s. s. 2005 , in essential science in hubble s final years , ed . m. livio , stsci ( preprint astro - ph/0408201 ) larsen , s. s. 2006 , in globular clusters guides to galaxies , eds . t. richtler & s. s. larsen ( preprint astro - ph/0606625 ) larsen , s. s. , & brodie , j. p. 2000 , , 120 , 2938 larsen , s. s. , brodie , j. p. , huchra , j. p. , et al . 2001 , , 121 , 2974 larsen , s. s. , & richtler , t. 2000 , , 354 , 836 mclaughlin , d. e. 1994 , , 106 , 47 meylan , g. , & heggie , d. c. 1997 , , 8 , 1 oort , j. h. 1958 , in ricerche astronomiche , 5 , 63 , proc . of a conference at vatican observatory , oconnell parmentier , g. , & gilmore , g. 2005 , , 363 , 326 peebles , p. j. e. , & dicke , r. h. 1968 , , 154 , 891 peng , e. w. , ct , p. , jordn , a. , et al . 2006 , , 639 , 838 prieto , j. l. , & gnedin , o. y. 2006 , , submitted ( preprint astro - ph/0608069 ) richtler , t. 2003 , in stellar candles for the extragalactic distance scale , eds . d. alloin and w. gieren , lecture notes in physics , vol . 635 , p.281 - 305 salpeter , e. e. 1955 , , 121 , 161 schweizer , f. 1987 , in nearly normal galaxies : from the planck time to the present . new york , springer , p. 18 schweizer , f. 2006 , in globular clusters guides to galaxies , eds . t. richtler & s. s. larsen , new york , springer ( preprint astro - ph/0606036 ) searle , l. , & zinn , r. 1978 , , 225 , 357 shapley , h. 1930 , star clusters , new york : mcgraw - hill book company , inc . , sharina , m. e. , puzia , t. h. , & makarov , d. i. 2005 , , 442 , 85 spitzer , l. 1940 , , 100 , 396 spitzer , l. 1958 , , 127 , 17 spitzer , l. 1987 , dynamical evolution of globular clusters , princeton series in astrophysics spitler , l. , larsen , s. s. , strader , j. , et al . 2006 , , in press strader , j. , brodie , j. p. , spitler , l. , & beasley , m. a. 2006 , , submitted ( preprint astro - ph/0508001 ) terlevich , e. 1987 , , 224 , 193 toomre , a. , & toomre , j. 1972 , , 178 , 623 trumpler , r. j. 1930 , lick obs . bulletin , 420 , 154 van den bergh , s. 1957 , , 125 , 445 van den bergh , s. 1982 , , 94 , 459 van den bergh , s. 2003 , , 590 , 797 van den bergh , s. , & lafontaine , a. 1984 , , 89 , 1822 van den bergh , s. , & mcclure , r. d. 1980 , , 88 , 360 vesperini , e. , & zepf , s. e. 2003 , 587 , 97 vesperini , e. , zepf , s. e. , kundu , a. , & ashman , k. m. 2003 , , 593 , 760 von hoerner , s. 1958 , z. astrophys . , 44 , 221 whitmore , b. c. , zhang , q. , leitherer , c. , et al . 1999 , , 118 , 1551 whitmore , b. c. 2003 , in a decade of hst science , eds . m. livio , k. noll , & m. stiavelli , cambridge university press , p. 153 wielen , r. 1971 , , 13 , 309 wielen , r. 1985 , in dynamics of star clusters : proceedings of the symposium , princeton , nj . dordrecht : reidel , p. 449 zhang , q. , & fall , s. m. 1999 , , 527 , 81

current observational constraints on the dynamical evolution of star clusters are reviewed . theory and observations now agree nicely on the mass dependency and time scales for disruption of young star clusters in galactic disks , but many problems still await resolution . the origin of the mass function of old globular clusters , and its ( near ) invariance with respect to host galaxy properties and location within the host galaxy remain prominent puzzles . most current models fail to reproduce the globular cluster mass function as a result of dynamical evolution from an initial power - law , except under very specific conditions which are not generally consistent with observations . how well do we actually know the proper initial conditions ? the cluster initial mass function ( cimf ) seems to be consistent with a power - law with exponent @xmath0 in most present - day star forming galaxies , but the limits of the mass range over which this approximation is valid remain poorly constrained both observationally and theoretically . furthermore , there are hints that some dwarf galaxies may have cimfs which deviate from a power - law .

in this note shell examine vibration and show possible non feedback control of chaos in a simple , one degree of freedom , system subjected to external excitation with a non - symmetric stiffness given by the following equation : @xmath0 where @xmath1 is displacement @xmath2 is linear damping , @xmath3 is an external excitation while @xmath4 and @xmath5 are linear and quadratic force terms : @xmath6 such systems , where quadratic term brakes the symmetry of a potential @xmath7 @xmath8 have been a subject of studies for many years @xcite . these investigations were motivated by possible applications in description of physical systems mostly mechanical @xcite and electrical systems @xcite . they were also linked to possible metastable states of atoms and appear in problems within the elastic theory @xcite . systems which show homoclinic orbits and can be tackled analytically by perturbation methods . namely by the mielnikov method treating @xcite excitation and damping terms in higher order . such a treatment has been performed to selected problems with both symmetric and non - symmetric nonlinear forces @xcite to derive the necessary condition for transition to chaotic motion . on the other regular and chaotic regions of solutions in system parameters can be stabilised by using an additional weak resonant excitation @xcite . in this note we shell apply this method to the nonlinear system given by eq . [ eq1 ] . combined with the mielnikov approach it will predict analytically the range of parameters which tam the chaotic behaviour . the paper is divided into 5 sections . after this introduction ( sec . 1 ) we perform mielnikov analysis in sec . this discussion is followed by sec . 3 where we include a week resonant excitation term . its useful role in system control is shown there . the analytic predictions are confirmed by means of numerical simulations ( sec . we ending up in sec . 5 with conclusions . note in this section we follow the discussion initiated by thompson @xcite where he derived the analytic formula for a critical amplitude of a nonlinear oscillator described by a similar ( to our eq . 1 ) equation . we decided to include this section as an important introductory part to our main results to be given in the next section . thus we start our study from the second order equation of motion [ eq1 ] . transforming it into two differential equations of the first order we get @xmath9 . \nonumber\end{aligned}\ ] ] looking for stable and unstable manifolds we have introduced small parameter @xmath10 to the above equations and renormalised parameters @xmath11 and @xmath12 via @xmath13 and @xmath14 , respectively . the corresponding unperturbed hamiltonian have the following form : @xmath15 where @xmath16 is the potential of a non - symmetric well plotted in fig . this function has the local peak at the point @xmath17 existence of this point with a horizontal tangent make possible homoclinic bifurcations of the system i.e. potential transition from a regular to chaotic solution . after simple integration ( appendix a ) we get homoclinic orbits ( fig . [ fig1]b ) as : @xmath18 note the characteristic saddle point @xmath19 is going to be reached in exactly defined albeit infinite time @xmath20 corresponding to @xmath21 and @xmath22 for stable and unstable orbits , respectively . in case of perturbed orbits @xmath23 and @xmath24 the distance between them is given by the mielnicov function @xmath25 : @xmath26 where the corresponding differential forms @xmath27 as the gradient of unperturbed hamiltonian ( eq . [ eq3 ] ) leading to equations of motion @xmath28 while @xmath29 as its perturbation form of the above ( eq . [ eq4 ] ) : @xmath30 are defined on homoclinic manifold @xmath31 ( eq . [ eq6 ] , fig . [ fig2]b ) . from the above ( eqs . [ eq8]-[eq11 ] ) the mielnikov integral is given by @xmath32 after substituting @xmath33 and @xmath34 by formulae given in eq . [ eq8 ] and taking @xmath35 we get : @xmath36 where @xmath37 after evaluation of these elementary integrals we get condition of homoclinic transition to chaos , corresponding to a horseshoe type of cross - section and can be written as : @xmath38 evaluating above integrals ( eq . [ eq14 ] ) after some lengthly algebra the last condition ( eq . [ eq15 ] ) leads to a critical value of excitation amplitude @xmath39 for which @xmath40 as a result we get the critical amplitude @xmath39 versus frequency @xmath41 , which is plotted in fig . [ fig2](a ) ( the middle curve for @xmath42 ) . one should note here that the function has a local minimum at the point @xmath43 . note that in spite of using @xmath44 in place of @xmath45 , in the external excitation , discussed by thompson @xcite in the external excitation this result appears to be the same . let us consider an additional excitation term in starting equation ( eq . [ eq1 ] ) @xmath46 where @xmath47 is a scaling coefficient while @xmath48 represents a phase of a weak resonant excitation . now instead of eq . [ eq4 ] one can separate unperturbed and small perturbation parts in the following differential equations of the first order : @xmath49 . \nonumber\end{aligned}\ ] ] now one can repeat most of calculations from the previous section assuming that the excitation term is composed of two parts . after simple algebra we get : @xmath50 where @xmath51 therefore in this case the critical amplitude @xmath39 depends on control parameters @xmath47 and @xmath48 : @xmath52 this is our principal result in this paper . in fig . [ fig2]a we have plotted the results of @xmath39 for @xmath53 and @xmath54 , 0.0 , 0.45 . note that in case of @xmath42 the additional weak resonant excitation is absent but for any other cases it influences the system vibrations . it can drive the system away ( @xmath55 ) , or into ( @xmath54 ) the regions with a potential chaotic solution . to show the separation of regions with regular solutions and potential chaotic ones we calculated function @xmath56 for a properly chosen @xmath57 ( eq . [ eq15 ] ) : in our case we defined @xmath58 as follows : @xmath59 in fig . [ fig2]b we present the corresponding nodal lines for given amplitudes @xmath60 = 0.04 , 0.05 , 0.06 , 0.08 , 0.10 and 0.15 , respectively . on the other hand in figs . [ fig3]a and b we show the @xmath58 as a function of @xmath47 and @xmath48 , for @xmath60 = 0.1 and 0.05 ( [ fig3]a and b respectively ) . note , the nodal lines separating regular region from the regions where chaotic solutions occur can be easily obtained by cross - section with @xmath61 plane . to confirm the analytic predictions we have done numerical simulations for system parameters chosen as in point denoted with arrow in fig . [ fig2]a . in fig . [ fig4 ] we have plotted phase portraits and corresponding poincare sections for @xmath42 ( a ) , @xmath55 ( b ) and @xmath62 . as expected from our initial discussion , based on approximate mielnikov approach , we find chaotic solution in fig . the maximal lyapunov exponent appeared to be positive ( @xmath63 . on the other hand fig . [ fig4]b shows a regular type of motion synchronised with a periodic excitation force . note that the above numerical ( fig . [ fig4 ] ) results confirms the analytic investigations ( fig . [ fig2 ] ) . to show the fractal structure the strange attractor ( in fig . [ fig4]a ) has been also magnified in fig . note , different range of axes in fig . [ fig5]a - c . the characteristic double lines structure occur with the scaling factor which was estimated to be 4 . using the mielnikov method we have got the analytical formula for transition to chaos in a one degree of freedom , system subjected to parametric excitation with a non - symmetric stiffness with self - excitation term . including a weak resonant term we have been able to control the type of solution . namely it suppressed the chaotic solution by shrinking the lower bound lines of chaos in a phase diagram ( fig . [ fig2]b ) . in our numerical simulations of system vibration we have used the same initial conditions @xmath64 and @xmath65 representing the point in the phase plane relatively close saddle one @xmath66 . our basic chaotic solution were very close to that one obtained by thompson @xcite with ( @xmath67 and @xmath68 ) . although we have not discussed the problem of escape from the potential well we changed slightly his parameters ( @xmath69 and @xmath70 ) purposely . this has helped us to have more robust chaotic solution away the escape point . in the present analysis we have used only positively defined @xmath71 and @xmath72 ( see fig . [ fig1]a ) . nevertheless we claim that our results are general . note that another choice of @xmath71 sign would only mirror our solution along the @xmath1 axis ( @xmath73 ) . on the other hand changing @xmath74 would also rescale @xmath1 axis and simultaneously shift the saddle point as well as the local minimum of the potential : @xmath75 where @xmath76 . we would like to acknowledge partial support from polish state committee of scientific research . starting from unperturbed hamiltonian @xmath77 ( eq . [ eq5 ] ) we note that at the saddle point @xmath19 ( eq . [ eq7 ] ) the system velocity is zero @xmath78 and the energy has only its potential part @xmath79 transforming eq . [ eq5 ] for chosen constant energy ( eq . a1 ) @xmath80 we get the following expression for velocity : @xmath81 now one can perform integration over @xmath1 @xmath82 where @xmath57 represents an integration constant . finally , we get so called homoclinic orbits ( fig . @xmath83 99 szabelski k , samodulski w. drgania ukladu z niesymetryczna charakterystyka sztywnosci przy parametrycznym i zewnetrznym wymuszeniu . i stosowana 1985;23:22338 . thompson jmt . chaotic phenomena triggering the escape from a potential well . proceedings of the royal society of london a 1989;421:195225 . szabelski k. the vibrations of self - excited system with parametric excitation and non - symmetric elasticity characteristic , journal of theoretical and applied mechanics 1991;29:5781 . szempliska - stupnicka w , rudowski j. bifurcattions phenomena in a nonlinear oscillator : approximate analytical studies versus computer simulation results . physica d 1993;66:36880 . szempliska - stupnicka w. the analytical predictive criteria for chaos and escape in nonlinear oscillators : a survey . nonlinear dynamics1995;7:12947 . rega g , salvatori a , benedettini f. numerical and geometrical analysis of bifurcation and chaos for an asymmetric elastic nonlinear oscillator . nonlinear mechanics 1995;7:249 - 72 . litak g , warmiski j , szabelski k. regular and chaotic vibrations of a self - excited system with parametric excitation and non - symmetric elasticity . in : proceedings of iutam / iftomm symposium on synthesis of nonlinear dynamical systems , 24 - 28 august 1998 , riga , latvia . e lavendelis and m zakrzhevsky , riga technical university ; riga:1998 pp . rusinek r , warmiski j , vibrations of rayleigh - mathieu oscillator with quadratic elasticity characteristic . folia societatis scientiarum lublinensis 2000;9:14251 . topics in nonlinear dynamics with computer algebra . gordon and breach ; new york:1994 . rand rh , lecture notes on nonlinear vibrations . ithaca : the internet - first university press ; 2003 . http://www.tam.cornell.edu / randdocs/. thompson jmt , hunt gw . elastic instability phenomena wiley;chichester:1984 . guckenheimer j , holms p. nonlinear oscillations . dynamical systems and bifurcations of vectorfields . springer;new york:1983 . wiggins s. introduction to applied nonlinear dynamical systems and chaos . spinger;new york:1990 . chacon r , palmero f , balibrea f. taming chaos in a driven josephson junction , int j. bifurcation and chaos 2001;11:1897909 . cao hj , chi xb , chen gr , suppressing or inducing chaos in a model of robot arms and mechanical manipulators j sound vib . litak g and friswell mi . nonlinear vibrations in gear systems , in : nonlinear dynamic effects of production systems , g. radons , r. neugebauer ( eds . ) wiley - vch;weinheim:2004 , pp .

we examine the mielnikov criterion for transition to chaos in case of one degree of freedom nonlinear oscillator with non symmetric potential . this system subjected to an external periodic force shows homoclinic transition from regular vibrations to chaos just before escape from the potential well . especially we study the effect of a second resonant excitation with different phase on the system transition to chaos and propose a way of its control . nonlinear vibration , mielnikov criterion , bifurcation

"Ms. Delgado was involved in the planning and the commission of the offense," Geron said. "It was a murder for hire," he said. Hatcher was fatally shot in the parking garage of her upscale apartment building. Two days later, police arrested a suspect, 23-year-old Crystal Cortes. Investigators have said Cortes was offered $500 to serve as a getaway driver in what was supposed to be a robbery, but the accomplice shot Hatcher instead. Police, citing witnesses, said in search warrants that Delgado had ended a two-year relationship with Hatcher's boyfriend earlier in 2015. Related: Could Love Triangle Be Behind Dallas Dentist's Killing? Cortes allegedly told investigators that Delgado used a black iPhone "that was used to track the location of the complainant's cell phone" — referring to Hatcher — before the murder, according to the search warrants. Geron would not comment Friday on whether a device was used to track Hatcher before she was killed. Love is being held in lieu of $2.5 million bail on charges of capital murder and unlawful possession of firearm by a felon, Geron said. Love allegedly had the weapon believed to be used in the murder when he was arrested, Geron said. Delgado has not yet been arrested. "All I will suggest to her specifically is that she turn herself in as quickly as possible," Geron said. “She is a fugitive wanted at this point for capital murder." ||||| Skip Ad Ad Loading... x Embed x Share Dallas police announced they have arrested the man suspected of fatally shooting Dr. Kendra Hatcher in the garage of her Uptown apartment complex last month. They also have issued an arrest warrant for the woman suspected of planning the crime. VPC Kendra Hatcher (Photo: LinkedIn) Police arrested a man for fatally shooting a popular Texas dentist and are searching for the woman suspected of paying him to carry out the murder, authorities said Friday. Kristopher Love, 31, was arrested and charged with capital murder in the Sept. 2 death of Kendra Hatcher, Dallas police spokesman Max Geron said. When Love was arrested, he had the suspected murder weapon in his possession, police told reporters on Friday. Love, a former felon, was also charged with unlawful possession of a firearm. A capital murder arrest warrant has also been issued for Brenda Delgado, 33, a woman who used to date Hatch er's boyfriend. Police said Delgado was involved in the planning and the commission of the murder. Delgado dated Hatcher's boyfriend for two years, before the relationship ended in 2015. According to the arrest warrant affidavit, Love admitted his role in the Sept. 2 slaying of Kendra Hatcher. He is being held on $2.5 million bond. Brenda Delgado, seen here in a mugshot taken in Sept. 2015, after she was arrested on outstanding traffic warrants in Plano. (Photo: WFAA) Maj. Geron encouraged Delgado to turn herself into authorities and said she is a fugitive at this time. Hatcher was murdered in the parking lot of her apartment complex last month. Delgado was questioned by police in early September as authorities investigated the case, but she was released. She was mentioned numerous times in search warrants related to the case obtained after the arrest of Crystal Cortes, who police believe drove the alleged shooter to the Gables apartment complex. Cortes remains in jail at this time, also charged with capital murder. Read or Share this story: http://usat.ly/1L9ZZ5c

– Police say a dental hygienist planned and commissioned the murder of a popular Dallas dentist last month, the New York Daily News reports. "It was a murder for hire," Maj. Max Geron told reporters Friday. Police have issued a warrant for the arrest of 33-year-old Brenda Delgado, who is accused of paying to have Kendra Hatcher killed. According to NBC News, Hatcher was dating Delgado's ex-boyfriend, but police have not identified a motive for the killing. Delgado was questioned and released by police in the days following the Sept. 2 murder, according to USA Today. "All I will suggest to her specifically is that she turn herself in as quickly as possible," Geron said. "She is a fugitive wanted at this point for capital murder." Police also announced the arrest and charging of 31-year-old felon Kristopher Love, who is accused of actually pulling the trigger in Hatcher's death, NBC reports. He is being held on $2.5 million bail. Police say 23-year-old Crystal Cortes drove Love to the parking garage of Hatcher's apartment building for the murder. Cortes was arrested two days after the murder and reportedly claimed Delgado used an iPhone to track the location of Hatcher's phone prior to the crime. She claims she was paid $500 to be the getaway driver for what she thought was only supposed to be a robbery.

There has been an unconfirmed sighting of missing Iowa jogger Mollie Tibbetts in Kearney, Missouri. Interested in Mollie Tibbetts? Add Mollie Tibbetts as an interest to stay up to date on the latest Mollie Tibbetts news, video, and analysis from ABC News. Add Interest Kearney police responded on July 26 to a possible sighting of Tibbetts, 20, at a truck stop in the area, police told ABC News affiliate KMBC. The location is more than 230 miles away from where Tibbetts was last seen. Officers conducted a search of the area, spoke with witnesses and reviewed any potential surveillance video. A report was sent to the investigative task force regarding the sighting, Sgt. Joe Kantola told KMBC. No other additional details of the sighting were released. Facebook Tibbetts was reported missing after she failed to show up for work in Brooklyn, Iowa, a farming community of about 1,500 people where she was living over the summer with her longtime boyfriend. At a press conference Monday, police released no specific details about new developments in the case but said the search is active. "Law enforcement and hundreds of others have devoted countless hours to the investigation," said Kevin Winker, the director of investigative operations for the Iowa Department of Public Safety. Canine searches have been used and investigators are poring over any clues they could gather from undisclosed technology, Winker said. Earlier in the investigation, officials said that they were going to be examining her Fitbit, a device that tracks physical activity and has a GPS feature. Winker said the he was "not going to draw any conclusions about the circumstances of her disappearance other than it's not consistent with her past." More than 200 leads have been collected as part of the investigation, police said. KCRG Tibbetts' father said he believes there's someone else with information that could help locate his daughter. “It doesn’t matter what we’re going through, we just need people to think -- because somebody knows something and they don’t even know it’s important,” Rob Tibbetts said. ABC News' Meghan Keneally and Karma Allen contributed to this report ||||| Investigators say they have concluded that a woman spotted in northwest Missouri was not a missing Iowa college student. Iowa Division of Criminal Investigation special agent Mike Krapfl confirmed Thursday that the reported sighting of Mollie Tibbetts wasn't substantiated and has been ruled out by investigators. Advertisement Police in Kearney, Missouri, said an employee at a truck stop reported Sunday that she saw someone resembling Tibbetts eating at a Taco Bell. Kearney is about 25 miles northeast of Kansas City. The Kearney Police Department said in a statement that it spoke to witnesses and reviewed video footage before forwarding a report to a task force investigating Tibbetts' disappearance. Tibbetts, a 20-year-old University of Iowa student, hasn't been seen since July 18 . Copyright 2018 The Associated Press. All rights reserved. PREVIOUSLY Authorities in western Missouri said Wednesday they responded to reports of a possible sighting of 20-year-old Mollie Tibbetts, a missing University of Iowa student who hasn’t been seen in two weeks. Sgt. Joe Kantola, with the Kearney, Missouri, Police Department told KMBC that officers responded Thursday at a truck stop within their jurisdiction at Interstate 35 and Missouri 92 Highway after someone reported seeing who they believe could have been Tibbetts, who went missing around July 18. “Officers conducted a thorough search, spoke with all possible witnesses and reviewed all available footage,” Kantola said in a statement. It is unclear whether the search turned up anything fruitful leading to the discovery of Tibbetts. Several KCCI viewers sent screenshots of a Facebook post saying there was a possible sighting of Tibbetts and that she “might have been drugged, looked disoriented and was with a truck driver.” However, a spokesperson with the Iowa Division of Criminal Investigation said authorities are aware of the possible sighting. They are investigating but couldn’t immediately confirm whether the tip was legitimate. A report was sent to the investigation task force regarding the possible sighting. Dozens of state and federal investigators are working to determine what happened to Tibbetts, but they still don’t know what happened to her. A reward jumped to $30,000 on Wednesday for any information leading to Tibbetts’ safe return. Family members and Crimestoppers officials will talk about the reward Thursday at 11 a.m. in Brooklyn. KCCI will live stream the event on The KCCI News App and KCCI.com. AlertMe

– Roughly one week after Mollie Tibbetts vanished in Iowa, police received a tip of a possible sighting of the 20-year-old in Missouri. KMBC reports the Kearney Police Department fielded a tip from someone who saw a woman who looked like Tibbetts at a truck stop near I-35 and Missouri 92 Highway on July 26; that location is about 230 miles from where Tibbetts was last seen, reports ABC News. Kearney officers "spoke with all possible witnesses, and reviewed all available video footage," per a statement. A rep for the department says if they had seen Tibbetts in the footage that would have been mentioned in the statement; it was not, indicating there is no footage that backs up the witness' claim. As for the claim, the rep added police only spoke with one person who reported seeing a Tibbetts lookalike at the truck stop. Des Moines station KCCI says a number of its viewers sent it screenshots of a Facebook post regarding the possible sighting, which noted Tibbetts "might have been drugged, looked disoriented, and was with a truck driver." KCCI did not share that post. Tibbetts was last seen jogging in Brooklyn, Iowa, on July 18.

SECTION 1. SHORT TITLE. This Act may be cited as the ``High-Tech Port Security Act of 2003''. SEC. 2. DEFINITIONS. In this Act: (1) Captain-of-the-port.--The term ``Captain-of-the-Port'', with respect to a port, means the individual designated by the Commandant of the Coast Guard as the Captain-of-the-Port at that port. (2) Container.--The term ``container'' means a cargo container designed or used for the international transportation of merchandise by vessel. (3) Blast-resistant container.--The term ``blast-resistant container'' means a container that incorporates blast-resistant technology and has been certified as a blast-resistant container by the Secretary pursuant to section 101. (4) Regulated container.--The term ``regulated container'' means a container that is manufactured after the date that is 15 months after the date the Secretary prescribes regulations under section 101. (5) Secretary.--The term ``Secretary'' means the Secretary of the Department of Homeland Security. (6) Vessel.--The term ``vessel'' has the meaning given that term in section 401 of the Tariff Act of 1930 (19 U.S.C. 1401). TITLE I--PORT SECURITY AND SAFE CARGO SEC. 101. BLAST-RESISTANT CONTAINERS. (a) Regulations.--Not later than 90 days after the date of the enactment of this Act, the Secretary shall prescribe regulations-- (1) establishing standards for the certification of blast- resistant containers; (2) establishing the procedure by which interested parties may apply for such certification, including the submittal of prototypes and cost estimates; and (3) requiring that, effective on and after the date that is 15 months after the date such regulations are prescribed by the Secretary, no vessel carrying 1 or more regulated containers and seeking to enter the United States shall be allowed such entry unless all such regulated containers are certified blast- resistant containers pursuant to the standards and procedures described in this section. (b) Certification.--The Secretary shall evaluate each application for certification submitted pursuant to the regulations described in paragraphs (1) and (2) of subsection (a), and shall notify each applicant whether such container is certified as blast-resistant-- (1) not later than the date that is 90 days after the application is submitted, if such application is submitted not later than the date that is 90 days after the Secretary prescribes such regulations under subsection (a); or (2) not later than such other date as may be established by the Secretary pursuant to such regulations, if such application is submitted after the date that is 90 days after the date the regulations are prescribed. (c) Deadline.-- (1) Generally.--Not later than 15 months after the date the Secretary prescribes regulations under subsection (a), the Secretary shall deny entry of a vessel into the United States if any of the regulated containers carried by such vessel are not certified under subsections (a) and (b). (2) Extension of deadline.--The Secretary may extend the deadline under paragraph (1) for up to 1 year if the Secretary-- (A) determines that none of the prototypes with respect to which applications have been submitted prior to such deadline are economically feasible; and (B) submits a report (which may be in classified form) to the Committee on Commerce, Science, and Transportation of the Senate and the Committee on Transportation and Infrastructure of the House of Representatives describing-- (i) the reasons for such extension; and (ii) such steps as the Secretary deems necessary or appropriate to ensure that economically feasible prototypes exist prior to the extended deadline. SEC. 102. SCREENING PRIOR TO DEPARTURE FROM PORT. (a) Regulations.--Not later than 90 days after the date of the enactment of this Act, the Secretary shall prescribe regulations-- (1) establishing standards for the certification of equipment designed to screen a container carried by a vessel entering the United States for radioactive and explosive materials before the container leaves the port; (2) establishing the procedure by which interested parties may apply for such certification, including the submittal of prototypes and cost estimates; and (3) requiring that, effective on and after the date that is 15 months after the date such regulations are prescribed by the Secretary, every container carried by a vessel entering the United States shall be screened for radioactive and explosive materials before the container leaves the port. (b) Certification.--The Secretary shall evaluate each application for certification submitted pursuant to the regulations described in paragraphs (1) and (2) of subsection (a), and shall notify each applicant whether the screening equipment is certified for purposes of screening containers for radioactive and explosive materials-- (1) not later than the date that is 90 days after the application is submitted, if such application is submitted not later than the date that is 90 days after the Secretary prescribes such regulations under subsection (a); or (2) not later than such other date as may be established by the Secretary pursuant to such regulations, if such application is submitted after the date that is 90 days after the date the regulations are prescribed. (c) Screening Equipment Deployment.-- (1) Twenty largest ports.--The Secretary shall take all necessary action, including providing grants to ports, to ensure that, not later than 15 months after the date the Secretary prescribes regulations under subsection (a), the 20 largest ports in the United States, as determined by the Secretary under section 201(a)(1), and any other United States ports determined by the Secretary to be highly vulnerable, have deployed screening equipment certified under subsections (a) and (b). (2) Other ports.--The Secretary shall take all necessary action to ensure that every other port in the United States deploys such certified screening equipment as soon as practicable. (d) Mandatory Screening Deadline.--Not later than the date that is 15 months after the date the Secretary prescribes regulations under subsection (a), the Secretary shall require that any container carried by a vessel entering any of the 20 largest ports in the United States, and any other United States port determined by the Secretary to be highly vulnerable, shall be screened for radioactive and explosive materials before the container leaves the port. TITLE II--PROTECTION OF LARGEST PORTS SEC. 201. COMMAND AND CONTROL CENTERS. (a) Establishment of Command and Control Centers.--Not later than 90 days after the date of the enactment of this Act, the Secretary shall-- (1) identify the 20 largest ports in the United States, as measured by the number of containers processed annually at each port; and (2) in coordination with the Captain-of-the-Port and other officials responsible for security matters at each such port, develop a plan to establish a command and control center for the purpose of coordinating, monitoring, and managing all of the security operations at the port. (b) Grants.-- (1) In general.--The Secretary shall establish a grant program for providing funds to port authorities, facility operators, and State and local agencies to develop and implement the command and control centers under subsection (a)(2). (2) Application.--Each entity seeking a grant under this subsection shall submit an application to the Secretary at such time, in such manner, and accompanied by such information as the Secretary may reasonably require. TITLE III--AUTHORIZATION OF APPROPRIATIONS SEC. 301. AUTHORIZATION OF APPROPRIATIONS. There is authorized to be appropriated to the Secretary $100,000,000 for the purpose of carrying out this Act.

High-Tech Port Security Act of 2003 - Instructs the Secretary of the Department of Homeland Security to prescribe regulations: (1) establishing certification standards and procedures for blast-resistant containers; and (2) prohibiting entry into the United States of any vessel carrying regulated containers after such regulations are prescribed unless they are all certified blast-resistant. Directs the Secretary to: (1) establish standards for the certification of equipment designed to screen a container carried by a vessel entering the United States for radioactive and explosive materials before the container leaves the port; (2) take action to ensure that the twenty largest domestic ports (and any others determined highly vulnerable) have deployed such certified screening equipment; and (3) establish command and control centers at the twenty largest domestic ports.

from the very advent of nuclear physics , ground - state properties of nuclei mainly mass and binding energies have occupied special fancy of the physicists after the formulation of the celebrated bethe - weizsacker semi - empirical mass formula , which of course is based on the classical liquid drop picture of the nucleus . in due course , the interest was confined to explore possible existence of symmetry in nuclear dynamics , in developing mass formulas such as the garvey - kelson @xcite mass formula that connects masses of six neighboring nuclei . therefore it was natural to expect such symmetry to be manifested in the properties other than the ground - states and specifically in the excited states . in this regard ross and bhaduri @xcite have succeeded to some extent to find difference equations involving the reduced transition probabilities @xmath0 of the neighboring even - even nuclei . patnaik et al . @xcite on the other hand have also succeeded in establishing even more simpler difference equations connecting these values of four neighboring even - even nuclei . here in the present work we have made an attempt first to obtain a possible relation involving the reduced transition probability of a given nucleus with its derivatives with respect to neutron and proton numbers , instead of the usual difference equations . we could achieve this based on the local energy @xmath2-differential equation of the infinite nuclear matter ( inm ) model @xcite of atomic nuclei . in passing one may note , that the @xmath2-relation connecting the partial derivatives of the local energies in the inm model is primarily responsible for the success @xcite of the inm model as a mass - formula . such a differential equation in @xmath2 was possible in the model due to its very foundation , i. e. , the hugenholtz - van hove(hvh ) theorem @xcite of many - body theory . apart from this , the inm model has succeeded in resolving @xcite the so - called @xmath3-paradox and also in determining the value of nuclear incompressibility from known masses of nuclei . it is needless to mention here that any relation in the form of a differential equation of any physical quantity is intrinsically sound enough to posses a good predictive ability . this philosophy has been well demonstrated in the inm model , specifically for the prediction @xcite of masses of nuclei throughout the nuclear chart . the local energy of a nucleus as per the inm model basically constitutes the shell and deformation energies , and has been shown @xcite to carry the shell structure of a given nucleus [ for a comprehensive account of all these aspects readers may refer our recently published book @xcite ] . therefore it is likely that this physical quantity @xmath2 has a good one - to - one correspondence with the properties of excited states of a given nucleus in general , and in particular the reduced transition probability . in view of all these facts , the local energy relation has been taken as the basis for formulating a similar differential equation connecting the @xmath0 value of a given nucleus with its derivatives with respect to neutron and proton numbers . in sec . ii , we show how such a relation in the form of a differential equation can be formulated followed by its possible theoretical justification . sec . iii deals with how the same differential equation can be used to derive two recursion relations in @xmath0 , connecting in each case three different neighboring even - even nuclei . finally we present in section iv , their numerical validity when subjected to known @xcite experimental data through out the nuclear chart , and their possible utility for purpose of predictions . it may be mentioned here that one of the basic physical quantities of a given nucleus as per the inm model is the the local energy @xmath2 that satisfies the inm equation @xcite @xmath5,\ ] ] where z , n , a refer to proton , neutron and mass numbers respectively , while @xmath6 is the usual asymmetry parameter given by ( n - z)/a . @xmath2 in conjunction with two other physical quantities @xmath7 and @xmath8 defines the ground - state energy @xmath9 of a given nucleus given by @xmath10 @xmath11 being the energy of asymmetric nuclear matter and @xmath12 being the energy of the inm sphere are global in nature , while @xmath2 characterizing a finite nucleus is considered local in contrast . consequently these three quantities are considered distinct in the sense that each of them refers to a specific characteristic of the nucleus and as such , are more or less independent of each other . conceptually the local energy equation ( [ eta ] ) could be obtained when eq . ( [ efe ] ) is subjected to the generalized hvh theorem @xcite of many - body theory given by @xmath13/2.\ ] ] @xmath14 and @xmath15 are respectively the neutron and proton fermi energies of nuclear matter . physically the local energy @xmath2 embodies all the characteristic properties of a given nucleus , mainly the shell and deformation , and has been explicitly shown @xcite to carry the shell - structure . therefore it is likely to have some characteristic correspondence with the properties of excited states of a given nucleus in general and in particular , the reduced transition probability @xmath0 . accordingly the above @xmath2-equation ( [ eta ] ) can be used as an ansatz to satisfy a similar relation involving the @xmath0 of a given nucleus . as a result we write on analogy , a similar equation for @xmath0 as @xmath16/ a}={1\over 2 } \left[(1+\beta){\bigl(\partial b(e2 ) / \partial n\bigr)}_z + ( 1-\beta){\bigl(\partial b(e2)/ \partial z}\bigr)_n\right].\ ] ] thus we see that we have a relation ( [ be2 ] ) that connects the @xmath0 value of a given nucleus ( n , z ) with its partial derivatives with respect to neutron and proton numbers n and z. it is true that our proposition of this differential equation for @xmath0 is purely on the basis of intuition and on analogy with a similar relation for the local energy of a nucleus in the inm model . however to what extent it is true , that needs to be established . this we show in the following . for a theoretical justification of the above equation , we use the approximation of expressing @xmath0 as the sum of two different functions @xmath17 and @xmath18 as @xmath19}= b_1(n ) + b_2(z).\ ] ] the goodness of this simplistic approximation can only be judged from numerical analysis of the resulting equations that follow using the experimental data . secondly we use the empirical fact [ see fig . 1 ] that @xmath0s are more or less slowly varying functions of n and z locally . this assumption however can not be strictly true at magic numbers and in regions where deformations drastically change . in fact known @xmath0 values plotted as isolines for isotopes and isotones in fig . 1 , convincingly demonstrate this aspect in most of the cases . the usual typical bending and kinks at magic numbers like 50 , 82 and also across z@xmath2066 [ fig . 1(f ) ] can be seen as a result of sharply changing deformations . consequently @xmath21 and @xmath22 can be written directly proportional to n and z respectively as @xmath23 where @xmath24 and @xmath25 are arbitrary constants and vary from branch to branch across the kinks . then one can easily see that just by substitution of the above two eqs . ( [ f],[f2 ] ) , the differential eq . ( [ be2 ] ) gets directly satisfied . thus the proposed differential equation for @xmath0 analogous to the local energy relation in the inm model gets theoretically justified . however , the differential eq . ( [ be2 ] ) has its own limitations , and need not be expected to remain strictly valid across the magic - number nuclei as well as in regions where deformations sharply change because of the very approximations involved in proving it . in order to utilize the differential eq . ( [ be2 ] ) for all practical purposes , it is desirable to obtain possible recursion relations in @xmath0 for even - even nuclei in ( n , z ) space . the partial derivatives occurring in this equation at mathematical level are defined for continuous functions . however for finite nuclei , these derivatives are to be evaluated taking the difference of @xmath0 values of neighboring nuclei . since our interest is to obtain recursion relations for even - even nuclei , we use in the above equation the usual forward and backward definitions for the partial derivatives given by @xmath26-b(e2 ) [ n , z]\bigr ] , \nonumber \\ \bigl ( { \partial b(e2)/ \partial z}\bigr)_n & \simeq&{1\over 2 } \bigl [ b(e2 ) [ n , z+2]-b(e2)[n , z ] \bigr ] , \\ & & and \nonumber \\ \bigl({\partial b(e2)/ \partial n}\bigr)_z & \simeq&{1\over 2 } \bigl [ b(e2)[n , z]-b(e2 ) [ n-2,z]\bigr ] , \nonumber \\ \bigl ( { \partial b(e2)/ \partial z}\bigr)_n & \simeq&{1\over 2 } \bigl [ b(e2 ) [ n , z]-b(e2)[n , z-2 ] \bigr ] .\end{aligned}\ ] ] substituting the above two pairs of definitions for the derivatives in eq . ( [ be2 ] ) separately , we arrive at the following two recursion relations for @xmath0 connecting neighboring even - even nuclei . these are @xmath27 & = & { n \over { a-2}}\ : b(e2 ) [ n-2,z ] + { z \over { a-2}}\:b(e2 ) [ n , z-2 ] , \\ \label{b2b } b(e2 ) [ n , z ] & = & { n \over { a+2}}\ : b(e2 ) [ n+2,z]+{z \over { a+2}}\ : b(e2 ) [ n , z+2 ] .. \end{aligned}\ ] ] the first recursion relation ( [ b2f ] ) connects three neighboring nuclei ( n , z ) , ( n-2,z ) and ( n , z-2 ) while the second one ( [ b2b ] ) connects ( n , z ) , ( n , z+2 ) and ( n+2,z ) . thus both these relations connect only three neighboring even - even nuclei . the first one relates @xmath0s of lower to higher mass nuclei while the second one relates higher to lower mass and hence they can be termed as forward and backward recursion relations termed as , b(e2)-f and b(e2)-b respectively . thus depending on the availability of @xmath0 data , one can use either or both of these two relations to obtain the corresponding unknown values of neighboring nuclei . having derived the recursion relations in @xmath0 from the differential equation ( [ der ] ) , it is desirable to test their numerical validity to see to what extent they stand the known experimental data throughout the nuclear chart . this would also numerically support the differential eq . ( [ be2 ] ) from which the recursion relations are derived . for this purpose we use the experimentally adopted @xmath0 data set of raman et al . @xcite in the above relations and compute the same of all possible anchor nuclei , that are characterized by the neutron and proton numbers ( n , z ) occurring in the left hand sides of the relations ( [ b2f],[b2b ] ) in the mass range of a=10 to 240 . for better visualization of our results , we calculate the deviation of the computed @xmath0 values from those of the experimental data in terms of the percentage errors following raman et al . @xcite . the percentage error of a particular calculated quantity is as usual defined as the deviation of that quantity from that of the experiment divided by the average of the concerned data inputs and then expressed as the percentage of the average . obviously the larger the percentage error larger is the deviation of the concerned computed value . these percentages so computed are plotted in the figures 2 and 3 against proton and neutron number respectively . this is done to ascertain to what extent large deviations occur at proton and neutron magic numbers . from the presented results we see , that in most of the cases both forward and backward recursion relations ( [ b2f],[b2b ] ) give reasonably good agreement with experiment . the deviations in 119 out of 187 cases for the forward relation [ b(e2)-f ] and 124 out of 186 cases for the backward relation [ b(e2)-b ] lie within @xmath2825% error [ shown within broken lines in the figures ] . it should be noted that even the experimental data themselves vary quite widely from one experiment to another for the same nucleus [ see for instance table ii of the data compilation by raman et al . just to cite two examples of such wide variation , the @xmath0 value for the nucleus @xmath29 lies in the range 0.256 to 0.437 units , while the adopted value is 0.265 units and the same for @xmath30 varies from 3.45 to 6.8 units , the adopted value being 4.36 units @xcite . such wide variation in the experimental values are almost prevalent in most of the cases . in view of this , the agreement of the model recursion relations with those of experiment can be considered rather good . however one can see from the figures 2 and 3 , that the percentage errors ( deviations ) are relatively higher for some nuclei in the neighborhood of the magic numbers 20 , 82 , 126 and semi - magic number 40 . such increase in the vicinity of the magic numbers is expected as the differential eq . ( [ be2 ] ) from which the recursion relations are derived , need not be strictly valid at the magic numbers . for sake of comparison of our results with those of algebraic relations of other authors , we present here calculated values using the difference equations of patnaik et al . one should note that they used the sum rule approach of the garvey - kelson type given by @xmath31 = b(e2)[n+2,z]+b(e2)[n , z+2]-b(e2)[n+2,z+2].\ ] ] it may be easily noted that this difference equation connects four nuclei namely ( n , z ) , ( n+2,z ) , ( n , z+2 ) and ( n+2,z+2 ) in contrast to three in our recursion relations ( [ b2f],[b2b ] ) . these results are presented as b(e2)-p in the graph ( c ) of figures 2 and 3 . as can be seen that these results are almost similar to ours . numerically we find that the deviations up to 25% error from experiment exists in 117 out of 178 cases . to bring out the contrasting features of our results in a better way , we also present our results in fig . 4 in the form of histograms , which represent number of cases having different ranges of percentage errors . as can be seen , the sharply decreasing heights of the vertical pillars with the increasing range of errors are a clear testimony of the goodness of our recursion relations . similar behavior can be seen also with those of patnaik et al . @xcite . for exact numerical comparison , we present in table i , results obtained in our calculation along with those of experiment @xcite for some of the nuclides randomly chosen all over the nuclear chart . one can easily see that the agreement of the predictions with the measured values is exceedingly good in most cases . in few cases such as @xmath32 , @xmath33 there exists some discrepancy in between the predicted value and those of experiment . but we should also note , that the actual experimental data for these two nuclei lie in the range of 0.203 - 0.380 and 0.133 - 0.220 units respectively , which we quote here from table ii of raman et al . @xcite . therefore in the light of such variations in the experimental data , predictions of our recursion relations appear to be reasonably good and hence can be relied upon . now coming to the possible agreement in between the predictions of the two recursion relations ( [ b2f ] ) and ( [ b2b ] ) , we see that more or less they agree well . however there exists some disagreement in between them in few cases such as @xmath34 and @xmath35 . this may be attributed to the widely varying experimental inaccuracy of the concerned data inputs in our recursion relations . for instance , in case of @xmath36 , the predictions differ from each other by about 17% while the corresponding data inputs @xmath37 and @xmath38 have experimental error bars 0.20,0.70,0.20 and 0.17 units respectively . thus all except the second data input has a relatively higher error , thereby possibly causing the difference in predictions . thus in general both the recursion relations more or less can be relied upon for predicting the @xmath0 values . .comparison of the predicted referred to as b(e2)-b [ eq . ( [ b2b ] ) ] and b(e2)-f [ eq . ( [ b2f ] ) ] and experimentally adopted @xcite @xmath0 values presented in terms of the standard units[@xmath39 . the bracketed numbers refer to uncertainties in the last digits of the experimentally quoted values . [ cols="^,^,^,^,^,^,^,^ " , ] the same are also plotted in fig . 5 to get a better view of the results . our predictions are confined only for those isotopes for which measured values were quoted by pritychenko et al . one can easily see that in all the cases except for @xmath40 and @xmath41 , the agreement between the predictions with those of the experiment are remarkably good . for these two nuclei , the discrepancies may be attributed to the possible sub - shell effect as the neutron numbers are 38 and 40 respectively . for sake of comparison we have also presented in fig . 5 results obtained from two shell - model calculations @xcite marked here as sm1 and sm2 by employing two different effective interactions gxpf1a @xcite and jun45 @xcite . one should note here , that the first one because of its own limitations did not succeed in getting reliable values for nuclei having neutron number beyond n=36 . hence the second shell - model with jun45 effective interaction was performed by pritychenko et al . @xcite for the nuclei @xmath42 and @xmath43 . one can easily see that the shell - model values sm1 almost agree with those of ours for almost all the isotopes . even for @xmath44 where there is a little bit of discrepancy in between ours and the experiment , sm1 value is closer to ours . sm2 values more or less agree with those of experiment . we have just demonstrated as shown above the utility of the recursion relations for predicting @xmath0 values for some of the even - even isotopes of cr , fe , ni and zn in agreement with the latest experimental @xcite data . therefore it is desirable to find out whether the model is good enough for such predictions in the higher mass regions of the nuclear chart . however in these regions there is no new data to compare with and hence we can only compare with the data set of raman et al . @xcite . with this view , we repeated our calculations for higher isotope series following the same methodology outlined above . since the main aim of our present investigation is just to establish the goodness of our model , we present here results of only few such series for which experimental data exist for a relatively large number of isotopes . accordingly we have chosen four isotope series z=40 , 48 , 66 and 78 covering nuclei both in mid - mass and heavy - mass regions . our choice of the first two series namely z=40 and 48 is again to see to what extent our model works across the semi - magic number 40 and magic number 50 . our predictions along with those of experimental data of raman et al . @xcite are presented in fig . 6 . from the presented results , it is fair enough to say that the agreement of the model values with experiment in most of the cases is good . it is remarkable that even sharply changing deformations at neutron numbers n=46 and 56 for zr [ fig . ( a ) ] are well reproduced . however we find few exceptions such as @xmath45 and @xmath46 , for which some discrepancies exist . since we use the recursion relations for our predictions , such random cases may be attributed to the possible experimental inaccuracy of @xmath0 values in their neighborhood . for instance , the experimental inaccuracy in case of @xmath47 is almost 66% of the quoted value [ fig . 6 ( b ) ] , which is rather much larger than the discrepancy of our model value . use of such input data in the recursion relations are possibly affecting predicted values in few cases . we have also shown in fig . 6 results of the two well - known theoretical models namely finite range droplet model ( frdm ) @xcite and single - shell asymptotic nilsson model ( ssanm ) @xcite just for sake of comparison . one can see that in most of the cases for these two models , the discrepancies from experiment are rather high . now taking stock of all the results discussed so far , we can fairly say that the recursion relations work reasonably well almost throughout the nuclear chart . even across the magic numbers and sharply changing deformations , these relations have succeeded in reproducing the experimental data to a large extent with a little bit of deviation here and there . elsewhere there exists few exceptions but the discrepancies are not that large as to make the relations untrue . in a nutshell , the recursion relations for the reduced transition probability @xmath0 derived here can be termed sound enough as to have passed the numerical test both in reproducing and predicting the experimental values , and thereby vouches for the goodness of the differential equation ( [ be2 ] ) from which they originate . in conclusion we note , that we have succeeded in deriving for the first time , a novel relation for the reduced transition probability @xmath0 of a given nucleus in terms of its derivatives with respect to neutron and proton numbers . we could obtain such a differential equation on the basis of one - to - one correspondence with the local energy , that satisfies a similar relation formulated in the inm model of atomic nuclei . we have also succeeded in establishing its theoretical foundation using the empirical fact , that @xmath0s are more or less slowly varying functions of neutron and proton numbers except across the magic numbers . we further exploited the usual definitions of the two derivatives with respect to neutron and proton numbers occurring in the equation , to derive two recursion relations in @xmath0 . both these relations are found to connect three neighboring even - even nuclei from lower to higher mass and vice - verse . their numerical validity was then established using known experimental data set compiled by raman et al . @xcite in the mass range of a=10 to 240 . apart from this their utility was further established by comparing our predictions with the latest experimental data set of pritychenko et al . @xcite for the isotopes of cr , fe , si and ni . the results so obtained convincingly show the goodness of the recursion relations and thereby their parent differential equation . 99 g. t. garvey and i. kelson , phys . * 16 * ( 1966 ) 197 c. k. ross and r. k. bhaduri , nucl . phys . * a 196 * ( 1972)369 r. patnaik , r. patra and l. satpathy , phys . rev.*c12 * ( 1975 ) 2038 l. satpathy , j.phys.*g13*(1987 ) 761 l. satpathy and r. c. nayak , at . data and nucl . data tables * 39 * ( 1988 ) 213 r. c. nayak and l. satpathy , atom . data and nucl . data tables * 73 * ( 1999)213 r. c. nayak and l. satpathy , atom . data and nucl . data tables * 98 * ( 2012)616 r. c. nayak , phys . rev.*c 60 * ( 1999 ) 064305 n.h . hugen holtz and w. van hove , physica * 24 * , 363 ( 1958 ) l.satpathy and r. c. nayak , phys . * 51 * ( 1983)1243 r. c. nayak and l. satpathy , phys . rev.*c23 * ( 1981 ) 2368 - 2370 l. satpathy , v. s. uma maheswari and r.c . nayak , phys . * 319 * ( 1999 ) 85 l.satpathy and r. c. nayak , infinite nuclear matter model of atomic nuclei , lap lambert academic publishing , germany , 2013 . s. raman , c. w. nestor , jr , p. tikkanen , atom . data and nucl . data tables 78(2001)1 - 128 s. raman , c. w. nestor , k. h. bhatt , phys . rev . * c 37*(1988 ) 805 b. pritychenko , j. choquette , m. horoi , b. karamy and b. singh , atom . data and nucl . data tables 98(2012)798 - 811 h. monna , t. otsuka , b. a. brown , t. mizusaki , eur . j. , a25 ( suppl . 1 ) ( 2005)499 . h. monna , t. otsuka , t. mijusaki , m. hojorth - jensen , phys . rev . * c 80 * ( 2009)064323 . p. moeller , and j. r. nix , w. d. myers and w. j. swiatecki , atom . data and nucl . data tables * 59 * ( 1995)185 . s. raman , j. a. sheikh and k. h. bhatt , phys . rev.*c 52 * ( 1995 ) 1380

we obtain here a new relation for the reduced electric quadrupole transition probability @xmath0 of a given nucleus in terms of its derivatives with respect to neutron and proton numbers based on a similar local energy relation in the infinite nuclear matter ( inm ) model of atomic nuclei , which is essentially built on the foundation of the hugenholtz - van hove theorem of many - body theory . obviously such a relation in the form of a differential equation is expected to be more powerful than the usual algebraic difference equations . although the relation for @xmath0 has been perceived simply on the basis of a corresponding differential equation for the local energy in the inm model , its theoretical foundation otherwise has been clearly demonstrated . we further exploit the differential equation in using the very definitions of the derivatives to obtain two different recursion relations for @xmath0 , connecting in each case three neighboring even - even nuclei from lower to higher mass numbers and vice - verse . we demonstrate their numerical validity using available data throughout the nuclear chart and also explore their possible utility in predicting @xmath0 values . @xmath1 this is a slightly modified version of the article just published in int . jou . of mod . phys . * e23*(2014)1450022 .

eruptive nevus , which is associated with local cutaneous inflammation or immunosuppression , is defined as the development of eruptive pigmented lesions due to melanocytic growth factors secreted by the impaired immune pathway in genetically predisposed individuals.[13 ] the literature contains case reports of eruptive nevus that accompany malignancies , toxic epidermal necrolysis and severe bullous diseases like erythema multiforme , which are associated with pregnancy and that develop after transplantation , in immune failure conditions and in association with chemotherapy.[49 ] we present a case of postchemotherapy - eruptive compound nevus . an 8-year - old male patient presented at our polyclinic due to brown spots that formed on his body . anamnesis of the patient showed that he had been diagnosed with acute lymphoblastic leukemia 4 years ago , received 120 cures of chemotherapy and developed brown spots that started on the trunk and spread throughout his body 3 months after chemotherapy . his dermatological examination revealed a total of 142 monomorphic brown macules , of which the largest was 1 cm 1 cm and the smallest was 0.1 cm 0.1 cm in size , and 13 were on the face , 48 on the trunk , 34 on the upper extremities , 21 on the lower extremities , 19 in the palmar area , five on the plantar area and two on the oral mucosa [ figures 1 and 2 ] . after obtaining the patient 's written consent , the macules were photographed and biopsy samples were taken . monomorphic , brown macules , the largest of which is 1 cm 1 cm and the smallest is 0.1 cm 0.1 cm in size on the trunk numerous brown macules in the bilateral palmar area when the biopsy material taken from the lesion on the right femoral area of the patient was histopathologically examined , nest structures composed of nevus cells with oval nuclei and eosinophilic cytoplasm starting from the dermoepidermal junction and extending toward the lower dermis were observed and the material was positively stained with melan - a [ figure 3 ] . the patient , who was diagnosed with post - ct eruptive compound nevus on the basis of detailed anamnesis , clinical evaluation and histopathologic examination , was scheduled for a 6-month regular dermatologic follow - up . nest structures composed of nevus cells with oval nuclei and eosinophilic cytoplasm starting from the dermoepidermal junction and extending toward the lower dermis ( hematoxylin and eosin , 40 ) although the pathophysiology of eruptive benign nevi has not been clearly understood yet , there are three hypotheses on this topic . the first is that the immune process disrupted in the skin could contribute to the development of lesions in immune - compromised patients . the second hypothesis asserts that subclinical lesions might culminate in the nevi due to triggering factors such as chemotherapy and medical immunosuppression . lastly , it has been claimed that the concerned lesions might be associated with drugs.[36 ] the most widely accepted theory in this respect is that the intact immunological profile inhibits the proliferation of melanocytic lesions , but that immunosuppression and even a modification of t cells induces melanocyte - stimulating hormone ( msh ) , which is an endogenous growth factor for normal melanocytes , or melanoma growth stimulatory activity ( mgsa ) . impaired regulation of the mgsa gene results in elevated expression of the mgsa protein , which leads to melanocyte growth and development . that some areas like the palmoplantar area are more susceptible to melanocytic growth factor explains why lesions concentrate in these areas . the literature includes cases of eruptive nevus that resulted from the hyperplasia of melanocytes in the areas affected by severe bullous diseases like toxic epidermal necrolysis and erythema multiforme , which appeared as eruptive spitz nevus during pregnancy , occurring in cancer patients receiving chemotherapy and in aids patients as well as cases that developed following renal transplantation.[711 ] it was noted in the concerned reports that there was a strong correlation between the duration of immunosuppression and the number of nevi that developed , and it was stressed that the impaired immune pathway played a role in this process . although eruptive pigmented lesions are diffusely observed on the body , palmoplantar areas are more commonly involved . reported two cases of post - sorafenib use eruptive melanocytic nevi ; of these two , one had palmoplantar localization while the other was in a diffuse form . it was emphasized in the concerned report that sorafenib caused these lesions by inhibiting human dendritic cell functions and , may be , immunomodulation too , but that it was not clear whether the development of melanocytic lesions was caused by sorafenib use or the underlying immunosuppression . in another case report that described a case who developed eruptive compound nevus as the preliminary sign of chronic myeloid leukemia , the development of eruptive compound nevus in the patient who had not yet received chemotherapy was attributed to the immunosuppression caused by leukemia . a case who developed postchemotherapy multiple eruptive dysplastic nevus and melanoma in situ was reported in the literature , and it was emphasized that this condition could pose a risk for melanoma development . in our case , our case had nevi in both the palmoplantar area and in the diffuse form ; besides , as opposed to the cases reported in the literature , he had oral mucosal involvement . in conclusion , it is recommended that patients should be regularly followed - up for the risk of developing eruptive melanocytic nevus , dysplastic nevus and melanoma in all immunosuppression situations .

an 8-year - old male patient who had been diagnosed as acute lymphoblastic leukemia ( all ) 4 years ago and received 120 cures of chemotherapy presented at our clinic complaining of spots on his body 3 months after the end of chemotherapy . anamnesis of the patient revealed that the lesions started 3 months after the last cure of chemotherapy on the abdomen and spread throughout the body . it was learnt that the number of spots increased very rapidly in a period of 2 months , and exceeded 100 . a dermatological examination of the patient showed 142 hyperpigmented macules , the largest of which was 1 cm 1 cm and the smallest was 0.2 cm 0.2 cm in size , diffusely scattered to the skin and oral mucosa . when the biopsy material taken from the lesions was histopathologically examined , nest structures composed of nevus cells with oval nuclei and eosinophilic cytoplasm starting from the dermoepidermal junction and extending toward the lower epidermis were observed and found to be consistent with the compound nevus . we present this rare case who was diagnosed as eruptive compound nevus on the basis of clinical signs , all diagnosis , chemotherapy history and histopathologic evaluation .

single electron control in semiconductor quantum dots would be valuable for spintronics , quantum information , and spin qubits@xcite . adiabatic time evolution of degenerate eigenstates of a quantum system provides a means for controlling individual electrons since mixing between degenerate levels generates a matrix berry phase@xcite . it has been shown that universal quantum computation is possible by means of non - abelian unitary operations@xcite . recently several proposals on how to generate matrix berry phases have been made in semiconductor systems@xcite . in one of these proposals it has been suggested that a _ single electron _ in a n - type semiconductor quantum dot with spin - orbit terms can have matrix berry phases@xcite . all the discrete energy levels of quantum dots possess a double degeneracy because the rashba and/or dresselhaus spin orbit coupling terms have time reversal symmetry@xcite . in ref.@xcite it was suggested that the adiabatic transformation can be performed _ electrically _ by changing the confinement potentials of the quantum dot . it was shown that matrix berry phases can be produced only when the parity symmetry of two - dimensional harmonic potentials is broken . a degenerate pair of states also exists in quantum rings@xcite . the relevant symmetry of this system is the combined operation of time reversal and large gauge transformations . however , it is often not easy to populate a quantum dot or ring with just one electron and usually there are several electrons in it@xcite . it is not certain that many body groundstates are doubly degenerate in the presence of time reversal symmetry . moreover , it is unclear how the effects of exchange and correlation many body physics change the non - abelian vector potentials . these issues are investigated in the present paper . before we give a summary of the main points of the present paper let us give a brief introduction of the basic ideas behind matrix berry phases . consider a degenerate pair of states @xmath0 and @xmath1 , which may be _ single particle or many body states_. if the system is in a superposition state @xmath2 at time t=0 an adiabatic evolution of the parameters @xmath3 can transform this state into another state @xmath4 after some time @xmath5 . here the orthonormal basis states @xmath6 are the instantaneous eigenstates of the hamiltonian . for a cyclic change with the period @xmath7 , represented by a closed contour @xmath8 in the parameter space , the states @xmath9 and @xmath10 return to the initial states @xmath11 and @xmath12 , but the coefficients @xmath13 and @xmath14 may not return the initial values . in such a case a @xmath15 matrix berry phase ( non - abelian berry phase ) @xmath16 is generated @xmath17 the expansion coefficients @xmath18 and @xmath19 satisfy the time - dependent schr@xmath20dinger equation @xmath21 the matrix elements @xmath22 are given by @xmath23 , where the sum over @xmath24 in @xmath22 is meant to be the sum over @xmath3 . the non - abelian vector potentials @xmath25 are @xmath15 matrices @xmath26 note that the wavefunctions @xmath27 and @xmath28 are _ degenerate_. the role of the non - abelian vector potentials is to keep the energy degeneracy intact while the system parameters change . our investigation shows that when even number of electrons are present the many body groundstate may not be doubly degenerate . however , when odd number of electrons are present the groundstate may be doubly degenerate . in the simplest possible approximation the antisymmetry of many body wavefunctions can be ignored . then the degenerate groundstates for three electrons are given by @xmath29 and @xmath30 , where @xmath31 are single electron wavefunctions , see fig.[fig : single ] . in this case one can show that the solutions of the time dependent schroedinger equation , eq.([eq : time_schrod ] ) , have the form @xmath32 the function @xmath33 depends on the single electron non - abelian vector potentials of the _ first _ shell , and the functions @xmath34 and @xmath35 depend on the single electron non - abelian vector potentials of the _ second _ shell , see fig.[fig : single ] ( the function @xmath33 is periodic with the period @xmath7 ) . the probability to find an electron in the state @xmath36 is @xmath37 . so these probabilities are _ independent _ of the phase factor @xmath38 , i.e. , of the non - abelian vector potentials of the first shell . in the next simplest possible approximation the antisymmetry of many body wavefunctions can be included . in this case the doubly degenerate many body groundstates may be taken to be two slater determinant wavefunctions , @xmath39 and @xmath40 , that are time reversed states of each other , see fig.[fig : many ] . it will be shown below that the antisymmetry of these slater determinant wavefunctions does _ not _ change the results obtained above for the matrix berry phase . in addition to the antisymmetry one can include correlation effects . this can be done by including four basis vectors @xmath39 , @xmath40 , @xmath41 and @xmath42 , see fig.[fig : many ] . in this case the groundstates are given by linear combinations of these four states and are thus correlated . it can be shown that the non - abelian gauge potentials for a correlated electron system are related to non - abelian gauge potentials for single electrons , provided that the definition of single electron non - abelian gauge potentials is extended to @xmath43 when @xmath44 and @xmath45 belong to _ different _ single electron energy shells . we will call these _ inter shell non - abelian gauge potentials_. in sec . ii we describe the hamiltonian of the system in detail , and in sec . iii we discuss why matrix berry phases can be produced only when the parity symmetry of two - dimensional harmonic potentials is broken . a computational scheme to include systematically many electron physics is explained in sec.iv . the absence of a matrix berry phase for the two - electron case is shown in sec . v. in sec.vi we show that a matrix berry phase is present in the three - electron case . correlation effects are discussed in vii and conclusions are given in sec . an electric field @xmath46 is along the z - axis and electrons are confined in a triangular potential @xmath47 . when the the width of the quantum well along the z - axis is sufficiently _ small _ we may include only the lowest subband state along the z - axis . we denote this wavefunction by @xmath48 . from the expectation value @xmath49 we estimate the characteristic length scale along the z - axis : @xmath50 . the hamiltonian in the absence of the spin orbit coupling is @xmath51 we take the two - dimensional potential to be @xmath52 . the strengths of the harmonic potentials are denoted by @xmath53 and @xmath54 . they may be varied by _ changing gate potentials _ of the quantum dot system . the characteristic lengths scales along x- and y - axis are @xmath55 . the potential @xmath56 is chosen in such a way that the parity symmetry of electron wavefunctions is broken . we can choose it to be @xmath57 . it represents an electric field along the y - axis and its strength @xmath58 may be _ varied electrically_. in a periodic crystal potential of a semiconductor the spin orbit interaction has two contributions . the rashba spin orbit term@xcite is @xmath59 here @xmath60 are pauli spin matrices and @xmath61 are momentum operators ( @xmath62 and similarly with @xmath63 . ) . the constant @xmath64 _ depends on the external electric field _ @xmath46 applied along the z - axis . the dresselhaus spin orbit term@xcite is @xmath65 there is another term of the form @xmath66 in the dresselhaus spin orbit term but it vanishes since the expectation value @xmath67 for the first subband along z - axis . the constant @xmath68 represents breaking of inversion symmetry by the crystal in zinc blende structures . the total single electron hamiltonian of semiconductor quantum dot is @xmath69 . when several electrons are present in the dot the total hamiltonian consists of single particle hamiltonians and two - particle interaction terms @xmath70 , where @xmath71 and @xmath72 with @xmath73 . ( @xmath74 is the single particle hamiltonian for the ith electron and @xmath75 is the background dielectric constant ) . the total many electron hamiltonian is invariant under time reversal symmetry . the eigenenergies of the single electron hamiltonian is depicted in fig.[fig : single ] . each energy is doubly degenerate . an eigenstate of the hamiltonian @xmath76 may be expanded as a linear combination of the eigenstates of @xmath77 . a lowest energy state can be written as @xmath78 in the basis states @xmath79 the quantum number @xmath80 and @xmath81 label the harmonic oscillator levels along the x - axis ( y - axis ) and the component of electron spin . the subband wavefunction @xmath48 is suppressed in the notation @xmath82 . the wavefunction @xmath83 can also be written as a column vector @xmath84 , where @xmath85 and @xmath86 . the expansion coefficients satisfy a matrix equation @xmath87 the single electron wavefunctions used in this section are self - consistent hartree - fock single electron states if @xmath76 is replaced by the hf single electron hamiltonian . in the absence of the zeeman term the single particle hamiltonian is invariant under time reversal symmetry : @xmath88 and @xmath89 . the time reversal operator is @xmath90 , where the operator @xmath8 stands for complex conjugation . the time reversed state of @xmath91 is @xmath92 this can also be written as a column vector @xmath93 . note that @xmath94 . these two states are degenerate and orthonormal . we have suppressed the bloch wavefunction of the conduction band in applying the time reversal operator since it is unaffected by the operator @xmath7 . our wavefunctions are all effective mass wavefunctions and only the conduction band bloch wavefunction at @xmath95 is relevant . even in the presence of doubly degenerate states a matrix berry phase may not always exist . it was shown numerically that only distorted two - dimensional harmonic potentials breaking the parity symmetry generate matrix berry phases@xcite . here reasons for this effect for the single electron case is given in detail . in this argument only one electron is assumed to be present in the dot , @xmath96 , and @xmath97 . the adiabatic parameters are @xmath98 and @xmath99 . let us consider @xmath100 as a perturbation and apply a perturbation theory to @xmath101 @xmath102 where @xmath103 . the wavefunction of @xmath104 has even parity . the matrix element @xmath105 couples @xmath104 only to odd parity states @xmath106 . therefore the wavefunction corresponding to the second term in eq.([eq : symm ] ) has odd parity with spin down . the wavefunction of the third term in eq.([eq : symm ] ) has even parity with spin up . this perturbation series indicates that the exact lowest energy state has the form @xmath107 , where @xmath108 and @xmath109 even and odd functions . the time reversed wavefunction is @xmath110 . for this particular pair of degenerate states the off - diagonal elements of non - abelian vector potentials are zero : @xmath111 here @xmath112 with @xmath113 such that the two - dimensional harmonic wavefunctions @xmath114 are even functions . the function @xmath115 with @xmath116 are such that @xmath117 are odd functions ( note that one can show @xmath118 ) . since the off - diagonal non - abelian vector potentials are zero the matrix berry phase is absent . in what follows a distorted two - dimensional harmonic potential is assumed . the adiabatic parameters are @xmath64 and @xmath58 . a computational scheme that includes systematically many electron physics is explained here . we find an efficient computational scheme of computing eigenstates and eigenvalues of the many electron hamiltonian of a semiconductor quantum dots with an arbitrary shape of the confinement potential . we follow the following steps . single electron hamiltonian is first solved in the presence of spin - orbit terms . this can be done by following the steps given in sec.iii . the number of single electron basis states @xmath119 can be truncated to a reasonable number by comparing the relative magnitude of the single particle energy spacing and the strength of the coulomb interaction . using _ these _ single electron eigenstates slater determinant states @xmath27 and their time reserved states @xmath120 are formed . @xmath120 is obtained from @xmath27 by replacing the single electron wavefunctions with their time reversed states : @xmath121 . it will be inefficient to use two dimensional harmonic potential wavefunction @xmath122 to build these slater determinant states . the following relation hold for two arbitrary states @xmath123 and @xmath124 : @xmath125 . from this relation it follows that the hamiltonian matrix elements have the following properties : @xmath126 , @xmath127 , and @xmath128 . when there are odd number of electrons the basis vectors of many electron hamiltonian are chosen to include time reversed pairs : @xmath129 , see fig . [ fig : many ] . the eigenstates are doubly degenerate in the odd electron case . let us show this for the three electron case using the following slater determinant wavefunctions as the basis vectors in the many body hilbert space @xmath130 . these states are depicted in fig.[fig : many ] . the wavefunctions of the lowest energy degenerate pair are @xmath131 and @xmath132 . clearly @xmath133 . note @xmath134 and @xmath135 are a time reversed pair , orthogonal , and satisfies @xmath136 . the two eigenvalues of @xmath137 are each doubly degenerate . when there are even number of electrons the basis vectors of the many electron hamiltonian are chosen as @xmath138 . in this scheme the groundstate is non degenerate . this can be shown shown , for example , in an approximation that includes five many body basis vectors in the presence of two electrons , see fig . [ fig : many2 ] . the groundstate can then be written as a linear combination @xmath139 . its time reversed state is @xmath140 . clearly these two states are _ not _ orthogonal . since @xmath141 and @xmath142 one finds that the energy expectation values are non degenerate , @xmath143 , i.e. , time reversed states are non degenerate . the matrix berry phase is thus absent . in the simplest possible approximation the groundstate @xmath144 of two electron system is given by the single slater determinant made of the single particles states @xmath145 . in this case the initial state should return to itself after the adiabatic cycle . it is instructive to verify this explicitly by transforming each single particles states . the initial state is @xmath146 the transformed two electron slater determinant is @xmath147 , which is @xmath148 . since the transformed single electron states are time reversed states of each other @xmath149 . so the factor in the transformed wavefunction is @xmath150 . now consider odd number of electrons , for example , three electrons in a dot . in the simplest possible approximation with fermionic antisymmetry two many body basis states , @xmath39 and @xmath40 , can be included . these are slater determinant states and are depicted in fig.[fig : many ] . this approximation is well justified when the typical single electron energy spacing is larger than the characteristic coulomb energy . clearly @xmath39 and @xmath40 are orthogonal @xmath151 . the hamiltonian matrix is @xmath152 the off - diagonal matrix elements of the hamiltonian matrix is zero since @xmath153 , which follows from @xmath125 . it is instructive to show this explicitly by evaluating the matrix element @xmath154+[\langle 13 |v|14 \rangle-\langle 13 |v|4 1 \rangle].\nonumber\\\end{aligned}\ ] ] here the first and third terms are direct coulomb matrix elements while the second and fourth terms are their exchange counter parts . the direct coulomb matrix elements are zero since @xmath155 . so only their exchange counter parts remain , which are given by @xmath156 and @xmath157 one can show @xmath158 this is because @xmath159 which follows from @xmath160 , @xmath161 , and @xmath162 note that the second and third terms are equal except for the minus sign . the off - diagonal elements are thus zero , and @xmath163 this implies that @xmath39 and @xmath40 are eigenstates and are degenerate in energy . during the adiabatic change the wavefunction of three electrons evolves as @xmath164 . the coefficients @xmath18 and @xmath19 satisfy the schroedinger equation eq.([eq : time_schrod ] ) governed by the non - abelian vector potentials @xmath165 it can be shown using eqs.([eq : diag ] ) and ( [ eq : matrixover ] ) that these can be written in terms of the non abelian vector potentials for single particle states @xmath166 where the non - abelian vector potentials involving the lowest energy single electron states are @xmath167 and involving the second lowest single electron states are @xmath168 the solution of the time dependent schroedinger equation has the form @xmath169 . the function @xmath170 depends on the electrons in the _ first _ shell . it satisfies @xmath171 , where @xmath172 . the solution of this differential equation is a phase factor @xmath173 note that @xmath174 appears in the diagonal elements of the non abelian vector potentials @xmath175 and @xmath176 . the functions @xmath34 and @xmath35 are the solutions of the time dependent schroedinger equation @xmath177 with the following non - abelian gauge potentials . @xmath178 this is precisely the non abelian vector potentials for the _ second _ energy shell . the probability to find an electron in the state @xmath36 is @xmath37 . so these probabilities are _ independent _ of the non - abelian vector potentials of the first energy shell . in addition it should be noted that the antisymmetry of the many electron wavefunction does _ not _ change the value of the matrix berry phase obtained from the wavefunctions without the antisymmetry , see eq.([eq : berry ] ) . this is the main conclusion of this section . correlation effects can be taken into account by writing many body eigenstates as a linear combination of single slater determinant wavefunctions @xmath179 . these wavefunctions arranged in the increasing order of the total kinetic energy @xmath180 . note that @xmath181 for all i and j. if the groundstate is doubly degenerate one of the degenerate groundstates can be written as @xmath182 then its time reversed state has the form latexmath:[\[\begin{aligned } since @xmath7 is an antiunitary operator . note that @xmath184 are ordered as follows @xmath185 . the states @xmath186 and @xmath187 are eigenstates of the truncated hamiltonian with the dimension @xmath188 . ( note that as @xmath189 the energy @xmath46 will approach the exact eigenvalue . ) . some of the slater determinant states @xmath190 are depicted in fig.[fig : many ] . clearly @xmath186 and @xmath187 are orthogonal . the matrix element between them is zero : @xmath191=0 . these two states are degenerate since @xmath192 . the non - abelian vector potentials are @xmath193 in terms of many body basis states they can be written as @xmath194 in the three electron case with the basis vectors given in fig.[fig : many ] the diagonal matrix elements @xmath195 and @xmath196 are given by @xmath197 similarly one can find off - diagonal matrix elements @xmath198 these results follow from eq.([eq : matrixover ] ) . usually the non abelian vector potentials are defined between two degenerate states , see eq.([eq : vector_pot ] ) . when electron correlations are important the matrix elements between two single electron states belonging to _ different _ energy shells are relevant ( see the last four equations in eq.([eq : result ] ) ) . we will call these inter shell non - abelian vector potentials . physically the mixing between the second and third shells is facilitated by them . note that @xmath199 . we have developed a scheme of computing eigenstates and eigenvalues of the many electron hamiltonian of a semiconductor quantum dot with an arbitrary shape of the confinement potential . the basis vectors of this many electron hamiltonian are chosen to include time reversed pairs of slater determinant states . in this scheme the groundstate is non degenerate when an even number of electrons are present while the eigenstates are doubly degenerate when an odd number of electrons are present . using this computational scheme we have investigated matrix berry phases when several electrons are present in a semiconductor quantum dot with spin - orbit coupling terms . when an odd number of electrons is present a matrix berry phase exists . the effect of the antisymmetry of many electron wavefunctions does not affect the value of the matrix berry phase . electron correlation effects can be treated by including the inter shell coupling . in this case the many body non - abelian vector potentials can be written as a sum of those of the single electron non - abelian vector potentials , provided that the inter shell non - abelian vector potentials , @xmath200 with @xmath45 and @xmath201 non degenerate , are introduced to represent the shell coupling . it would be interesting to investigate the role of these inter shell non - abelian vector potentials in parabolic dots . optical dipole transitions@xcite can be used to detect matrix berry phases even when several electrons interact strongly with each other . this is because the dipole oscillator strength will depend on the matrix berry phase@xcite . however , our results in sec . v indicate the matrix berry phases will be independent of many body physics when the energy level spacing between the shells is larger than the characteristic coulomb energy . in self assembled quantum dots with wetting layers this condition is satisfied@xcite . in this case only the intra shell non - abelian vector potentials , @xmath200 with @xmath45 and @xmath201 degenerate , are relevant , and the value of the matrix berry phase can be calculated as in ref.@xcite . we leave it as a future study to investigate numerical values of the matrix berry phases for strongly interacting electrons . in ii - vi semiconductors the rashba term is expected to be larger than the the dresselhaus coupling and in iii - v semiconductors the opposite is true@xcite . the typical value of the energy scale associated with the rashba constant depends on the electric field applied along the z - axis and the semiconductor material : it is of order @xmath202 , where the length scale @xmath203 is the lateral dimension of the quantum dot . the second adiabatic parameter @xmath204 represents the strength of the distortion potential @xmath205 : the expectation value of the distortion potential is @xmath206 . its magnitude is of order @xmath207 , depending on the electric field applied along the y - axis . in self - assembled inas quantum dots@xcite the level spacing can be larger than the characteristic coulomb energy , and our investigation shows that in such a case the many problem essentially reduces to a single particle problem ( the energy @xmath208 associated with the length scale @xmath209 is typically of order 20 - 40mev in self - assembled quantum dots ) . in this regime , as we explained above , the exchange effect disappears in matrix berry phases and it is only the last singly occupied electron that matters . the presence of the other electrons in the inert filled shells will just modify the confinement potential . thus the matrix berry phase can be calculated following the method outlined in ref[11 ] , and below we give some typical values of the matrix berry phases . we take an elliptic adiabatic path given by @xmath210 . for the parameters @xmath211 , @xmath212 , @xmath213 , and @xmath214 we find @xmath215 , respectively , for different values of the semiaxis of the ellipse @xmath216 ( the initial state is @xmath217 ) . note that the parameter for the semiaxis @xmath218 can be varied experimentally either by changing the rashba field @xmath219 or the size of the dot through @xmath208 . we have verified that two different values of the frequency @xmath220 give the same values of @xmath221 as long as the other parameters are unchanged , confirming that the matrix berry phase is a geometric phase@xcite . this should be tested in any experimental investigation of matrix berry phases . experimental data of single quantum dots would be less complicated than data of an ensemble of dots with various sizes of dots , and can thus be compared directly with our theoretical results . let @xmath222 consists of @xmath223 and let @xmath1 consists of @xmath224 : the diagonal elements of the non - abelian gauge potential between the slater determinant wavefunctions are @xmath227 let us find the off - diagonal non - abelian vector potential elements @xmath228 between the two slater determinant wavefunctions @xmath229 and @xmath230 . when @xmath231 is replaced with @xmath232 the state @xmath222 transforms into @xmath1 . we find @xmath233 . this result may be easily generalized to @xmath234 particle slater determinant wavefunctions . in general the non - abelian vector potential element between two _ different _ slater determinant wavefunctions , @xmath190 and @xmath235 , is non zero when @xmath190 can be transformed into @xmath235 by replacing one single electron wavefunction in @xmath190 with another wavefunction in @xmath235 . if these single electron wavefunctions are denoted by @xmath236 with @xmath237 then we find @xmath238 if more than two single electron wavefunctions in @xmath190 must be exchanged with those in @xmath235 to transform @xmath190 into @xmath235 then @xmath239 . this work was supported by grant no . r01 - 2005 - 000 - 10352 - 0 from the basic research program of the korea science and engineering foundation and by quantum functional semiconductor research center ( qsrc ) at dongguk university of the korea science and engineering foundation . in addition this work was supported by the second brain 21 project . d. d. awschalom , d. loss , and n. samarth , semiconductor spintronics and quantum computation ( springer , berlin , 2002 ) . e. i. rashba and al . l. efros , phys . lett . * 91 * , 126405 ( 2003 ) . , edited by a. shapere and f. wilczek ( world scientific , singapore , 1989 ) . f. wilczek and a zee , phys . rev . lett . * 52 * , 2111 ( 1984 ) . p. zanardi and m. rasetti , phys * 264 * , 94 ( 1999 ) . j. pachos , p. zanardi and m. rasetti , phys . a * 61 * , 010305(r ) ( 2000 ) ; j. pachos and p. zanardi , int . j. mod b * 15 * , 1257 ( 2001 ) . b. a. bernevig and s .- c . zhang , phys . b * 71 * , 035303 ( 2005 ) . serebrennikov , phys . b * 70 * , 064422 ( 2004 ) . p. solinas , p. zanardi , n. zanghi , and f. rossi , phys . rev.a * 67 * , 062315 ( 2003 ) . d. parodi , m.sassetti , p. solinas , p. zanardi , and n. zanghi , phys . rev.a * 73 * , 052304 ( 2006 ) . s .- eric yang and n.y . hwang , phys . b * 73 * , 125330 ( 2006 ) . m. valin - rodriquez , a. puente , and l. serra , phys . b * 69 * , 085306 ( 2004 ) . s .- eric yang , phys . b * 74 * , 075315 ( 2006 ) . l. p. kouvenhoven , c. m. marcus , p. l. mceuen , s. tarucha , r. m. westervelt , and n. s. wingreen , in nato asi conference proceedings , section 5.1 , edited by l. p. kouvenhoven , g. schn , and l. l. sohn ( kluwer , dordrecht , 1977 ) . s. d. lee , s. j. kim , y. b. cho , j. b. choi , sooa park , s .- r . eric yang , s. j. lee and t. h. zyung , appl . 89 , 023111 ( 2006 ) . rashba , physica e , * 34 * , 31 ( 2006 ) . g. dresselhaus , phys . rev . * 100 * , 580 ( 1955 ) . d. heitmann and j. p. kotthaus , phys . today * 56 * ( 6 ) , 56 ( 1993 ) ; the effect of many electron physics on dipole absorption spectra are investigated in parabolic dots in the presence of spin orbit terms in the following papers : p. lucignano , b. jouault , a. tagliacozzo , and b. l. altshuler , phys . b * 71 * , 121310(r ) ( 2005 ) ; p. pietilinen and t. chakraborty , phys . rev . b * 73 * , 155315 ( 2006 ) . to detect matrix berry phases it is desirable to investigate similar effects in non - parabolic dots with parity breaking terms . p. m. petroff , a. lorke , and a. imamoglu , phys . today * 54 * ( 5 ) , 46 ( 2001 ) .

adiabatic time evolution of degenerate eigenstates of a quantum system provides a means for controlling electronic states since mixing between degenerate levels generates a matrix berry phase . in the presence of spin - orbit coupling in n - type semiconductor quantum dots the electron hamiltonian is invariant under time reversal operation and the many body groundstate may be doubly degenerate . this double degeneracy can generate non - abelian vector potentials when odd number of electrons are present . we find that the antisymmetry of many electron wavefunction has no effect on the matrix berry phase . we have derived equations that allow one to investigate the effect of electron correlations by expressing the non - abelian vector potentials for many electron system in terms of single electron non - abelian vector potentials .

the existence of the black hole horizon is essential to the hawking radiation @xcite . the horizon causes an extremely large redshift on an outgoing wave of a matter field during propagating from a vicinity of the horizon to the asymptotically flat region . this redshift results in the planckian distribution of quantum mechanically created particles at the future null infinity . although the hawking radiation has not yet been confirmed observationally , it has been pointed out that the similar phenomenon appears on phonons in a transonic flow of a fluid . this theoretical phenomenon in the fluid is called the sonic analogue of hawking radiation , and the transonic fluid flow on which the sonic analogue of hawking radiation occurs is called the acoustic black hole @xcite . in the transonic flow , the boundary between a subsonic and a supersonic region is the sonic point . the sonic point corresponds to the black hole horizon and called the sonic horizon . the region apart form the sonic point in the subsonic region corresponds to the asymptotically flat region in a black hole spacetime . the sound wave which propagates from a vicinity of the sonic point to the subsonic region receives the extremely large redshift and the sonic analogue of hawking radiation appears on phonons . the hawking temperature @xmath0 of the acoustic black hole is given by the gradient of the fluid velocity at the sonic point @xmath1 @xcite : @xmath2 where @xmath3 and @xmath4 are the sound velocity and the fluid velocity , respectively . for an ordinary system with typical size @xmath5 m and @xmath6 m / s , we obtain @xmath7 k. thus , in a practical experiment in a laboratory , it is very difficult to detect the sonic analogue of hawking radiation with such an extremely low temperature . while it is very hard to detect the sonic analogue of hawking radiation on phonons , which is a quantum origin , a classical sound wave with a sufficiently large amplitude can be available for detecting the effect of the acoustic black hole on a propagation of sound waves in practical experiments . indeed , the thermal nature of hawking radiation is not a quantum origin ; it comes from a large redshift on the wave propagating from a vicinity of the horizon to the asymptotically flat region , and has nothing to do with the quantum effect ( see appendix ) . therefore , if we can construct a classical quantity from sound waves which shows the thermal distribution , then such a quantity can be interpreted as a classical counterpart to hawking radiation . a candidate for the classical counterpart has already been introduced in the references @xcite by using a fourier component of an outgoing wave from a vicinity of the horizon . by the way , since a realistic fluid is composed of molecules , the effect of the molecule size discrepancy of the fluid becomes one of the important issues of the acoustic black hole . this effect appears in the modified dispersion relation at high energies of phonons . however , in the expansion by the molecule size discrepancy , the zeroth order form of the quantum expectation value of the number operator @xmath8 of phonons results in the thermal spectrum at least not so high energy region . that is , the effect of the molecule size discrepancy is not dominant in the sonic analogue of hawking radiation . therefore , before proceeding to the issue of the molecule size discrepancy , it is necessary to detect the ordinary hawking radiation ( thermal spectrum ) by a real experiment in laboratory , and the molecule size discrepancy is not in the scope of this paper . hence we concentrate on the construction of the practical procedure to extract the evidence of the hawking radiation ( thermal spectrum ) from the experimental data . to do so , we make use of the classical counterpart to hawking radiation . we should emphasize here that the hawking temperature ( [ eq : h - temp ] ) includes the planck constant @xmath9 and we can not consider the temperature @xmath0 in discussing the `` classical '' counterpart to hawking radiation . however we can consider the surface gravity @xmath10 of the black hole horizon which is a purely classical quantity and relates to the hawking temperature as @xmath11 . hence , for the acoustic black hole , we consider the surface gravity @xmath12 of the sonic horizon instead of the hawking temperature , @xmath13 in this paper , we aim to construct a practical procedure of the data analysis to obtain the classical counterpart to hawking radiation in a realistic setting of the acoustic black hole . to do so , we perform a numerical simulation of a fluid flow in a practical experimental setting , and demonstrate that our procedure works well to detect the classical counterpart to hawking radiation . we organize the paper as follows . in the section [ sec : counterpart ] , we review the acoustic black hole in a laval nozzle and define the classical counterpart to hawking radiation . the section [ sec : numerical ] is devoted to the introduction of our numerical method to simulate a transonic flow , and to the construction of the practical procedure of the data analysis . in the section [ sec : result ] , our numerical results are presented and we determine the surface gravity of the sonic horizon . finally the summary and conclusion are in the section [ sec : summary ] . we consider an acoustic black hole with a fluid in a laval nozzle as proposed in @xcite . the laval nozzle , as shown in the right panel in fig . [ fig : nozzle ] , has a throat where the cross section of the nozzle becomes minimum . the fluid is accelerated from the up stream to the down stream and the flow has the sonic point at the throat when a sufficiently large velocity is given at the inlet of the nozzle . even if we prepare an initial flow which has no sonic point ( e.g. the lower part of the right panel in fig . [ fig : nozzle ] ) , the flow can settle down to a stationary transonic flow ( e.g. the upper part of the right panel in fig . [ fig : nozzle ] ) with appropriate boundary conditions at the inlet and the outlet of the nozzle . this is the sonic analogue model which corresponds to the gravitational collapse . here we note that , if a stationary transonic flow is prepared from the beginning ( which corresponds to the eternal black hole ) , we can not expect to obtain the classical counterpart to the hawking radiation ; for the eternal case , the tunneling of phonons across the sonic point can result in the hawking radiation and this is the purely quantum effect . hence , when we are interested in the `` classical '' counterpart to hawking radiation , it is necessary to consider the situation of the sonic point formation in course of the dynamical evolution of the fluid flow . as seen below , the sound wave which is prepared on the fluid flow before the formation of the sonic point becomes the classical counterpart to the quantum fluctuation which causes the classical counterpart to hawking radiation . we consider a perfect fluid and treat the flow in a laval nozzle as one dimensional for simplicity . the basic equations are the mass conservation equation and the euler equation : [ eq : fluid ] @xmath14 where @xmath15 is the mass density , @xmath16 is the fluid velocity , @xmath17 is the pressure of the fluid and @xmath18 is the cross section of the laval nozzle . we assume the adiabatic ideal gas type equation of state @xmath19 where @xmath20 is the adiabatic index . the sound velocity @xmath3 is given by @xmath21 for a stationary background flow , we can obtain the sound velocity @xmath3 and the cross section @xmath22 of the nozzle as a function of the mach number @xmath23 of the flow : @xmath24 where quantities with subscript `` in '' represent the values at the inlet of the nozzle . the spatial derivative of the mach number at the sonic point @xmath25 is @xmath26 and this value relates to the surface gravity of the sonic horizon by eq . . figure [ fig : mach ] shows the structure of the stationary flow for @xmath27 and @xmath28 . here we set that the inlet is at @xmath29 , the throat at @xmath30 and the outlet at @xmath31 . that is , the fluid flows downward from @xmath29 to @xmath31 , then @xmath32 and fig . [ fig : mach ] shows the absolute value of @xmath33 . the boundary condition is given by the mach number @xmath34 at the inlet of the nozzle , and each line in fig . [ fig : mach ] corresponds to a different value of @xmath34 . the blue line which passes the sonic point @xmath35 is given by @xmath36 and represents the stationary transonic flow . for the case @xmath37 , we find @xmath38 and the surface gravity given by eq . is @xmath39 here it should be emphasized that , because the cross section of the nozzle is set @xmath28 with @xmath40 , the spatial scale is normalized by @xmath41 , where @xmath42 is the length of the nozzle , and that the temporal scale is normalized by @xmath43 , where we set @xmath44 . we have not considered the perturbation of the fluid flow so far . in the following sections , the perturbation ( sound wave ) is introduced on the fluid flow , and the classical counterpart to hawking radiation is defined . then in the section [ sec : result ] , we compare this surface gravity ( [ eq : temp - th ] ) with the surface gravity of the sonic horizon which is obtained through the observation of the classical counterpart to hawking radiation in our numerical simulation . . each line represents the stationary solution of the flow with different boundary value @xmath45 . the blue lines represent transonic flows . ] as originally shown in the reference @xcite , the perturbation of the velocity potential for the transonic fluid flow obeys the same equation as a massless free scalar field in a black hole spacetime . therefore the classical counterpart to hawking radiation of the acoustic black hole in the laval nozzle should be observed by the sound wave on the transonic fluid flow . the most important sound wave is the one which starts to propagate against the stream from the outlet of the nozzle before the formation of the sonic point ( the lower part of the right panel in fig . [ fig : nozzle ] ) and passes through the throat just before the moment of the sonic point formation to reach the inlet of the nozzle ( the upper part of the right panel in fig . [ fig : nozzle ] ) . this sound wave receives the extremely large redshift which will cause the classical counterpart to hawking radiation . when the fluid flow is irrotational and we introduce the velocity potential @xmath46 which relates with the fluid velocity as @xmath47 , the evolution equation of the perturbation @xmath48 of @xmath46 is obtained from eqs . , @xmath49\left(\frac{s\,\rho}{c_s^2}\right)\left[{\partial}_t+v{\partial}_x\right]\phi -\frac{1}{s\,\rho}{\partial}_x\!\left(s\,\rho{\partial}_x\phi\right)=0.\ ] ] this corresponds to the klein - gordon equation @xmath50 with the acoustic metric @xmath51,\ ] ] where the location of the sonic horizon ( sonic point ) @xmath1 is given by @xmath52 . here we should note that , because we consider the one dimensional flow along @xmath53-axis as mentioned at the beginning of the previous section [ sec : counterpart : basic - eq ] , the two dimensional section of @xmath54 coordinate is omitted in obtaining eq . from @xmath50 . in the following analysis , we omit the two dimensional section of @xmath54 coordinate . in order to describe the extremely large redshift which causes the classical counterpart to hawking radiation , we introduce the following null coordinates for the first , @xmath55 and the acoustic metric becomes @xmath56 , which has a coordinate singularity at @xmath1 . in order to eliminate the coordinate singularity , we introduce the new null coordinates @xmath57,\quad w=\frac{1}{c_{s0}'+v_0'}\exp\left[(c_{s0}'+v_0')w\right],\ ] ] where @xmath58 and quantities with subscript @xmath59 denotes values at the sonic point @xmath1 . then the acoustic metric and the evolution equation of the perturbation @xmath48 become @xmath60\,du\,dw \equiv -f\,du\,dw , \label{eq : metric2 } \\ \square\phi&=\frac{1}{f}{\partial}_{uw}\,\phi=0.\end{aligned}\ ] ] the form of this metric near the sonic horizon is @xmath61 , where @xmath62 is used . this denotes explicitly that the coordinate @xmath63 does not have coordinate singularities and corresponds to the kruskal - szekeres coordinate of the schwarzschild spacetime . here it should be recalled that , in the spacetime of the gravitational collapse ( the left panel in fig . [ fig : nozzle ] ) , the kruskal - szekeres coordinate is appropriate to describe the rest observer at the spacetime region before the formation of the black hole @xcite . hence the outgoing normal mode of the sound wave which corresponds to the zero point fluctuation of the quantized matter field before the formation of the black hole ( i.e. the mode function on the flat spacetime ) is given by @xmath64 where @xmath65 is the initial frequency and @xmath66 is the amplitude of this mode . in the original coordinate @xmath67 , this mode behaves as @xmath68.\ ] ] this yields the temporal wave form at the observation point @xmath69 in the asymptotic region : @xmath70 . \label{eq : output}\ ] ] fourier component of this mode is defined by @xmath71 and the power spectrum is @xmath72 where the quantity @xmath73 is defined by @xmath74 here it should be noted that , because the existence of the sonic point is assumed in the above discussion , the form of @xmath75 of eq . must be obtained after the formation of the sonic horizon in the fluid flow . one may think it is strange that the initial frequency @xmath65 does not appear in the power spectrum . it is the fact that the initial frequency @xmath65 does appear in the power spectrum in the context of the quantum field theory , because the amplitude @xmath66 is determined by the normalization condition for the mode functions to be @xmath76 . however , in the calculation for the classical counterpart to hawking radiation , the initial frequency @xmath65 appears only in the phase of the fourier component @xmath77 and the power @xmath78 does not explicitly depend on @xmath65 . the power spectrum has the planckian distribution for @xmath79 and this is the classical counterpart to the quantum hawking radiation @xcite . for the quantum hawking radiation , the magnitude of the power is determined by the zero point oscillation of the quantized field . however , for the classical counterpart to hawking radiation , the magnitude of the power depends on the amplitude @xmath80 of the input signal and it is expected that we can detect the thermal distribution of the power spectrum for the sound wave of a sufficiently large amplitude in practical experiments . as long as concerning one dimensional fluid flow , the amplitude of the sound wave does not decrease during propagating from the outlet to the inlet of the nozzle . the one dimensional transonic fluid flow corresponds to the two dimensional black hole spacetime in which no curvature scattering occurs . the theoretically expected power is equivalent to the formula of the hawking radiation for black holes derived ignoring the curvature scattering . our purpose is to observe this thermal spectrum via the numerical simulation of a transonic flow in the laval nozzle , and to construct the practical procedure of the data analysis . because the observable sound wave is a real valued one , we prepare the following real valued input mode at the outlet of the nozzle before the formation of the sonic horizon : @xmath81 , \label{eq : real - input}\ ] ] where @xmath82 is the initial phase of the wave , @xmath83 is given by eq . , and @xmath84 is the location of the outlet of the nozzle . here we should note that , although the outlet of the nozzle is the `` exit '' of the background fluid flow , the sound wave can propagate against the background flow from the outlet to the inlet of the nozzle . then , since the amplitude of the sound wave on one dimensional fluid flow does not decrease , the input mode of eq . causes the following sound wave in the fluid flow , @xmath85.\ ] ] the effect of the redshift due to the formation of the acoustic black hole gradually appears on the observed sound wave . the temporal evolution of the observed sound wave is affected by the formation of the acoustic black hole . that is , the information of the classical counterpart to hawking radiation is encoded in the observed sound wave . therefore , using the output form , the resulting output signal after the formation of the sonic horizon is given by @xmath86,\ ] ] and referring eq . , the fourier component of this output signal is given by @xmath87 hence , because the initial phase @xmath82 appears in @xmath88 , we can not obtain the pure fourier component @xmath89 by observing once the real valued output signal @xmath90 . in order to retrieve the pure fourier component @xmath91 from the mixed fourier component @xmath88 , we have to superpose two output modes @xmath92 and @xmath93 , and obtain @xmath94 it is obvious that the power spectrum of this fourier component gives the same form as eq . . therefore , in order to obtain the planckian distribution in the power spectrum @xmath78 of the observed sound wave from real valued input signals , we have to combine at least two output modes of which the input phases differ by @xmath95 . our numerical simulation is designed to generate a one dimensional transonic fluid flow from the initial configuration with no sonic point . we prepare the input signal at the outlet of the nozzle and observe the sound wave at the inlet of the nozzle . at the same time , the practical procedure of the data analysis is constructed . for the numerical calculation , we rewrite the fluid eqs . using @xmath3 and @xmath4 , @xmath96 this set of equations is not suitable for a numerical simulation of wave propagation in a transonic flow . we transform these equations to the advection form . we introduce the riemann invariants @xmath97 as follows @xmath98 then the basic equations become [ eq : num ] @xmath99 where @xmath100 the left hand side of eqs . are of the advection form . that is , if @xmath101 and @xmath102 , @xmath103 propagates upward along @xmath104 const . and @xmath105 propagates downward along @xmath106 const . this form of the equations is suitable to treat the propagation of waves numerically . in the sonic analogue of hawking radiation , the perturbation of the velocity potential ( sound wave ) corresponds to the scalar field in a black hole spacetime as shown by eq . . therefore , in a practical experiment of an acoustic black hole , we should calculate the velocity potential by integrating the observed velocity of the fluid : @xmath107 where @xmath108 is the observation point of sound waves and @xmath109 defines the origin of the velocity potential . however , since our experimental setting is designed to observe the sound wave at a fixed spatial point @xmath110 , the observational data is a temporal sequence of @xmath111 and we must devise the other method to obtain the velocity potential at the observation point . in the upstream subsonic region of the transonic flow where the effects of the sonic horizon is negligible and the flow is stationary , the sound wave propagates along the `` null '' direction as indicated by eq . @xmath112 and we can obtain the value of the velocity potential at @xmath108 by integrating the velocity with respect to time @xmath113 where @xmath114 defines the origin of the potential . we use this formula to evaluate the velocity potential at the observation point . we use the laval nozzle with the cross section of the following form , @xmath115 we make the fluid flow against @xmath53-axis and assume @xmath116 . the inlet of the nozzle is at @xmath117 , the throat at @xmath118 and the outlet at @xmath119 . the input wave is prepared at the outlet of the nozzle and the wave propagates against the flow from @xmath119 to @xmath117 . after the flow settles down to a stationary transonic flow , since @xmath120 at the inlet , the set of eqs . gives @xmath121 at the inlet . this means that the inlet of the nozzle corresponds to the asymptotically flat region in the gravitational collapse spacetime . hence we make the observation of the sound wave at the inlet and set @xmath122 . we prepare a flow with a homogeneous velocity distribution as the initial configuration , @xmath123 this initial configuration of flow has no sonic point and corresponds to the flat spacetime region before the formation of a black hole . since our evolution equations are of the advection form , it is enough to set the boundary conditions for @xmath103 at the outlet and @xmath105 at the inlet : @xmath124 where @xmath125 is a constant that represents the amplitude of the perturbation of @xmath103 at @xmath31 , and the values @xmath126 and @xmath127 are determined consistent with eq . and eq . . these boundary conditions mean that sound waves of constant amplitude continue to emerge from the outlet toward the inlet of the nozzle all the time of the numerical simulation . here recall that the perturbation @xmath48 of the velocity potential @xmath46 plays the role of the scalar field in the ordinary hawking radiation . the second term in @xmath128 at the outlet @xmath129 causes perturbations of the velocity potential and results in the classical counterpart of hawking radiation at the inlet of the nozzle . because the amplitude of the sound wave in one dimensional fluid flow does not decrease , the amplitude of the input mode of the velocity potential is given by @xmath130 where @xmath131 and @xmath132 are respectively the sound velocity and the fluid velocity at @xmath29 , and the relation of the perturbations @xmath133 at the outlet is used ( see eqs . and ) . in order to extract the perturbation part @xmath48 from the `` full '' velocity potential @xmath46 of eq . which includes the `` background '' flow of the fluid , we should prepare three input modes with different initial phases @xmath134 and @xmath135 . if the amplitude @xmath125 of the perturbation part of @xmath103 is small enough , then the backreaction effects in the velocity potentials @xmath136 ( @xmath137 ) at the observation point ( @xmath29 ) are negligible and we can subtract the common background contribution by taking the difference among them . hence we obtain the fourier components of the perturbation ( sound wave ) at the observation point as follows [ eq : out - signal ] @xmath138 where @xmath139 is the fourier component of @xmath136 . these fourier components correspond to the real valued output signal of eq . . here we note that , according to the boundary condition , the perturbation parts of @xmath103 which produce the output signals of eqs . are given by @xmath140 where we used @xmath141 . hence we obtain the pure fourier component @xmath77 of the output sound wave by eq . , and its power spectrum is given by @xmath142 where the factor @xmath143 is introduced to eliminate the factor @xmath144 which appears in the amplitude @xmath145 of the input signals . when we carry out a realistic experiment of the acoustic black hole , the power spectrum gives the classical counterpart to hawking radiation and it has to be compared with the theoretical form . hence , it is recognized that we have to perform at least three independent experiments with three different input phases and observe three independent output signals to obtain the classical counterpart to hawking radiation . with our setting of the fluid flow in the laval nozzle , we carry out the numerical simulation by the finite difference method . we use the cubic - interpolated pseudoparticle ( cip ) method @xcite for the interpolation between neighboring spatial mesh points . this method enables us to treat the shock which appears after the formation of the sonic point . we note here that the shock arises in the supersonic region and it does not affect the subsonic region where we observe the output signal . the procedure of the numerical simulation to observe the thermal power spectrum of the perturbation of the velocity potential is as follows : generate the transonic fluid flow three times with three different initial phase values , @xmath146 , @xmath147 and @xmath148 . then , using eq . , obtain the full velocity potentials @xmath136 @xmath149 . calculate the quantities @xmath150 and @xmath151 . then compute the fourier components of them , @xmath152 and @xmath153 . calculate the power spectrum @xmath154 this is the observationally obtained power spectrum for the perturbation of the velocity potential . then compare this power spectrum with the theoretically expected one @xmath155 and determine the surface gravity @xmath12 of the sonic horizon . here note that the quantity @xmath156 in the amplitude of @xmath157 is the effective input frequency given by the following discussion . we must note here that there arises an extra redshift effect on the sound wave . in our numerical simulation , the initial fluid flow has homogeneous velocity distribution . then the system starts to evolve dynamically and settles down to the stationary transonic fluid flow finally . therefore , the observed frequency shifts due to the evolution of the `` background '' flow . according to the null coordinate , the outgoing wave with frequency @xmath158 is @xmath159 and the effective frequency of the wave at @xmath29 is given by @xmath160 the second term in eq . gives a negative contribution in our non - stationary setting of numerical experiment and the observed frequency @xmath156 at @xmath29 becomes smaller than @xmath158 . the theoretically expected form of the power spectrum in our setting should be given by replacing @xmath158 to @xmath156 in the formula . we use the parameters @xmath161 , @xmath162 and @xmath163 . the number of spatial mesh points are 10001 and the size of one mesh becomes @xmath164 . the size of one temporal step is set @xmath165 , and we calculate 900000 steps in time . the numerical simulation runs in the temporal range @xmath166 . the spatial scale is normalized by @xmath41 , where @xmath42 is the length of the nozzle . the temporal scale is normalized by @xmath167 , where we set @xmath168 as denoted by the initial condition . for the initial fluid velocity @xmath169 , we do not observe the formation of an acoustic black hole . figure [ fig : mach1 ] shows the evolution of the mach number . after @xmath170 , the mach number at @xmath30 reaches a constant value and a stationary flow is realized . .,title="fig : " ] .,title="fig : " ] . ] the spatial distribution of the fluid velocity at @xmath171 ( fig . [ fig : final - mach1 ] ) coincides with the stationary solution with @xmath172 and no sonic point appears . figure [ fig : dv1 ] shows the time derivative of the observed velocity at @xmath29 which should disappear when the fluid flow becomes stationary . until @xmath173 , the initial burst mode appears , which is peculiar to our initial and boundary conditions . then , the output signal decays exponentially . for @xmath174 ( with input perturbation ) , the output signal oscillates with a constant amplitude after the `` background '' flow settles down to the stationary flow . at @xmath29 . the left panel is @xmath175 case and the right panel is @xmath174 case.,title="fig : " ] at @xmath29 . the left panel is @xmath175 case and the right panel is @xmath174 case.,title="fig : " ] figures [ fig : diagram1 ] and [ fig : diagram11 ] show the spacetime distribution of the velocity perturbation for @xmath174 with @xmath176 . , [ fig : diagram11],[fig : diagram2 ] and [ fig : diagram22 ] , we used the smaller value of the perturbation frequencty @xmath176 to visualize the propagation of the wave in the spacetime diagram . ] in fig . [ fig : diagram11 ] , to subtract the `` background '' flow , we have defined @xmath177 where @xmath178 denotes the fluid velocity with the input phase @xmath179 . we can see that the sound wave propagates from @xmath31 to @xmath29 . around the throat @xmath30 , the fluid velocity has larger value compared to the other region and the phase velocity of the outgoing wave becomes smaller . thus the slope of the constant phase line becomes larger around the throat . for @xmath169 with @xmath180 . colors are assigned according to the value of @xmath181 . ] for @xmath169 with @xmath180 . colors are assigned according to the value of @xmath182 . ] figure [ fig : phi1 ] shows the perturbation of the velocity potential at @xmath29 . we set @xmath183 in eq . to obtain the velocity potential . the observed perturbation of the velocity potential oscillates with a constant amplitude . and @xmath184.,title="fig : " ] and @xmath184.,title="fig : " ] for the velocity potential.,title="fig : " ] for the velocity potential.,title="fig : " ] for the velocity potential.,title="fig : " ] for the velocity potential.,title="fig : " ] the power spectrum @xmath185 obtained from the perturbations are shown in fig . [ fig : power1 ] . the frequency of the observed signal evolves in time . this is due to the non - stationarity of the background flow as denoted by eq . . until the flow settles down to the stationary flow which is determined by the given boundary condition , the background flow evolves in time and causes the shift of the frequency of the observed perturbation . after a sufficiently long time has passed and the fluid flow becomes stationary , the observed frequency coincides with the input frequency @xmath186 as expected by eq . . for the initial fluid velocity @xmath187 , we observe the formation of the acoustic black hole . figure [ fig : mach2 ] shows the evolution of the mach number . .,title="fig : " ] .,title="fig : " ] . ] at @xmath188 , the mach number at the throat @xmath30 reaches unity and the sonic point appears ( formation of the acoustic black hole ) . at the same time , the discontinuity of the derivative of the mach number appears in the supersonic region @xmath189 as shown in fig . [ fig : final - mach2 ] . this discontinuity is due to the shock formed in the transonic flow . the formation of the shock is peculiar to our boundary condition which determines the riemann invariants @xmath190 at the inlet and the outlet of the nozzle . however , since the shock occurs in the supersonic region after the formation of the sonic point , the effect of the shock never propagate into the subsonic region after the formation of the sonic point . hence the shock never affect the sonic analogue of hawking radiation , and we do not have to pay attention to the effect of the shock formation . figure [ fig : dv2 ] is the time derivative of the fluid velocity at @xmath29 . after the burst mode @xmath173 , we can observe the quasi - normal oscillation @xcite of the acoustic black hole with a period @xmath191 . at @xmath29 . the left panel is @xmath175 case and the right panel is @xmath174 case . as the amplitude of the input perturbation is far smaller than the change of the background , we can not see the oscillation of the perturbation in the figure ( right panel).,title="fig : " ] at @xmath29 . the left panel is @xmath175 case and the right panel is @xmath174 case . as the amplitude of the input perturbation is far smaller than the change of the background , we can not see the oscillation of the perturbation in the figure ( right panel).,title="fig : " ] the value of this period can be estimated as follows . in our simulation , the value of @xmath105 at the inlet of the nozzle is fixed to be constant by the boundary condition . hence after the formation of the sonic horizon , the boundary condition for the ingoing perturbation @xmath192 becomes @xmath193 for the outgoing perturbation @xmath194 , @xmath195 by these boundary condition , a quarter of the wavelength of the quasi - normal mode is equal to a half length of the laval nozzle and the wavelength of the quasi - normal mode becomes 4 in the present case . thus , we obtain the period 4 of the quasi - normal mode by assuming @xmath196 . the spacetime distribution of the time derivative of the fluid velocity and the perturbation is shown in fig . [ fig : diagram2 ] and fig . [ fig : diagram22 ] , respectively . for @xmath187 with @xmath197 . colors are assigned according to the value of @xmath181 . ] for @xmath187 with @xmath197 . colors are assigned according to the value of @xmath182 . ] the time evolution of the observed perturbation of the velocity potential is shown in fig . [ fig : phi2 ] . after the formation of the sonic horizon @xmath188 , the frequency of the observed perturbation gradually decreases to zero . and @xmath198.,title="fig : " ] and @xmath198.,title="fig : " ] the time evolution of the power spectrum of the observed signal is shown in fig . [ fig : power2 ] , fig . [ fig : power3 ] and fig . [ fig : power4 ] . the effective frequency @xmath156 of the input perturbation observed at the inlet of the nozzle is @xmath199 . figure [ fig : power2 ] shows that , after @xmath170 , the power spectrum of the observed perturbation spreads out toward the low @xmath200 range by the redshift effect due to the formation of the sonic horizon , and the divergence of the power @xmath185 appears at @xmath201 . this indicates that the observed spectrum approaches the theoretically expected form which diverges at @xmath201 as @xmath202 . to remove this divergence , we plot @xmath203 in fig . [ fig : power3 ] and fig . [ fig : power4 ] . for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal.,title="fig : " ] for the output signal in the range @xmath204.,title="fig : " ] for the output signal in the range @xmath204.,title="fig : " ] for the output signal in the range @xmath204.,title="fig : " ] for the output signal in the range @xmath204.,title="fig : " ] figure [ fig : fit ] shows the observed power spectrum @xmath205 at @xmath171 given by eq . and the theoretically expected power @xmath206 given by eq . . in different ranges of @xmath207 . the solid lines are the observed power spectrums and the red dotted lines are theoretically expected power with @xmath208.,title="fig : " ] in different ranges of @xmath207 . the solid lines are the observed power spectrums and the red dotted lines are theoretically expected power with @xmath208.,title="fig : " ] in different ranges of @xmath207 . the solid lines are the observed power spectrums and the red dotted lines are theoretically expected power with @xmath208.,title="fig : " ] we fits the theoretical power spectrum to the numerical one in the range @xmath209 with the parameters @xmath210 and @xmath211 , where the value of @xmath156 is read off from the location of the highest peak of the power in fig . [ fig : power3 ] . then we obtain the surface gravity of the sonic horizon @xmath212 this value is consistent with the theoretically expected value 0.355 given by eq . . here we discuss about two points . the first is about the oscillation of the numerical power spectrum . this oscillation is due to the finite size fourier transformation . this oscillation will disappear if the numerical calculation is carried out with larger value of @xmath158 . the second point is the deviation of the numerical power from the theoretical one in the high @xmath200 range . this deviation is due to the input sound wave given in the boundary condition . the input sound wave emerges from the outlet of the nozzle toward the inlet of the nozzle , and the observation is done at the inlet . before the formation of the sonic point , the input sound wave comes from the outlet to the inlet without receiving a large redshift . then , as the fluid flow evolves in time , the redshift on the observed sound wave becomes larger , and the observed frequency continues to decrease until the sonic point appears , as denoted by eq . . hence , although the input sound wave is a monochromatic wave at the outlet of the nozzle ( the starting point of the propagation ) , the observed sound wave at the inlet of the nozzle has a broad power spectrum after the formation of the sonic point because of the stimulated effect of the redshift before the formation of the sonic point . the peak of this broad spectrum appears obviously in fig . [ fig : power3 ] around @xmath213 . this broadness in the power spectrum is the origin of the deviation of the numerical power from the theoretical one in fig . [ fig : fit ] . the perfect thermal spectrum should be realized at the infinite future , and that the theoretical power spectrum is the form evaluated at the infinite future . however we have to make the observation in a finite temporal interval . therefore , when we plot the numerical result in an appropriately large range of @xmath200 , it is impossible to avoid some deviation of the numerical power from the theoretical one . if we carry out the numerical calculation longer and longer , a better agreement have to be obtained in fig . [ fig : fit ] . from above discussions , we conclude that fig . [ fig : fit ] shows the good agreement between the numerically obtained power and the theoretically expected form of the classical counterpart to hawking radiation . for the acoustic black hole , the classical counterpart to hawking radiation is given by the power spectrum of the perturbation of the velocity potential of the fluid and detectable in practical experiments . to demonstrate its detectability , we performed the numerical simulation of the acoustic black hole in the laval nozzle and observed the classical counterpart to hawking radiation . we obtained the good agreement of the numerically observed power spectrum with the theoretically expected one . through our numerical simulation , we have obtained two noteworthy points for data analysis of the experiments of the acoustic black hole : the first one is that a single input wave can not give us necessary information of the classical counterpart to hawking radiation . we need to carry out several independent observations of the sound waves with different initial phases to retrieve the thermal distribution of the power spectrum . the second one is that we can evaluate the velocity potential at the observation point by integrating the fluid velocity at that point with respect to time ( see eq . ) . therefore , it is not necessary to observe the sound wave at every spatial points in the fluid . in our calculation presented here , we have considered the sound wave with small amplitude . however our numerical code is applicable beyond perturbation , in which the non - linear effect of the sound wave becomes important . by analyzing such a situation , we may be able to discuss the backreaction effect on the classical counterpart to hawking radiation . as the next step , we are planning to extend our simulation of transonic flows in a laval nozzle to include quantum effects . then , we expect to obtain implications for quantum aspects of hawking radiation using the sonic analogue model of black hole . we would like to express our gratitude to satoshi okuzumi and masa - aki sakagami . their numerical calculation of the perturbation equation ( not a full order calculation ) of the velocity potential was very impressive for us and we were led to refine our numerical simulation . we briefly review the hawking radiation in a spacetime of a gravitational collapse forming a schwarzschild black hole , and clarify the distinction between the quantum effects and the classical effects in the occurrence of the hawking radiation . for simplicity , we consider a massless free scalar field @xmath46 as a representative of the matter field , and set @xmath214 . for the first , we start with the classical effects . because the spacetime is dynamical , the positive frequency modes and the negative frequency modes of the scalar field are mixed as the system evolves in time . this mixing is represented by the bogoliubov transformation between the positive frequency mode @xmath215 of @xmath46 at the past null infinity and that mode @xmath216 at the future null infinity @xmath217 \ , , \label{eq - cc.bogo.trans}\ ] ] where @xmath218 is the negative frequency mode at the future null infinity . the bogoliubov coefficients @xmath219 and @xmath220 are obtained by solving the classical wave equation @xmath221 with appropriate boundary conditions at the past and future null infinities and with the following relation , @xmath222 = \delta_{{\omega}_1{\omega}_2 } \,,\ ] ] which comes from the normalization condition @xmath223 with respect to the klein - gordon inner product of @xmath46 @xcite . this means that the derivation of @xmath219 and @xmath220 is purely classical . next , in the classical framework , we consider the wave mode which propagates from the past null infinity to the future null infinity via a vicinity of the black hole horizon ( see the left panel in fig . [ fig : nozzle ] ) . this wave mode is ingoing at the past null infinity and becomes outgoing at the future null infinity . the ingoing positive frequency mode @xmath215 at the past null infinity is given by @xmath224 where @xmath225 is the ingoing null coordinate appropriate for the rest observer at the past null infinity . when this wave mode @xmath226 propagates to the future null infinity via a vicinity of the horizon , it evolves to be @xmath227 at the future null infinity under the geometrical optics approximation , where @xmath228 is the outgoing null coordinate appropriate for the rest observer at the future null infinity . the function @xmath229 expresses the extremely large redshift which the mode @xmath226 receives during propagating from the past null infinity to the future null infinity . this redshift effect can be decomposed into two parts : one is the redshift during the propagation from the past null infinity to the vicinity of the horizon , and the other part is the redshift after passing through the vicinity of the horizon . the first contribution is not so large and the mixing of positive and negative frequency modes does not occur . however , the second contribution is large enough to make the bogoliubov coefficient @xmath230 non zero . by matching the null coordinates @xmath225 and @xmath228 along a null geodesic which connects the past and future null infinities via the vicinity of the horizon , the function @xmath229 is obtained @xcite : @xmath231 where @xmath10 is the surface gravity of the black hole horizon , @xmath232 is an arbitrary constant denoting the freedom of choosing the origin of @xmath225 , and the constant @xmath233 is determined by the first part of the redshift . the exponential form @xmath234 in the eq . comes from the second part of the redshift and implies that the wave length of the outgoing wave is exponentially stretched during propagating from a vicinity of the horizon to the future null infinity . that is , the wave @xmath227 is no longer a pure positive frequency mode but becomes a superposition of positive and negative frequency modes at the future null infinity . in order to calculate the superposition , we need the outgoing positive frequency mode @xmath235 at the future null infinity : @xmath236 then , using the definition of the bogoliubov transformation , the wave @xmath237 at the future null infinity is decomposed as @xmath238 . \label{eq - cc.mode.future}\ ] ] the bogoliubov coefficients are obtained using the inner product @xmath239 and @xmath240 , and we find @xmath241 the square of the bogoliubov coefficients do not depend on the constants @xmath233 and @xmath232 , and the following relation holds : @xmath242 all the above phenomena are the classical effects . finally we proceed to the quantum effects . when @xmath46 is quantized , the harmonic operators @xmath243 and @xmath244 with respect to the past mode @xmath215 are related to those @xmath245 and @xmath246 with respect to the future mode @xmath235 as follows@xcite : @xmath247=\hbar\,\delta_{\omega_1\omega_2},\quad [ \tilde a_{\omega_1},\tilde a^{\dagger}_{\omega_2}]=\hbar\,\delta_{\omega_1\omega_2}.\end{aligned}\ ] ] then the number of particles at the future null infinity is obtained @xmath248 where @xmath249 is the vacuum state at the past null infinity , @xmath250 . therefore , for the mode @xmath215 which passes a vicinity of the horizon and propagates to the future null infinity , using eqs . and an appropriate regularization method @xcite , we obtain @xmath251 it is concluded that a black hole emits a thermal radiation of @xmath46 with the hawking temperature @xmath252 . it should be emphasized that , although the creation of particles is just the quantum effect , however the planckian distribution ( [ eq-cc.hr ] ) of the emitted particles is purely the classical effect due to eqs . . the thermal nature of the spectrum comes from the bogoliubov coefficient @xmath253 which has the planckian distribution with respect to @xmath254 . that is , the thermal nature of the hawking radiation comes from the extremely large redshift for the wave mode @xmath215 which passes the vicinity of the horizon . if we take the classical limit @xmath255 , the number of created particles and the hawking temperature become zero but @xmath256 is not affected .

a numerical simulation of fluid flows in a laval nozzle is performed to observe the formation of an acoustic black hole and the classical counterpart to hawking radiation under a realistic setting of the laboratory experiment . we aim to construct a practical procedure of the data analysis to extract the classical counterpart to hawking radiation from experimental data . following our procedure , we determine the surface gravity of the acoustic black hole from obtained numerical data . some noteworthy points in analyzing the experimental data are clarified through our numerical simulation .

The midcentury modernistic steel-and-glass house in Highland Park and the nearby auto pavilion that together are commonly known as the Ferris Bueller home for their prominence in the 1986 film “Ferris Bueller’s Day Off” sold on Thursday for $1.06 million. And the buyers, an investment banker and a lawyer, are nearby residents and Northwestern University alumni. The deal brought to a close a more than five-year-long sales odyssey for the 5,300-square-foot house and its iconic, detached, glass-enclosed auto pavilion, which perches over a ravine on steel pilings. Since May 2009, the Rose family -- the home’s only owners -- had had the property on and off the market. The final sale price was for less than half of the $2.3 million that the Rose family initially had sought for the property in May 2009. It later was reduced to $1.8 million and then to $1.65 million before coming off the market in 2011 for some light rehab work. For a time, the property remained off the market but still informally listed. In August the Rose family relisted the property for $1.5 million and later cut its asking price to $1.375 million, $1.275 million and $1.25 million before finally going under contract in January. The four-bedroom main house was built in 1953 and designed by Ludwig Mies van der Rohe disciple A. James Speyer, while the pavilion was designed by David Haid and constructed about 20 years later to house an exotic car collection. In a classic scene late in the film “Ferris Bueller’s Day Off,” the titular character’s best friend, Cameron Frye, sends a classic 1961 Ferrari crashing through the pavilion’s plate glass windows into the ravine. Features in the pavilion include a kitchen, a bath and room for four cars. The sellers recently renovated the pavilion’s windows and steel. The agent for the buyers, Mindy Shea of @properties, declined to comment on the purchase. News of the sale was first reported by Crain's Chicago Business. ||||| Five years after it first came on the market, the two-building modernist home in Highland Park that played a memorable role in “Ferris Bueller's Day Off” sold today. The final sale price was $1.06 million, said Craig Hogan, regional director at Coldwell Banker Previews, the luxury division of the real estate brokerage, which represented the house. That's less than half the $2.3 million that the sellers, the family of Francis and the late Ben Rose, originally listed it for in 2009. By the time of the sale, the asking price had been cut to $1.2 million. “Talk about a journey,” Mr. Hogan said. After the home first went on the market, it attracted worldwide media attention because of its movie role. In the 1986 John Hughes film, the smaller of the home's two black, glassy buildings is the garage where the father of Ferris' friend Cameron keeps a precious 1961 Ferrari 250 GT California Spyder convertible that the teenagers take out for a joyride.

– After more than five years on and off the market, an Illinois home made famous in Ferris Bueller's Day Off has sold. The home, located in the Chicago suburb of Highland Park, is the one where Bueller's best friend Cameron lives in the movie—and where he sends his dad's classic Ferrari through the plate glass windows of the home's auto pavilion and into a ravine after the characters' iconic joyride. The detached pavilion, too, was included in the $1.06 million sale, which went through Thursday, the Chicago Tribune reports. The Rose family, the only owners of the 5,300-square-foot midcentury modernistic home, initially listed the property in May 2009 for $2.3 million; the price was later reduced and reduced again before the home came off the market to get work done in 2011. It was re-listed in August for $1.5 million, followed by three more price reductions; it finally went under contract in January after the price was cut to $1.25 million. After it was re-listed, Coldwell Banker began emphasizing the property's "architectural pedigree," Crain's Chicago Business notes; the steel and glass "box" was designed in 1953 by James Speyer. The buyers are an investment banker and a lawyer, both alums of Northwestern University.

After more than two years of delays, Boeing Co. said Thursday that it plans to fly its new 787 Dreamliner for the first time as early as next Tuesday. The exact timing of the much-anticipated first flight depends on external factors, such as the weather at the airport near Seattle, the company said in a statement. The Dreamliner's first flight-which has been pushed back multiple times-will be a major milestone for Boeing's marquee commercial airplane program. Boeing plans to fly the plane on a four to five hour test flight departing from Boeing's factory at Paine Field in suburban Everett, ... ||||| Boeing 787 first flight window opens Dec. 15 The window for the first flight of the 787 Dreamliner will open at 10 a.m. Dec. 15, Boeing announced Thursday evening. "This date is dependent on final internal reviews, taxi tests and receiving the final experimental ticket from the U.S. Federal Aviation Administration," the company said in a media notice. Boeing issued the notification shortly after announcing that it had validated the side-of-body fix to the composite aircraft and finished gauntlet testing, which simulates flight.

– Boeing's Dreamliner will make its maiden flight next week after two years of delays. The high-tech aircraft could be airborne on a test flight of about five hours Tuesday if Seattle's weather permits, reports the Post-Intelligencer. Boeing has much staked on the plane, made of 50% composite material. It's locked in a fierce fight with Airbus to deliver the fuel-saving jet of the future, notes the Wall Street Journal. It has nearly 900 planes on order but can't deliver any until the model passes muster with the FAA.

the term of `` glassy - dynamics '' is now commonly used to describe out - of - equilibrium systems that display such generic features as very slow kinetics that prevent the system from reaching equilibrium in any reasonable experimental timescale , aging phenomena , history - dependent processes like hysteresis and memory effects . among such systems are the `` not - too - strongly '' vibrated granular materials@xcite . in the recent years , there has been a surge of research activity in this field@xcite , partly driven by the goal of providing a statistical - mechanical description of these out - of - equilibrium situations@xcite@xcite . in this note , we consider an approximate statistical - mechanical description of the parking - lot - model ( plm ) for vibrated granular materials@xcite that is based on the formalism proposed by edwards and coworkers@xcite . despite its simplicity , the one - dimensional model of random adsorption - desorption of hard particles ( plm ) has the merit of being a microscopic , off - lattice model that mimics many features of the compaction of a vibrated column of grains . it also has , we hope , a didactic value as to the nature of several canonical characteristics of `` glassy dynamics '' . many of the properties of the model , that can be obtained either analytically or by computer simulation , have been already described in the literature@xcite . our main focus here is on memory effects , including the so - called kovacs effect first observed in glassy polymers@xcite(see also@xcite ) , and on the ingredients that are needed in a statistical - mechanical description to account for such effects . the parking - lot model is one - dimensional process in which hard rods of length @xmath1 are deposited at random positions on a line at rate @xmath2 and are inserted successfully only if they do not overlap with previously adsorbed particles ; otherwise they are rejected . moreover , all deposited particles can desorb , i.e. , be removed from the line at random with a rate @xmath3 . for convenience , the unit time is set to @xmath4 , and the unit length to @xmath1 . with this choice of units , the only control parameter in the model is @xmath5 . when desorption is forbidden ( @xmath6 ) , the model corresponds to the purely irreversible one - dimensional random sequential adsorption ( rsa ) process@xcite , also known as the car parking problem , and all the properties of the system as a function of time can be obtained exactly . connection to the compaction of a vibrated column of grains is made by considering the line as average layer ( a @xmath7-dimensional model would be more realistic , but the qualitative behavior would not be altered ) , the time as the number of taps , and @xmath8 as the tapping strength that controls the fraction of particles ejected from the layer at each tap . when @xmath8 is not strictly equal to zero , adsorption and desorption are competing mechanisms that drive the system to a steady state corresponding to an equilibrium fluid of hard rods at a constant activity @xmath8 . all the properties of the steady - state can also be obtained exactly . the compaction kinetics of the parking - lot model at constant @xmath9 is described by @xmath10 where @xmath11 the density of hard rods on the line at time @xmath12 and @xmath13 is the fraction of the line that is available at time @xmath12 for inserting a new particle , i.e. , the probability associated with finding an interval free of particles ( a `` gap '' ) of length at least @xmath14 . the quantities @xmath15 and @xmath16 can be obtained from the @xmath17gap distribution function @xmath18 which is the density of gaps of length @xmath19 at time @xmath12 via a number of `` sum rules '' : @xmath20 the @xmath17gap distribution function @xmath18 obeys a kinetic equation that also involves @xmath0gap distribution function . similarly , the kinetic equation of the @xmath7-gap distribution involves the @xmath21gap distribution function , and so on@xcite . the resulting infinite hierarchy of coupled equations can not in general be solved analytically ( exceptions are the rsa , when @xmath6 and equilibrium when @xmath22 ) . the description of the kinetics of the parking lot model at large , constant @xmath9 ( i.e. small , constant tapping strength ) can be summarized as follows : the density increases monotonically during the process , and the kinetics can be considered as a succession of four different regimes ( see fig . [ fig:1 ] ) : during a first stage , the density increases rapidly until a value of around @xmath23 , and it is followed by an algebraic approach toward the saturation density , @xmath24 of the model without desorption ( rsa ) ; around this density there is a crossover to a still slower @xmath25 compaction regime that is reminiscent of what is exactly observed when @xmath26 , and finally there is an exponential approach to the steady - state ( equilibrium ) density with a rate @xmath27 . for the two first regimes , desorption has a negligible effect and only the two last regimes are relevant for the compaction kinetics of vibrated granular materials ( although the approach to equilibrium may be prohibited when @xmath9 is very large ) . experimentally , it has been observed that granular compaction exhibits history - dependent phenomena . in particular , josserand _ et . al_@xcite have shown that memory effects are seen when changing the tapping strength during the compaction kinetics . similar effects have been found in the parking - lot model , when the tapping strength @xmath8 is switched at a given time to a larger ( or smaller ) value : see fig . [ fig:2 ] the obvious lesson that one can draw such memory effects is that whereas equilibrium is fully described by one thermodynamic parameter , the density @xmath15 , out - of - equilibrium situations require at least one additional `` thermodynamic '' parameter . this parameter can not simply be the tapping strength since the system can be found in states characterized by the same tapping strength @xmath8 and the same density @xmath15 , that nonetheless evolve in different ways under further tapping with the same strength @xmath8 : this is illustrated in fig . [ fig:2]b . a natural candidate for an additional thermodynamic parameter is the available line fraction @xmath16 . one can indeed check that the two states described above do correspond to distinct values of @xmath16 . following the ideas put forward by edwards and coworkers@xcite , we consider a statistical - mechanical description of the system in which all possible microstates characterized by a ( small ) number of fixed macroscopic quantities are assumed to be equiprobable ( `` flat '' or microcanonical distribution ) . in addition to fixing the density @xmath15 , the parameter originally selected in the compactivity - based description of granular media by edwards and coworkers , we also constrain the microcanonical ensemble by fixing the available line fraction @xmath16 to account for the above discussion . denoting by @xmath28 the total length available for insertion of a particle center ( @xmath29 ) , the configurational integral with the constraints of fixed @xmath28 , fixed system size @xmath30 , and fixed number of particles @xmath31 is obtained as@xcite @xmath32 which can be rewritten as @xmath33\right)\ ] ] where @xmath34 and @xmath35 denote two closed contours . in the macroscopic limit , @xmath36 , @xmath37 , @xmath38 with @xmath15 and @xmath16 fixed , one can use a saddle - point method to evaluate the integrals , which leads to @xmath39 where the entropy density @xmath40 is given by @xmath41 with @xmath42 and @xmath43 solutions of the two coupled equations @xmath44 the gap distribution functions can also derived along the same lines@xcite , which leads to @xmath45 it can also be shown that the multi - gap distribution functions satisfy a factorization property , e.g. , @xmath46 . note that the @xmath14-gap distribution function is a piecewise continuous function that obeys the exact sum rules , eqs . ( [ eq:2 ] ) and ( [ eq:3 ] ) . a detailed comparison between the predictions of this statistical - mechanical treatment and simulation data _ at the same @xmath15 and @xmath47 _ can be found in ref.@xcite . the conclusion is that although not exact , and even missing some qualitative features in the limiting case of a purely irreversible rsa process , the approach provides an overall good description of the data . ( it becomes of course exact in the steady state since this latter corresponds to an equilibrium situation . ) a quasi - thermodynamic approach is useful because it allows to predict the structure of the system ( correlation functions ) as well as the fluctuations at any given state point ( here assumed to characterized by @xmath15 and @xmath16 ) . in the cases where phase transitions occur , it can also provide interesting constraints and relations between the parameters characterizing the phases at the transition or help to determine the limit of stability of the phases in mean - field like treatments . however , one still faces the problem of predicting the state of the system _ for a given protocol and a given history _ : in the simplest case , for a given time @xmath12 and a given tapping strength @xmath8 . we thus want to push the edwards formalism one step further . predicting the trajectory made by the system in the @xmath48 diagram for a given protocol amounts to determine a system of equations relating @xmath15 and @xmath16 with @xmath12 and @xmath9 . ( [ eq:1 ] ) is one such equation . to obtain another equation for the evolution of @xmath16 , we start for the exact kinetic equation for the @xmath17gap distribution function for @xmath49 : @xmath50 where @xmath51 is the @xmath7-gap distribution function that satisfies the `` sum rule '' @xmath52 note that the approximate @xmath0gap distribution function @xmath53 satisfies the above sum rule . by multiplying eq . ( [ eq:8 ] ) by @xmath54 , integrating over @xmath19 from @xmath14 to @xmath55 , and using the sum rules , eqs . ( [ eq:2 ] ) , ( [ eq:3 ] ) and ( [ eq:9 ] ) , one obtains an exact equation for the evolution of @xmath16 : @xmath56 if one now inserts the approximate expression of the @xmath14-gap distribution function , eq . ( [ eq:7 ] ) , in the above equation , one gets @xmath57 eqs . ( [ eq:1 ] ) , ( [ eq:5 ] ) , ( [ eq:6 ] ) and ( [ eq:11 ] ) form a closed set of equations whose solution for given initial conditions completely characterizes the system and its evolution . we first test the accuracy of the above approximate kinetic description in two limiting cases for which the exact solution is known : the purely irreversible rsa case ( @xmath58 ) and the approach to the steady state ( @xmath22 ) for a given rate @xmath9 . the steady state corresponds to the solution @xmath59 , @xmath60 , where @xmath61 is the equilibrium density of hard rods at constant activity @xmath8 : @xmath62 with @xmath63 ; it is thus the exact result . the approach to the steady state is obtained by linearizing the kinetic equations around the equilibrium solution . one then obtains the following coupled linear differential equations : @xmath64 the associated eigenvalues are all negative and that corresponding to the inverse of relaxation time goes for large @xmath9 as @xmath65 the relaxation time is of the same order of magnitude as that obtained in the simple adiabatic approximation@xcite and is much smaller than the exact result ( see above ) . the error comes from the inability of the edwards approximation to account for the non - exponential behavior of the @xmath17gap distribution function for @xmath66 . one the other hand the approximate kinetic description is very good in the purely irreversible case , @xmath58 , ( but it still misses some features , as discussed above and in ref.@xcite ) . then eqs . ( [ eq:1 ] ) and ( [ eq:11 ] ) simplify to @xmath67 where @xmath68 and @xmath69 are related to @xmath15 and @xmath16 by eqs . ( [ eq:5 ] ) and ( [ eq:6 ] ) . it is easy to show that at long times @xmath70 goes to a finite limit whereas @xmath71 goes to @xmath72 as @xmath12 . as a result the kinetics approaches a non - trivial jamming limit with an algebraic @xmath73 behavior . the numerical solution of the approximate equation shows that the saturation density at the jamming limit @xmath74 is very close to the exact value , @xmath75 . the overall agreement with the exact density evolution is very good , as shown in fig . [ fig:3 ] . finally , we apply the approximate kinetic equations to the description of memory effects . by introducing @xmath16 as the second state variable , one expects to obtain a response to a sudden change of the tapping strength that captures these memory effects . this is indeed illustrated in fig . [ fig:4]a that shows how the density evolves when @xmath9 is changed at @xmath76 from @xmath77 to @xmath78 and from @xmath77 to @xmath79 . at longer times , note that the density curve corresponding to the change from @xmath77 to @xmath79 crosses two times the density curve calculated when @xmath79 is kept constant along the process . this is the signature of a kovacs - like effect which is more clearly displayed in the parametric plot of fig . [ fig:4]b : instead of going monotonically to the final value , the density decreases first and passes by a minimum after increasing again . this non - monotonic behavior of the density ( or the volume ) is precisely the kovacs effect . the same phenomenon is illustrated for different values of the tapping strength in figs [ fig:5]a and b : @xmath9 is switched from @xmath80 to @xmath81 or from @xmath80 to @xmath82 after a time @xmath83 . in the former case , the density reached at @xmath83 when @xmath9 is changed is higher than the final ( equilibrium ) density reached at @xmath77 ; nonetheless , the density starts by first decreasing to a value less than the final density until it reaches a minimum and finally increases again . on the other hand , no minimum is observed in the latter case . the kovacs effect is traditionally represented as a `` hump '' in the volume as a function of time@xcite . the position and the height of the hump vary with the waiting time , i.e. , the time spent at the initial tapping strength ( recall that the process of compaction is always out of equilibrium ) , and with the amplitude of the shift in the tapping strength ( or in other glassy systems , the shift in temperature ) . the same behavior is found here . it is illustrated in fig . [ fig:6 ] where we show the evolution of the inverse density for different protocols to reach the equilibrium steady state at @xmath77 : in the upper curve , @xmath9 is switched from @xmath80 to @xmath81 at @xmath84 , in the intermediate curve @xmath9 is switched from @xmath82 to @xmath81 at @xmath85 and in the lower curve @xmath86 at @xmath87 . the waiting time @xmath88 is chosen that the density reached at that time is equal to final density , @xmath89 . one observes that the height of the hump increases as the amplitude of the shift increases . the kovacs effect , also observed in the simulation data ( not shown here ) , results from competing trends that are qualitatively well accounted for by the present description in terms of two thermodynamic parameters . including @xmath16 in the statistical - mechanical treatment is crucial for reproducing such behavior . we have applied a two - parameter statistical - mechanical formalism inspired by the work of edwards and coworkers to describe the compaction kinetics of the parking - lot model . the approximation gives a fair description of the kinetics , although it underestimates the relaxation time characteristic of the final approach to equilibrium . inclusion of a second thermodynamic parameter allows one to qualitatively reproduce experimentally observed memory effects in granular compaction and to predict a kovacs effect similar to what is observed in many glassy systems . bouchaud , in _ slow relaxations and nonequilibrium dynamics in condensed matter _ , vol . 77 of _ les houches - ecole dete de physique theorique _ , edited by j. l. barrat , m. feigelman , j. kurchan , and j. dalibard ( springer - verlag , berlin , 2003 ) .

the parking - lot model provides a qualitative description of the main features of the phenomenology of granular compaction . we derive here approximate kinetic equations for this model , equations that are based on a @xmath0parameter generalization of the statistical - mechanical formalism first proposed by edwards and coworkers . we show that history - dependent effects , such as memory and kovacs effects , are captured by this approach .

the main goal of endodontics is to restore the function and esthetic of the involved tooth . from a biomechanical perspective , this means cleaning , shaping , and disinfection that would allow for three - dimensional obturation of the root canal system . one of the main reasons for the failure of root canal treatment is the inadequate removal of pulp tissue and microorganisms from the root canal system . it is therefore of utmost importance that the dentist has a thorough knowledge of root canal morphology of the tooth being treated . the mandibular first molar is a frequently treated tooth and has a wide variety of root canal configurations . variations in the morphology of the dental pulp are caused by genetic and environmental influences , and there is very definite need for clinicians to be made aware of the frequency of racially determined forms . the major variant in mandibular first molars is the presence of a supernumerary root that can be found distolingually and has a curve at the apex . this macrostructure , first mentioned by carabelli , is called radix entomolaris , which in general is smaller than distobuccal and mesial roots and can be separate from or partially fused with these other roots . the morphology and buccolingual width of the mesial root allow for intercanal communications and isthmuses . currently , the isthmus ( anastomosis ) is defined as a pulpal passageway connecting 2 or more canals in the same root . studies on the root canal anatomy of mandibular first molar have been performed on several populations . an extensive literature search showed that there is only one study on the root canal morphology of indian mandibular first molars . the root canal anatomy of indian teeth by clearing technique has not been studied to date except for studies on premolars and mandibular second molars . hence , the purpose of this study was to prepare detailed investigation of root canal anatomy of mandibular first molar in an indian population by using clearing technique and to compare these findings with the published reports of different population . one hundred and fifty mandibular first molars were collected from the department of oral and maxillofacial surgery of the government dental college and hospital , nagpur in india . it was ensured that the teeth belonged to indigenous indians , and no teeth from other minority ethnicities were included . the collection of every tooth was accompanied by a case record stating and confirming the ethnicity of the patients . the teeth were washed under tap water immediately after extraction and stored in 10% formalin ( qualigens fine chemicals , mumbai , india ) . the residual soft tissues , bone fragments , and calculus were cleansed and removed by curettes and ultrasonic scalers . the specimens were then placed in 5.25% sodium hypochlorite ( prime dental products pvt ltd . , mumbai , india ) for 24 hours in order to dissolve organic debris and pulp remnants . the specimens were first decalcified at room temperature in 5% nitric acid ( qualigens fine chemicals , mumbai , india ) that was changed daily for 3 - 4 days . the acid was agitated thrice daily with glass rod , and the end point of decalcification was determined by periodic radiographs . after completion of decalcification , the specimens were washed under running tap water for 4 hours to remove traces of nitric acid . the specimens were dehydrated using ascending concentrations of ethyl alcohol ( thermo fisher scientific india pvt ltd . , mumbai , india ) starting with 70% for 12 hours , followed by 90% for an hour and 3 rinses of 1 hour each for 100% . the dehydrated specimens then were placed in methyl salicylate ( rankem fine chemicals ltd . , new delhi , india ) which made them transparent after approximately 2 hours . mumbai , india ) was injected into the pulp chamber with a 27-gauge needle on disposable syringe . the dye then was drawn through the canal system by applying negative pressure to the apical end of the tooth with the help of vacuum suction system . the excess ink was removed from the root surface with gauze soaked in 100% ethyl alcohol . two separate canals leave the pulp chamber and join short of the apex to form one canal . one canal leaves the pulp chamber , divides into two within the root , and then merges to exit as one canal . type v. one canal leaves the pulp chamber and divides short of the apex into two separate and distinct canals with separate apical foramina . two separate canals leave the pulp chamber , merge in the body of the root , and redivide short of the apex to exit as two distinct canals . one canal leaves the pulp chamber , divides and then rejoins within the body of the root , and finally redivides into two distinct canals short of the apex . the specimens were vertically sectioned in buccolingual direction through the furcation , to separate the mesial and distal halves . sectioning was done to avoid the overlapping of mesial and distal or distolingual roots during photography . the results of this study are summarized in ( tables 1 , 2 and 3 ) . of the 150 mandibular first molars , 94.6% had two roots , and 5.3% had extra distal roots ( distolingual root or radix entomolaris ) . in addition , 64% of the cases had three root canals ( mesiobuccal , mesiolingual and distal ) , and 36% had four root canals ( mesiobuccal , mesiolingual , distobuccal and distolingual ) ( table 1 ) . both the mesial and distal roots showed wide variations in canal configuration . in mesial root , type iv configuration was most prevalent ( 54% ) followed by type ii ( 36.6% ) , type vi ( 8% ) , and type v ( 0.6% ) ( figure 1(a)1(d ) ) . type ( 2 - 1 - 2 - 1 ) ( figure 1(e ) ) . in distal root , type i configuration was most prevalent ( 65.3% ) followed by type ii ( 20.6% ) , type iv ( 9.3% ) , type v ( 3.3% ) , and type iii ( 1.3% ) ( figure 2(a)2(e ) ) . in the three rooted molars , all distolingual roots possessed type i ( 100% ) canal configuration ( table 2 ) . isthmi ( intercanal communications ) ( figure 1(f ) ) were found in 30% of the cases in mesial and 10% of the cases in distal roots . apical deltas ( figure 2(f ) ) were found in 10% of the cases in mesial and 6% of the cases in distal roots ( table 3 ) . the methods used to study root canal morphology are replication technique [ 3 , 9 ] , clearing technique [ 68 , 1015 ] , use of radiopaque dyes and radiographs [ 2 , 1620 ] , sectioning of teeth , and recently , spiral computed tomography ( sct ) and cone beam computed tomography ( cbct ) . additionally , it is not necessary to gain an access into the specimen with instruments , thus original form and relationship of the canals are maintained . these include development of opaque areas due to incomplete dehydration , which can be correctable by additional dehydration in 100% ethyl alcohol . another common problem is the development of opacity after air drying ; however , this is readily reversible by immersion in methyl salicylate solution . in the present study , the prevalence of three rooted mandibular first molars among the indian population was 5.3% , similar to the study of garg et al . . this figure is lower than several earlier studies [ 8 , 14 , 16 , 22 ] , but higher than that reported by skidmore and bjorndal for caucasians , zaatar et al . for kuwaitis , sperber and moreau for africans , and al - qudah and awawdeh for a jordanian population . in this study , it was found that 36% of mandibular first molars had four canals . these results are similar to those of hartwell and bellizzi , who reported 35.1% of teeth and had four canals . this value is lower than the findings of several earlier authors [ 14 , 15 , 20 , 22 ] , but higher than that reported by skidmore and bjorndal , zaatar et al . , sperber and moreau , gulabivala et al . , and reuben et al . owing to the high percentage of two distal canals , classical triangular access preparation during root canal treatment should be extended towards the distolingual direction in a rectangular form to improve canal identification . in mesial root , type iv configuration was most prevalent ( 54% ) followed by type ii ( 36.6% ) , type vi ( 8% ) , and type v ( 0.6% ) configuration . this is consistent with the findings of most of the earlier studies [ 3 , 7 , 8 , 1215 , 17 , 21 , 22 ] , except the studies by zaatar et al . and al - nazhan which reported type ii being the most prevalent followed by type iv . in the present study , one mesial root showed an additional configuration type ( 2 - 1 - 2 - 1 ) as described by gulabivala et al . . identification , preparation , and obturation of type iv , type ii , and type vi are relatively straightforward . however , identification of canals in type v , where the canal further divides within the root , is more difficult . the presence of gulabivala 's type ( 2 - 1 - 2 - 1 ) needs extra efforts , because failure to debride and disinfect this complex anatomy might have a direct effect on the treatment outcome . there are published reports indicating the presence of type viii configuration in the mesial root , with the incidence of 0.2% to 5% [ 7 , 8 , 1215 , 22 ] . but in the present study , none of the samples had three canals in the mesial root . the most prevalent configuration in the distal root was type i ( 65.3% ) followed by type ii ( 20.6% ) , type iv ( 9.3% ) , type v ( 3.3% ) , and type iii ( 1.3% ) configuration . in terms of type ii and type iv configuration , this figure is lower than the studies of caliskan et al . , ahmed et al . , and al - nazhan , but higher than that reported by skidmore and bjorndal , vertucci , gulabivala et al . , and pineda and kuttler . the external morphology of the distal root is more rounded than the mesial one and therefore less likely to accommodate two separate canals . however , type iii and type v configurations in distal root need extra efforts to negotiate and prepare . one of the two canals , the one most continuous with the large main passage , is usually amenable to adequate enlarging and filling procedure , the preparation and filling of the other canal is often extremely difficult . in the three rooted molars , all distolingual roots possessed type i ( 100% ) canal configuration . in the present study , isthmi ( anastomosis ) were observed in 30% of the cases in mesial , and 10% of the cases in distal roots . this figure is lower than several earlier studies [ 7 , 8 , 12 , 13 , 15 ] . apical deltas were observed in 10% of the cases in mesial and 6% of the cases in distal roots , which is similar to the findings of vertucci and caliskan et al . , but higher than that reported by pineda and kuttler , gulabivala et al . , and al - qudah and awawdeh . the presence of isthmi and apical deltas may be of clinical significance , because it may be difficult to debride and fill these ramifications adequately . the use of sodium hypochlorite , preferably agitated by ultrasonics may help to reach the uninstrumented parts of the root canal system . furthermore , these ramifications can be more satisfactorily obturated by using some thermoplasticized gutta - percha technique rather than cold lateral condensation of gutta - percha points . the root canal morphology of 150 indian mandibular first permanent molars shows higher incidence of four canals ( 36% ) and extradistal roots ( 5.3% ) . therefore , the clinician must always look for a second canal in the distal root of indian mandibular first molars . the most prevalent canal configuration in the mesial root was vertucci type iv ( 54% ) , and in distal root type i ( 65.3% ) . an additional configuration , gulabivala type ( 2 - 1 - 2 - 1 ) , was found as a rare entity ( 0.6% ) in mesial root . as isthmi and apical deltas were observed in high percentage in mesial and distal root , efficient delivery and activation of irrigants are more essential . variations in the number of roots or canals and teeth with unusual root canal configurations have a definite impact on treatment . to achieve long - term success , clinician must use all the armamentaria at their disposal to locate and treat the entire root canal system .

an in vitro study was performed to determine the number of roots , root canals per tooth , root canal configurations , and frequency of isthmi and apical deltas in mandibular first permanent molars in an indian population . hundred and fifty mandibular first permanent molars were collected and subjected to clearing technique . the cleared teeth were examined in a stereomicroscope under 7.5x magnifications . the canal configurations were categorized using vertucci 's classification . overall 94.6% of the mandibular first molars had two roots , and 5.3% had extradistal roots ( distolingual root ) . in addition , 64% of the specimens had three root canals , and 36% had four root canals . the most common canal configurations of mesial and distal roots were vertucci type iv ( 54% ) and type i ( 65.3% ) , respectively . clinician should be aware of the complex root canal morphology of mandibular first molars among the indian population before and during the root canal treatment .

SECTION 1. SHORT TITLE. This Act may be cited as the ``American Working Families Tax Relief Act of 2009''. SEC. 2. STATE AND LOCAL SALES TAX DEDUCTION MADE PERMANENT. (a) In General.--Paragraph (5) of section 164(b) of the Internal Revenue Code of 1986 is amended by striking subparagraph (I). (b) Effective Date.--The amendment made by subsection (a) shall apply to taxable years beginning after December 31, 2009. SEC. 3. DEDUCTION FOR QUALIFIED TUITION AND RELATED EXPENSES MADE PERMANENT. (a) In General.--Section 222 of the Internal Revenue Code of 1986 is amended by striking subsection (e) (relating to termination). (b) Sunset Not To Apply.--Section 901 of the Economic Growth and Tax Relief Reconciliation Act of 2001 shall not apply to provisions of, and amendments made by, section 431 of such Act (relating to deduction for higher education expenses). (c) Effective Date.--The amendment made by this section shall apply to taxable years beginning after December 31, 2009. SEC. 4. MORTGAGE INSURANCE PREMIUMS TREATED AS INTEREST MADE PERMANENT. (a) In General.--Subparagraph (E) of section 163(h)(3) of the Internal Revenue Code of 1986 is amended by striking clause (iv). (b) Effective Date.--The amendment made by this section shall apply to amounts paid or accrued after December 31, 2009. SEC. 5. EXPANSION AND MODIFICATION OF THE HOMEBUYER CREDIT. (a) Extension.-- (1) In general.--Section 36(h) of the Internal Revenue Code of 1986 is amended by striking ``December 1, 2009'' and inserting ``December 31, 2009''. (2) Conforming amendment.--Section 36(g) of such Code is amended by striking ``December 1, 2009'' and inserting ``December 31, 2009''. (b) Expansion to All Purchasers of Principal Residence.-- (1) In general.--Subsection (a) of section 36 of such Code is amended by striking ``who is a first-time homebuyer of a principal residence'' and inserting ``who purchases a principal residence''. (2) Conforming amendments.-- (A) Subsection (c) of section 36 of such Code is amended by striking paragraph (1) and by redesignating paragraphs (2), (3), (4), and (5) as paragraphs (1), (2), (3), and (4), respectively. (B) Section 36 of such Code is amended by striking ``first-time homebuyer credit'' in the heading and inserting ``home purchase credit''. (C) The table of sections for subpart C of part IV of subchapter A of chapter 1 of such Code is amended by striking the item relating to section 36 and inserting the following new item: ``Sec. 36. Home purchase credit.''. (D) Subparagraph (W) of section 26(b)(2) of such Code is amended by striking ``homebuyer credit'' and inserting ``home purchase credit''. (c) Modification of Recapture.-- (1) Repeal of general recapture rule.--Subsection (f) of section 36 of such Code is amended by striking paragraph (1) and by redesignating paragraphs (2) through (7) as paragraphs (1) through (6), respectively. (2) 3-year recapture period.--Paragraph (6) of section 36(f) of such Code, as so redesignated, is amended to read as follows: ``(6) Recapture period.--For purposes of this subsection, the term `recapture period' means the 36-month period beginning on the date of the purchase of such residence by the taxpayer.''. (3) Conforming amendments.-- (A) Paragraph (1) of section 36(f) of such Code, as so redesignated, is amended to read as follows: ``(1) In general.--If a taxpayer disposes of the principal residence with respect to which a credit was allowed under subsection (a) (or such residence ceases to be the principal residence of the taxpayer (and, if married, the taxpayer's spouse)) before the end of the recapture period, the tax imposed by this chapter for the taxable year of such disposition or cessation shall be increased by the amount of the credit so allowed.''. (B) Section 36(f)(2) of such Code, as so redesignated, is amended-- (i) by striking ``paragraph (2)'' and inserting ``paragraph (1)'', and (ii) by striking the second sentence. (C) Section 36(f)(3) of such Code, as so redesignated, is amended-- (i) by striking ``Paragraphs (1) and'' in subparagraph (A) and inserting ``Paragraph (1)'', (ii) in subparagraph (B)-- (I) by striking ``Paragraph (2)'' both places it appears and inserting ``Paragraph (1)'', and (II) by striking ``paragraph (2)'' and inserting ``paragraph (1)'', (iii) in subparagraph (C)-- (I) by striking ``paragraph (2)'' in clause (i) and inserting ``paragraph (1)'', and (II) by striking ``paragraphs (1) and (2)'' and inserting ``paragraph (1)'', and (iv) by striking subparagraph (D). (4) Conforming amendment.--Subsection (g) of section 36 of such Code is amended by striking ``subsection (c)'' and inserting ``subsections (c) and (f)(4)(D)''. (d) Effective Dates.-- (1) Extension.--The amendment made by subsection (a) shall take effect on the date of the enactment of this Act. (2) 1st time homebuyer.--The amendment made by subsection (b) shall apply to purchases on or after the date of the enactment of this Act. (3) Modification of recapture.--The amendments made by subsection (c) shall take effect as if included in the amendments made by section 3011(c) of the Housing and Economic Recovery Act of 2008.

American Working Families Tax Relief Act of 2009 - Amends the Internal Revenue Code to make permanent the tax deductions for state and local sales taxes, qualified tuition and related expenses, and mortgage insurance premiums. Modifies the first-time homebuyer tax credit by: (1) allowing all purchasers of a principal residence, not just first-time homebuyers, to claim such credit; (2) eliminating the requirement to repay credit amounts over a 15-year period; and (3) imposing a recapture requirement for taxpayers who dispose of a residence within 36 months after purchase. Extends such credit through December 31, 2009.

in 1957 andrew keller reported that polyethylene formed chain - folded lamellar crystals from solution.@xcite this discovery was followed by the confirmation of the generality of this morphology lamellar crystals are formed on crystallization from both solution and the melt@xcite for a wide variety of polymers and the basic phenomenological laws describing such properties as the thickness and growth rate.@xcite in particular , the crystal thickness , @xmath0 , has been found to be inversely proportional to the supercooling,@xcite which is interpreted as resulting from @xmath0 being slightly larger than @xmath1 , the minimum thickness for which a lamellar crystal is stable with respect to the solution or melt , i.e. @xmath2 , where @xmath3 is small . surprisingly , however , no theoretical consensus has yet been reached as to the mechanism of this seemingly simple behaviour . in particular , two of the most well - known theories the lauritzen - hoffman ( lh ) surface nucleation theory@xcite and the sadler - gilmer ( sg ) entropic barrier model@xcite present very different explanations of thickness selection.@xcite of course , in such a situation , one would like to determine which of the theories , if any , is closest to the truth . there are two aspects to such a task . firstly , the predictions of the theories should be critically compared with experimental results . in the case of polymer crystallization both the lh and sg theories are able to reproduce the basic behaviour : the observed temperature dependence of the thickness and the growth rate . additionally , hoffman and coworkers have further developed the surface nucleation approach in order to explain some of the more detailed behaviour of crystallizing polymers , for example the regime transitions in the growth rate.@xcite however , this comparison does not conclusively favour one of the theories . this situation illustrates the fact that although consistency with experiment is an important first hurdle for any theory , it does not automatically imply the correctness of a theory . there may be a number of different ways of generating a particular experimental law . furthermore , the number of parameters in a complex theory may give the theory sufficient plasticity to fit a wide variety of scenarios . secondly , it is important that the assumptions of a theory , particularly those about the microscopic mechanisms , are critically examined . however , in the case of polymer crystallization this task is very difficult to achieve experimentally . by addressing this gap , computer simulations can potentially play an important role in this field . such simulations could range from examining simple models to performing realistic atomistic simulations of the crystal growth process . the former could allow the effects of relaxing some of the theoretical assumptions to be determined and the latter could provide a detailed molecular picture of the growth process . indeed , there has been an increasing number of computational studies pursuing these aims.@xcite in this paper i will review my efforts in this direction@xcite and hope to illustrate the positive role that computer simulations can play in helping to understand polymer crystallization . in particular , the aim of my simulations has been to critically examine the lh and sg theories . in the lh theory the growth of a new layer is modelled as the deposition of a succession of stems ( straight sections of the chain that traverse the growth face ) along the growth face from an initial nucleus , where the length of each stem is the same as the thickness of the lamella . the inset of figure [ fig : snfree ] illustrates the geometry of this mechanism . to analyse the kinetics of growth , a thermodynamic description of the nucleation and growth of a new layer is first required . the free energy of a configuration with @xmath4 complete stems is taken to be @xmath5 where @xmath6 and @xmath7 are the width and depth of a stem , @xmath0 is the thickness of the lamella , @xmath8 is the lateral surface free energy , @xmath9 is the fold surface free energy , and @xmath10 is the free energy of crystallization . the first term corresponds to the free energy of the two lateral surfaces created on the deposition of the first stem and is proportional to @xmath0 . the second term is the free energy of the new fold surface created on the deposition of subsequent stems . it is then assumed that at the barrier between configurations with different numbers of stems all the new surfaces have been created and that a fraction @xmath11 of the free energy of crystallization is released . this then gives the lh free energy profile that is illustrated in figure [ fig : snfree ] . from this free energy profile , @xmath12 , the flux over the barrier , can be obtained . the observed crystal thickness is then taken to correspond to the average @xmath13 this average thickness is close to the value of @xmath0 at the maximum in @xmath12 , which in turn is close to , but slightly above @xmath1 , thus reproducing the observed behaviour of @xmath0 . the maximum in @xmath12 is the result of two competing factors . the free energy barrier for deposition of the first stem increases with @xmath0 , thus making the growth of thick crystals prohibitively slow . however , as @xmath1 is approached from above , the thermodynamic driving force for crystallization goes to zero . it is important to note that by integrating over @xmath0 , equation ( [ eq : lave ] ) assumes that there are crystals with all values of @xmath0 greater than @xmath1 which all grow with constant thickness and contribute to the average @xmath14 . those crystals with a thickness close to the maximum in @xmath12 dominate this ensemble and contribute more to equation ( [ eq : lave ] ) because of their rapid growth . as was realized by frank and tosi,@xcite the results of experiments where the temperature is changed during crystallization argue against such an ensemble . the temperature jumps give rise to steps on the lamellae , showing that a crystal need not necessarily grow at constant thickness.@xcite we will come back to this issue later , but in this section we focus on the lh free energy profile . in particular , we compare this theoretical profile with ones computed from simulations of a simple polymer.@xcite in our model the polymer is represented by a self - avoiding walk on a simple cubic lattice . there is an attractive energy , -@xmath15 , between non - bonded polymer units on adjacent lattice sites and between polymer units and the surface , and an energetic penalty , @xmath16 , for kinks ( or ` gauche bonds ' ) in the chain . the parameter @xmath16 determines the stiffness of the chains . in our simulations we have included a surface which represents the growth face of a polymer crystal . to follow the crystallization of the polymer on the surface , we need to define an order parameter which determines the degree of crystallinity . we use @xmath17 , the largest fragment of the polymer with the structure of a target crystalline configuration . in our case , we examine the crystallization of a 200-unit chain into a structure with 5 stems of length 40 units . in order to compare with the theoretical profiles we have to constrain the other @xmath18 units in the chain to be disordered . the simulations were carried out using configurational - bias monte carlo,@xcite and the umbrella sampling technique@xcite was used to calculate the free energy profiles . the free energy profiles that we obtained are shown in figure [ fig : mcfree]a . they show the expected temperature dependence : at low temperature the crystal is most stable and at high temperature the disordered state is most stable . note that the value of @xmath17 for the disordered state is non - zero , because the disordered polymer is adsorbed on the surface . the adsorbed polymer is bound to have some short straight sections that qualify as crystalline by the definition of @xmath17 . the free energy profiles also have a sawtooth structure resembling that of the theoretical profile . the barriers occur immediately after the previous stem has been completed , and correspond to the formation of a new fold . they are followed by a monotonic decrease in energy as this new stem grows to completion . in the language of the lh theory @xmath19 for @xmath20 . however , there is no feature in the simulation profiles that corresponds to the formation of the first fold . this is because the initial nucleus is not a single stem , but two stems connected by a fold that grow simultaneously . such a possibility had previously been suggested by point.@xcite confirmation of a two - stem nucleus comes from a simple model calculation of the free energy profile . we can write the free energy as @xmath21 where the sum is over all possible crystalline configurations which are @xmath17 units long , @xmath22 is the energy of the crystalline configuration , and @xmath23 is the free energy of an ideal two - dimensional coil . the resulting profile is very similar to the simulation profile ( figure [ fig : mcfree]b ) . in particular , there is no feature due to the formation of the first fold . however , when we force the initial nucleus to be a single stem by restricting the sum in the above equation to only those crystalline configurations with one incomplete stem , a free energy barrier associated with the formation of the first fold appears . the reason for the preference for a two - stem nucleus is simply energetic . for @xmath24 the two - stem nucleus is lower in energy because of the interaction between the two stems . our simulations were performed on a surface that was infinite . whether a two - stem nucleus would be expected , when , as with a lamellar crystal , the thickness of the growth face is finite , depends upon how this critical size compares to the thickness of the lamella . it can be clearly be seen from figure [ fig : mcfree]b that the two - stem nucleus significantly reduces the nucleation barrier . in particular , it will no longer be proportional to @xmath0 . this has significant implications for the lh theory given the key role played by this initial free energy barrier in constraining @xmath14 to a value close to @xmath1 . before we move on we should make a number of comments . first , the polymer model is very simple , and although there is no obvious reason why the thermodynamic reasons behind the two - stem nucleus should not also apply to a real polymer , there may be factors that are not included in our model that come into play . second , the profiles reflect our choice of order parameter . as we monitor crystallization unit by unit , during the growth of the first two stems the lateral surface energy is paid for at the same time as the free energy of crystallization is released . therefore , in this size range @xmath11 is effectively equal to 1 , albeit with the possibility of a two - stem nucleus . hoffman , however , advocates a @xmath11=0 version of the lh theory it has the advantage that it avoids a ` @xmath3-catastrophe ' ( a divergence of the lamellar thickness ) at large supercooling in which he postulates that prior to crystallization an aligned physisorbed state is formed that has lost its entropy but not yet gained the free energy of crystallization.@xcite such a state can not occur in our lattice model because there is no difference in the interaction with the surface for a disordered chain adsorbed on the surface and a crystalline layer . in an off - lattice model the interaction energy for the crystalline layer would be greater because the stems would fit into the grooves provided by the stems of the previous layer . third , a good order parameter must pass continuously through intermediate values when the system goes between two states . however , one can imagine a number of mechanisms by which this criterion for @xmath17 is broken . for example , in a realistic simulation of the surface crystallization of a long alkane into a once - folded configuration , the chain first formed non - adjacent crystalline stems connected by a loose fold which then came together by the propagation of a defect through one of the stems.@xcite another possibility that has been observed in simulations is the formation of crystallites in different portions of a chain that subsequently coalesce to form a single crystallite.@xcite in the previous section , in order to compare the lh free energy profile with those from simulation , we had to constrain the @xmath18 units not having the target structure to be disordered . if we had not done this , at temperatures where the crystal is most stable the rest of the chain would have formed a crystalline configuration with stem lengths different from the target configuration . this naturally raises questions about the lh assumption that the stems in a new layer must all have the same thickness as the previous layer . in this section , we examine the effects of relaxing some of the lh assumptions by studying a model in which the stems grow unit by unit and the length of a stem is unconstrained.@xcite we term it a multi - pathway model because it can take into account the many possible ways that a new crystalline layer can form . this idea is not new . frank and tosi,@xcite price@xcite and lauritzen and passaglia@xcite considered models where the stem length is not always constant , and point,@xcite and dimarzio and guttman@xcite studied models where the stems could grow unit by unit . all these studies were performed at a time when computational resources were much less , so approximations and simplifications had to be made in order to render the models tractable . the natural way to solve such problems , though , is through the use of computational techniques , such as kinetic monte carlo . however , the only applications of computational methods to this problem were in a short note by point@xcite and the continuation of this work in the phd thesis of dupire.@xcite some of the results presented in these earlier studies are similar to those we report here . in our model we grow a single new crystalline layer by the successive growth of stems across a surface that represents the growth face of a polymer crystal . the polymer interactions are the same as used in the previous section , and we only model the crystalline portion of the polymer explicitly the rest is assumed to behave like an ideal coil . an example configuration is illustrated in figure [ fig : mpmoves ] along with possible changes of configuration . these changes can only occur at the ends of the crystalline portion , and are selected using the kinetic monte carlo algorithm , in which a move is chosen with a probability proportional to the rate for that process . first , we shall examine the effect of the initial nucleus on the thickness of the layers grown . if the stem lengths are unconstrained and the initial nucleus is a single stem , one might imagine that one way of reducing the large initial free energy barrier in figure [ fig : snfree ] ( and achieving faster initial growth ) would be for the stem length to increase gradually to its average value as crystallization progresses . for this pathway , the lateral surface free energy is paid for ` in installments ' rather than all initially . this is exactly what we observe when we force the initial nucleus to be a single stem by only allowing growth from one end of the crystalline portion of the chain ( figure [ fig : mpnucleus]a ) . when a double - stem nucleus is allowed the initial growth is very different because there is now no longer a large initial free energy barrier to circumvent . the most important thing to note from these results is that , contrary to the lh theory , the thickness of the inital nucleus does not determine the thickness of the layer . further confirmation of this can be obtained when we examine the growth from initial seed crystals . whatever the thickness of the initial seed the thickness of the growing crystal converges to the same value ( figure [ fig : mpnucleus]b ) . this implies that the thickness of a crystalline layer must be determined by factors which are operating on the deposition of each stem and not those specific to the initial stems . to determine what these factors might be , in figure [ fig : mpthick ] we show how the thickness of a new layer depends on temperature . first , it is immediately obvious that the thickness of a new layer is not necessarily the same as that of the growth face . second , all the curves increase as the temperature approaches @xmath25 , the melting or dissolution temperature , because of the rise of @xmath1 . third , the thickness also increases at low temperature , in this instance because it becomes increasingly difficult to scale the free energy barrier for forming a fold and so on average the stems continue to grow for longer . however , this rise is checked by the thickness of the growth face . it is unfavourable for the polymer to overhang the edge of the growth face because these units do not interact with the surface . figure [ fig : mpthick ] only describes the growth of a single layer . however , as the thickness of the new layer is not generally the same as the thickness of the growth face , one needs to consider the addition of a succession of layers . if we assume that all the variations in the stem length within a layer are annealed out before a new layer begins to grow , this can be achieved using figure [ fig : mpattract]a , in which we have plotted for a single temperature the thickness of the new layer against the thickness of the growth face . by following the dotted lines one can see what would happen for growth on a growth face that is 50 units thick : the first layer is 36 units thick , the second 28 , the third 23 , thus , the thickness converges to the value @xmath26 at which the curve crosses @xmath27 , i.e. to the point where the thickness of the new layer is the same as the previous , and then the crystal continues to grow at this thickness . the mapping represented in figure [ fig : mpattract]a is a fixed - point attractor . a similar picture emerges if we explicitly perform simulations of multi - layer growth . figure [ fig : mp3d ] shows a cut through a typical configuration that results . within 510 layers the thickness of the crystal converges to its steady - state value @xmath26 and then growth continues at that thickness . the mechanism of thickness selection that occurs in our multi - pathway is at odds with the lh theory . it shows that it is inappropriate to compare the growth rates of crystals of different thickness because the thickness has only one dynamically stable value for which growth at constant thickness occurs . the ensemble of crystals assumed by equation ( [ eq : lave ] ) is fictitious . furthermore , the growth rate of a new layer slows down as @xmath26 is approached from above ( inset of figure [ fig : mpattract]a ) . however , we should note that in some of the multiple - pathway studies@xcite mentioned earlier , it was realized that stable growth can only occur at the one thickness where a new layer has the same thickness as the previous . since then this insight has for the most part been neglected . to analyse the reasons for the dynamical convergence of the thickness to the value @xmath26 we examine how the probability distributions for the stem length depend on the thickness of the growth face ( figure [ fig : mppstem ] ) . @xmath1 places one constraint on the stem length ; only a small fraction of the stems can be shorter than @xmath1 if the layer is to be thermodynamically stable . the thickness of the growth face places the second constraint on the stem length ; it is energetically unfavourable for the polymer to extend beyond the edges of the growth face . there is also a third weaker kinetic constraint on the stem length . at every step there is always a certain probability that a fold will be formed . therefore , even in the absence of the second constraint , i.e. an infinitely thick growth face , the probability distribution will decay exponentially to zero at large stem length ( figure [ fig : mppstem]a ) . although , this effect prevents the thickness from ever diverging in a @xmath3-catastrophe,@xcite it does not stop the thickness becoming very large . when the growth face is significantly thicker than @xmath1 there is a range of stem lengths between @xmath1 and the thickness of the growth face that are viable , and therefore the new layer will be thinner than the previous layer . however , as the thickness of the growth face decreases , the probability distributions of the stem length becomes increasingly narrow and the difference in probability between the stem length being greater or less than the surface thickness diminishes . finally , at @xmath26 , as the thickness of the growth face approaches @xmath1 , the probability distribution become symmetrical about the surface thickness and the thickness of the new layer becomes equal to the thickness of the growth face ( figure [ fig : mppstem]e ) . when the thickness is less than @xmath26 , the asymmetry of the probability distribution is reversed ( figure [ fig : mppstem]f ) . it is , therefore , through the combined action of the two thermodynamic constraints on the stem length that the thickness converges to a value close to @xmath1 . 2 the picture is not quite this simple at all temperatures . as the supercooling decreases , it becomes increasingly unfavourable for a stem to overhang the edge of the growth face . indeed , for sufficiently small supercoolings the probability distribution for the stem length never becomes symmetrical about the thickness of the growth face , not even when the thickness of the growth face is close to @xmath1 . this situation is illustrated in figure [ fig : mpattract]b . after the growth of two layers on a 50-unit thick surface , the crystal stops growing because the outer layer is too thin for a new layer to form . for these supercoolings , as in the sg model , the rounding of the crystal profile inhibits growth . to overcome this barrier requires a cooperative mechanism whereby a new layer takes advantage of ( and then locks in ) dynamic fluctuations in the outer layer to larger thickness . however , unlike the sg model , the current model has no interlayer dynamics we attempt to grow a new layer on an outer layer that is static and so growth stops . despite this it is clear that if this interlayer dynamics could be included , it would again lead to steady - state growth close to @xmath1 . we should note that this cessation of growth was also found in the model of frank and tosi at low supercoolings.@xcite lauritzen and passaglia were also aware of this effect , but they introduced an _ ad hoc _ energetic term in their rate constants to prevent it.@xcite however , in the restricted equilibrium model of price this effect was absent.@xcite in this study each new layer , but not the crystal as a whole , was allowed to reach equilibrium and so the kinetic constraint on the stem length is absent . finally , we should note that our multi - pathway model is not parameter - free , and that , like most other models of polymer crystallization ( including the lh theory@xcite , the sg model@xcite and the earlier multi - pathway models@xcite ) , for some choices of parameters ( not those used here ) the lamellar thickness begins to increase at sufficiently large supercooling.@xcite this effect occurs because the large driving force for crystallization at large supercoolings reduces the effect that the thickness of the growth face has in constraining the stem lengths . in this section we re - examine the model used by sadler and gilmer in order to see whether the mechanism of thickness selection that we found in the previous section for our multi - pathway model also occurs in the sg model . sadler and gilmer interpreted this model in terms of an entropic barrier . in particular , they argued that the rounding of the crystal profile gives rise to an entropic barrier , which can only be surmounted by a fluctuation to a squarer profile before growth can continue . as this barrier increases with lamellar thickness it constrains the thickness to a value close to @xmath1 . however , we shall not dwell on this interpretation here , but instead direct the interested reader to a critique of this argument in ref . . in the sg model the growth of a polymer crystal results from the attachment and detachment of polymer units at the growth face . the rules that govern the sites at which these processes can occur are designed to mimic the effects of the chain connectivity . in the original three - dimensional version of the model , under many conditions the growth face is rough and the correlations between stems in the direction parallel to the growth face are weak.@xcite therefore , an even simpler two - dimensional version of the model was developed in which lateral correlations are neglected entirely , and only a slice through the polymer crystal perpendicular to the growth face is considered.@xcite the geometry of the model is shown in figure [ fig : sgmoves ] . changes in configuration can only occur at the outermost stem and stems behind the growth face are ` pinned ' because of the chain connectivity . at each step , there are three possible changes in configuration : the outermost stem can increase in length , a new stem can be initiated and a polymer unit can be removed from the outermost stem . the model can be formulated in terms of a set of rate equations that can be easily solved by numerical integration.@xcite when we examine the dependence of the thickness of a layer on the previous , we again find a fixed - point attractor describing the convergence of the thickness to its steady - state value ( figure [ fig : sgattract ] ) . moreover , when we examine the probability distributions for the stem length we find evidence for the same three constraints as for the multi - pathway model ( figure [ fig : sgpstem]b ) . the weaker nature of the kinetic constraint is particularly clear from the much more rapid exponential decay of the probability for stems that extend beyond the growth face . the role played by the two thermodynamic constraints in the mechanism of thickness selection is particularly clear from figure [ fig : sgpstem]b . as the thickness of the growth face decreases the viable range of stem lengths decreases until the the thickness of the growth face meets @xmath1 at the fixed point . in this paper we have outlined evidence from computer simulations for a mechanism of thickness selection in lamellar polymer crystal that differs from the theories of lauritzen and hoffman , and sadler and gilmer . instead , the mechanism has much more in common with the results of earlier multi - pathway models.@xcite we find that a fixed - point attractor which describes the dynamical convergence of the crystal thickness to a value just larger than the minimum stable thickness , @xmath1 . this convergence arises from the combined effect of two constraints on the length of stems in a layer : it is unfavourable for a stem to be shorter than @xmath1 and for a stem to overhang the edge of the previous layer . it is encouraging to note that we find the same mechanism of thickness selection operating in two models which make very different assumptions about the microscopic growth processes . this provides evidence of the generality of this mechanism , and so suggests that , although the models described here have a very simplified description of the microscopic dynamics , the physical principles behind the mechanism could be general enough to apply to real polymers . this mechanism of thickness selection is also consistent with experiments where the temperature is changed during crystallization.@xcite the steps that result indicate that the thickness of the lamellar crystals dynamically converges to the steady - state thickness for the new temperature by a mechanism similar to that which we observe in our simulations . furthermore , if the step profiles could be characterized with sufficient resolution by atomic - force microscopy , it may be possible to extract the fixed - point attractor of a real polymers . however , for a temperature decrease the step profiles may also reflect the rounding of the crystal edge and for a temperature increase the roughness of the fold surface.@xcite furthermore , any annealing mechanisms that operate could change the shape of the step profile from its as - formed state . although the multi - pathway approach is , in some ways , an extension of the lh theory , the removal of many of the lh constraints leads to significantly different behaviour . in particular , our work undermines the lh assumptions that the initial nucleus determines the thickness of a layer , and shows that the approach embodied in equation ( [ eq : lave ] ) ( i.e. a comparison of the growth rates of the crystals in an ensemble of crystals of different thickness all of which grow at constant thickness ) is inappropriate because crystals of arbitrary thickness do not necessarily continue to grow at that thickness . although our results lead us to question the thickness selection mechanism in the lh theory , other aspects of the nucleation approach may not be affected by our critique . for example , the regime transitions are a result of the different functional dependence of the growth rate on the nucleation rate and the substrate completion rate in the different regimes.@xcite recently , there have been a number of alternative theoretical proposals that have made recourse to metastable phases . keller and coworkers suggested that crystallization of polyethylene could initially occur into the mobile hexagonal phase . these crystals would then thicken until a critical thickness was reached at which a phase transition to the orthorhombic phase would occur.@xcite olmsted _ et al . _ have argued that the density fluctuations resulting from the spinodal decomposition of a polymer melt@xcite assist the nucleation of crystals.@xcite strobl and coworkers have argued , on the basis of the thickness dependence of the crystallization and melting temperatures of syndiotactic polypropylene , and the granular texture in afm images of the same polymer , that the polymer first crystallizes into blocks , which are subsequently stabilized when they fuse into lamellae.@xcite our simulations can say little about these proposals since our polymer models are too simple to be able to capture such features . however , all these approaches are based on behaviour that has been observed in crystallization from the melt , so it is not clear how the ideas can apply to crystallization from solution , where the same basic laws for lamellar polymer crystals apply .

in this paper i describe the computer simulations that i have performed to critically examine the lauritzen - hoffman and the sadler - gilmer theories of polymer crystallization . in particular , i have computed the free energy profile for nucleation of a new crystalline layer on the growth face to compare with that assumed by the lauritzen - hoffman theory , i have analysed the mechanism of thickness selection in a multi - pathway model in which some of the constraints in the lauritzen - hoffman theory are relaxed , and i have re - examined the model used by sadler - gilmer . these investigations have lead to a mechanism of thickness selection of lamellar polymer crystals that differs from the two theories that i set out to examine . 2

Chris Christie and John Kasich are in. Rick Perry is out. And Donald Trump will be center stage. The jockeying to win a ticket to the first Republican presidential debate in Cleveland ended Tuesday afternoon, when Fox News announced the roster of 10 candidates who will be on the stage Thursday evening. Story Continued Below The candidates, drawn from an average of the five most recent national polls, ranked from first to 10th: Trump, former Florida Gov. Jeb Bush, Wisconsin Gov. Scott Walker, former Arkansas Gov. Mike Huckabee, neurosurgeon Ben Carson, Texas Sen. Ted Cruz, Florida Sen. Marco Rubio, Kentucky Sen. Rand Paul, Christie and Kasich. Perry, the former governor of Texas whose performance in the debates four years ago helped doom his campaign, finished in 11th place, eight-tenths of a point behind Kasich. Former Pennsylvania Sen. Rick Santorum, Louisiana Gov. Bobby Jindal, former Hewlett-Packard CEO Carly Fiorina, South Carolina Sen. Lindsey Graham, former Virginia Gov. Jim Gilmore and former New York Gov. George Pataki are farther behind. The top 10 candidates will debate in a two-hour event at 9 p.m. Eastern time on Thursday. The also-rans will be invited to appear at a separate, one-hour debate, which airs at 5 p.m. Eastern. Much about the debate criteria remained unclear right up until the 5 p.m. deadline Fox News set back in May. The network hadn’t revealed precisely which polls would be used to calculate its average. And when the network unveiled its criteria, it also raised the possibility of expanding beyond 10 participants in the event of a tie. Ultimately, the most controversial decision Fox News made in choosing the polls that would be used was dismissing an NBC News/Wall Street Journal poll conducted from July 26-30 and using a Quinnipiac University survey conducted July 23-28. The change would not have altered the composition of the top 10, however. Fox said it dismissed the NBC News/Wall Street Journal poll “because it did not meet our criterion that the poll read the names of each Republican candidate in the vote question.” Interviewers instead read the name of each candidate and asked respondents if they had a positive or negative opinion of that candidate. Following that battery of questions, respondents were asked which candidate they would favor, given a choice of 10 candidates (the 10 who made the final cut, except substituting Perry for Kasich), “or would you vote for one of the other candidates that were mentioned in the previous question?” Fox News’ decision to limit the field has shaped much of the race on the Republican side in recent weeks. Super PACs and other groups supporting Rubio, New Jersey Gov. Christie and Perry spent more than $4 million combined on national cable television advertising in an effort to boost the candidates’ name recognition. The candidates themselves eschewed trips to Iowa and New Hampshire for appearances on Fox News and other television networks. Some candidates sought other ways to earn free media coverage, either with funny, viral Internet videos or by attacking Trump, who has dominated headlines since declaring his candidacy in June. Kasich timed the declaration of his candidacy almost perfectly, using a post-announcement bounce to vault into the top 10. The Ohio governor staged his announcement rally on July 21, two days before the first of the decisive polls entered the field — the Quinnipiac survey, which showed Kasich at 5 percent, his high-water mark. By qualifying for the debate, Kasich avoids the embarrassment of being sidelined in his home state. But the 5 p.m. forum will also have a number of accomplished candidates: the former governors of three big states (Texas, Virginia and New York), a sitting senator, a former senator and a former Fortune 500 CEO who is also the field’s only female candidate. Some of the also-rans accepted the assignment in stride. Santorum was alone in taking aim at Fox News — and the Republican National Committee — for relegating him to the earlier debate. “The senator will be taking part in the earlier debate; however, the process employed by both Fox News and the RNC is incredibly flawed,” said Santorum spokesman Matthew Beynon. “The idea that they have left out the runner-up for the 2012 nomination, the former … governor of Texas, the governor of Louisiana, the first female Fortune [500] CEO, and the three-term senator from South Carolina due to polling seven months before a single vote is cast is preposterous. While Fox is taking a lot of heat, the RNC deserves as much blame for sanctioning this process. They should not be picking winners and losers. That’s the job of the voters, particularly those in Iowa and New Hampshire who have the role of voting first.” Jindal will also attend the earlier debate, but his campaign made clear that it is focused on Iowa. “The crowds are growing and the governor is rising in the Iowa polls,” said Jindal spokeswoman Shannon Dirmann. “That’s where our time will be spent.” Dylan Byers and Katie Glueck contributed to this report. ||||| That's according to a new study out with some interesting findings: Trump dominates the conversation in social media and traditional news sources. He's done little to leverage that into support. "Trump is making a lot of noise, but he's not necessarily doing the work" that would be needed "to turn that share of voice into actual votes," said Lara Brown, associate professor at George Washington University's Graduate School of Political Management, a co-author of the study. Hillary Rodham Clinton is a pro on social media, using it to bring in supporters. And perhaps most surprising at all, at least for those of us inside newsrooms: The public is even more focused than the media are on Trump. Details on the study from The Times' David Lauter:

– Fox has announced the 10 candidates who have qualified for Thursday's prime-time debate, and it's bad new for Rick Perry and some other familiar names, reports the Los Angeles Times. Fox averaged five recent polls, and Perry finished eight-tenths of a point behind No. 10 John Kasich, notes Politico. Those in: Donald Trump, Jeb Bush, Scott Walker, Mike Huckabee, Ben Carson, Ted Cruz, Marco Rubio, Rand Paul, Chris Christie, and John Kasich. Those out: Rick Perry, Rick Santorum, Bobby Jindal, Carly Fiorina, Lindsey Graham, Jim Gilmore, and George Pataki.

impaired respiratory function shows a high correlation with morbidity and mortality , and is the main characteristic of chronic obstructive pulmonary disease , along with dyspnea , cough , and increased sputum1 , 2 . normal respiratory function is important to the prognosis in patients with chronic obstructive pulmonary disease3 . impaired respiratory function is also a common cause of death in patients with parkinson s disease4 . in the elderly , impaired respiratory function is one factor leading to declining physical function and eventually to increased morbidity and mortality5 . several methods used to improve respiratory function have been studied , including pulmonary rehabilition6 , medicine therapy7 , operative methods8 , respiratory muscle strengthening exercise9 , and spinal manipulation therapy10 . however , evidence supporting the use of spinal manipulation to improve respiratory function is lacking , and further research is required11 . spinal manipulation has also been used to increase rib cage mobility to improve respiratory function . however , in prior studies , spinal manipulation was administered to the cervical and thoracic regions and the ribs10 , or to a designated level of the thoracic spine that is not related to joint mobility12 . therefore , the spinal level at which manipulation affects respiratory function is not clear . in this study , the aim of this study was to evaluate the immediate effect of spinal thoracic manipulation on respiratory function tests in healthy young subjects . thirty - five healthy participants between the ages of 20 and 38 years who were not currently taking any medication for a respiratory condition and had no pain in the thoracic region were recruited from the local university . social smokers and anyone with contraindications to spinal manipulation were excluded from the study . allocation to groups was randomized and concealed from all participants , with each participant selecting a sealed envelope from a set of prepared envelopes . number 1 assigned participants to the experimental group and number 2 assigned participants to the control group . before thoracic spinal manipulation , all participants underwent respiratory function testing . the participants were instructed to lie in a supine position with their arms folded horizontally across their chest . the therapist positioned a stabilizing hand in a pistol grip . the thoracic spinal manipulation component involved both high - velocity and low - amplitude ( hvla ) maneuvers , and was restricted to the thoracic region to maximize the effect on chest wall rigidity . the control group received placebo thoracic spinal manipulation in the same position , except that the therapist s hand was open and not in a pistol grip . because no force was applied the respiratory function measurements included forced vital capacity ( fvc ) and forced expiratory volume in one second ( fev1 ) , and were evaluated with a spirometer ( sp-1 , schiller , usa ) . the shapiro - wilk test was used to test variables for normality , and the independent t - test was used for comparisons of respiratory function between the experimental and control groups . comparison of pre- and post - spinal thoracic manipulation respiratory function in each group was analyzed using the paired t - test . , chicago , il , usa ) for windows was used for all analyses , and p values of < 0.05 were regarded as significant . this study was approved by the ethics committee of sahmyook university , and all participants provided informed consent before participation in the study . thirty - five healthy volunteers participated in this study . however , 5 volunteers were excluded from the study because they refused to receive spinal manipulation . after the intervention , the fvc and fev1 were significantly increased in the experimental group ( p<0.05 ) . however , the control group showed no difference after the intervention . differences between the 2 groups in pre- and post - intervention fvc and fev1 were significant ( table 1table 1.comparison of respiratory function within groups and between groupsexperimentalcontrolage ( years)21.2 2.122.5 4.8height ( cm)165.5 7.2167.9 9.3weight ( kg)58.8 9.760.2 10.3fvc ( l)pre2.8 0.52.7 0.4post2.9 0.5 * 2.7 0.4pre - post0.2 0.1 * 0.0 0.0fev1 ( l)pre2.5 0.52.3 0.4post2.6 0.5 * 2.3 0.3pre - post0.1 0.1 * 0.0 0.0values are expressed as mean sd . * fvc : forced vital capacity ; fev1 : forced expiratory volume in one second ) . this study was conducted to investigate the effects of thoracic spinal manipulation on respiratory function ( fvc and fev1 ) . after the intervention , only the experimental group showed improved respiratory function test results for both fvc and fev1 . these results are in agreement with those of previous studies . henley et al.13 proposed that manipulation therapy promotes autonomic activity , causing associated vasodilation , smooth muscle relaxation , and increased blood flow , leading to improved range of motion , decreased pain perception , and/or changes in the tissue . it would seem reasonable to consider manipulation therapy as an adjunctive therapeutic approach to increase thoracic mobility , reduce the work of breathing , and manage pain . the administration of manual therapy to the thoracic region may regulate the autonomic nerve supply to the respiratory muscles14 . in addition , a number of studies have shown that increasing thoracic joint mobility improves lung function in the short term in normal individuals15 , 16 . in this study , spinal manipulation was only applied to the thoracic region with reduced mobility . thoracic spinal manipulation may have increased thoracic joint mobility , and thus improved respiratory function test results in this study . however , the improvements in results after intervention in the experimental group were very small . this small amount of change in test results may be the result of treating healthy young volunteers . changes in respiratory function after thoracic spinal manipulation may be much greater in individuals with respiratory dysfunction . first , a larger and more diverse population of participants , including older individuals and patients with respiratory dysfunction , such as those with chronic obstructive pulmonary disease , will be necessary .

[ purpose ] the purpose of this study was to investigate the effects of thoracic spinal manipulation therapy on respiratory function including forced vital capacity and forced expiratory volume in one second in young healthy individuals . [ subjects and methods ] thirty young healthy subjects recruited from a local university participated in this study . subjects were randomly allocated into an experimental group ( n=15 ) and a control group ( n=15 ) . the experimental group received thoracic spinal manipulation and the control group received placebo thoracic spinal manipulation . respiratory function tests , including forced vital capacity and forced expiratory volume in one second , were measured before and after intervention . [ results ] the values for both tests were significantly higher in the experimental group . the control group showed no changes after the intervention . differences in pre- and post - intervention values for both tests were significantly different between the 2 groups . [ conclusion ] spinal manipulation therapy applied to the thoracic region improved respiratory function test results of participants in this study .

autosomal monoallelic expression ( mae ) refers to mitotically stable , epigenetically controlled allele - specific expression of autosomal genes , with the initial non - predetermined ( random ) choice of the transcriptional activity of the two alleles maintained in a given clonal cell lineage [ recent reviews include ( 13 ) ] . mae is a relatively recent addition to the number of known epigenetic mechanisms that involve separate regulation of the two alleles activity in mammalian cells , including x - chromosome inactivation ( 4 ) , allelic exclusion in immunoglobulin loci ( 5 ) and genomic imprinting ( 6 ) . after discovery of random allelic inactivation of olfactory receptor genes ( 7 ) , there were scattered reports of mae in a variety of mouse genes , including il4 ( 8) and innate immunity receptor tlr4 ( 9 ) . the advent of transcriptome - wide approaches based first on hybridization to arrays ( 10,11 ) or beads ( 12 ) and then rna sequencing ( 1316 ) revealed that mae is widespread in human and mouse cells . analysis of allelic expression in a limited number of clonal cell lines indicated that a small percentage of genes in a given cell type were subject to mae . importantly , for most genes subject to mae , in some clonal lines the gene was expressed equally from both alleles . this makes the detection of mae strongly dependent on the number of clonal lines available : the more lines analyzed , the higher the likelihood that mae status for a gene will be detected in at least one line . in addition to isogenic clonal cell lines , the approaches used in these studies depend on the existence of polymorphisms between maternal and paternal copies of a gene . accordingly , much higher polymorphism density in f1 hybrid mouse crosses [ e.g. ( 11 ) ] compared to heterozygosity in human samples [ e.g. ( 10 ) ] resulted in a much greater fraction of genes being informative . recently , it was shown that mae can be identified regardless of sequence variation , on the basis of a characteristic signature of chromatin modifications in human ( 13 ) and mouse ( 14 ) cells . based on this approach , the ability to classify genes as mae or biallelically expressed has become available for the entire genome in multiple tissues and cell types in two organisms , human and mouse , creating a need for better data access and dissemination . the database of autosomal mae genes described here is targeted to researchers interested in investigating mae in individual genes or groups of genes . we compiled information from multiple reports of allele - specific expression and chromatin signature of mae genes . note that the relationship between chromatin modifications we assessed and allele - specific silencing has not been established for imprinted genes ( 17 ) or genes on the x chromosome . the same is the case of olfactory receptor genes , the largest gene family in mammalian genomes , for which expression of one allele per neuron is thought to be obligatory ( 18 ) . finally , we did not incorporate data from single - cell sequencing studies of allele - specific expression [ e.g. ( 19 ) ] since it is not yet clear how to distinguish mitotically stable autosomal mae from stochastic transcription in single cells . dbmae contains two broad classes of data : direct measurement of allelic expression ( im)balance ( termed experimental ) and indirect chromatin - based inference ( inferred ) . the database maintains a clear distinction between these types of evidence , listing the entry 's mae status according to all available sources . the data are organized into separate tables containing gene information in the form of unique database i d a gene symbol , or refseq / entrez i d ; and experimental or prediction data for each unique gene i d in each tissue . at the time of this publication , transcript - specific data on monoallelic expression for example , ( 13,14 ) considered only the longest transcript for that gene , without parsing reads between overlapping isoforms . however , the database structure allows for seamless integration of future transcript specific data . the allelic expression data ( rna - seq and microarray ) is taken from six recent studies ( 10,11,1315 ) . to ensure uniform criteria of monoallelic and biallelic expression , the data are analyzed and curated according to the method described in ( 13 ) . briefly , biased expression in a clonal sample is called if a gene 's cumulative variant counts on phased snps pass the fdr - corrected binomial test , and the gene is biased at least 2:1 in favor of either allele . the former condition ensures that technical noise due to low coverage will not be translated into monoallelic calls . the latter condition buffers against the binomial test 's hypersensitivity to small deviations from 50:50 in highly covered genes . further , empirical monoallelic expression in a cell type is called if at least one clonal line belonging to this cell type has shown monoallelic expression . note that some instances of biased expression may be due to genetic bias rather than epigenetic mae . thus the experimental data are best interpreted in the broader context of all data available for the gene , and in conjunction with the predictions from chromatin analysis . the inference of mae from chromatin signature , described and validated in ( 13,14 ) , involves a decision - tree utilizing information about the overall input - normalized enrichment of h3k27me3 and h3k36me3 integrated over the gene body . inferred monoallelic or biallelic expression status in a given tissue is assigned if the gene : ( i ) has the chromatin signature of mae in that tissue and ( ii ) is ranked on the top half of all genes by expression level . this standard cut - off was adopted in ( 14 ) and retroactively applied to data from ( 13 ) to achieve a unified approach . since mae is known to be a tissue - specific phenomenon , it is sufficient for a gene to be inferred mae in one tissue to be classified as monoallelic in the database . in addition to the categories monoallelic and biallelic , we include a category undetermined , which indicates that evidence for mae exists only from chromatin - based method and is detected only at very low expression levels , where its validity has not been extensively studied . at the time of publication , the database contains mae calls for over 700 human and 16 000 mouse genes with experimental evidence of allelic bias as assessed in four tissue types . there are close to 5000 corresponding positively confirmed instances of biallelic expression in human and more than 21 000 in mouse . in addition , the database includes mae and biallelic calls based on genome - wide chromatin analysis for seven human and 21 murine cell types and tissues . searchable fields include gene name , cell or tissue type and organism as well as gene allelic expression status . the gene name field accepts common gene names , ensembl , refseq and entrez ids . search functionality is divided into basic and advanced modes ( see online supplementary ) . in basic mode , the user can check if a gene is inferred or measured to have monoallelic expression in mouse or human tissues ( e.g. msx2 ) , or how classes of genes behave ( by checking the search for gene class prefix option and entering a partial name , e.g. msx ) . for example , it is possible to check the status of a gene in a specific organism and tissue ( e.g. msx2 with organism : advanced mode also allows searching by status to check if a class of genes is inferred / known to be monoallelically expressed anywhere ( e.g. msx2 with status : monoallelic and organism / tissue : any organism ) , or if a gene is inferred / known to show monoallelic expression in mouse fibroblasts specifically ( msx2 with status : monoallelic and organism / tissue : mouse fibroblast ) . to maintain a balance between providing the user with all available evidence and presenting it in a usable form , as a first step , we indicate whether a gene shows any evidence for mae for a given context specified during the search ( e.g. in any tissue type in either organism , or in a specific tissue / organism ) . thus , a user is first presented with all matching searches in a summary page , where each matching entry is described as monoallelic if it is either inferred or empirically determined to be monoallelic in at least one tissue ( figure 1 ) . clicking on the entry of interest opens the tissue page , where inferred and experimental data are described for each tissue or cell type . clicking on the name of a specific tissue shows data used for prediction and/or allelic expression data from individual clones . results of queries to the databases can be examined to greater specificity by clicking on fields of interest . shown msx2. gene page : indicates overall gene status in the organisms currently in the database . monoallelic indicates that there is some evidence for monoallelic expression in at least one tissue . tissue page : accessed upon clicking one of the entries in the gene page ; indicates inferred and experimental status of the gene in the selected organism in each tissue . clicking the download as csv button results in a csv file with the data as presented on the page . tissue page. the chromatin mark section shows quantile rank values for the chromatin marks h3k27me3 and h3k36me3 in the selected tissue for the query gene . the experimental data section shows clonal cell lines derived from the tissue in question , and whether the query gene was positively called ( 1 " ) or undetermined ( 0 " ) to be either biased or unbiased in each line . in addition , we have implemented a basic batch mode , where multiple comma - separated gene ids can be entered . this yields all individual database entries for these ids , in a comma - separated format . note that the inferred and experimental data do not necessarily come from the same biological sample , but are nevertheless matched for comparison purposes . for example , the experimental data on neuronal progenitor cells derived from datasets gse54016 and e - mtab-1822 are presented as separate datasets , since they involve different experiments from different labs . at the same time , both are compared with the same chromatin - based inference on neuronal progenitor samples . furthermore , measured and inferred allelic expression statuses are not always identical for the same cell or tissue type . biological differences between samples , for instance due to genetic background or clonal derivation , may explain some of these inconsistencies . for instance , when assessing mae using rna - seq in heterozygous clonal lines , the number of clonal lines assessed may not be sufficient to capture mae that normally happens in a small proportion of cells . conversely , chromatin signature may capture unstable mae , or be confounded by bimodal distribution of expression across cells ( e.g. if a gene is completely shut down in some cells , but is biallelic in other cells , we will observe a co - occurrence of chromatin marks for silencing and active transcription similar to those observed with mae ) [ see ( 13,14 ) ] . these approaches are complementary and presenting allelic expression and chromatin signature data side by side should be beneficial to users . dbmae contains two broad classes of data : direct measurement of allelic expression ( im)balance ( termed experimental ) and indirect chromatin - based inference ( inferred ) . the database maintains a clear distinction between these types of evidence , listing the entry 's mae status according to all available sources . the data are organized into separate tables containing gene information in the form of unique database i d a gene symbol , or refseq / entrez i d ; and experimental or prediction data for each unique gene i d in each tissue . at the time of this publication , transcript - specific data on monoallelic expression for example , ( 13,14 ) considered only the longest transcript for that gene , without parsing reads between overlapping isoforms . however , the database structure allows for seamless integration of future transcript specific data . the allelic expression data ( rna - seq and microarray ) is taken from six recent studies ( 10,11,1315 ) . to ensure uniform criteria of monoallelic and biallelic expression , the data are analyzed and curated according to the method described in ( 13 ) . briefly , biased expression in a clonal sample is called if a gene 's cumulative variant counts on phased snps pass the fdr - corrected binomial test , and the gene is biased at least 2:1 in favor of either allele . the former condition ensures that technical noise due to low coverage will not be translated into monoallelic calls . the latter condition buffers against the binomial test 's hypersensitivity to small deviations from 50:50 in highly covered genes . further , empirical monoallelic expression in a cell type is called if at least one clonal line belonging to this cell type has shown monoallelic expression . note that some instances of biased expression may be due to genetic bias rather than epigenetic mae . thus the experimental data are best interpreted in the broader context of all data available for the gene , and in conjunction with the predictions from chromatin analysis . the inference of mae from chromatin signature , described and validated in ( 13,14 ) , involves a decision - tree utilizing information about the overall input - normalized enrichment of h3k27me3 and h3k36me3 integrated over the gene body . inferred monoallelic or biallelic expression status in a given tissue is assigned if the gene : ( i ) has the chromatin signature of mae in that tissue and ( ii ) is ranked on the top half of all genes by expression level . this standard cut - off was adopted in ( 14 ) and retroactively applied to data from ( 13 ) to achieve a unified approach . since mae is known to be a tissue - specific phenomenon , it is sufficient for a gene to be inferred mae in one tissue to be classified as in addition to the categories monoallelic and biallelic , we include a category undetermined , which indicates that evidence for mae exists only from chromatin - based method and is detected only at very low expression levels , where its validity has not been extensively studied . at the time of publication , the database contains mae calls for over 700 human and 16 000 mouse genes with experimental evidence of allelic bias as assessed in four tissue types . there are close to 5000 corresponding positively confirmed instances of biallelic expression in human and more than 21 000 in mouse . in addition , the database includes mae and biallelic calls based on genome - wide chromatin analysis for seven human and 21 murine cell types and tissues . searchable fields include gene name , cell or tissue type and organism as well as gene allelic expression status . the gene name field accepts common gene names , ensembl , refseq and entrez ids . search functionality is divided into basic and advanced modes ( see online supplementary ) . in basic mode , the user can check if a gene is inferred or measured to have monoallelic expression in mouse or human tissues ( e.g. msx2 ) , or how classes of genes behave ( by checking the search for gene class prefix option and entering a partial name , e.g. msx ) . for example , it is possible to check the status of a gene in a specific organism and tissue ( e.g. msx2 with organism : advanced mode also allows searching by status to check if a class of genes is inferred / known to be monoallelically expressed anywhere ( e.g. msx2 with status : monoallelic and organism / tissue : any organism ) , or if a gene is inferred / known to show monoallelic expression in mouse fibroblasts specifically ( msx2 with status : monoallelic and organism / tissue : mouse fibroblast ) . to maintain a balance between providing the user with all available evidence and presenting it in a usable form , as a first step , we indicate whether a gene shows any evidence for mae for a given context specified during the search ( e.g. in any tissue type in either organism , or in a specific tissue / organism ) . thus , a user is first presented with all matching searches in a summary page , where each matching entry is described as monoallelic if it is either inferred or empirically determined to be monoallelic in at least one tissue ( figure 1 ) . clicking on the entry of interest opens the tissue page , where inferred and experimental data are described for each tissue or cell type . clicking on the name of a specific tissue shows data used for prediction and/or allelic expression data from individual clones . results of queries to the databases can be examined to greater specificity by clicking on fields of interest . shown are data panels from pages resulting from simple query by gene symbol msx2. gene page : indicates overall gene status in the organisms currently in the database . monoallelic indicates that there is some evidence for monoallelic expression in at least one tissue . tissue page : accessed upon clicking one of the entries in the gene page ; indicates inferred and experimental status of the gene in the selected organism in each tissue . clicking the download as csv button results in a csv file with the data as presented on the page . data page : accessed upon clicking one of the entries in the tissue page. the chromatin mark section shows quantile rank values for the chromatin marks h3k27me3 and h3k36me3 in the selected tissue for the query gene . the experimental data section shows clonal cell lines derived from the tissue in question , and whether the query gene was positively called ( 1 " ) or undetermined ( 0 " ) to be either biased or unbiased in each line . in addition , we have implemented a basic batch mode , where multiple comma - separated gene ids can be entered . this yields all individual database entries for these ids , in a comma - separated format . note that the inferred and experimental data do not necessarily come from the same biological sample , but are nevertheless matched for comparison purposes . for example , the experimental data on neuronal progenitor cells derived from datasets gse54016 and e - mtab-1822 are presented as separate datasets , since they involve different experiments from different labs . at the same time , both are compared with the same chromatin - based inference on neuronal progenitor samples . furthermore , measured and inferred allelic expression statuses are not always identical for the same cell or tissue type . biological differences between samples , for instance due to genetic background or clonal derivation , may explain some of these inconsistencies . limitations intrinsic to both approaches may also play a role . for instance , when assessing mae using rna - seq in heterozygous clonal lines , the number of clonal lines assessed may not be sufficient to capture mae that normally happens in a small proportion of cells . conversely , chromatin signature may capture unstable mae , or be confounded by bimodal distribution of expression across cells ( e.g. if a gene is completely shut down in some cells , but is biallelic in other cells , we will observe a co - occurrence of chromatin marks for silencing and active transcription similar to those observed with mae ) [ see ( 13,14 ) ] . these approaches are complementary and presenting allelic expression and chromatin signature data side by side should be beneficial to users . pew scholar award [ to a.a.g . in part ] ; nih [ r01gm114864 to v.s . ,

recently , data on random autosomal monoallelic expression has become available for the entire genome in multiple human and mouse tissues and cell types , creating a need for better access and dissemination . the database of autosomal monoallelic expression ( dbmae ; https://mae.hms.harvard.edu ) incorporates data from multiple recent reports of genome - wide analyses . these include transcriptome - wide analyses of allelic imbalance in clonal cell populations based on sequence polymorphisms , as well as indirect identification , based on a specific chromatin signature present in mae gene bodies . currently , dbmae contains transcriptome - wide chromatin identification calls for 8 human and 21 mouse tissues , and describes over 16 000 murine and 700 human cases of directly measured biased expression , compiled from allele - specific rna - seq and genotyping array data . all data are manually curated . to ensure cross - publication uniformity , we performed re - analysis of transcriptome - wide rna - seq data using the same pipeline . data are accessed through an interface that allows for basic and advanced searches ; all source references , including raw data , are clearly described and hyperlinked . this ensures the utility of the resource as an initial screening tool for those interested in investigating the role of monoallelic expression in their specific genes and tissues of interest .

a total of 58 strains of v. cholerae o1 el tor isolated in calcutta before ( march december 1992 ; group i ) , during ( july november 1993 ; group ii ) , and after ( march 1994june 1995 ; group iii ) the v. cholerae o139 outbreak ( 8) were included in this study . these strains , belonging to ribotypes ri , rii , and riii , were maintained in brain - heart infusion broth supplemented with 15% glycerol at 70c and grown when needed ( 8) . the 3 conserved sequence of class i integrons is characterized by antibiotic resistance gene qace1 and the sulfonamide resistance gene sul1 . to identify class i integrons , primers atcgcaatagttggcgaagt ( accession no . x12869 ) , specific for 3 cs ( 5 ) , were amplified in this region by polymerase chain reaction as described ( 5 ) . a 0.8-kb product , found in 22 of the 58 isolates , was confirmed to be the 3 cs of class i integrons by sequencing ( table ) . to identify the gene cassette in the class i integrons , primers previously used to amplify the region between the 5 cs and 3 cs ( 5 ) were used . all 22 strains produced a 1.0-kb amplicon , which on sequencing was found to contain the aada1 gene that confers resistance against aminoglycosides , streptomycin , and spectinomycin ( 4,5 ) . ( 8) a , ampicillin ; cf , ciprofloxacin ; fz , furazolidone ; g , gentamycin ; n , neomycin ; na , nalidixic acid ; s , streptomycin ; sm , sulfamethizole ; t , tetracycline ; tr , trimethoprim . a total of 17 out of the 22 class i integron - bearing strains belonged to the before period . the remaining five , though isolated after june 1993 , probably represented carry - over strains . these five strains belonged to the same ri ribotype as the other 16 strains from the before period ( table ) and had a ctx structure identical to the other strains with ri ribotype ( 8) . resistance of v. cholerae isolates to ampicillin ( 10 g ) , ciprofloxacin ( 5 g ) , furazolidone ( 50 g ) , gentamycin ( 10 g ) , neomycin ( 30 g ) , nalidixic acid ( 30 g ) , streptomycin ( 10 g ) , sulfamethizole ( 100 g ) , tetracycline ( 30 g ) , and trimethoprim ( 25 g ) were examined by using commercial discs ( hi media , bombay , india ) as described ( 1 ) . an overall increase in the number of strains with resistance to a greater number of antibiotics was seen in the isolates of the post - o139 period ; a fourfold increase in resistance against trimethoprim , a drug often used for the treatment of cholera in children and pregnant women , was noted . almost all strains , from all isolation periods , were uniformly resistant to streptomycin and sulfamethizole , but none were found to be resistant to tetracycline , gentamycin , or ciprofloxacin . none of the strains belonging to the ribotypes rii and riii , which were all isolated during and after the o139 outbreak , carried the aada1 gene cassette ( coding for aminoglycoside resistance ) ; however , they were all resistant to streptomycin . further , all of the strains were resistant to trimethoprim . since strains of v. cholerae , which harbor the sxt element , are resistant to streptomycin and trimethoprim ( 7 ) , we sought to determine if the resistance of the post - o139 strains to streptomycin and trimethoprim could be traced to an sxt element . colony hybridization of the 58 strains with a 0.8-kb probe , specific for the sxt integrase gene ( 7 ) , showed that all trimethoprim - resistant strains from all isolation periods and all during and after streptomycin - resistant carried the sxt element ( table ) . further , five of these strains harbored both sxt and the aada1 gene cassette ( table ) . our survey thus suggested that while the streptomycin resistance of the strains isolated before the o139 outbreak was due to the aada1 gene cassette carried by the class i integrons , the sxt element was probably responsible for this phenotype in the post - o139 strains . since none of the strains harbored any plasmid and the resistance determinants present in the class i integrons and in the sxt element could account for only a few markers , other determinants of antibiotic resistance may exist . ( 4 ) found that the o1 strains isolated in vietnam in 1994 and after had the ribotype identical to that found in some of the o1 strains isolated in samutsakorn , thailand , during and after the 1993 o139 outbreak . both pre- and post - o139 isolates carried class i integrons with the aada2 gene cassette . this fact led dalsgaard et al . to conjecture that this distinct o1 strain might have been transferred between thailand and vietnam ( 5 ) . however , the possibility of its migrating from a third country could not be ruled out . the ribotype of the pre - o139 , o1 calcutta strains examined in this study was identical to that of the samutsakorn strains ( 4,5,8 ) . however , as can be seen from the data presented here , unlike the samutsakorn strains , these strains harbored aada1 gene cassette . the 3 conserved sequence of class i integrons is characterized by antibiotic resistance gene qace1 and the sulfonamide resistance gene sul1 . to identify class i integrons , primers atcgcaatagttggcgaagt ( accession no . x12869 ) , specific for 3 cs ( 5 ) , were amplified in this region by polymerase chain reaction as described ( 5 ) . a 0.8-kb product , found in 22 of the 58 isolates , was confirmed to be the 3 cs of class i integrons by sequencing ( table ) . to identify the gene cassette in the class i integrons , primers previously used to amplify the region between the 5 cs and 3 cs ( 5 ) were used . all 22 strains produced a 1.0-kb amplicon , which on sequencing was found to contain the aada1 gene that confers resistance against aminoglycosides , streptomycin , and spectinomycin ( 4,5 ) . sharma et al . ( 8) a , ampicillin ; cf , ciprofloxacin ; fz , furazolidone ; g , gentamycin ; n , neomycin ; na , nalidixic acid ; s , streptomycin ; sm , sulfamethizole ; t , tetracycline ; tr , trimethoprim . a total of 17 out of the 22 class i integron - bearing strains belonged to the before period . the remaining five , though isolated after june 1993 , probably represented carry - over strains . these five strains belonged to the same ri ribotype as the other 16 strains from the before period ( table ) and had a ctx structure identical to the other strains with ri ribotype ( 8) . resistance of v. cholerae isolates to ampicillin ( 10 g ) , ciprofloxacin ( 5 g ) , furazolidone ( 50 g ) , gentamycin ( 10 g ) , neomycin ( 30 g ) , nalidixic acid ( 30 g ) , streptomycin ( 10 g ) , sulfamethizole ( 100 g ) , tetracycline ( 30 g ) , and trimethoprim ( 25 g ) were examined by using commercial discs ( hi media , bombay , india ) as described ( 1 ) . an overall increase in the number of strains with resistance to a greater number of antibiotics was seen in the isolates of the post - o139 period ; a fourfold increase in resistance against trimethoprim , a drug often used for the treatment of cholera in children and pregnant women , was noted . almost all strains , from all isolation periods , were uniformly resistant to streptomycin and sulfamethizole , but none were found to be resistant to tetracycline , gentamycin , or ciprofloxacin . none of the strains belonging to the ribotypes rii and riii , which were all isolated during and after the o139 outbreak , carried the aada1 gene cassette ( coding for aminoglycoside resistance ) ; however , they were all resistant to streptomycin . further , all of the strains were resistant to trimethoprim . since strains of v. cholerae , which harbor the sxt element , are resistant to streptomycin and trimethoprim ( 7 ) , we sought to determine if the resistance of the post - o139 strains to streptomycin and trimethoprim could be traced to an sxt element . colony hybridization of the 58 strains with a 0.8-kb probe , specific for the sxt integrase gene ( 7 ) , showed that all trimethoprim - resistant strains from all isolation periods and all during and after streptomycin - resistant carried the sxt element ( table ) . further , five of these strains harbored both sxt and the aada1 gene cassette ( table ) . our survey thus suggested that while the streptomycin resistance of the strains isolated before the o139 outbreak was due to the aada1 gene cassette carried by the class i integrons , the sxt element was probably responsible for this phenotype in the post - o139 strains . since none of the strains harbored any plasmid and the resistance determinants present in the class i integrons and in the sxt element could account for only a few markers , other determinants of antibiotic resistance may exist . ( 4 ) found that the o1 strains isolated in vietnam in 1994 and after had the ribotype identical to that found in some of the o1 strains isolated in samutsakorn , thailand , during and after the 1993 o139 outbreak . both pre- and post - o139 isolates carried class i integrons with the aada2 gene cassette . this fact led dalsgaard et al . to conjecture that this distinct o1 strain might have been transferred between thailand and vietnam ( 5 ) . however , the possibility of its migrating from a third country could not be ruled out . the ribotype of the pre - o139 , o1 calcutta strains examined in this study was identical to that of the samutsakorn strains ( 4,5,8 ) . however , as can be seen from the data presented here , unlike the samutsakorn strains , these strains harbored aada1 gene cassette . we had shown previously that the post - o139 , o1 strains isolated in calcutta could have migrated to guinea - bissau in africa ( 9 ) . further evidence has shown that this strain , which caused an outbreak in 19941995 , could have subsequently acquired class i integrons bearing the [ ant(3)-1a ] gene cassette by a 150-kb plasmid from an unknown source ( 10 ) . while the class i integron with aada1 gene cassette was widely distributed among the pre - o139 o1 strains isolated in calcutta , it was mostly absent in the post - o139 o1 strains ( figure ) . this finding is in contrast to other studies involving the sxt element ; 80% of all pre - o139 strains were devoid of sxt , whereas all post - o139 strains ( with the exception of a few carry - over strains ) had it ( figure ) . when the data presented in this paper are considered together with the information presented by others ( 4,5,8,10 ) , it appears that both pre- and post - o139 , o1 strains , isolated in calcutta , probably could have moved to other countries and became established there . distribution of class i integrons and sxt elements in vibrio cholerae el tor strains isolated before , during , and after the o139 outbreak .

we examined the distribution of class i integrons and sxt elements in vibrio cholerae o1 el tor strains , isolated in calcutta , india , before and after the v. cholerae o139 outbreak in 1992 . class i integrons , with aada1 gene cassette , were detected primarily in the pre - o139 strains ; the sxt element was found mainly in the post - o139 strains .

@xcite discovered that the universe is expanding by finding a correlation between a galaxy s recession velocity and its distance . since then , a reliable estimate of the expansion rate of the universe at the current epoch has been a central subject in observational cosmology . this expansion rate is denoted by the hubble constant , @xmath2 , and it characterizes the nature of the universe , such as the age of the universe , @xmath6 , the observable size of the universe , @xmath7 , and the critical mass density of the universe , @xmath8 , where @xmath9 is the speed of light , and @xmath10 is the gravitational constant . a variety of empirical distance - ladder methods have been proposed , which determine the distance to a galaxy through a series of steps , with each step calibrating the next more distant step , such as those with final steps based upon the period luminosity relation for cepheid variable stars , the maximum luminosity of type ia supernovae , etc . the results from these empirical methods have almost converged to a value of @xmath2 at around 73 km s@xmath5 mpc@xmath5 @xcite . on the other hand , a physical method has the advantage over the empirical methods in that it could , in principle , determine @xmath2 through a reasonable model parameterization without resorting to an empirical distance ladder . the sunyaev zeldovich effect @xcite and the use of gravitational lensing @xcite have been proposed . however , their results for @xmath2 have not converged to agree with those from the empirical methods , because uncertainties associated with parameters in these particular methods do not allow an accuracy comparable to the empirical methods @xcite . consequently , other physical methods that enable the measurement of extragalactic distances with higher accuracy are eagerly sought . in this letter , we propose a new physical method , using a model with simple physics , for extragalactic distance determination . our model is based on the dust reverberation in active galactic nuclei ( agns ) . we demonstrate the effectiveness of this method by determining @xmath2 with a value and accuracy comparable to that obtained by the hubble key project using cepheid variable stars . an agn consists of a hot central engine surrounded by a cooler dust torus ( e.g. , * ? ? ? * ; * ? ? ? dust near the central engine is sublimated , creating a gap between the central engine and the inner radius of the torus . dust grains beyond the sublimation radius , @xmath11 , absorb short wavelength light produced by the central engine , and re - emit the absorbed energy at long wavelengths . variations in the flux emitted by the central engine are mimicked at long wavelengths by the dust torus after a time delay , @xmath12 , corresponding to the light travel time between the central engine and the inner radius of the dust torus . apparently , @xmath11 is determined by the absolute luminosity , @xmath13 , of the central engine according to @xmath14 @xcite . thus , by measuring the time delay , @xmath15 , we can obtain the absolute luminosity of the agn , and its distance . we assume local energy balance between the absorbed short wavelength ultraviolet ( uv ) radiation and the re - emitted long wavelength near - infrared ( nir ) radiation at the inner radius of the dust torus : @xmath16 where @xmath17 in the uv to optical region with the power - law index @xmath18 , @xmath19 is the absolute luminosity in the @xmath20-band , @xmath21 is the plank function for the characteristic dust sublimation temperature @xmath22 , and @xmath23 is the absorption coefficient per dust grain of mean radius @xmath24 as a function of @xmath25 taken from literature @xcite . values of the three parameters , @xmath18 , @xmath22 , and @xmath24 , are set using observations of agn . we have @xmath26 taken from a composite qso spectrum @xcite . we adopt a rather large uncertainty of @xmath27 which well covers the observed range of qso to qso spectral index variation . with this @xmath28 , we truncate the uv spectrum at @xmath29 @xmath30 m , considering the uv turnover of qso spectrum ( e.g. , * ? ? * ; * ? ? ? * ) and the decrease of dust absorption efficiency at shorter wavelength below this truncation @xcite . we have @xmath31 k evaluated from the @xmath32 , @xmath33 , and @xmath34 color temperatures of the variable nir component for a sample of seyfert 1 galaxies observed with the magnum telescope @xcite . is evaluated from the nir color temperatures of the variable component rather than the average or single - epoch nir spectral energy distributions of the whole component which contains the contribution from the dust of lower temperatures at larger radii beyond @xmath11 ( e.g. , * ? ? ? * ; * ? ? ? agns in our sample show no burst - like flux variation but repeat the brighter and fainter states in turn ( figure 1 ) , keeping their nir colors almost constant @xcite . therefore , the dust temperature of the variable component is regarded as staying almost constant during the flux variation . note that the color temperatures can be determined without subtracting the host - galaxy flux , which would often be an origin of large uncertainty . ] the value for @xmath22 is consistent with the condensation temperature for solid carbon @xcite . since dust grains other than graphite grains sublimate below this temperature , the absorption coefficient of graphite grains is adopted for @xmath23 . the distribution of @xmath24 is assumed to have a power - law form of @xmath35 with @xmath36 , @xmath37 m , and @xmath38 m ( cf . the mean grain size for this distribution is larger than that in the interstellar medium , based on the analysis of uv extinction curves of radio - quiet agns @xcite . lcccccccc mrk 335 & 00 06 19.5 & @xmath3920 12 10.5 & 0.0258 & [email protected] & [email protected] & 0.118 & [email protected] & 145.6 @xmath40 17.3 + mrk 590 & 02 14 33.6 & @xmath4100 46 00.1 & 0.0264 & 7176.93@xmath40 551.52 & [email protected] & 0.124 & 36.8@xmath40 2.7 & 95.2 @xmath40 7.0 + iras 03450@xmath390055 & 03 47 40.2 & @xmath3901 05 14.0 & 0.0310 & [email protected] & [email protected] & 0.660 & 103.3@xmath40 4.7 & 90.4 @xmath40 4.1 + akn 120 & 05 16 11.4 & @xmath4100 08 59.4 & 0.0327 & [email protected] & [email protected] & 0.426 & [email protected] & 86.5 @xmath40 10.8 + mcg @xmath4108@xmath4111@xmath41011 & 05 54 53.5 & @xmath3946 26 22.0 & 0.0205 & 6541.04@xmath40 331.25 & [email protected] & 0.720 & [email protected] & 93.1 @xmath40 13.9 + mrk 79 & 07 42 32.8 & @xmath3949 48 34.8 & 0.0222 & 6753.90@xmath40 75.14 & [email protected] & 0.235 & 71.9@xmath40 3.3 & 90.5 @xmath40 4.2 + mrk 110 & 09 25 12.9 & @xmath3952 17 10.5 & 0.0353 & 10240.19@xmath40 587.93 & [email protected] & 0.043 & 88.5@xmath40 6.0 & 132.5 @xmath40 9.1 + ngc 3227 & 10 23 30.6 & @xmath3919 51 54.0 & 0.0039 & 1214.99@xmath40 35.56 & [email protected] & 0.075 & 13.9@xmath40 0.6 & 14.5 @xmath40 0.6 + ngc 3516 & 11 06 47.5 & @xmath3972 34 07.0 & 0.0088 & 3836.38@xmath40 844.97 & [email protected] & 0.140 & 51.2@xmath40 9.6 & 66.1 @xmath40 12.4 + mrk 744 & 11 39 42.5 & @xmath3931 54 33.0 & 0.0089 & [email protected] & [email protected] & 0.079 & 20.9@xmath40 2.2 & 74.3 @xmath40 7.8 + ngc 4051 & 12 03 09.6 & @xmath3944 31 52.8 & 0.0023 & 901.24@xmath40 128.74 & [email protected] & 0.043 & 14.6@xmath40 0.5 & 17.6 @xmath40 0.6 + ngc 4151 & 12 10 32.6 & @xmath3939 24 20.6 & 0.0033 & 1409.56@xmath40 299.65 & [email protected] & 0.092 & 47.2@xmath40 0.7 & 29.2 @xmath40 0.4 + ngc 4593 & 12 39 39.4 & @xmath4105 20 39.4 & 0.0090 & 3540.76@xmath40 545.81 & [email protected] & 0.082 & 43.6@xmath40 1.9 & 61.9 @xmath40 2.7 + ngc 5548 & 14 17 59.5 & @xmath3925 08 12.4 & 0.0172 & 6115.16@xmath40 486.34 & [email protected] & 0.068 & 49.5@xmath40 0.8 & 92.5 @xmath40 1.5 + mrk 817 & 14 36 22.1 & @xmath3958 47 39.4 & 0.0315 & [email protected] & [email protected] & 0.022 & 87.9@xmath40 8.1 & 107.6 @xmath40 10.0 + mrk 509 & 20 44 09.7 & @xmath4110 43 24.5 & 0.0344 & [email protected] & [email protected] & 0.190 & 144.5@xmath40 9.1 & 105.4 @xmath40 6.7 + ngc 7469 & 23 03 15.6 & @xmath3908 52 26.4 & 0.0163 & 3967.24@xmath40 906.33 & [email protected] & 0.228 & 48.4@xmath40 1.5 & 47.7 @xmath40 1.5 + [ tabdata ] in order to obtain @xmath42 in the rest frame of the agn , two cosmological effects must be considered . the observed @xmath15 must be corrected for time dilation , a factor of @xmath43 , where @xmath44 is the redshift . we also consider an effect that arises from the temperature gradient in the dust torus and the shift of the @xmath45-band , where our observations are made , to a different wavelength in the reference frame of the agn according to @xmath46 . at higher redshifts , we observe shorter wavelengths emitted by the agn from a hotter part of the dust torus that is closer to the central engine . this effect makes the observed @xmath15 shorter than would be the case if the same agn was observed at a smaller redshift . we formulate the correction to our @xmath45-band observations empirically , by using the mean delay of @xmath47-band to @xmath45-band , which is about 0.3 times the delay of @xmath20-band to @xmath45-band , as obtained from magnum telescope observations of nearby seyfert 1 galaxies @xcite . interpolating this band - dependent delay linearly with redshift , and correcting for the time dilation , we obtain the correction formula @xmath48 . for the redshift range in this letter , @xmath49 , the combined corrections are less than 1% and are unimportant . the magnum project was initiated in order to measure @xmath15 for agns over a range of redshifts @xcite . the observations were made with a multicolor imaging photometer @xcite mounted on a dedicated 2-m telescope located at the summit of haleakala on the hawaiian island of maui . monitoring observations from 2001 through 2007 were made simultaneously in two wavelength bands , the optical @xmath20 ( 0.55 @xmath30 m ) band and the nir @xmath45 ( 2.2 @xmath30 m ) band , to determine @xmath15 . variations in the short wavelength flux which heats the dust grains is synchronous with variations in the @xmath20-band ( e.g. , * ? ? ? * ; * ? ? ? * ) and dust near the sublimation temperature emits the most energy in the @xmath45-band ( e.g. , * ? ? ? * ; * ? ? ? * ) . in figure 1 , we present light curves in the @xmath20-band and @xmath45-band for ngc 5548 and iras 03450@xmath390055 , as examples . the flux variations in the @xmath20-band and @xmath45-band resemble each other in shape , with the @xmath45-band flux variations delayed with respect to those in the @xmath20-band . in this letter , we use the time - delay data for 17 seyfert 1 galaxies obtained by the magnum project . we only briefly describe the procedures of our data reduction and analysis here , because the details will be presented elsewhere ( s. koshida et al . , in preparation ) . the time delay , @xmath15 , was obtained by cross - correlating the @xmath20-band and @xmath45-band light curves using a bi - directional interpolation scheme which weights the observed flux data more than a simulated interpolation scheme with respect to time @xcite . before taking the cross correlation between the @xmath20-band and @xmath45-band light curves , we subtracted the accretion disk component from the observed @xmath45-band flux to derive the dust torus component in the @xmath45 band @xcite . emission from the central accretion disk extends into the nir wavelengths @xcite . variations of this component appear in the @xmath45 band , and make a measured @xmath15 shorter than the light travel time . we correct by estimating the contaminating flux as @xmath50 from the simultaneous @xmath20-band measurement , and subtracting it from the @xmath45-band measurement . we use @xmath51 obtained from a cross multiple regression analysis of our sample of nearby seyfert 1 galaxies @xcite . in the light curves of 17 seyfert 1 galaxies , we found 49 single incidents of a flux maximum or minimum which could be used to measure @xmath15 . we give the mean value of @xmath15 for those galaxies which underwent several incidents . in table 1 we give , for each of the 17 seyfert 1 galaxies that we monitored , our mean observed apparent magnitude , @xmath52 , the time delay , @xmath15 in days , and the luminosity distance , @xmath53 in mpc , from equation ( 2 ) @xmath54 where @xmath55 is galactic extinction @xcite , @xmath56 is the @xmath45-correction , and @xmath57 . the calibration factor , @xmath58 , was calculated from equation ( 1 ) using the physical model with the parameters described above . the @xmath45-correction was calculated assuming a power law spectrum in the uv to optical range , @xmath59 , to obtain @xmath60 , where @xmath61 . the heliocentric redshift , @xmath44 , is taken from published measurements , the cosmic recession velocity , @xmath62 , is the heliocentric velocity , @xmath63 , corrected for galactic rotation and the local velocity flow using the average of two different models of the local velocity flow @xcite , as was done for the cepheid distance determinations @xcite . the @xmath4 figures given for @xmath62 in table 1 represent the uncertainty in the flow models and are half the difference between the correction to @xmath62 obtained from the two models . in figure 2 , we present the velocity - distance diagram to compare the extragalactic distances measured using our agn time - lag method with distances obtained from cepheid variable stars . our agn time - lag method determines the distance , @xmath53 , through a reasonable physical parameterization , and directly provides the first step in the distance ladder . we obtain the hubble constant , @xmath64 km s@xmath5 mpc@xmath5 from a least squares fit to @xmath65 using our agn time - lag distances . the hubble constant found from empirically calibrated cepheid distances is @xmath66 @xcite . our agn time - lag method , which is based upon a physical model with no empirical calibration , agrees well with the cepheid distances and other empirical distance ladders @xcite , but extends to galaxies 10 times more distant than where cepheid distances can be measured , to where the cosmic recession velocity is not so badly afflicted by the local velocity flow . the systematic error in @xmath2 is estimated by changing the parameter values of @xmath28 and @xmath22 in their respective ranges of uncertainty , and by changing the distribution of @xmath24 , assumed to have a power - law form of @xmath35 . our calculation gives @xmath67 km s@xmath5 mpc@xmath5 and @xmath68 km s@xmath5 mpc@xmath5 for the uncertainty in @xmath28 and @xmath22 , respectively . the systematic error in @xmath2 from the uncertainty in @xmath69 is estimated using two extreme size distributions , such as the standard `` mrn '' distribution in the local interstellar medium for our galaxy ( @xmath70 , @xmath37 m , @xmath71 m ; * ? ? ? * ) , and the larger grain enhanced distribution for agns ( @xmath72 , @xmath37 m , @xmath38 m ) , because smaller dust grains are more efficiently sublimated by uv radiation from the central engine @xcite . we adopt an intermediate value of @xmath36 with @xmath37 m and @xmath38 m as our standard grain size distribution . nir flux - weighted averaging scheme over the full range of @xmath24 is then applied to equation ( 1 ) , and the calibration factor @xmath58 is calculated for the two extreme distributions as well as the intermediate one . the uncertainty in @xmath58 is within the limits of @xmath73 , so that @xmath74 is at most @xmath75 dex from equation ( 2 ) , which is currently the largest source of the systematic error in @xmath2 . this error in @xmath2 is much reduced for a sample of agns for which their @xmath28 , @xmath22 , and @xmath69 are individually measured , because the target to target variation of these parameters also contributes to the random error in the @xmath2 fitting . in particular , if monitoring observations of high - redshift agns were obtained , their uv optical spectrum could be determined directly from ground based spectroscopic observations , and the accuracy of the @xmath2 determination would be significantly improved . alternatively , if many of target agns were calibrated by other reliable distance indicators such as cepheids and type ia supernovae , their calibrated distances would not only provide a cross check on our method of distance determination , but also independently constrain the parameter values in a physical model of dust reverberation . two other reverberation methods of distance determination of agn have been proposed . one is a method based on the reverberation mapping of the broad line emitting region ( blr ) in agn @xcite , using an empirical relation between the radial distance of blr from the agn center and the agn luminosity . although the radius - luminosity relation of blr is well established now @xcite , the exact size of blr can not be predicted theoretically . therefore , this method remains as an empirical method in the sense that it must use empirical distance - ladder methods for calibration . another is a method based on the wavelength - dependent time delay of uv optical continuum emission from the central accretion disk in agn @xcite . this method is a physical one , like our method , which could , in principle , determine the distance without any distance calibration . however , this method gives @xmath764244 km s@xmath5 mpc@xmath5 , which is about a factor of 1.7 smaller than current standard estimates , and even below the recent lower estimate of 67 km s@xmath5 mpc@xmath5 based on planck measurements of the cosmic microwave background temperature @xcite . thus , this method seems to have some difficulties to be resolved , such as the adequacy of modeling the x - ray reprocessing for the flux variation of uv optical continuum emission . in fact , while some agns show a delay of the optical flux variation behind that of x - ray , which is consistent with the x - ray reprocessing , some others show a delay of the x - ray variation behind that of optical , or they show a poor correlation between the x - ray and optical variations ( e.g. , * ? ? ? * ) . in summary , we have demonstrated that our agn time - lag method can be used to measure extragalactic distances beyond what is possible with cepheids , and we have obtained a value of the hubble constant with our agn time - lag method of @xmath77 km s@xmath5 mpc@xmath5 for a sample of 17 seyfert 1 galaxies observed with the magnum telescope . we suggest that this method can be used with qsos to study the dark energy in the universe beyond what is possible with type ia supernovae . we thank the staff at the haleakala observatories for their help with facility maintenance . this research has been supported partly by the grants - in - aid of scientific research ( 10041110 , 10304014 , 11740120 , 12640233 , 14047206 , 14253001 , 14540223 , 16740106 , and 25287062 ) and the coe research ( 07ce2002 ) of the ministry of education , science , culture and sports of japan .

we have pioneered a new method for the measurement of extragalactic distances . this method uses the time - lag between variations in the short wavelength and long wavelength light from an active galactic nucleus ( agn ) , based on a quantitative physical model of dust reverberation that relates the time - lag to the absolute luminosity of the agn . we use the large homogeneous data set from intensive monitoring observations in optical and near - infrared wavelength bands with the dedicated 2-m magnum telescope to obtain the distances to 17 agns in the redshift range @xmath0 to @xmath1 . these distance measurements are compared with distances measured using cepheid variable stars , and are used to infer that @xmath2 @xmath3 73 @xmath4 3 ( random ) km s@xmath5 mpc@xmath5 . the systematic error in @xmath2 is examined , and the uncertainty in the size distribution of dust grains is the largest source of the systematic error , which is much reduced for a sample of agns for which their parameter values in the model of dust reverberation are individually measured . this agn time - lag method can be used beyond 30 mpc , the farthest distance reached by extragalactic cepheids , and can be extended to high - redshift quasi - stellar objects .

A Los Angeles attorney faces a possible six-month suspension for posting doctored photos on her firm's website that implied she mingled with high-profile politicians and celebrities, including President Obama, George Clooney and Kim Kardashian. The photos -- more than 50 -- are published on lawyer Svitlana Sangary's website under a tab titled "publicity." They appear to show Sangary with dozens of politicians and celebrities, including Bill and Hillary Clinton, Vice President Joe Biden, Donald Trump, Arnold Schwarzenegger, Leonardo DiCaprio and Dr. Phil. But during a July trial, experts testified that "many, and perhaps all" of the photos were Photoshopped "to make it appear as though [Sangary] was in the presence of a celebrity," according to a report by a judge of the State Bar Court of California who recommended the six-month suspension. In his 18-page decision, which was first reported in the legal newspaper The Recorder, Judge Donald F. Miles said Sangary had committed four counts of misconduct. Miles said they included one count related to posting the photographs, two counts of failing to cooperate with state bar investigators and another count of refusing to forward a former client's legal file to the client's new attorney. In his decision, the judge described "grave concerns" about Sangary's "demonstrated lack of insight and her contemptuous conduct during these proceedings." "[Sangary's] failure to remove the deceptive images from her website, even after the State Bar brought this issue to her attention, and her demonstrated disregard for the disciplinary process gives little reason to believe that her misconduct will not continue," Miles wrote. Sangary said in an email Thursday that she had "a lot to say" about the recommendation and was "working on it," but did not elaborate. She said she had a 30-day window to request a review of the recommendation, and would provide a comment before then. [Sangary's] failure to remove the deceptive images from her website ... gives little reason to believe that her misconduct will not continue. — Judge Donald F. Miles, in his written decision The photos remained online even after the bar began its inquiry and later filed charges, Miles wrote. They were still on Sangary's website as of Thursday afternoon. "By posting and maintaining several images on her website falsely depicting [Sangary] posing with various public figures, when in fact [Sangary] was not actually photographed in the company of those public figures, [Sangary] communicated an advertisement or solicitation directed to the general public that was false and deceptive." The judge said Sangary failed to appear for several hearings, including a deposition, and failed to meet some deadlines in the case. Instead, he wrote, she filed erratic responses that had "little to no rational connection to the charges at hand." In one 16-page filing, Sangary repeatedly referred to herself in the third person and launched into tangential discussions that appeared to have nothing to do with her case, such as Natalie Portman's performance in "Black Swan." Records showed Sangary was admitted to the California bar in 2004 after attending law school at Pepperdine University. She had no prior disciplinary actions. According to her website, Sangary "is committed to the highest standards of professionalism and integrity in meeting her client's legal challenges." The judge also recommended probation for Sangary. The California Supreme Court will ultimately decide on the recommendations. Follow @katemather for crime and court news from across Southern California. ||||| Why am I seeing this? LexisNexis® is now the exclusive third party online distributor of the broad collection of current and archived versions of ALM's legal news publications. LexisNexis® customers will be able to access and use ALM's content by subscribing to the LexisNexis® services via Lexis Advance®. This includes content from the National Law Journal®, The American Lawyer®, Law Technology News®, The New York Law Journal® and Corporate Counsel®, as well as ALM's other newspapers, directories, legal treatises, published and unpublished court opinions, and other sources of legal information. ALM's content plays a significant role in your work and research, and now through this alliance LexisNexis® will bring you access to an even more comprehensive collection of legal content. For questions call 1-877-256-2472 or contact us at [email protected] ||||| Svitlana Sangary is in danger of having her California State Bar license suspended following accusations that she posted a series of fake photos of herself posing with celebrities and public officials—including Barack Obama, Kim Kardashian, the Clintons, George Clooney, and Donald Trump—to her professional website. The photos were apparently Photoshopped, and they're pretty good! State Bar Court Judge Donald Miles, in issuing his recommendation that Sangary have her license suspended for six months, said that the Los Angeles attorney used the 50-odd photos "to confuse, deceive and mislead the public." Sangary had apparently been told two years earlier that the photos on her site amounted to "deceptive advertising." She responded to the bar's accusations, The Recorder reports, with 148 pages of exhibits and includes what Miles describes as "a 16-page soliloquy with little or no rational connection to the charges at hand" that includes this bizarre passage about Natalie Portman: Also with regard to false statements and misleading advertisement, none other than Natalie Portman comes to mind. The online media extensively covers the controversy surrounding Natalie Portman's performance in the film Black Swan. The ballet dancer who performed in the Black Swan, Sarah Lane, has come forward to revel [sic] a "cover up" and says that Natalie Portman's head was superimposed onto Sarah Lane's body, and that Natalie Portman lied…Despite the foregoing, Natalie Portman has won an Oscar for her performance in Black Swan. Sangary also includes an email purporting to be from President Obama asking for a campaign donation (though, as the Washington Post points out, the email uses language seen previously in a Democratic National Committee newsletter). She references this email in the conclusion to her response: SANGARY's American dream has come true, as she has been able to achieve a point wherein now, in her thirties, SANGARY is a prominent donor and philanthropist, supporting important social causes, who had recently received the email from President Obama, with the subject line 'I need your help today', asking SVITLANA SANGARY for an additional donation….God Bless America! The judge's recommendation to suspend Sangary is awaiting approval from the California Supreme Court. [H/T The Recorder // Image via californiacivillawyer.comn] ||||| Starting in 1996, Alexa Internet has been donating their crawl data to the Internet Archive. Flowing in every day, these data are added to the Wayback Machine after an embargo period.

– California attorney Svitlana Sangary apparently wanted to drum up publicity for her firm, so she posted some 50-plus pics of herself on her work website posing with a variety of high-profile luminaries, the Los Angeles Times reports. There she is, mugging with the likes of Kim Kardashian, George Clooney, the Clintons, even the late James Gandolfini—which would be impressive if the images were actually real. In a report that first appeared in the Recorder, a legal newspaper, and is now cited by the Times, State Bar Court Judge Donald F. Miles is recommending Sangary be suspended for six months for the "deceptive" images, of which "many, and perhaps all" of the photos were digitally altered "to make it appear as though [Sangary] was in the presence of a celebrity," experts reportedly testified at a July trial. In his decision, Miles mentions his "grave concerns" about Sangary's lack of judgment and how she has blown off the court, allegedly failing to show for hearings about the photos, missing court deadlines, and sending in rambling responses that the judge says have "little to no rational connection to the charges at hand." Gawker, which calls her Photoshop work "pretty good," links to her bizarre 16-page response to the judge that discusses, among other things, actress Natalie Portman's fraudulent dance moves in Black Swan. Sangary also repeatedly refers to herself in the third person (in all caps) in her response, the Washington Post reports, and claims President Obama directly solicited donations from her—though the email she attached to her response appears to be a pickup of text from a Democratic National Committee newsletter, notes the Post.

ultrasound ( us ) is a reliable imaging technique for the early diagnosis of renal cell carcinoma ( rcc ) . it is a readily accessible , cost - effective , noninvasive imaging modality that provides real - time features . however , it may not provide differentiation in special cases of rcc and renal angiomyolipoma ( aml ) . although most rccs are hypoechoic on us , approximately 30% of small rccs appear hyperechoic , similar to small amls , which typically appear very bright , homogeneous , and sharply marginated . in addition , the incidence of atypical iso - hypoechoic and slightly hyperechoic amls account for 6% and 29% of small renal masses , respectively . the usefulness of us is limited because of its lower accuracy in the characterization of such small renal masses . rcc is a malignant neoplasm , which requires total or partial nephrectomy , and thus definite distinction between rcc and aml is essential . patients with uncharacterized small renal masses have to be examined by further imaging study such as contrast - enhanced computed tomography ( ct ) and magnetic resonance imaging ( mri ) . however , the sensitivity and specificity for the differentiation of rcc from other tumors has been reported to be from 73% to 100% and from 84% to 91% , respectively . additionally , issues of nephrotoxicity of the contrast media , radiation hazard , and high cost have also been raised . recently , the development of new contrast media and imaging techniques has enabled contrast - enhanced ultrasound ( ceus ) , which is already being actively used in organs such as the liver . ceus can be used to observe the continuous micro- and macrocirculation of a renal mass , which may also be useful in the diagnosis of a renal mass , although the blood supply of renal masses and liver masses differs . in addition , the ultrasound contrast agent is relatively harmless with a lower incidence of side effects such as nephrotoxicity . the purpose of this study was to determine whether ceus could improve the diagnostic accuracy of us examination for small renal masses . between january 2011 and december 2013 , a total of 85 consecutive patients underwent ceus after being diagnosed with renal masses first detected by baseline us . the ceus studies were performed by a single radiologist ( y.h.l . ) at our institution ( wonkwang university school of medicine & hospital ) . among the patients , 49 with solid renal tumors with diameters of 4 cm or less the 49 included patients were 35 men ( 71.4% ) and 14 women ( 28.6% ) aged 37 to 83 years ( mean age , 61 years ) . specimens were obtained from surgical resections , which were all performed by a single surgeon ( i.y.s . ) . the final diagnosis was confirmed by histopathological examination as rcc ( n=38 ) or aml ( n=11 ) . after obtaining approval from the institutional review board the us contrast agent used in our study was sonovue ( bracco , milan , italy ) , a sulfur hexafluoride - filled microbubble contrast agent that was stabilized by phospholipids . perfusion through the renal mass was checked in real time for 3 to 4 minutes from the beginning of injection . injections were repeated 15 minutes after the first injection if a tumor was incompletely assessed owing to its large size . conventional us was used to scan the renal mass , and the tumor was targeted . then , color doppler sonography was performed to estimate the vascularity of the renal mass such as pulsatile arterial or continuous venous flow . digital video clips of characteristic conventional us and ceus images were stored for off - line analysis . a routine diagnostic approach , consisting of conventional ultrasound and ceus , was applied in each case . on conventional us , the lesion echogenicity was divided into hypoechoic and hyperechoic regions with respect to the echogenicity of the renal cortex . ceus images of characteristic changes during enhancement were evaluated and recorded , e.g. , the tumor enhancement extent , pattern , and their dynamic change along with the ceus process , as well as other special changes during enhancement . the enhancement pattern of the tumor in comparison with the normal renal cortex was classified as hyperenhancement , hypoenhancement , and nonenhancement . perilesional rim - like enhancement was defined as a peripheral nodular lesion with centripetal fill - in enhancement around the tumor , which became more distinct in the late phase ( fig . the conventional us appearance of renal aml is that of a typically hyperechoic lesion against the backdrop of a hypoechoic renal cortex , owing to the other components in the interfaces between fatty and nonfatty tissue of the mass . in ceus , aml typically appears as a hypoenhancing lesion with a progressive hypoenhancement in the late phase ( fig . 2 ) . in a recent study , aml of the liver appeared as a dot - like pattern with a wide range of enhancement patterns ( fragmentation ) without sharp discrimination , in comparison with hepatocellular carcinoma . after the image analysis the value of these features was calculated , independently and in various combinations , in differentiating the diagnosis between rcc and aml . on the basis of the characteristic images , the sensitivity , specificity , positive predictive value , negative predictive value , and accuracy for rcc diagnostic efficacy were calculated . all statistical analyses were performed by using ibm spss statistics ver . 19.0 ( ibm co. , armonk , ny , usa ) . the results in the differences of the enhancement time between rcc and aml were compared by using the mann - whitney test . fisher exact test was applied to compare the differences in the characteristic image of rcc and aml on ceus . between january 2011 and december 2013 , a total of 85 consecutive patients underwent ceus after being diagnosed with renal masses first detected by baseline us . the ceus studies were performed by a single radiologist ( y.h.l . ) at our institution ( wonkwang university school of medicine & hospital ) . among the patients , 49 with solid renal tumors with diameters of 4 cm or less the 49 included patients were 35 men ( 71.4% ) and 14 women ( 28.6% ) aged 37 to 83 years ( mean age , 61 years ) . specimens were obtained from surgical resections , which were all performed by a single surgeon ( i.y.s . ) . the final diagnosis was confirmed by histopathological examination as rcc ( n=38 ) or aml ( n=11 ) . after obtaining approval from the institutional review board the us contrast agent used in our study was sonovue ( bracco , milan , italy ) , a sulfur hexafluoride - filled microbubble contrast agent that was stabilized by phospholipids . perfusion through the renal mass was checked in real time for 3 to 4 minutes from the beginning of injection . injections were repeated 15 minutes after the first injection if a tumor was incompletely assessed owing to its large size . conventional us was used to scan the renal mass , and the tumor was targeted . then , color doppler sonography was performed to estimate the vascularity of the renal mass such as pulsatile arterial or continuous venous flow . digital video clips of characteristic conventional us and ceus images were stored for off - line analysis . a routine diagnostic approach , consisting of conventional ultrasound and ceus , was applied in each case . on conventional us , the lesion echogenicity was divided into hypoechoic and hyperechoic regions with respect to the echogenicity of the renal cortex . ceus images of characteristic changes during enhancement were evaluated and recorded , e.g. , the tumor enhancement extent , pattern , and their dynamic change along with the ceus process , as well as other special changes during enhancement . the enhancement pattern of the tumor in comparison with the normal renal cortex was classified as hyperenhancement , hypoenhancement , and nonenhancement . perilesional rim - like enhancement was defined as a peripheral nodular lesion with centripetal fill - in enhancement around the tumor , which became more distinct in the late phase ( fig . the conventional us appearance of renal aml is that of a typically hyperechoic lesion against the backdrop of a hypoechoic renal cortex , owing to the other components in the interfaces between fatty and nonfatty tissue of the mass . in ceus , aml typically appears as a hypoenhancing lesion with a progressive hypoenhancement in the late phase ( fig . the liver appeared as a dot - like pattern with a wide range of enhancement patterns ( fragmentation ) without sharp discrimination , in comparison with hepatocellular carcinoma . the value of these features was calculated , independently and in various combinations , in differentiating the diagnosis between rcc and aml . on the basis of the characteristic images , the sensitivity , specificity , positive predictive value , negative predictive value , and accuracy for rcc diagnostic efficacy were calculated . all statistical analyses were performed by using ibm spss statistics ver . 19.0 ( ibm co. , armonk , ny , usa ) . the results in the differences of the enhancement time between rcc and aml were compared by using the mann - whitney test . fisher exact test was applied to compare the differences in the characteristic image of rcc and aml on ceus . the diameter of the renal masses ranged from 1.2 to 4.0 cm ( mean , 2 . 890.81 cm ) for rccs and from 1.3 to 4.0 cm ( mean , 2.850.85 cm ) for amls . the size of the renal masses was not significantly different between rccs and amls ( p=0.904 ) . on ceus , the intervals between the beginning of contrast injection and initial enhancement of the renal cortex for 38 rccs were 15.35.2 seconds ( range , 8 - 24 seconds ) and 17.55.9 seconds ( range , 8 - 29 seconds ) , respectively ( p>0.05 ) . the corresponding intervals for the 11 amls were 14.85.5 seconds ( range , 9 - 25 seconds ) and 14.15.6 seconds ( range , 8 - 22 seconds ; p>0.05 ) . also , there was no significant difference between rccs and amls in the timing of enhancement ( p=0.631 ) . on conventional us , rccs were heterogeneously or homogeneously hypoechoic in 23 cases ( 23/38 , 60.5% ) and hyperechoic in 15 cases ( 15/38 , 39.5% ) . for amls , 3 cases ( 3/11 , 27.3% ) were hypoechoic , whereas 8 cases ( 8/11 , 72.7% ) were hyperechoic ( fig . the echogenicity of renal tumors observed in conventional us was similar to the findings of other studies , but approximately 39.5% of small rccs were hyperechoic in our study ( table 1 ) . the enhancement degree and pattern were different between the two types of renal masses ( table 2 ) . the rccs usually showed heterogeneous enhancement ( 30/38 , 78.9% ) rather than homogeneous enhancement ( 8/38 , 21.1% ) , whereas most amls showed homogeneous enhancement ( 8/11 , 72.7% ) rather than heterogeneous enhancement ( 3/11 , 27.3% ) . sustained hyperenhancement was observed in most ( 9/11 , 81.8% ) of the amls , whereas washout from hyperenhancement to hypoenhancement was observed in most ( 28/38 , 73.7% ) of the rccs . in 23 of 49 tumors , rim - like enhancement around the tumors was found in various vascular phases . during the cortical phase , perilesional rims were hyperenhancing or iso - enhancing , whereas in the corticomedullary and late phases , the rims all became hyperenhancing relative to the adjacent renal cortex ( fig . these characteristic images were able to show the boundary of the tumor more distinctly and may be a criterion for partial nephrectomy . twenty - two of 38 rccs ( 57.9% ) showed perilesional rim - like enhancement , whereas 1 of 11 amls ( 9.1% ) showed incomplete perilesional rim - like enhancement . most amls were observed to have hyperechogenicity on conventional ultrasound and hypoenhancement on ceus . in the present study , 27.3% of amls showed hypoechogenicity , and some atypical amls ( 4/11 , 36.4% ) showed a rapid hyperenhancement in ceus . 2 ) was observed in 7 of the aml lesions ( 63.6% ) and 3 of the rcc lesions ( 7.9% ) . these features were significantly different between the two groups ( p=0.000 ) . compared with the difference in ceus findings between clear cell carcinoma and papillary carcinoma , diffuse heterogeneous enhancement was observed in 26 of 33 clear cell carcinomas ( 78.8% ) and in 4 of 5 papillary carcinomas ( 80.0% ) . washout in the late phase was observed in 24 of 33 clear cell carcinomas ( 72.7% ) and in 4 of 5 papillary carcinomas ( 80.0% ) . perilesional rim - like enhancement was observed in 19 of 33 clear cell carcinomas ( 57.6% ) and in 3 of 5 papillary carcinomas ( 60.0% ) . statistical analysis using a small number of papillary carcinoma patients was difficult , but both groups showed similar characteristics in the ceus findings ( table 3 ) . the features of diffuse heterogeneous enhancement , washout , and perilesional rim - like enhancement differed significantly between rccs and amls ( p<0.05 ) . using these features , ceus had the sensitivity , specificity , positive predictive value , negative predictive value , and accuracy for rcc diagnostic efficacy of 86.8% ( 33/38 ) , 63.6% ( 7/11 ) , 89.2% ( 33/37 ) , 58.3% ( 7/12 ) , and 81.6% ( 40/49 ) , respectively ( table 4 ) . since its introduction into clinical practice , the usefulness of conventional us for earlier diagnosis of renal masses has been well established . in recent studies , as many as 70% of renal tumors were reported to have been discovered incidentally , and almost 83% of these asymptomatic tumors were originally found in a baseline us examination . although us has been widely used for evaluating the kidney , many reports have shown its limitations for tumor detection and characterization . about 77% of small rccs were observed to have various echogenicity , and a minority showed hyperechogenicity ( 32% ) such that these lesions could not be distinguished from renal amls . convertsely , atypical amls containing a small amount of fat or less vascular structure often appear as iso- or hypoechoic on conventional us . therefore , conventional us has limited ability to characterize renal tumors , and further imaging examination such as ct or mri is currently required . already , ceus has been shown to have high diagnostic efficacy in characteristic images of liver tumors compared with conventional us . unlike the contrast agents used in ct and mri , ceus contrast agents are present in microbubbles , which do not diffuse through the vascular endothelium into the interstitium . these molecular features allow evaluation of both the micro- and macrocirculation of kidney and tumor tissues and can provide a better approach of vascular morphology and characteristic image enhancement . in addition , second - generation us contrast agents have been reported to increase the diagnostic confidence for renal tumors in terms of improved renal lesion conspicuity and effective delineation of tumor microvessels . most importantly , there are no reported side effects such as nephrotoxicity in humans to date . also , the lack of renal excretion explains the absence of renal toxicity of these agents , which can , therefore , be used in nephropathic patients . in the present study , diffuse heterogeneous enhancement , washout in the late phase , and perilesional rim - like enhancement were the most common findings for rccs . these were characteristic patterns in rccs with sensitivity , specificity , positive predictive value , negative predictive value , and accuracy of 86.8% , 63.6% , 89.2% , 58.3% , and 81.6% , respectively . it is generally acknowledged that homogeneity in contrast - enhanced dynamic ct correlates with the existence of necrotic degeneration or intratumoral cysts in histologic specimens . also , the washout and heterogeneous enhancement pattern on ceus might relate to the pathologic features of rcc such as a large amount of intratumoral blood flow , numerous thin - walled blood vessels , and hemorrhage . the pseudocapsule results from tumor growth producing compression , ischemia , and necrosis of adjacent normal tissue , which is a subsequent change of fibrous tissue . a recent study reported that perilesional rim enhancement was a characteristic feature of rcc with pathological pseudocapsules on ceus , and the authors of that study concluded that ceus could be used for ultrasound diagnosis of pseudocapsules in rcc and that the sensitivity of this technique may be competitive to that of mri in presurgical detection of pseudocapsules . in the present study , the presence of pseudocapsules was a useful sign both in the differential diagnosis of rcc and in the choice for nephron - sparing surgery . in the study by zhou et al . , ceus was found to possibly improve the diagnostic confidence of rcc , providing abundant information on tumor vasculature and the blood supply . it was expected that the enhancement observed in aml would help to differentiate aml from rcc , because of higher angiogenesis in malignant tumors . most solid rccs show lower echogenicity than aml in conventional ultrasound . in the present study , some atypical amls showed a rapid enhancement during the arterial phase , which was not significantly different from what was observed in rcc . hyperechogenicity on conventional us and hypoenhancement on ceus should not be used as a definitive finding for aml . also , the relative amounts of fat , smooth muscle , and blood vessels vary , and a subset of amls contain a minimal fat component that is only microscopically detectable , which accounted for the preoperative misdiagnosis of rcc in a recent study . in the present study , some amls showed an enhancement pattern similar to that of rccs with hyperenhancement , whereas most amls revealed a dot - like pattern on ceus . these features allow confirmation of renal tumors suspected on conventional ultrasound imaging and differentiation between aml and rcc . first , only a small number of patients with renal masses were included in this study . second , ceus is limited by interference from bowel gas , the ribs , or obesity and can be influenced by lesion locations , as with conventional us . the examination involves an operator - dependent imaging modality and requires sufficient experience , skill , and training . also , the diagnostic efficacy of ceus is still lower than that of ct or mri . a large - scale and prospective study is necessary to further assess and extend these results . additional techniques , such as quantitative ceus analysis and other specific images , should be evaluated in future studies . our results suggest that ceus features of diffuse heterogeneous enhancement , washout in the late phase , and perilesional rim - like enhancement allow confirmation of rcc , distinguishing rcc from aml , in small renal masses . ceus improves the diagnostic efficacy of conventional us . it may decrease the necessity of additional diagnostic studies and support decisions about treatment strategy in patients with small renal masses

purposeultrasound ( us ) is highly sensitive in the detection of renal masses . however , it may not be able to differentiate benign and malignant lesions in smaller masses . the purpose of this study was to determine the diagnostic efficacy of contrast - enhanced ultrasound ( ceus ) for small renal masses.materials and methodsfrom january 2011 to december 2013 , a total of 85 patients underwent ceus for evaluation of renal masses . of these patients , ceus findings were retrospectively analyzed for small renal cell carcinoma ( rcc ) cases ( n=38 ) and angiomyolipoma ( aml ) cases ( n=11 ) . the tumor echogenicity and enhancement patterns and degrees were evaluated . the diagnostic efficacy of ceus in differentiating the two diseases was compared.resultson ceus , the findings of diffuse heterogeneous enhancement ( observed in 78.9% of rccs and 27.3% of amls , p=0.003 ) , washout from hyperenhancement or iso - enhancement to hypoenhancement in late phase ( 73.7% of rccs and 18.2% of amls , p=0.001 ) , and perilesional rim - like enhancement ( 57.9% of rccs and 9.1% of amls , p=0.006 ) were significantly different between aml and rcc cases . the corresponding sensitivity , specificity , positive predictive value , negative predictive value , and accuracy were 86.8% ( 33/38 ) , 63.6% ( 7/11 ) , 89.2% ( 33/37 ) , 58.3% ( 7/12 ) , and 81.6% ( 40/49 ) , respectively.conclusionsour results suggest that the characteristic ceus features could have diagnostic value in the evaluation of small renal mass . ceus showed a higher diagnostic efficacy than conventional us for differentiating rcc and aml .

celem bada byo okrelenie , czy wystpuj rnice w gruboci kompleksu intima - media ( imt ) ttnic szyjnych pomidzy grup pacjentw z toczniem trzewnym ukadowym ( sle ) i grup kontroln , a jeli tak , to czy rnice te s nastpstwem tocznia czy niezalenych czynnikw rozwoju miadycy . grupa badana ( n = 25 , redni wiek : 39,8 roku ) obejmowaa chorych na tocze trzewny ukadowy . do podgrupy badanej ( n = 13 , redni wiek : 39,2 roku ) wczono pacjentw chorujcych jedynie na sle , bez adnych chorb towarzyszcych . do grupy kontrolnej wczono 25 zdrowych pacjentw ( redni wiek : 37,1 roku ) , bez cech sle lub innych schorze tkanki cznej . w analizie przeprowadzonej z uyciem testu u manna - whitneya wykazano , e dla obu ttnic szyjnych zachodzi znamienna statystycznie rnica wartoci imt pomidzy grup kontroln a badan ( p = 0,006 dla lcca i p < 0,001 dla rcca ) , lecz brakuje takiej zalenoci pomidzy grup kontroln a podgrup badan ( p = 0,86 dla rcca i p = 0,095 dla lcca ) . w grupie chorych na sle stwierdzono wiksz grubo kompleksu intima - media w porwnaniu z populacj ludzi zdrowych . wykazano ponadto istotny wpyw niezalenych czynnikw rozwoju miadycy na zwikszenie gruboci kompleksu intima - media u pacjentw z toczniem trzewnym ukadowym . over 90% of cases of stricture or obstruction of internal carotid arteries are caused by atherosclerosis . atherosclerotic plaques are usually localized in the area of artery bifurcation most often within the common carotid artery bulb and in the ostia of internal and external carotid arteries , more rarely in the proximal part of the common carotid artery . the development of ultrasound diagnostics has enabled non - invasive evaluation of atherosclerotic changes through the examination of echogenicity , the structure and some dimensions of vessels . the measurement of the intima - media thickness is of special importance in diagnosing atherosclerotic changes [ 1 , 2 ] . the intima - media complex is a structure of the arterial wall from the tunica adventitia - tunica media borderline to the tunica media - vessel lumen borderline . ultrasound examinations of the intima - media thickness ( imt ) were introduced into clinical diagnostics in the 1980s . insufficient resolution of the early ultrasound devices entailed lower precision of the measurements , and this in turn contributed to considerable divergences in the results obtained by different centers conducting the studies . as a consequence of the technical advancement of ultrasound devices , the imt measurement was made automated and the examination itself became more significant in the diagnostic process . according to the concept of parallel and simultaneous development of atherosclerosis [ 35 ] in many arterial areas , atherosclerotic processes occurring in carotid arteries are representative of analogous processes occurring in other vessels . common carotid arteries are easy to be imaged by ultrasonography , and so the imt measurement in those arteries provides a precious source of information about atherosclerotic processes progressing in arteries in the areas difficult to access for diagnosis . the increased imt was shown to correlate with the presence of atherosclerotic changes in the coronary , renal and lower limb arteries . the imt measurement in the carotid artery in its extracranial part can serve as an early marker of atherosclerotic changes and a risk factor for atherosclerotic organic complications [ 1 , 2 ] . this very thickening of the complex triggers a long process of building the atherosclerotic plaque , whose fracturing in the future activates a cardiovascular incident . independent studies show that there is a relation between the increased thickness of the imt complex in the common carotid artery and the risk of both cerebral stroke and myocardial infarction . these studies have also found that the increased imt measurement in the carotid artery is accompanied by a raised susceptibility to myocardial infarction and ischemic cerebral stroke [ 10 , 11 ] . according to the standards established by the polish ultrasound society in 2008 , the normal imt value is less than 1 mm . in patients with imt values of 1.00 - 1.29 mm , the thickening of the imt complex is diagnosed , while a value of imt higher than 1.3 mm should be treated as an indicator of diffuse atherosclerotic changes . the european society of arterial hypertension ( 2003 ) recognized imt exceeding 0.9 mm as a sign of organ damage . moreover , there are suggestions in the literature to treat imt values higher than 1 mm as the equivalent of a coronary disease . it is not only the absolute imt value , but also the annual growth of this parameter , which is of great significance . a further increase of imt by 0.1 mm increases the risk of myocardial infarction by 10 - 15% and that of a cerebral stroke by 13 - 18% . systemic lupus erythematosus ( sle ) is one of the diseases a common manifestation of which is a morbid process that occupies the heart or vessels . the two - degree mortality model for patients with sle assumes that infection and nephropathy are an early cause of death , while cardiovascular incidents are late causes . it should be noted that symptomatic atherosclerosis occurs only in 6 - 10% of sle patients , but the presence of subclinical atherosclerosis can be confirmed in as many as 30 - 40% [ 16 , 17 ] . arterial hypertension , hyperlipidemia and diabetes are additional , independent factors of atherosclerosis development in patients with sle , which is why identifying patients from the cardiovascular incident risk group becomes a substantial matter . one of the diagnostic tests of atherosclerosis development in sle patients can be the imt measurement in the ultrasound examination [ 18 , 19 ] . this examination is noninvasive , does not require contrast media , is cheap and widely accessible , and , therefore , it allows one to identify patients from the cardiovascular risk group . the aim of the study was to determine : whether there are differences in the thickness of the carotid arteries intima - media complex between the group of patients with systemic lupus erythematosus and the control group , andwhether these differences are a consequence of lupus or independent factors of atherosclerosis development . whether there are differences in the thickness of the carotid arteries intima - media complex between the group of patients with systemic lupus erythematosus and the control group , whether these differences are a consequence of lupus or independent factors of atherosclerosis development . the imt of common carotid arties was compared in two patient groups : the study group consisted of 25 patients , including 21 women and 4 men at the age of 29 - 52 years ( mean age 39.8 years ) , suffering from systemic lupus erythematosus . the lupus diagnosis was proposed on the basis of the criteria developed by the american college of rheumatology ( updated in 1997 ) . the mean duration of the disease at the time of taking the imt measurement was 4 years . the accompanying diseases in this group included arterial hypertension ( 7 cases grade 1 or higher according to the esh / esc classification ) , hyperlipidemia ( 12 cases diagnosis : tc 5 mmol / l and/or ldl - c 3.0 mmol or tg 1.7 mmol / l ) , diabetes type 2 ( 2 cases , diagnosed according to the who criteria ) . at the time of the examination the imt measurement was performed as part of the diagnostics of the cardiovascular condition.the control group consisted of 25 healthy patients , including 20 women and 5 men at the age of 20 - 51 years ( mean age 37.1 years ) , who underwent routine check - up examinations and in whom neither any criteria of lupus or any other disease of the connective tissue , nor any features of the metabolic syndrome , arterial hypertension , hyperlipidemia or pathologic glucose tolerance were found . the study group consisted of 25 patients , including 21 women and 4 men at the age of 29 - 52 years ( mean age 39.8 years ) , suffering from systemic lupus erythematosus . the lupus diagnosis was proposed on the basis of the criteria developed by the american college of rheumatology ( updated in 1997 ) . the mean duration of the disease at the time of taking the imt measurement was 4 years . the accompanying diseases in this group included arterial hypertension ( 7 cases grade 1 or higher according to the esh / esc classification ) , hyperlipidemia ( 12 cases diagnosis : tc 5 mmol / l and/or ldl - c 3.0 mmol or tg 1.7 mmol / l ) , diabetes type 2 ( 2 cases , diagnosed according to the who criteria ) . at the time of the examination the control group consisted of 25 healthy patients , including 20 women and 5 men at the age of 20 - 51 years ( mean age 37.1 years ) , who underwent routine check - up examinations and in whom neither any criteria of lupus or any other disease of the connective tissue , nor any features of the metabolic syndrome , arterial hypertension , hyperlipidemia or pathologic glucose tolerance were found . lipid disorders , diabetes and arterial hypertension are independent atherosclerosis development factors , which is why a subgroup of patients suffering only from systemic lupus erythematosus and without any accompanying diseases was selected from the study group . the subgroup included 13 patients ( 11 women , 2 men ) at the age of 29 - 50 years ( mean age 39.2 years ) . a usg vivid 7 device with a 3.6 mhz probe was used in the study . the thickness of the intima - media complex of both common carotid arteries ( lcca , rcca ) was measured at the distance of about 1 cm from the bulb . the imt measurement was taken at the cross section of the vessel , the innermost layers , where the focus of the device was set . the distance between the first , clearly separated bright line ( vessel lumen tunica media borderline ) and the second bright line ( tunica media tunica adventitia borderline ) determined the complex thickness . the observations that did not fit into the range of mean value 1 standard deviation were treated as odd values and were removed from the series . the character of random variable distribution was assessed by means of the kolmogorov - smirnov test . variance cohesion in groups was determined on the basis of levene 's test at the significance level of p = 0.05 . the data obtained from the test were analyzed by the anova single - factor variance analysis ( with scheffe 's post - hoc test analysis ) or its non - parametric equivalent , the anova kruskal - wallis test ( in this case , the mann - whitney u test with the significance level of p = 0.05 was used in the post - hoc analysis for each pair of groups ) . basic descriptive statistics of the study groups are shown in table i. the analysis of the result of the kolmogorov - smirnov test indicates that the distribution of the random variable differs from the normal one . in levene 's test , the homogeneity ( p = 0.3351 ) for the rcca variable was proved , while for the lcca variable there was no variance homogeneity in the groups ( p = 0.068 ) . a further analysis involved non - parametric tests ( kruskal - wallis and mann - whitney u tests ) . descriptive statistics of the variables the performed anova kruskal - wallis test showed a statistically significant difference of mean imt values in the analyzed groups ( for lcca p = 0.024 , for rcca p = 0.005 ) . mean imt values of the left and right carotid artery in the analyzed groups a further analysis performed with the mann - whitney u test indicated ( table ii , table iii ) that a statistically significant difference of imt values for both carotid arteries occurs between the control and the study groups ( p = 0.006 for lcca and p < 0.001 for rcca ) , while there is no such relation ( p = 0.86 for rcca and p = 0.095 for lcca ) between the control group and the study group of patients suffering only from lupus ( without coexisting diseases as independent factors of atherosclerosis development ) . results of the mann - whitney u test for the study group versus the control group results of the mann - whitney u test for the study subgroup versus the control group numerous studies show that there is a relation between an increased imt in the common carotid artery and the risk of both cerebral stroke and myocardial infarction [ 1 , 2 , 711 , 13 , 19 , 22 ] . it was found that the increased thickness of the intima - media complex of internal and external carotid arteries is accompanied by increased susceptibility to myocardial infarction and ischemic cerebral stroke [ 10 , 11 ] . the thickness of the imt complex is an independent risk factor of those diseases . according to the concept of parallel atherosclerosis development [ 35 ] , early atherosclerotic changes observed in the lumen of peripheral arteries are a reflection of a generalized atherosclerotic process in other vessels . for that reason , measurement of the intima - media complex is presently a recognized evaluation method both of the initial and advanced atherosclerotic changes and also a control method of the applied pharmacotherapy efficiency . the method of imt measurement is also used in determining the probability of the occurrence of coronary disease and evaluation of the risk of cardiovascular incidents in the general population . studies performed in numerous research centers [ 16 , 17 , 24 , 25 ] indicate faster progression of the atherosclerotic process in people suffering from diseases of the connective tissue , including systemic lupus erythematosus . however , the results presented in this study show that such progression occurs mainly in patients with additional factors of atherosclerosis development , such as lipid disorders , diabetes or arterial hypertension . the statistical analysis of results , due to the lack of normal distribution of the random variable in the study groups , used non - parametric tests , i.e. the anova kruskalwallis and mann - whitney u tests [ 26 , 27 ] . these tests can be used for measurable and ordinal data , the distribution of which does not comply with student t - test assumptions . in the case of measurable data , it is assessed that the strength of the mannwhitney u test is about 95% of that of the student t - test . in the present study , the test strength in the pair of study - control groups was 0.89 , while in the control - subgroup pair it was 0.53 . it is assumed that a satisfactory test strength is over 0.75 , and so the results of the comparison between the control group and the subgroup should be treated cautiously . the results of the studies show that the intima - media complex thickness among the patients with systemic lupus erythematosus is statistically bigger than among the healthy subjects of the same age . the mean imt value for the study group was from 0.2 mm ( lcca ) to 0.3 mm ( rcca ) higher than for the control group . there were some people in both groups who had minimal values ( 0.4 mm ) and maximal values ( 1.3 mm ) , yet the number of people with a thickened intima - media complex ( imt equal to or higher than 1.0 mm ) was considerably higher in the study group . these explicit tendencies did not occur between the control group and the subgroup suffering only from lupus . in this case , the difference was only 0.15 mm . following the criteria of the polish ultrasound society , only 4% of cases of the imt value in the whole study group were understood as indicating the presence of diffused atherosclerotic changes , while as many as 72% of cases had a justified diagnosis of thickened intima - media complex . the important fact is that not a single case was diagnosed in the group suffering only from lupus , where the imt > 1.3 mm , while the number of cases with a thickened complex was almost two times smaller and amounted to 41% . these observations confirm the results obtained by other research centers , which proved fast progression of the atherosclerotic process among people suffering from systemic diseases of the connective tissue , including lupus [ 16 , 17 , 24 ] . however , they also indicate that the dynamics of this process depend on additional , coexisting factors , such as hyperlipidemia , arterial hypertension or diabetes . this disease can develop at any age , but the incidence peak falls at the age of 20 to 40 years . clinical experience suggests that the inflammatory process develops in the cardiovascular system in a high percentage of patients suffering from sle ( up to 60% ) . it was proved that it can involve the pericardium , myocardium , endocardium , valves and coronary and peripheral vessels . early vessel atherosclerosis , occurring even in pediatric patients , is a complication common for systemic diseases of the connective tissue . the imt examination should become a fundamental one for all patients with diagnosed diseases of the connective tissue and should be performed regularly in order to prevent the unfavorable consequence of developing atherosclerosis . the doctor also should recommend to this group a lifestyle that will prevent the occurrence of other factors of atherosclerotic changes . the group of patients with sle was found to have increased thickness of the intima - media complex in comparison with the population of healthy subjects . moreover , the unfavorable influence of independent factors of atherosclerosis development on the increase of the imt value in patients with lupus was observed . it provides priceless time , during which a proper treatment can be administered and a long - term observation can be carried out . the fact that imt measurement is cheap , repeatable and easy to perform is of great importance , which is why we believe that it should be used more widely as a non - invasive screening test in atherosclerosis diagnostics and monitoring . this research received no specific grant from any funding agency in the public , commercial , or not - for - profit sectors .

the aim of the studythe aim of the study was to determine whether there are any differences in the intima - media thickness ( imt ) of carotid arteries between the group of patients with systemic lupus erythematosus ( sle ) and the control group , and whether these differences are a consequence of sle or independent factors of atherosclerosis development.material and methodsthe patients were divided into three groups : the study group ( n = 25 , mean age : 39.8 years ) consisting of patients suffering from sle ; the subgroup ( n = 13 , mean age : 39.2 years ) consisting of patients suffering only from sle without any accompanying diseases ; and the control group ( n = 25 , mean age : 37.1 years ) consisting of healthy patients ( not suffering from sle or any other disease of the connective tissue ) . the imt of the left and right common carotid arteries ( lcca , rcca ) was measured by means of ultrasound.resultsthe analysis performed with the mann - whitney u test showed that a statistically significant difference of imt occurs between the control group and the study groups ( p = 0.006 for lcca and p < 0.001 for rcca ) , while there is no such relation ( p = 0.86 for rcca and p = 0.095 for lcca ) between the control group and the subgroup.conclusionsthe group of patients with sle was found to have an increased imt in comparison with the reference group . the unfavorable influence of independent factors of atherosclerosis development on the increase of the imt value in patients with lupus was thus indicated . this observation suggests a faster atherosclerotic process in this group of patients .

Updated at 7:57 p.m.: Roy Moore spoke for 29 minutes Monday night in rural northeast Alabama, took no questions from his audience or the media, left the room 20 seconds after he spoke his final word and received two standing ovations. Before he even spoke a word, the Alabama Senate Republican nominee saw his audience stand and applaud at a community center in Henagar - a one stop light town located about 20 miles northwest of Fort Payne. "I liked everything he said," said Robert Dunlap of Crossville, who sat in the front row as a crowd of about 200 people squeezed into a room so crowded it would have made a fire marshal wince. Moore gave no new insight on the allegations that have hounded his campaign for the past 21/2 weeks, saying again the accusations he made unwanted romantic or sexual advances on teenage girls almost 40 years ago are "completely false." "I don't know any of (the women)," he said. Meanwhile, he spent much of his speech blasting the policies of his opponent, Democrat Doug Jones, while receiving ovations as he recited points illustrating how his philosophies are different. He also said that the investigation into Russian interference in the 2016 presidential campaign are nothing more than an effort to distract the public from Congress failing to implement President Trump's agenda. In explaining why he has come under attack, Moore compared it to the Russia probe. "This is extravagant," Moore said of the "false attacks" made against him - including not only the allegations from the women, he said, but also his family and his Foundation for Moral Law. "this is beyond being attacked for various things, having your family attacked. Politicians stop at nothing. They'll publish false polls - which they are doing today. In trying to distort this, they'll go to false attacks. "Why are they doing this? I'm going to tell you why they are doing this. They are trying to hide the true issues which affect the people of this country and this state that they want resolved. It's no different than when The Washington Post brought out the Russia investigation at a time when President Trump is trying to get his agenda passed. That's exactly what they are doing. They are taking the attention away and they're not getting anything they are doing. They are taking attention away from the Senate and from the Congress, who can't pass legislation. The people of this country want movement. They don't want false attacks like this. And that's exactly what's happening." The crowd responded with cheers. Moore addressed the allegations against him about one-third of the way through his speech. "Now with just two weeks remaining (before the election), pictures of young children - whose names are not mentioned and I do not know - appear conveniently on the opposition's ads," Moore said. "These allegations are completely false. They are malicious. Specifically, I do not know any of these women nor have I ever engaged in sexual misconduct with anyone." Moore continued defending himself against the allegations. "Now with just two weeks remaining (before the election), pictures of young children - whose names are not mentioned and I do not know - appear conveniently on the opposition's ads," Moore said. "These allegations are completely false. They are malicious. Specifically, I do not know any of these women nor have I ever engaged in sexual misconduct with anyone." Jones has run a campaign ad with photos of Moore's accusers but the names of each woman accompanied their photos. Moore also said that he has never known victims of sexual abuse to want their pictures circulated in the media. "As a former judge and prosecutor, I know the seriousness of charges like this - and they should be serious if it happens," he said. "When a young lady is abused - and I've represented many victims on cases such as this - I have not seen one who wants her picture posted on national TV, especially in a political advertisements. This is simply dirty politics." The crowd -- which received Moore for Senate stickers upon arriving -- again responded with applause. "That's what they are - they are allegations and they are not true," said Jan Cox of Leesburg. She spoke outside the community center after the speech, saying that she had voted for Moore every time he's been on the ballot in the past and has heard him speak on multiple occasions. "You wouldn't convince me that they are (true)," Cox said. "Because of all the years we've known Judge Moore's record and nothing has ever come out like this. They are scared to death and they are pulling all the punches and just seeing what will stick and trying anything they can to defeat this godly man." Like Cox, Dunlap said after the speech, "I don't believe it. I know several of his neighbors who live down there (in Moore's hometown of Gallant in Etowah County). I just don't think it's there. Why wait 40 years for it to be brought out? "And be brought in by a lawyer and evidently, she wrote her speech and told her what to say," he said, referring to accuser Beverly Young Nelson, who made her allegations against Moore at a New York press conference accompanied by celebrity attorney Gloria Allred. Moore concluded his speech by describing the ordeal he's facing as a "spiritual battle." And he promised a ferocious response. "Ladies and gentlemen, I ask myself why am I put in this position? And I want to tell you. I have vowed, when I get to Washington D.C. as a United States senator, to take a knowledge of the Constitution and to God, upon whom it is founded - and that's it. They don't want to hear it. "Politicians today are not out to serve. I'm not saying all - there are some good ones. But many of them are confused about the rule of law. They are confused about the Constitution, why it's there, what it's there for. And they certainly don't want to talk about morality. That's why we're having dirtiness in campaigns. Everybody knows I have not run one negative ad. But I'm going to take off the gloves and show the truth in this campaign. "I'm a fighter and I don't hesitate to say that. I've done that all my life." Original story: For the first time in nearly two weeks, and with only two weeks remaining until the special election, former Alabama Chief Justice Roy Moore tonight publicly addressed an audience gathered in support of his Senate run. The 120 seats quickly filled tonight at the Henagar Event Center in the small town in DeKalb County. Seven television satellite trucks, from local stations as well as NBC News and Fox News, are parked nearby. Moore did not take questions his DeKalb County campaign chairman said at the beginning of the event. He repeatedly asked for "no outbursts" and threatened people with removal by security. Outside the center, the chairman grabbed a television camera as a journalist attempted to film Moore's arrival. Moore took the stage shortly after 6 p.m. Raw video: Man wearing Roy Moore sticker physically attacked a cameraman attempting to film Moore's arrival outside campaign rally a few minutes ago here in Henagar, Alabama. Another man w/ Moore sticker verbally assaulted a second cameraman. pic.twitter.com/faJVV8YpE0 -- Connor Sheets (@ConnorASheets) November 28, 2017 "Well there is 14 days left," Moore said. "We're going to be very busy." He then went through the steps that led Alabama to this point, beginning with Jeff Sessions' appointment to U.S. Attorney General and Luther Strange to replace him on the U.S. Senate. "There is an established group of people in Washington that doesn't want change," Moore said. "Lots of money has been spent on this election...They don't want me as a senator." "We've seen malicious and false attacks," Moore said. "This is corrupt politics." "This hurts me personally" he said of sexual misconduct allegations. He said the accusations had never arisen in his many years in public life. "These allegations are false," Moore said, saying he did not know any of the accusers. Moore said he had worked with victims of sexual abuse and none, he said, wanted publicity. "This is simply dirty politics and it's sign of the immorality of our times...Politicians will stop at nothing to win an election." Moore said his opponents are releasing "false polls." Packed house at this Roy Moore rally here in rural Henagar, Alabama tonight pic.twitter.com/VkV7cJ2UrA -- Connor Sheets (@ConnorASheets) November 27, 2017 Although others have spoken on his behalf publicly and he has met privately with supporters, this is Moore's first public appearance since Nov. 16. Moore at that time said the allegations from accusers who claimed he either sexually assaulted, harassed or dated them when they were teenagers were politically motivated. "This is an effort by Mitch McConnell and his cronies to steal this election from the people of Alabama, and they will not stand for it," he said, adding that McConnell needs to "step down" as Senate majority leader. This appearance came just hours after The Washington Post reported a woman, possibly working with a group seeking to discredit its reporters, shared false claims about Moore, which the Post debunked. The deadline to register to vote in the Dec. 12 special election is tonight at 11:59 p.m. ||||| (CNN) Senate candidate Roy Moore said at a campaign event Monday that the sexual allegations he faces are "completely false" and "malicious," and said he doesn't know any of the women levying them. The Alabama Republican compared the allegations to the probe into 2016 Russian meddling in the US election and potential connections between President Donald Trump's campaign and Russians. "The people of this country want movement. They don't want false attacks like this. That's exactly what's happening in this case," Moore said. "They want to hide the true issues of immigration and health care, military readiness, taxes, abortion and transgender rights. They also not only want to hide the issues, they don't want my opponent's issues revealed; how he stands on these issues. I'll tell you how he stands: completely contrary to the people of this state and this country." Several women have come forward and accused Moore of pursuing relationships with them when they were teenagers and he was in his 30s, and several others also have accused him of assault. On Monday, Moore cast the allegations as "malicious, false attacks, which reflect the immorality of our time." He compared the Washington establishment's opposition to him to former President Barack Obama's remarks about those who cling to guns and religion. Read More

– Roy Moore doubled down on his denials of sexual misconduct at an Alabama rally Monday night—and received a standing ovation from a crowd of around 200 people. The Senate candidate, making his first public appearance since Nov. 16, likened the accusations against him to the Russia investigation and said he is being targeted because he wants to take morality to Washington, AL.com reports. "These allegations are completely false. They are malicious," said Moore, whose Democratic opponent, Doug Jones, has been running ads with pictures of the women who accuse Moore of misconduct. "I do not know any of these women nor have I ever engaged in sexual misconduct with anyone," Moore said. Moore, who has refused to debate Jones, attacked the Democrat for supporting transgender rights, CNN reports. "I know how to strengthen the military, and it isn't by putting transgender troops and opposing President Trump's ban on transgender troops in the military," he said. Moore concluded the speech by describing his campaign as a "spiritual battle" and declined to take questions afterward. Trump has attacked Jones as a "Schumer/Pelosi puppet," though he hasn't campaigned for Moore and the White House said Monday that he is too busy to "do anything between now and Election Day," which is Dec. 12, for the Republican, the AP reports. (A retired Marine entered the race as an independent Monday.)

Brendan Mcdermid / Reuters Traders work on the floor of the New York Stock Exchange. Stock prices tumbled on Wall Street Friday after a report showed job growth in May was the weakest in a year and employers added fewer jobs in the prior two months than previously reported -- another blow to investors worried about global growth. The Dow Jones industrial average was lately down over 200 points. Other stocks indexes also fell sharply. The Labor Department’s latest jobs report showed U.S. employers created only 69,000 jobs in May, the fewest in a year, as the nation’s unemployment rate rose to 8.2 percent from 8.1 percent in April -- the first increase in 11 months. The government also said the economy created far fewer jobs in the previous two months than first thought, revising numbers down to show 49,000 fewer jobs created. The market had discounted a mildly negative employment report, said Barton Biggs, a hedge fund manager at Traxis Partners. “But it hadn’t discounted the kind of numbers we saw this morning,” he told CNBC Friday. The dismal jobs data are likely to stoke fears that the U.S. economy is struggling. It could also weigh on President Barack Obama's re-election hopes and lead the U.S. Federal Reserve to take more steps to prop up the economy. Republican presidential candidate Mitt Romney called the jobs report “devastating news” and a sign that President Obama's economic policies have failed. "Today's weak jobs report is devastating news for American workers and American families," he said in a statement. He called the May report "a harsh indictment of the President's handling of the economy." "It is now clear to everyone that President Obama's policies have failed to achieve their goals and that the Obama economy is crushing America's middle class. The president's re-election slogan may be 'forward,' but it seems like we've been moving backward," he said. The troubles in the euro zone were also a focus for Wall Street, as investors digested the latest economic data from the region. Unemployment the euro zone was 11 percent in April. The figure was unchanged from March, but still at the highest level since records started in 1995. Spain’s had the highest rate in the region at 24.3 percent. Treasury yields hit their lowest level in hundreds of years and global stock indexes dropped toward 2012 lows as investors scrambled for lifelines amid worries about Spain's parlous finances and China's growth outlook. Chinese demand seen slowing, record after record has tumbled across asset classes as investors seek security for their cash. The German two-year bond yield fell below zero for the first time, meaning investors are paying for the right to hold that debt. Other "safe havens" Denmark and Switzerland said they were prepared to set negative interest rates to prevent their currencies spiraling. Oil fell below the psychologically key level of $100 a barrel, striking an eight-month low. "We've had constant worries about Greece, Spain, the euro, poor data from the U.S., and overnight the Chinese data was not positive," said Tony Machacek, an oil futures broker at Jefferies Bache. The euro hit its lowest against the dollar in nearly two years at $1.2316 while 10- and 30-year German Bund yields hit all-time lows. The dollar index rose to a 21-month high. Madrid's need to recapitalize its troubled banks and shore up its heavily indebted regions is the latest focus for turbulent markets, though IMF Managing Director Christine Lagarde denied late on Thursday that the Fund was preparing financial assistance for Spain. Spaniards alarmed by the dire state of their banks are squirreling money abroad at the fastest rate since records began, figures showed on Thursday. The gloomy economic news was not confined to Europe. Weighing on the global demand outlook, China's official purchasing managers' index fell to 50.4 in May from April's 13-month high of 53.3. Earlier, European stocks fell to their lowest levels this year. Reuters contributed to this report. ||||| Stocks fell sharply Friday after the release of a dismal report on job creation in the United States. The Dow Jones industrial average dropped more than 200 points, erasing what was left of its gain for the year. The Standard & Poor's 500 index and Nasdaq composite index both fell more than 1.5 percent in early trading. American employers added just 69,000 jobs in May, the fewest in a year, and the unemployment rate ticked up to 8.2 percent from 8.1 percent. Economists had forecast a gain of 158,000 jobs. A little more than an hour into trading, the Dow was down 215 points at 12,178, leaving it with a loss of 0.3 percent for the year. Earlier this year, the Dow was up more than 8 percent. "The big worry now is that this economic slowdown is widening and accelerating," said Sam Stovall, chief equity strategist at S&P Capital IQ, a market research firm. The weak jobs report sent traders stampeding into U.S. government bonds as a safe investment. Bond prices rose sharply, and the yield on the benchmark 10-year U.S. Treasury note fell to 1.46 percent, the lowest on record. The Standard & Poor's 500 index was down 22 points at 1,287. The Nasdaq was off 52 at 2,775. Both of those indexes were still up for the year _ about 2 percent for the S&P and 6 percent for the Nasdaq. May was by some measures the worst month for the stock market in two years. That was primarily because investors were worried about a worsening debt crisis in Europe. But the jobs report returned the United States to the flashpoint of market fear, said Todd Salamone, director of research for Schaeffer's Investment Research in Cincinnati. "The weaker jobs report translates into anticipation of slower growth ahead and weaker corporate earnings, and that ratchets stock prices lower," Salamone said. Stovall said that traders are waiting to see what governments and central banks might do to juice global economic activity. Otherwise, the losses would be even deeper, he said. The Fed launched bond-buying programs in 2009 and 2010 to lower interest rates and help stock prices, but it has resisted a third round of that approach, known as quantitative easing. Anticipation of bond-buying by the Fed "might put in a little bit of a floor to the market, but the overall economic picture is still bad," said Bob Gelfond, CEO of MQS Asset Management, a New York hedge fund. The price of gold shot higher. It rose $37 an ounce to $1,601. For much of the past three years, investors have bought gold for safety during a turbulent time for the world economy. The dollar weakened. The euro rose half a penny against the dollar to $1.24. Gold spiked and the dollar fell partly because traders expect more intervention by the Federal Reserve, Gelfond said. Bond-buying adds to the supply of money coursing through the economy and leads some investors to worry about inflation later, which would make the dollar less valuable. Traders buy gold as a hedge against inflation. Stocks fell broadly. Only 20 companies in the S&P were higher for the day. Energy companies and financial stocks led the market lower. The price of a barrel of oil fell more than $3 to $83.54, extending a monthlong slide. Caterpillar, which depends heavily on world economic demand, fell $2.63, or 3 percent, to $85.03. It was among the worst performers of the 30 stocks that make up the Dow. The job picture remained dark elsewhere in the world. Unemployment in the 17 countries that use the euro currency stayed at a record-high 11 percent in April, and unemployment rose spiked to almost 25 percent in Spain. There were also signs that growth in China, which was a bulwark during the global recession, is slowing significantly. China's manufacturing weakened in May, according to surveys released Friday. Stocks were down considerably in Europe. The benchmark stock index fell more than 3 percent in Germany and Greece and more than 2 percent in France. British stocks were down but fared slightly better.

– The Dow's gain for the year is gone, thanks to today's terrible jobs report. The Dow fell more than 200 points following the report, according to the AP. At 11am EDT, it was at 12,170, down 224 points. That's a loss of about 0.3% for the year. The S&P 500 and the Nasdaq dropped more than 1.5% in early trading, although both were still up for the year. MSNBC adds that the VIX index, which measures investor fear, rose to hit levels last seen in December.

The search giant has unveiled its annual Year In Search results that show the top Google searches in various categories globally and by country. Hurricane Irma topped the search charts in both the U.S. and globally with Matt Lauer being the most searched for person in the U.S. and the world. Here’s the rundown of the top 10’s in the U.S. and globally:

– Hurricane Irma and Matt Lauer were hot topics in 2017, Fast Company notes—hot enough to propel both to the top of Google's annual "Year in Search" results. Per the site, the results were culled "based on search terms that had a high spike in traffic in 2017 as compared to 2016." Searches for the mega-storm and disgraced TV personality made both the US and worldwide top 10, as did Tom Petty and the fidget spinner. Here, results from more local computers, tablets, and smartphones: Searches in the US: Hurricane Irma Matt Lauer Tom Petty Super Bowl Las Vegas shooting Mayweather vs. McGregor fight Solar eclipse Hurricane Harvey Aaron Hernandez Fidget spinner Continue on to see what trended worldwide:

calculation abilities have followed a long process from the initial quantification systems up to modern algebra , geometry , and physics . some rudimentary numerical concepts are observed in animals , and there is no question that pre - historic man used some quantification . however , the ability to represent quantities , the development of a numerical system , and the use of arithmetical operations are found only in old civilizations . this paper reviews the evolution of calculation abilities , including numerosity and counting in non - human animals , calculation abilities in primitive and modern humans , and links between language and number concepts throughout human history . in addition , the paper reviews contemporary studies of the neurological substrates of numerical abilities and discusses the implications of technological advances with regard to continued evolution of these abilities . the origin of mathematical concepts can be traced to sub - human species . throughout recent history different reports have argued that animals ( horses , rats , dogs , chimpanzees , dolphins , and even birds ) can use numerical concepts and perform arithmetical operations . some others , however , are rigorous and highly controlled scientific studies ( e.g. , rugani et al . , 2009 ) . there is , in general , agreement that some rudimentary numerical concepts are observed in animals . these basic numerical skills can be considered as the real origin of the calculation abilities found in contemporary man . for instance , pigeons can be trained to peck a specific number of times on a board , and rats can be trained to press a lever a certain amount of times to obtain food ( koehler , 1951 ; mechner , 1958 ; capaldi and miller , 1988 ) . it could be conjectured that pigeons and rats can count , at least up to a certain quantity ; that is , they can recognize how many times a motor act to peck on a board or to press a lever has been repeated . whether or not this behavior can really be interpreted as counting however , this behavior is observed , at least after a long and painstaking training . nonetheless , these animal responses ( to peck or to press the lever ) are not precise but just approximate . in other words , when the rat is required to press the lever seven times , the rat presses it about seven times ( i.e. , 5 , 6 , 7 , 8 times ) . as dehaene ( 1997 ) emphasizes , for an animal , 5 plus 5 does not make 10 , but only about 10 . according to him , such fuzziness in the internal representation of numbers prevents the emergence of exact numerical arithmetical knowledge in animals . using highly controlled and sophisticated designs , it has been pointed out that chimpanzees can even use and add simple numerical fractions ( e.g. , 1/2 + 1/4 = 3/4 ) ( woodruff and premack , 1981 ) . these observations support the assumption that some quantity concepts can be found in different animals . counting ( or rather , approximately counting ) motor responses is just a motor act as is walking or running . counting lever pressings is not very different from estimating the effort ( e.g. , number of steps or general motor activity ) required in going from one point to another . counting in such a case could be linked to some proprioceptive and kinesthetic information . in the human brain kansaku et al . ( 2006 ) identified a network of areas involved in enumerating small numbers of auditory , visual , and somatosensory stimuli , and in enumerating sequential movements of hands and feet , in the bilateral premotor cortex , presupplementary motor area , posterior temporal cortex , and thalamus . the most significant consistent activation across sensory and motor counting conditions was observed in the lateral premotor cortex . lateral premotor activation was not dependent on movement preparation , stimulus presentation timing , or number word verbalization . furthermore , movement counting , but not sensory counting , activated the anterior parietal cortex . not only chimpanzees , but also rats and many other animals , can distinguish numerosity ( i.e. , global quantification ) ; for instance , they prefer a bowl containing a larger number of nutritive elements ( such as chocolates or pellets ) when selecting between two bowls containing different amounts ( davis and perusse , 1988 ) . it may be conjectured that global quantification ( numerosity perception ) and counting ( at least the approximate counting of motor responses ) represent kinds of basic calculation abilities found at the animal level . rats prefer a bowl containing 20 pellets to a bowl containing only 10 pellets ; however , they do not prefer a bowl containing 20 pellets to a bowl containing 21 pellets . obviously , numerosity perception is related to the size and shape of the visual image projected to the retina . it can be assumed that 20 pellets in a bowl result in a larger and more complex retinal image than 10 pellets . but the visual image corresponding to 20 pellets is difficult to distinguish from the visual image corresponding to 21 pellets . chimpanzees are capable of various forms of numerical competence , including some correspondence constructions ( that is , comparing two collections of elements ) for low quantities ( premack , 1976 ; davis and perusse , 1988 ) . homo sapiens antecessors may have been capable of using correspondence constructions in some social activities , such as food sharing . it has been proposed that homo habilis ( ancestor of homo erectus , living about 2.3 million to 1.4 million years ago ) needed to use correspondence constructions when butchering large animal carcasses ( parker and gibson , 1979 ) . distributing pieces of a divided whole ( e.g. , prey ) into equal parts required the ability to construct one - to - one correspondences . probably , paleolithic man was able to match the number of objects in different groups and , eventually , the number of objects in a collection with the number of items in some external cue system , e.g. , fingers or pebbles ( incidentally , calculus means pebbles ) . the immediate recognition of certain small quantities is found not only in animals , but also in small children . animals and children can readily distinguish one , two , or three objects ( fuson , 1988 ; wynn , 1990 , 1992 ; cook and cook , 2009 ) . antell and keating ( 1983 ) observed that newborn infants were able to discriminate among visual stimulus arrays consisting of few a dots . it was found that infants were able to discriminate between small numbers ( 2 versus 3 ) but not for larger sets . this ability for discriminating and also representing and remembering small numbers of items has also been reported by other authors ( e.g. , starkey and cooper , 1980 ) . interestingly , evoked potentials at 3 months are already capable of marking changes in the nature and number of a set of objects , and these activation changes relate to the parietal lobe ( dehaene and dehaene - lambertz , 2009 ) . noteworthy , in normally developing children and adults , the increase in arithmetic competence is associated with shift of activation from frontal brain areas to parietal areas . a shift of activation is also observed within the parietal lobe from the intraparietal sulci to the left angular gyrus ; experts arithmetic proficiency depends on a more extended activation than the network found in beginners . in expert individuals with solid , extensive mathematical training , specific brain activation changes are also observed ( zamarian et al . , 2009 ) . oneness , twoness , and threeness seemingly are basic perceptual qualities that our brain can distinguish and process without counting . it can be conjectured that when pre - historic humans began to speak , they may have been able to name only the numbers one , two , and three , corresponding to specific perceptions . to name them was probably no more difficult than naming any other sensory attribute ( dehaene , 1997 ) . of note , all world languages can count up to three , even though three may represent many , several , or a lot ( hurford , 1987 ) . one is obviously the unit , the individual ( the speaker may also be one ) . ( for example , in english and also in spanish , second is related with the verb to second and the adjective secondary ) . ( for example , troppo , which in italian means too much , is seemingly related with the word three -tre ) . in the original indo - european language , one , one and another ( two ) , and a lot , interestingly , in some contemporary languages , two different plurals are found : a plural for small quantities ( usually two , sometimes three and four ) and a second plural for larger quantities ; for instance , in russian , one house is , two , three , or four houses is dva , tri , cheterye doma but five houses is pyat domov . of note , in different world languages , the word one does not have any apparent relationship with the word first ; and the word two is also not related with the word the conclusion is obvious : for small quantities ( one , two , three ) , cardinals and ordinals must have a different origin . for larger quantities , ordinal numbers are derived from cardinals . as a matter of fact , one / first and two / second correspond to different conceptual categories . it may be speculated that for pre - historic man the first person and the second person in a line ( or the first animal and the second animal during hunting , or other similar concepts ) do not seem to be related with the number one and the number two . for small children i go first ) whereas second is related to later or after these words have a temporal and also spatial meaning , but not an evident numerical meaning . one and first , and two and second seems a relatively advanced process in the development of numerical concepts . that is , the numerical meaning of first and second seems to appear after its temporal and spatial meaning . the association between ordinals and cardinals becomes evident only for larger quantities ( more than three ) and seems to represent a later acquisition in human evolution and the complexization of numerical concepts . moreover , in many contemporary languages ( e.g. , the huitoto language , spoken by the huitoto indians in the amazonian jungle1 ) there are no ordinal numbers . for first counting not simply recording the approximate amount of motor responses required for obtaining reinforcement , but actually saying aloud a series of number words that correspond to a collection of objects is relatively recent in human history . counting also occurs relatively late in child development . in human history , as well as in child development , counting using number words begins with sequencing the fingers ( i.e. , using a correspondence construction ) ( hitch et al . , 1987 ) . the name of the finger and the corresponding number can be represented using the very same word ( that means the very same word is used for naming the thumb and the number one ; the very same word is used to name the index finger and the number two , etc . ) . the fingers [ and toes ; as a matter of fact , many languages such as spanish use a single word ( dedo ) to name both the fingers and toes ] are usually sequenced in a particular order . this strategy represents a basic procedure found in different ancient and contemporary cultures around the world ( levybruhl , 1910/1947 ; cauty , 1984 ; klein and starkey , 1987 ; dansilio , 2008 ) . interestingly , it has been demonstrated that children with low arithmetical skills also present a finger misrepresentation on the draw - a - person test ( pontius , 1989 ) . difficulty in recognizing and naming the fingers represents a reliable predictor of developmental dyscalculia ( kaufmann , 2008 ) . taking a typical example as an illustration , the colombian sikuani or guahibo amazonian jungle indians2 count in the following way : the person ( an adult when counting or a child when learning to count ) places his / her left hand in supination ; to point to number one , the right index points to the left little finger , the order followed in counting is always from the little finger to the index . to point to number five , the hand is turned and the fingers opened ; for six , both thumbs are joined , the left fingers are closed , and the right opened ; they are opened one after the other for seven , eight , nine and ten . between 11 and 20 , the head points to the feet and the sequence is re - initiated . the lexicon used is : 1 : kae ( the unit , one ) 2 : aniha - behe ( a pair , both ) 4 : penayanatsi ( accompanied ; that is , the fingers together ) 5 : kae - kabe ( one hand ) numbers from six to nine , are formed with one hand and ( a certain number ) of fingers . ten becomes two hands : 6 : kae - kabe kae - kabesito - nua ( one hand and one finger ) 7 : kae - kabe anih - akabesito - behe ( one hand and a pair of fingers ) 10 : anih - akabe - behe ( two hands ) two hands is maintained between 10 and 20 . toes ( taxawusito ) are added between 11 and 14 ; and one foot ( kaetaxu ) is used in 15 . twenty is two hands together with two feet : 11 : aniha - kabe - behe kae - taxuwusito ( two hands and one toe ) 12 : aniha - kabe - behe aniha - tuxuwusito - behe ( two hands and two toes ) 15 : aniha - kabe - behe kae - taxu - behe ( two hands and one foot ) 16 : aniha - kae - behe kae - taxu - behe kaetaxuwusito ( two hands , one foot , and one toe ) 20 : aniha - kabe - behe aniha - taxu - behe ( two hands and two feet ) fingers are named according to their order in counting ( as mentioned above , counting begins always with the little finger of the left hand ) . the sikuani language possesses number words only up to three ( kae , aniha - behe , akueyabi ) . four ( penayanatsi = accompanied , together ) represents a correspondence construction . strictly speaking , , they use a correspondence construction , not really counting ; and for higher quantities , they resort to a global quantification . sometimes not only the fingers ( and toes ) but also other body segments may be used in counting : the wrist , the shoulders , the knees , etc . ( levy - bruhl , 1910/1947 ; cauty , 1984 ; dansilio , 2008 ) . however , sequencing the fingers ( and toes ) represents the most universal procedure in counting . some languages ( e.g. , some mayan dialects and greenland eskimo ) use the same word to denote the number 20 ( that is , all the fingers and all the toes ) and a person . in different amerindian languages , for higher than 10 or 20 figures , most often many is used ( global quantification principle ) ( cauty , 1984 ; ifrah , 2000 ) . or , they can refer to other people 's hands ( correspondence construction ) ( e.g. , thirty - five might be something like my two hands , my two feet , my father 's two hands , my father 's one foot ) . it is interesting to note that in some contemporary languages ( like english and spanish ) one means the unit , but it is also used as a sort of indefinite personal pronoun . in english and spanish twenty is found to be the base number in the mayan numerical system ( swadesh , 1967 ; cauty , 1984 ) . in many contemporary languages , latin number notation was originally etruscan ( turner , 1984 ) and referred ( as in other languages ) to the fingers . one , two , and three were written simply by making vertical strokes . in four , five ( v ) represented the whole hand with the arm bent ( that is , all the fingers of the hand ) , and ten ( x ) the two arms crossed . from a neuropsychological perspective , a strong relationship between numerical knowledge , finger gnosis , and even lateral ( right left ) knowledge is evident ( ardila and rosselli , 2002 ; kaufmann , 2008 ) . finger agnosia ( and probably right left discrimination disturbances ) could be interpreted as a restricted form of autotopagnosia ( inability to recognize or localize the various body parts ) ( ardila et al . it is not surprising to find that a decimal ( or vigesimal , i.e. , with a base of 20 ) system has been most often developed . simultaneously or very close in time , decimal systems appeared in different countries ( sumer , egypt , india , and crete ) . different symbols were used to represent 1 , 10 , 100 , and 1000 ( childe , 1936 ; dansilio , 2008 ) . there is , however , an interesting and intriguing exception : sumerian and later babylonians ( about 2,000 bc ) developed not only a decimal but also a sexagesimal system : a symbol represented 60 or any 60-multiple and another different symbol represented the number 10 and any 10-multiple . thus , for example , the number 173 was then represented : 2 60 ( the symbol for 60 repeated twice ) + 5 10 ( the symbol for 10 repeated five times ) + 3 ( a symbol for units repeated three times ) . a base of 60 has remained for some contemporary time measures ( e.g. , minutes and seconds ) . second - order unit ( e.g. , a dozen ) . evidently , 60 results from five times twelve . it might be speculated that 12 means the 10 fingers plus the two feet or even the two elbows or the two shoulders or the two knees ( individuality of components is easier to appreciate in the hands than in the feet ) . but this is only speculation , although it is feasible according to our knowledge about counting procedures used in different cultural groups ( levy - bruhl , 1910/1947 ; ifrah , 2000 ; dansilio , 2008 ) . maya indians developed a similar system , but had 20 as a base ( leon - portilla , 1986 ) . they used different symbols to represent 20 , 400 ( 20 20 ) , and 8000 ( 20 20 20 ) ( cauty , 1984 ) . thus , reviewing the history of numerical concepts , it is found that world languages developed a base 10 ( 10 fingers ) or 20 ( 10 fingers plus 10 toes ) or even five ( five fingers ) to group quantities . in some contemporary languages a residual 20-base can be found ( e.g. , in french 80 can be four twenties ) . in many contemporary languages , onward , numbers are formed simply with the words twenty plus one , twenty plus two , for instance , in the amerindian language tanimuca in south america3 , speakers count up to five . between five and 10 , numbers are five one , five two , and so on . writing numbers appeared earlier in history than writing language . some cultures ( e.g. , incas ) developed a number representing system , but not a language representing system ( swadesh , 1967 ) . pebbles , marks , knots , or any other element were used as a correspondence construction to record the number of elements ( people , cows , fishes , houses , etc ) . in sumer , the first number writing system has been found ( about 3,000 bc ) ( childe , 1936 ; ifrah , 2000 ) : instead of using pebbles , fingers , or knots , it was simpler just to make a mark ( a stroke or a point ) on the floor , on a tree branch , or on a board if one wanted to keep the record . in egypt , india and later in crete , a similar system was developed : units were represented by a conventional symbol ( usually a stroke ) repeated several times to mean a digit between one and nine ; a different symbol was used for 10 and 10-multiples . positional digit value is clearly evident in babylonians , and around 1,000 bc the zero was introduced . positional value and zero are also evident in maya indians ( leon - portilla , 1986 ) . small fractions ( 1/2 , 1/3 , and 1/4 ) are relatively simple numerical concepts , and even chimpanzees can be trained to use small fractions ( woodruff and premack , 1981 ) . as pointed out , recognition of individual marks or elements up to three is easy : it represents an immediate perception readily recognizable . beyond three , the number of marks ( strokes or dots ) usually has to be counted and errors are more likely . furthermore , it is rather time - consuming and cumbersome to be constantly counting marks . interestingly , the different digit notational systems always represent one , two and three with strokes ( or points , or any specific mark ) . in other words , the numbers one , two and three are written making one , two or three strokes . but beyond these figures , digit writing may give way to other strategies . in our arabic digit notation system , one is a vertical line whereas two and three were originally horizontal lines that became tied together by being handwritten ( ifrah , 2000 ) . this observation may be related with the inborn ability to perceptually recognize up to three elements . beyond three , perceptually distinguishing eight and nine strokes is not as easy as distinguishing between two and three strokes . the introduction of a different representation for quantities over three was a useful and practical simplification . the numerical system , along with measurement units , were developed departing from the body dimensions ( fingers , hands , arm , steps , etc . ) . this tendency to use the human body not only to count but also as measure units is still observed in some contemporary measurement units ( e.g. , foot ) . adding , subtracting , multiplying and dividing were possible in the egyptian system , but of course , following procedures quite different from those procedures we currently use . egyptians based multiplication and division on the duplication and halving method ( childe , 1936 ) . interestingly , this very same procedure ( duplicating and halving quantities ) is also observed in illiterate people when performing arithmetical operations . thus , to multiply 12 18 in the egyptian system the following procedure was followed : ( the number 18 is duplicated one or several times , and the amounts corresponding to 12 ( 4 + 8 in this example ) are selected and summed up : 72 + 144 = 216 . to divide , the inverse procedure was used . therefore , the procedure used to divide 19 by 8 would be : that is , 2 + 4 + 8 ( 2 + 1/4 + 1/8 ) , which is 2.375 in brief , different steps were followed in the development of arithmetical abilities : representing quantities , initially as correspondence constructions ( i.e. , one mark represents one element ) , later new marks were added to represent larger quantities ( usually 10 ) ; providing a positional value to the marks ; using fractions ; and computing quantities ( adding and subtracting ; and later multiplying and dividing ) . since primary acalculia ( a basic defect in computational ability ) was initially described by henschen ( 1925 ) it has been associated with left posterior parietal damage ( e.g. , mazzoni et al . , 1990 ; ardila et al . , 2000 . furthermore , it was suggested that different cerebral pathways are responsible for processing rote numerical knowledge ( e.g. , multiplication tables ) and semantic knowledge of numerical quantities . dehaene and cohen ( 1997 ) have proposed that a left subcortical network contributes to the storage and retrieval of rote verbal arithmetical facts , whereas an inferior parietal network is dedicated to the mental manipulation of numerical quantities . neuroimaging techniques ( e.g. , fmri ) have been used to analyze the pattern of brain activity during diverse calculation tasks . it has been demonstrated that different brain areas are active during arithmetical tasks , but the specific pattern of brain activity depends on the particular type of task that is used . at minimum , the following brain areas become activated during calculation : the upper cortical surface and anterior aspect of the left middle frontal gyrus ( burbaud et al . , 1995 ) ; the supramarginal and angular gyrus ( bilaterally ) ( rueckert et al . , 1996 ) ; the left dorsolateral prefrontal and premotor cortices , broca 's area , and the inferior parietal cortex ( burbaud et al . , 1999 ) ; and the left parietal and inferior occipitotemporal regions ( lingual and fusiform gyri ) ( rickard et al . , 2000 ) . the diversity of brain areas involved in arithmetical processes supports the assumption that calculation ability represents a multifactor skill , including verbal , spatial , memory , body knowledge , and executive function abilities ( ardila and rosselli , 2002 ) . 2004 ) , however , proposed that regardless of the diversity of areas that become active during arithmetical tasks , the human ability for arithmetic is associated with activation of very specific brain areas , in particular , the intraparietal sulcus . neuroimaging studies with humans have demonstrated that the intraparietal sulcus is systematically activated during a diversity of number tasks and could be regarded as the most crucial brain region in the understanding and use of quantities ( ashkenazi et al . , 2008 ) . these observations have been supported using brain electrostimulation ( roux et al . , 2009 ) . other brain areas , such as the precentral area and the inferior prefrontal cortex , are also activated when subjects engage in mental calculations . rosca ( 2009 ) has proposed that there exists a fronto parieto subcortical circuit responsible for complex arithmetic calculations and that procedural knowledge relies on a visuo - spatial sketchpad that contains a representation of each sub - step of the procedure . traditionally , calculation defects have been associated with posterior left parietal damage ( henschen , 1925 ; boller and grafman , 1983 ) , and frequently included in the so - called gerstmann 's ( or angular gyrus ) syndrome . symptoms of gerstmann 's syndrome ( acalculia with agraphia , disorders in right - left orientation , and finger agnosia ) ( gerstmann , 1940 ) can be found during direct cortical stimulation in the angular gyrus region ( roux et al . , 2003 ) . using fmri , it has been observed that the left angular gyrus is not only involved in arithmetic tasks requiring simple fact retrieval , but may show significant activations as a result of relatively short training of complex calculation ( delazer et al . , 2003 ) . ( 2005 ) investigated numerical abilities in a split - brain patient using experiments that examined the hemispheres abilities to make magnitude comparisons . one experiment examined the ability to enumerate sets of stimuli , and another two experiments required judgments about two concurrently presented stimuli that were either identically coded ( i.e. , two arabic numerals , two number words , or two arrays of dots ) or differently coded ( e.g. , an arabic numeral and a number word ) . both hemispheres were equally able to enumerate stimuli and make comparisons between numerical representations regardless of stimuli coding . however , the left hemisphere was more accurate than the right when the task involved number words . ( 2000 ) reported a patient with a lesion in the left perisylvian area who showed a severe impairment in all tasks involving numbers in a verbal format , such as reading aloud , writing to dictation , or responding verbally to questions of numerical knowledge . in contrast , her ability to manipulate non - verbal representation of numbers , i.e. , arabic numerals , was comparatively well preserved . this observation supports the proposal that language and calculation disorders can be dissociated ( basso et al . , 2000 ) . some authors have assumed that language and numerical concepts are differently organized in the brain and follow distinct developmental patterns in children ( gelman and butterworth , 2005 ) . other authors have suggested that calculation and language are mediated by partially different and also partially overlapped brain systems ( baldo and dronkers , 2007 ) . ( 2006 ) have emphasized that calculation and language usually share the same hemisphere . in summary , diverse brain areas are activated during the performance of different arithmetical tasks , although contemporary evidence suggests that the intraparietal sulcus seems to the play the most crucial role . during the learning of new calculation abilities , additional brain areas become involved and the specific pattern of brain activity depends on the particular type of test that is used . it can be assumed that during human history , the development of new numerical abilities was correlated with the involvement of new brain areas during the performance of progressively more complex numerical tasks . most likely , during the stone - age , only simple counting up to three and , of course , bigger and smaller ( magnitude judgment ) concepts were present . finger knowledge and counting represent , to a certain extent , the same cognitive ability , as is still evident in some contemporary languages , such as sikuani . counting , finger gnosis , and even lateral spatial knowledge may present a common historical origin . seemingly , calculation abilities were derived from finger sequencing . number representation and arithmetical operations currently , calculation abilities are rapidly evolving due to the introduction of modern technology and resulting cognitive demands . right - left discrimination ( as well as the use of other spatial concepts ) most likely was present in pre - historic man , because requirements of spatial abilities may have been very high , even higher than in contemporary man ( hours , 1982 ; ardila and ostrosky , 1984 ; ardila , 1993 ) . rightleft discrimination and finger gnosis are strongly interdependent , and even they can be interpreted as components of the autotopagnosia syndrome . it seems , in consequence , that there is a rationale for finding a common brain activity for finger gnosis , calculation , and right - left discrimination ( and in general , spatial knowledge mediated by language ) ( ardila and rosselli , 2002 ) . contemporary neuroimaging techniques , specifically fmri , have demonstrated that the left parietal lobe , particularly the intraparietal sulcus is systematically activated during a diversity of number tasks ; other areas , particularly the frontal lobe , are also involved in processing numerical information and solving arithmetical problems . also , it has been suggested that there exists a fronto parieto subcortical circuit responsible for complex arithmetic calculations and procedural knowledge . it can be conjectured that numerical abilities continue evolving due to advances in mathematical knowledge and the introduction of new technologies ; for instance , instead of writing numbers down on paper and applying certain computational rules , we more often require the ability to use a pocket calculator or a computer program . brain representation of calculation may be taking a new direction , and even the acalculia syndrome may present different clinical manifestations . the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .

some numerical knowledge , such as the immediate recognition of small quantities , is observed in animals . the development of arithmetical abilities found in man 's evolution as well as in child 's development represents a long process following different stages . arithmetical abilities are relatively recent in human history and are clearly related with counting , i.e. , saying aloud a series of number words that correspond to a collection of objects . counting probably began with finger sequencing , and that may explain the 10-base found in most numerical systems . from a neuropsychological perspective , there is a strong relationship between numerical knowledge and finger recognition , and both are impaired in cases of left posterior parietal damage ( angular or gerstmann 's syndrome ) . writing numbers appeared earlier in human history than written language . positional digit value is clearly evident in babylonians , and around 1,000 bc the zero was introduced . contemporary neuroimaging techniques , specifically fmri , have demonstrated that the left parietal lobe , particularly the intraparietal sulcus , is systematically activated during a diversity of tasks ; other areas , particularly the frontal lobe , are also involved in processing numerical information and solving arithmetical problems . it can be conjectured that numerical abilities continue evolving due to advances in mathematical knowledge and the introduction of new technologies .

the high mobility group box ( hmgb ) protein family is the most represented protein family among the high mobility group proteins . the hmgb are highly conserved and have four members ( hmgb14 ) . hmgb are types of protein motifs that are involved in dna - binding [ 2 , 3 ] . hmgb1 ( also hmg1 ; hmg-1 ; hmg 1 ; amphoterin ; p30 ) is the most highly expressed of all the hmg family members . hmgb in addition to their nuclear functions have extracellular activity ; that is , hmgb1 belongs to the damage associated molecular pattern molecules damps also known as alarmins are danger signals , which are released from damaged sort necrotic cells and alert the immune system by the activation of the inflammasome through the pattern recognition receptors ( prrs ) found on the plasma membrane , inside endosomes after endocytosis , and in the cytosol ( i.e. , toll - like receptors ) , advanced glycosylation end product - specific receptor ( rage ) , rig - i - like receptors , nod1-like receptors , and aim2-like receptors [ 7 , 8 ] . nuclear hmgb1 is involved in many dna activities such as dna replication , repair , recombination , and transcription and in genomic stability . it also plays a significant role outside the cell in inflammation and immunity , as a mediator for cell growth , proliferation , and death [ 9 , 10 ] . chronic obstructive pulmonary disease ( copd ) is characterised by a progressive airflow obstruction , airway inflammation , and systemic effects or comorbidities . ageing itself and cigarette smoking are the most studied risk factors but not the only causative agents . infections and chronic inflammation , together with oxidative stress , are involved in the etiopathogenesis of the disease . current anti - inflammatory therapies are poorly effective in maintaining lung function and symptoms of copd . this underlines the need for finding new molecular targets involved in disease pathogenesis in order to block pathology progression [ 11 , 12 ] . this review aims to analyse latest advances on hmgb1 role , utilisation , and potential application in copd . for this purpose , we reviewed experimental studies that investigated this alarmin as marker as well as a potential treatment in chronic obstructive pulmonary disease . this systematic review has been conducted according to prisma guidelines employing two databases : pubmed and sciencedirect . on these websites we searched for articles from january 1 , 2005 , to october 2015 using key terms related to copd : copd , emphysema , bronchitis , and smoke and one key term related to hmgb1 : hmgb1 . the electronic search strategy applied for pubmed is reported as an example in table 1 . we decided to use as a rule of thumb the fact that the abstracts of those articles whose titles indicated they might have examined the association between copd and hmgb1 were to be read . the entire article was read if the abstract indicated the article potentially met the inclusion criteria . lastly we reviewed and searched references of the selected articles and the ones whose titles suggested that they could have researched the association between copd and hmgb1 in order to identify additional studies that met the inclusion criteria . articles were included in the following review according to the following inclusion criteria : english language , publication in peer reviewed journals , and year of publication at least 2005 . articles were excluded by title , abstract , or full text for irrelevance to the topic in question . further exclusion criteria were review articles and editorial comments . furthermore , we arbitrarily decided to start our research from 2005 to give a more recent view of copd findings . three authors ( marco casciaro , sebastiano quartuccio , and giovanni trapani ) performed the initial search and independently reviewed and selected the references based on the inclusion and exclusion criteria . data derived from our research of articles includes study author names , publication dates , study designs ( i.e. , case - control , cross - sectional , and longitudinal ) , groups studied , clinical and biological variables , and outcome of interest of the study . principal outcome of interest included studies about advanced molecular targets on animals and humans as either disease marker or pathogenic mechanisms . given considerable heterogeneity in the study designs and subjects of the selected studies ( in terms of biological and clinical variables ) , characteristics of the studied populations and protocols are summarised and the study outcome is reported using descriptive statistics without conducting any meta - analyses . in figure 1 the flow of articles retrieved for the review is reported . as summarised in table 2 a total of 13 studies assessing the association between hmgb1 and copd were identified . as mentioned in methods we decided to include only experimental studies since 2005 to provide a more recent perspective of hmgb1 in copd . according to table 2 , shang et al . in fact , they collected serum from a total of 271 patients ( 145 patients with non - small - cell lung cancer , 77 patients with copd , and 49 controls patients ) . serum hmgb1 levels in patients with lung cancer were significantly higher than those in copd patients and healthy patients . these results pushed more studies about this possible association . in 2010 ferhani et al . while looking whether or not it was possible to use hmgb1 as an inflammation marker analysed bronchoalveolar lavage ( bal ) of 20 never - smoker patients , 20 smokers , and 30 smokers with copd . the immunolocalization of hmgb1 and rage was assessed on bronchial biopsy and lung tissue sections . bal levels of hmgb1 were comparable in never - smoker healthy subjects and in smokers without copd but these levels were augmented in smokers with copd . there was also a significant correlation between the individual bal levels of hmgb1 and values of functional respiratory tests . bal levels of hmgb1 were also related positively to tnf - rii and il-1b , and they were negatively related to il-1ra with no correlation with tnf-. hmgb1-positive cells were found in high concentration in bronchial mucosa of smokers with copd , more often than in healthy smokers . finally , ferhani et al . found that rage was overexpressed in the airway epithelium and in smooth muscle of copd patients and that it colocalized with hmgb1 . hou et al . selected 61 asthmatic patients , 47 copd patients , and 34 healthy people . compared with controls , hmgb1 levels in induced sputum were higher in asthmatic patients and in copd patients . plasma hmgb1 levels were similar to the ones obtained in sputum for exception of patients with mild asthma , in which levels were normal . moreover , patients with copd showed a higher concentrations of sputum hmgb1 than patients with all severities of asthma . hmgb1 levels in plasma and in induced sputum in all subjects showed a negative correlation with lung function parameters . conducted a study in which they exposed mice to long - term cigarette smoking developing emphysema . after the spread of the chronic disease they analysed mice bal noticing higher levels of alveolar macrophages and neutrophils than in control mice . in particular , mmp-12 and hmgb-1 were detected at high levels in alveolar macrophages from cs - exposed animals . kanazawa et al . performed tc , functional respiratory tests , and bal on 14 nonsmokers subjects , on 13 smokers without copd , and on 30 smokers with copd . the analysis showed that hmgb1 levels from bal performed on central airways did not significantly differ among the three groups ; instead those levels from bal obtained from peripheral airways were significantly higher in copd patients than in nonsmokers or smokers without copd . in copd patients there was no correlation between hmgb1 level in central airways and indexes of pulmonary function . on the contrary , hmgb1 level in peripheral airways was related to the functional tests . finally , what emerged from high resolution tc was a low - attenuation area significantly correlated with hmgb1 level in peripheral airways . wang et al . investigated how nuclear factor-b ( nf-b ) affected hmgb1 expression in an animal model of copd . they administered a nf-b inhibitor to 48 rats ( normal control , copd rats , and copd rats complicated with hypoxia ) . they reported an augmented level of hmgb1 mrna and nf-b expression in lung tissue of rats affected by copd . after administration of the nf-b inhibitor , hmgb1 mrna and protein expression in lung tissues were significantly reduced . eleven of them were smokers with copd , eight smokers without copd , and nine nonsmokers without copd . hmgb1 expression was augmented in submucosa cells , in epithelium cell , and in alveolar cells in smoker subjects with copd . none of these augmented expressions were confirmed in smokers without copd and in healthy subjects . they measured plasma levels of hmgb1 , srage , fibrinogen , and serum levels of high - sensitivity c - reactive protein while patients had an acute exacerbation of copd . they observed that there was a decline of hmgb1 , srage , and hscrp from the acute phase to the convalescence phase . hmgb1 and srage levels were related to disease severity . furthermore , hmgb1 and srage levels were higher in smoker copd patients compared with nonsmokers with copd and exsmokers with copd , respectively . zabini et al . investigated whether levels of hmgb1 were significantly higher in both patients with idiopathic pulmonary arterial hypertension ( ipah ) ( n = 14 ) and copd pulmonary hypertension ( n = 14 ) . bioptic lung tissue revealed the presence of hmgb1-positive cells surrounding remodelled vessels both in copd with pulmonary hypertension and in ipah lung samples . moreover , they exposed these cells to progressively higher doses of hmgb1 in vitro , demonstrating hmgb1 proliferation effects on pulmonary arterial smooth muscle cells and human arterial endothelial cells . di stefano et al . performed a study on 55 subjects 32 patients were affected by a stable copd , 12 patients were smokers with normal lung function , and 11 were nonsmokers with normal lung function . bal concentration of hmgb1 was significantly diminished in patients with stable copd compared with control healthy subjects ( smokers and nonsmokers ) . however , after matching patients for age and smoking history this difference was lost . iwamoto and his group conducted a study , of the duration of 4 years , on 3 groups of patients ( 32 nonsmokers , 212 smokers without copd , and 51 smokers with copd ) . the only relevant data was the baseline plasma srage lower concentration in smokers with and without copd versus nonsmoker subjects . starting from the well - known cigarette smoking ( cs ) causative effect on copd development , heijink et al . performed a study trying to demonstrate whether or not cs led to the release of damps ( i.e. , hmgb1 ) which are known to amplify innate immune response . an in vivo - in vitro analysis of human bal neutrophilic concentration was conducted together with an animal lung tissue and sputum dosage . conducted a post hoc analysis of hmgb1 levels in serum of 40 copd patients collected both during an exacerbation and during the stable phase . the same analysis was performed on the inducted sputum of almost the same patients ( n = 35 ) . no significative differences were found in sputum levels . on the contrary , serum levels of hmgb1 during copd exacerbations were augmented . they also noticed a gender difference , with higher serum levels of hmgb1 in women during the acute phase . intracellular hmgb binds to the minor groove of dna , stabilizing nucleosome formation and regulating gene transcription and the activity of steroid hormone receptors . on the other hand , hmgb1 extracellularly has been demonstrated to have a role in inflammatory processes , neural outgrowth , smooth muscle cell chemotaxis , migration and proliferation of mesoangioblast cells , and cell proliferation in tumor and metastasis [ 2628 ] . also other authors confirmed that hmgb1 mediated cell transformation , growth , and resistance in neoplastic cells [ 2931 ] . extracellular hmgb1 functions are mediated via binding to specific membrane receptors including the receptor for advanced glycation end products ( rage ) . rage activation gives origin to an intracellular cascade leading to the activation of the nuclear factor-b ( nf-b ) pathway and also of mitogen activated protein kinase ( mapk ) and type iv collagenase ( mmp-2/-9 ) which are fundamental for cancer cell characteristic [ 26 , 29 , 32 ] . it has been demonstrated that the blocking of the rage - hmgb1 axis suppresses tumor growth and metastasis [ 29 , 30 , 33 ] . damps , including hmgb1 , are released either by a damaged or by a necrotic cell and actively by the immune system . it has been seen that hmgb1 sustains the inflammatory process and promotes the proliferation of epithelial and mesenchymal cells ( i.e. , smooth muscle cells ) . these data support the hypothesis that hmgb1 could contribute to the pathogenesis of many diseases [ 3438 ] . due to these data focused their attention both on neoplastic and chronic inflammatory diseases by evaluating patients with lung cancer and patients with copd . they first demonstrated that serum hmgb1 levels were significantly augmented both in patients with lung cancer and in patients with copd . because of hmgb1 high affinity to rage and their intimate link , some studies about this molecule demonstrated that rage is present at very low concentration in many healthy tissues and that it is upregulated by high levels of hmgb1 . further studies revealed that , on the contrary , rage is expressed at high concentration in normal lung tissue suggesting a role in regulating lung homeostasis [ 3941 ] . confirmed data previously obtained by demonstrating that smokers with copd had higher levels of hmgb1 in their bal fluid . in the same study they determined that macrophages , bronchial epithelial cells , and airway smooth muscle cells ( asm ) of smoker patients had a high expression of hmgb1 and rage . these cells appear to represent a potential source of the secreted soluble form of hmgb1 in the airways . with hmgb1-rage being overexpressed in all these cells , the hypothesis that lung tissue remodelling , typical in copd , could be a consequence of this overexpression was advanced . hmgb1-positive cells surrounding remodelled vessels of patients affected by copd with secondary pulmonary hypertension were reported by zabini et al . data obtained suggest a proliferation effect on pulmonary arterial smooth muscle cells . according to these findings and hypothesis , another study evaluated sputum and plasma concentrations of hmgb1 in patients affected by asthma and copd . high concentration of the alarmin was found in both biological fluids of these patients . a neutrophil count positive correlation emerged . previously , ito et al . reported hmgb1 secretion by neutrophils and rowe et al . postulated the theory of a positive feedback loop between hmgb1 and neutrophils , sustaining in ammation . observed higher levels of neutrophil and macrophage cells in bal of a mice model of copd . data obtained by heijink et al . confirmed that cs induces neutrophils necrosis with a subsequent release of damps . as mentioned before hmgb1 interaction with rage activates nf-b pathway sustaining inflammation ; wang et al . tried to target nf-b with an inhibitor on mice with copd obtaining a downregulation of hmgb1 in lung tissue adding more elements in a blockage strategy of inflammation in an early phase of copd . in another study , bal analysis of peripheral airways showed significantly higher levels of hmgb1 in copd patients with positive correlation with functional respiratory tests . ko et al . reported that hmgb1 expression was augmented also in plasma , epithelium , submucosa , and alveolar cells in patients with copd with a negative correlation with pulmonary tests . zhang et al . studies both con rmed increased levels of serum hmgb1 in acute exacerbation of copd [ 8 , 21 ] . according to zhang et al . the only study that , after delating possible outliers among patients , revealed no difference between bal hmgb1 levels in copd patients , smokers , and healthy subjects was the one made by di stefano et al . . a more recent research emerged in order to evaluate the pathophysiological role of high mobility group box 1 and in particular its involvement in copd remodelling . in this study ojo et al . inhibited rage and tlr4 signalling . this blockage attenuated hmgb1 ability to increase epithelial cell reparation . these findings seem to better explain the role for hmgb1 in airway remodelling . for a better understanding of hmb1 role in the development of chronic inflammatory diseases and about inflammatory stimuli leading to copd , another recent study focused on the potential therapeutic effect of probiotics on cells exposed to cigarette smoking ( cs ) . stimulated human macrophage with cs extract in the presence and absence of l. rhamnosus and b. breve . what emerged was a minor ability of cs to induce hmgb1 release in these cells . this data may open a new scenario on probiotics as anti - inflammatory agents in the prevention of diseases caused by a chronic inflammation stimulus such as cs . our group decided to focus on the role of hmgb1 in copd and more specifically on giving a better comprehension about its pathophysiological role in the development of the disease . our objective was to propose , while possible , new therapeutic strategies in facing the irreversible damage and subsequent substitution of healthy lung tissue with repair tissue , associated with a chronic inflammatory stimulus ( i.e. , cigarette smoking ) on lungs themselves . almost every study confirmed an augmentation of either plasmatic or lung tissue levels of hmgb1 in patients affected by copd [ 8 , 1422 ] . these levels were higher during the acute phase of copd [ 8 , 21 ] and in patients with pulmonary neoplasia . analysing cited literature , it emerges that the involvement of the hmgb1-rage axis is fundamental in the inflammatory - regenerative process . the interaction of hmgb1 with nf-b appears to be equally important ; once these processes escape from physiological control they could determine neoplastic degeneration [ 2731 ] . so it seems that hmgb1 level correlates with lung tissue damage and with the incipit of reparation processes . on the other hand , the level of this alarmin diminishes in a postacute phase . as represented in figure 2 , in a potential therapeutic key , blocking the binding of hmgb1 to the dna minor groove may help in controlling the subsequent intracellular mechanism leading to gene transcription . in figure 2 another potential therapeutic target is also shown ; in fact , the extracellular interaction of hmgb1 with its receptor ( rage ) has been demonstrated , together with the above cited intracellular interaction , having a role in cell outgrowth . interfering with these links may avoid permanent lung tissue damage and lung cells neoplastic transformation . in conclusion in almost all the studies the fact that hmgb1 levels are augmented in smokers and in patients affected by copd emerged . by the years it emerged that hmgb1 is an alarmin , a protein that warns and activates inflammation . the studies reviewed let us to a better comprehension on how this alarmin is involved in the development of copd . according to these studies it emerged that cigarette smoking , the most well - known causative factor of copd , induces neutrophils death and necrosis . the necrosis of neutrophil cells leads to damps release , in particular hmgb1 , which recruits other neutrophils in a self - maintaining process . it emerged also that damps could activate the inflammatory process by the interaction with the rage and worsen copd exacerbation . in addition it was reported that blocking the nf-b led to an underexpression of hmgb1 in lung tissue . given these premises , both inhibiting hmgb1-rage axis and blocking neutrophils necrosis should be the aim of future further studies .

hmgb1 is an alarmin , a protein that warns and activates inflammation . chronic obstructive pulmonary disease ( copd ) is characterised by a progressive airflow obstruction and airway inflammation . current anti - inflammatory therapies are poorly effective in maintaining lung function and symptoms of copd . this underlines the need for finding new molecular targets involved in disease pathogenesis in order to block pathology progression . this review aims to analyse latest advances on hmgb1 role , utilisation , and potential application in copd . to this purpose we reviewed experimental studies that investigated this alarmin as marker as well as a potential treatment in chronic obstructive pulmonary disease . this systematic review was conducted according to prisma guidelines . in almost all the studies , it emerged that hmgb1 levels are augmented in smokers and in patients affected by copd . it emerged that cigarette smoking , the most well - known causative factor of copd , induces neutrophils death and necrosis . the necrosis of neutrophil cells leads to hmgb1 release , which recruits other neutrophils in a self - maintaining process . according to the results reported in the paper both inhibiting hmgb1 and its receptor ( rage ) and blocking neutrophils necrosis ( inducted by cigarette smoking ) could be the aim for further studies .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Advancement in Pediatric Autism Research Act''. SEC. 2. FINDINGS. The Congress finds as follows: (1) Infantile autism and autism spectrum disorders are biologically-based neurodevelopmental diseases that cause severe impairments in language and communication and generally manifest in young children sometime during the first two years of life. (2) Best estimates indicate that 1 in 500 children born today will be diagnosed with an autism spectrum disorder and that 400,000 Americans have autism or an autism spectrum disorder. (3) There is little information on the prevalence of autism and other pervasive developmental disabilities in the United States. There have never been any national prevalence studies in the United States, and the two studies that were conducted in the 1980s examined only selected areas of the country. Recent studies in Canada, Europe, and Japan suggest that the prevalence of classic autism alone may be 300 percent to 400 percent higher than previously estimated. (4) Three-quarters of those with infantile autism spend their adult lives in institutions or group homes, and usually enter institutions by the age of 13. (5) The cost of caring for individuals with autism and autism spectrum disorder is great, and is estimated to be $13.3 billion per year solely for direct costs. (6) The rapid advancements in biomedical science suggest that effective treatments and a cure for autism are attainable if-- (A) there is appropriate coordination of the efforts of the various agencies of the Federal Government involved in biomedical research on autism and autism spectrum disorders; (B) there is an increased understanding of autism and autism spectrum disorders by the scientific and medical communities involved in autism research and treatment; and (C) sufficient funds are allocated to research. (7) The discovery of effective treatments and a cure for autism will be greatly enhanced when scientists and epidemiologists have an accurate understanding of the prevalence and incidence of autism. (8) Recent research suggests that environmental factors may contribute to autism. As a result, contributing causes of autism, if identified, may be preventable. (9) Finding the answers to the causes of autism and related developmental disabilities may help researchers to understand other disorders, ranging from learning problems, to hyperactivity, to communications deficits that affect millions of Americans. (10) Specifically, more knowledge is needed concerning-- (A) the underlying causes of autism and autism spectrum disorders, how to treat the underlying abnormality or abnormalities causing the severe symptoms of autism, and how to prevent these abnormalities from occurring in the future; (B) the epidemiology of, and the identification of risk factors for, infantile autism and autism spectrum disorders; (C) the development of methods for early medical diagnosis and functional assessment of individuals with autism and autism spectrum disorders, including identification and assessment of the subtypes within the autism spectrum disorders, for the purpose of monitoring the course of the disease and developing medically sound strategies for improving the outcomes of such individuals; (D) existing biomedical and diagnostic data that are relevant to autism and autism spectrum disorders for dissemination to medical personnel, particularly pediatricians, to aid in the early diagnosis and treatment of this disease; and (E) the costs incurred in educating and caring for individuals with autism and autism spectrum disorders. (11) In 1998, the National Institutes of Health announced a program of research on autism and autism spectrum disorders. A sufficient level of funding should be made available for carrying out the program. SEC. 3. EXPANSION, INTENSIFICATION, AND COORDINATION OF ACTIVITIES OF NATIONAL INSTITUTES OF HEALTH WITH RESPECT TO RESEARCH ON AUTISM. Part B of title IV of the Public Health Service Act (42 U.S.C. 284 et seq.) is amended by adding at the end the following section: ``autism ``Sec. 409C. (a) In General.-- ``(1) Expansion of activities.--The Director of NIH (in this section referred to as the `Director') shall expand, intensify, and coordinate the activities of the National Institutes of Health with respect to research on autism. ``(2) Administration of program; collaboration among agencies.--The Director shall carry out this section acting through the Director of the National Institute of Mental Health and in collaboration with any other agencies that the Director determines appropriate. ``(b) Centers of Excellence.-- ``(1) In general.--The Director shall under subsection (a)(1) make awards of grants and contracts to public or nonprofit private entities to pay all or part of the cost of planning, establishing, improving, and providing basic operating support for centers of excellence regarding research on autism. ``(2) Research.--Each center under paragraph (1) shall conduct basic and clinical research into the cause, diagnosis, early detection, prevention, control, and treatment of autism, including research in the fields of developmental neurobiology, genetics, and psychopharmacology. ``(3) Services for patients.--A center under paragraph (1) may expend amounts provided under such paragraph to carry out a program to make individuals aware of opportunities to participate as subjects in research conducted by the centers. The program may provide fees to such subjects. The program may, in accordance with such criteria as the Director may establish, provide to such subjects health care, referrals for health and other services, and such incidental services as will facilitate the participation of individuals as such subjects. ``(4) Coordination of centers; reports.--The Director shall, as appropriate, provide for the coordination of information among centers under paragraph (1) and ensure regular communication between such centers, and may require the periodic preparation of reports on the activities of the centers and the submission of the reports to the Director. ``(5) Organization of centers.--Each center under paragraph (1) shall use the facilities of a single institution, or be formed from a consortium of cooperating institutions, meeting such requirements as may be prescribed by the Director. ``(6) Number of centers; duration of support.--The Director shall, subject to the extent of amounts made available in appropriations Acts, provide for the establishment of not less than five centers under paragraph (1). Support of such a center may be for a period not exceeding 5 years. Such period may be extended for one or more additional periods not exceeding 5 years if the operations of such center have been reviewed by an appropriate technical and scientific peer review group established by the Director and if such group has recommended to the Director that such period should be extended. ``(c) Facilitation of Research.--The Director shall under subsection (a)(1) provide for a program under which samples of tissues and genetic materials that are of use in research on autism are donated, collected, preserved, and made available for such research. The program shall be carried out in accordance with accepted scientific and medical standards for the donation, collection, and preservation of such samples. ``(d) Public Input.--The Director shall under subsection (a)(1) provide for means through which the public can obtain information on the existing and planned programs and activities of the National Institutes of Health with respect to autism and through which the Director can receive comments from the public regarding such programs and activities. ``(e) Funding.--For the purpose of carrying out this section, there are authorized to be appropriated $33,000,000 for fiscal year 2000, and such sums as may be necessary for each of the fiscal years 2001 through 2004. Such authorizations of appropriations are in addition to any other authorization of appropriations that is available for such purpose.''. SEC. 4. INFORMATION AND EDUCATION. (a) In General.--The Secretary shall establish and implement a program to provide information and education on autism to health professionals and the general public, including information and education on advances in the diagnosis and treatment of autism and training and continuing education through programs for scientists, physicians, and other health professionals who provide care for patients with autism. (b) Stipends.--The Secretary may use amounts made available under this section to provide stipends for health professionals who are enrolled in training programs under this section. (c) Authorization of Appropriations.--To carry out this section, there is authorized to be appropriated $6,000,000 for each of the fiscal years 2000 through 2004. SEC. 5. AUTISM COORDINATING COMMITTEE. (a) Establishment.--The Secretary shall establish a committee to be known as the ``Autism Coordinating Committee'' (in this section referred to as the ``Committee'') to coordinate all efforts within the Department of Health and Human Services concerning autism, including activities carried out through the National Institutes of Health and the Centers for Disease Control and Prevention under this Act (and the amendment made by this Act). (b) Membership.-- (1) In general.--The Committee shall be composed of ex officio members in accordance with paragraph (2) and 11 appointed members in accordance with paragraph (3). (2) Ex officio members.--The following officials shall serve as ex officio members of the Committee: (A) The Director of the National Institutes of Health. (B) The Director of the National Institute on Mental Health. (C) The Director of the Centers for Disease Control and Prevention. (D) The Administrator of the Health Resources and Services Administration. (3) Appointed members.--Appointments to the Committee shall be made in accordance with the following: (A) Two members shall be research scientists with demonstrated achievements in research related to autism and related developmental disabilities. The scientists shall be appointed by the Secretary in consultation with the National Academy of Sciences. (B) Five members shall be representatives of the 5 national organizations whose primary emphasis is on research into autism and other pervasive developmental disabilities. One representative from each of such organizations shall be appointed by the Secretary in consultation with the National Academy of Sciences. (C) Two members shall be clinicians whose practice is primarily devoted to the treatment of individuals with autism and other pervasive developmental disabilities. The clinicians shall be appointed by the Secretary in consultation with the Institute of Medicine and the National Academy of Sciences. (D) Two members shall be individuals who are the parents or legal guardians of a person or persons with autism or other pervasive developmental disabilities. The individuals shall be appointed by the Secretary in consultation with the ex officio members under paragraph (1) and the 5 national organizations referred to in subparagraph (B). (c) Administrative Support; Terms of Service; Other Provisions.-- The following shall apply with respect to the Committee: (1) The Committee shall receive necessary and appropriate administrative support from the Department of Health and Human Services. (2) Members of the Committee shall be appointed for a term of 3 years, and may serve for an unlimited number of terms if reappointed. (3) The Committee shall meet not less than 2 times per year. (4) Members of the Committee shall not receive additional compensation for their service. Such members may receive reimbursement for appropriate and additional expenses that are incurred through service on the Committee which would not have incurred had they not been a member of the Committee. SEC. 6. REPORT TO CONGRESS. Not later than January 1, 2000, and each January 1 thereafter, the Secretary shall prepare and submit to the appropriate committees of Congress, a report concerning the implementation of this Act and the amendments made by this Act.

Advancement in Pediatric Autism Research Act - Amends the Public Health Service Act to direct the Director of the National Institutes of Health (NIH) to expand, intensify, and coordinate the activities of NIH with respect to autism. Requires the Director, among other things, to make awards of grants and contracts to public or nonprofit entities for centers of excellence regarding research on autism. Authorizes appropriations. Requires the Secretary of Health and Human Services (HHS) to establish a program to provide information and education on autism to health professionals and the general public. Authorizes appropriations. Directs the Secretary to establish an Autism Coordinating Committee to coordinate HHS efforts concerning autism.

diffusion dynamics of hard - core interacting particles in one dimension ( 1d ) is known as the single - file diffusion ( sfd ) . the sfd occurs for instance in narrow biological pores@xcite , inside the zeolites@xcite , during the sliding of proteins along the dna@xcite . other examples comprise migration of adsorbed molecules on surfaces@xcite , diffusion in nanotubes@xcite , carrier migration in polymers and superionic conductors@xcite . advances in technology now allow to study artificial single - file systems such as solid - state nanopores@xcite , confined colloid particles@xcite , charged spheres in circular channel@xcite , or millimetric steel balls in plane condenser@xcite . in all these systems , the mutual passage of the particles is forbidden which results in deviation of tagged particle s dynamics from the classical diffusion . the concept of sfd was first introduced in the mathematical literature by harris@xcite . he proved that the mean - square displacement of the tagged particle increases with time as @xmath2 in contrast to its linear increase for the free particle . for a comprehensible review of the present state of the art in the theory of sfd cf . introduction in ref . ) . despite the long history of sfd phenomena , exactly solvable models of single - file systems are rare and they have occurred only recently . the exact solution of the diffusion equation for @xmath1 hard - core interacting particles has been first derived in ref . for the diffusion on an infinite line ( it has been rederived in ref . ) . the sfd of @xmath1 particles within the finite interval has been solved through the bethe ansatz in ref . . in ref . , the present authors have generalized the previously known exact solutions to the case of an arbitrary time- and space - dependent force acting on particles . all these exact solutions can describe real physical situations , however , they all concern the systems with a conserved number of particles . often the opposite is true and the single - file systems should be treated as open systems with _ variable _ number of particles . many such systems are listed in the first paragraph . the single - file conditions in combination with a variable number of particles are two prerequisites for a proper understanding of kinetics of diffusion - limited catalytic reaction in crowded environments@xcite . also the search for corrections to smoluchowski theory which would incorporate the effects of excluded volume@xcite stimulates the interest in one - dimensional models@xcite with hard - core interaction and particle absorption . to our knowledge , the only work that presents analytical study of dynamics of a tagged particle in an open system is ref . where the finite interval with two perfectly absorbing boundaries was briefly discussed . however , the approximative tagged particle probability density function ( pdf ) obtained in the thermodynamic limit was only considered . in the present paper we develop a new general formalism that allows an exact analytical treatment of the sfd problem with the absorbing boundary ( such boundary can represent , e.g. , the open end of the biological pore , a fixed reactant , a binding site inside the pore , etc . ) . the approach is a logical outgrowth of our earlier method@xcite and its characteristic feature is that the exact solution of the sfd problem can be given whenever the exact solution of the corresponding single - particle problem is known . formally , our analysis is based on a hierarchical system of coupled generalized diffusion equations describing the evolution periods when the pore contains a definite number of particles . we were able to solve the hierarchy . the solution yields the complete information concerning the many - particle dynamics . the physical consequences of the particle interaction manifest themselves most transparently if we follow the motion of an individual tagged particle . we were able to derive the exact expression for the tagged particle pdf and for its survival probability . the hard - core inter - particle interaction induces entropic forces which radically alter the character of the escape process comparing to the corresponding problem of noninteracting particles . the paper is organized as follows . [ sec : model ] contains the definition of the model . [ sec : evolutioneqs ] comprises four subsections . first , for the sake of a latter reference , subsec . [ subsec : singleparticle ] presents the complete solution of the underlying single - particle case . in subsec . [ subsec : evolutioneqs ] we formulate the hierarchy of coupled generalized diffusion equations for the partial pdfs . the appropriate choice of the initial conditions is discussed in subsec . [ subsec : initialconditions ] . in subsec . [ subsec : mapping ] the sfd dynamics is translated into the diffusion of a single compound particle in a special @xmath1-dimensional domain . [ sec : solution ] contains the exact solution of our model ( some purely technical steps are particularized in appendixes ) . the eqs . ( [ theorem1 ] ) and ( [ theorem2 ] ) in subsec . [ subsec : partialpdfs ] give the exact solution of the hierarchy of coupled diffusion equations from which the tagged particle s pdf ( eq . ( [ marginalf ] ) ) is derived in subsec . [ subsec : taggedpdfs ] . we then turn , in sec . [ sec : escapeprocess ] , to a detailed analysis of the escape process . [ subsec : survival ] discusses the survival probabilities and their asymptotic behavior . the exit times are analyzed in subsec . [ subsec : escapetime ] . diffusing particles and the partially absorbing boundary at the origin ( the exit from the pore ) . the diffusing particles interact as hard spheres and hence their initial ordering @xmath3 is retained during the time evolution . ] consider @xmath1 identical brownian particles , each with the diffusion constant @xmath4 , diffusing in the one - dimensional semi - infinite pore . the particles are subject to the following two interactions : * _ the particle - particle hard - core interaction . _ as the consequence , particles can not pass each other . their initial ordering @xmath5 is preserved during the subsequent diffusion process . * _ the particle - boundary interaction . _ we assume a partially absorbing boundary at @xmath6 . the particle that hits the boundary is either removed from the pore , or it is immediately reflected and it continues to diffuse inside the pore . the boundary will be implemented through the radiation boundary condition @xcite . the `` particle - capture capacity '' of the boundary is characterized by the parameter @xmath7 . the value @xmath8 corresponds to a reflecting boundary , the limit @xmath9 yields a totally absorbing boundary . the particles can not enter the pore from the outside and they can leave it only through the boundary at the origin . the number of particles inside the pore either decreases or remains constant over time . in order to introduce basic concepts needed in the following , let us first consider the simplest situation @xmath10 . that is , at the initial time @xmath11 , there is only _ one _ particle in the pore and it is located at the position @xmath12 , @xmath13 . the initial pdf @xmath14 for the particle position is the dirac delta function @xmath15 inside the pore ( i.e. , for @xmath16 ) , the time - evolution of the initial condition ( [ initialcond ] ) is governed by the diffusion equation @xmath17 at the boundary , we require the radiation boundary condition ( bc ) @xmath18 the exact solution of eq . ( [ diff0 ] ) with the initial condition ( [ initialcond ] ) and bc ( [ boundarycond ] ) reads @xmath19}}{\sqrt{4 \pi d t } } + \label{psol } \frac{\exp{\!\!\left[\!- ( x+y)^{2}/(4dt)\right]}}{\sqrt{4 \pi d t}}-\\ \notag & & - \frac{\kappa}{d}\exp{\!\ ! \left[\!\frac{\kappa}{d}(x+y)\!+\!\kappa^{2}\!\frac{t}{d}\right ] } { \rm{erfc}}\!\ ! \left(\frac{x+y}{\sqrt{4dt}}+\kappa\sqrt{\frac{t}{d}}\right),\end{aligned}\ ] ] where @xmath20 stands for the complementary error function @xcite . it can be derived , e.g. , by the laplace transform method@xcite . let @xmath21 , @xmath22 , be an arbitrary pdf describing the initial particle position . having calculated the green function ( [ psol ] ) , the time evolution of the initial condition is given as @xmath23 the probability of finding the particle at the time @xmath24 within the interval @xmath25 is given by the cumulative distribution function @xmath26 the probability that the particle has not exited the pore by the time @xmath24 , i.e. , its survival probability , reads @xmath27 it is an important feature of our setting that all subsequent @xmath1-particle results can be formulated through the single - particle functions @xmath28 , @xmath29 , @xmath30 , and only through them . suppose that , at the initial time @xmath31 , there are @xmath1 particles in the pore and that their positions @xmath32 , cf . fig . 1 , are distributed according to the joint pdf @xmath33 , @xmath34 . having in mind that the total number of particles inside the pore _ is not conserved _ , we introduce partial @xmath35-particle pdfs @xmath36 , @xmath37 , @xmath38 . we give them the following meaning : @xmath39 is the probability that , at the time @xmath24 , there are @xmath0 particles in the pore ( this is stressed by the superscript ) _ and _ that these particles are located in @xmath40 . altogether , we have @xmath1 partial pdfs . further , let @xmath41 be the probability that , at the time @xmath24 , there are no particles left in the pore . the knowledge of the partial pdfs and of the probability @xmath41 represents the complete probabilistic description of the resulting single - file diffusion problem . the partial pdf @xmath42 varies in time due to the following two reasons : a ) the motion of @xmath1 interacting particles , b ) the possible exit of the particle no . @xmath1 out of the pore . the diffusion equation @xmath43 together with the `` non - crossing '' boundary conditions @xmath44 @xmath45 , account for the diffusion of @xmath1 hard - core interacting particles inside the pore . the non - crossing boundary conditions ( [ nnc ] ) can be derived by introducing the @xmath1-particle probability _ current _ and by assuming that the normal component of the current vanishes at the hyperplanes @xmath46 , @xmath47 . their derivation and the further discussion can be found in ref . , ( 3)-(5 ) . bcs ( [ nnc ] ) ensure that the initial ordering of the particles is preserved . hence , it is only the leftmost particle ( the particle no . @xmath1 ) that can leave the pore . the exit process is incorporated by the radiation bc ( cf . ( [ boundarycond ] ) ) @xmath48 the diffusion equation ( [ fneq ] ) must be supplemented by an initial condition @xmath33 . this will be done in subsec . [ subsec : initialconditions ] . let us now focus on the partial pdf @xmath49 . it varies due to the following _ three _ reasons : a ) the motion of @xmath50 interacting particles , b ) a possible exit of the particle no . @xmath51 out of the pore , c ) the possible exit of the particle no . @xmath1 while the remaining particles are situated in the infinitesimal domain @xmath52 . we thus arrive at an _ inhomogeneous _ generalized diffusion equation with a source term on its right - hand side : @xmath53 the last term on the right - hand side accounts for the above point c ) . the hard - core interaction of @xmath51 particles is again incorporated through non - crossing bcs @xmath54 @xmath55 . the radiation bc describing the possible escape of the particle no . @xmath50 reads @xmath56 presently , the initial condition supplementing eq . ( [ fn-1eq ] ) is simply @xmath57 . this follows from the probabilistic interpretation of pdf @xmath49 and from the assumption that , at @xmath11 , there are @xmath1 particles inside the pore . following a similar reasoning , the generalized diffusion equation that governs the evolution of the partial pdf @xmath36 , @xmath58 , reads @xmath59 again , the equation is supplemented by the bcs @xmath60 @xmath61 , by the radiation bc @xmath62 and by the initial condition @xmath63 . of course , in the case @xmath64 , there is no non - crossing bc . in the last step of the recursive scheme we focus on the time evolution of the probability @xmath41 . it increases due to the escape of the last remaining particle and it obeys the simple evolution equation @xmath65 with the initial condition @xmath66 . summing up the above steps , we have obtained a _ hierarchy of @xmath67 coupled evolution equations _ ( [ fneq ] ) , ( [ fn - keq ] ) for @xmath68 , and ( [ f0eq ] ) . the diffusion equation ( [ fneq ] ) is _ closed_. together with eqs . ( [ nnc ] ) , ( [ nrc ] ) and with the initial condition @xmath33 it constitutes a well - defined initial - boundary value problem with a unique solution , the partial pdf @xmath42 . suppose that we know it . then we insert its value at @xmath69 into the source term on the rhs of the inhomogeneous generalized diffusion equation ( [ fn-1eq ] ) . then the inhomogeneous equation ( [ fn-1eq ] ) , supplemented by eqs . ( [ n-1nc ] ) , ( [ n-1rc ] ) , @xmath57 constitutes again a closed initial - boundary value problem . having obtained its solution , the partial pdf @xmath49 , we again evaluate it at @xmath70 and use as the source term in the equation for partial pdf @xmath71 . the hierarchy is terminated by the eq . ( [ f0eq ] ) . among all possible forms of initial distributions there exists one which leads to a considerable simplification of the subsequent analytical calculations . even more importantly , the distribution is physically quite natural for real single - file systems . it describes the state which emerges , e.g. , after previous constitution of a steady state@xcite , or after previous autonomous relaxation towards a thermodynamic equilibrium . namely , in this paper we consider the initial joint pdf for the @xmath1-particle system in the form @xmath72 0 & \,\ , \textrm{for } \,\ , \vec{x}_{n } \notin \mathcal{r}_{n } \,\ , , \end{array } \right.\ ] ] where @xmath73 denotes a _ phase space _ defined as a space of all possible configurations of @xmath1 hard - core interacting particles on the semi - infinite interval @xmath74 , i.e. , @xmath75 the symbol @xmath76 means that the components of the vector @xmath34 respect all the inequalities in ( [ phasespace ] ) . if @xmath77 , then at least one of them is violated . in general , the function @xmath21 in eq . ( [ inigeneral ] ) can be any pdf defined and normalized on the half - line @xmath78 . the normalization of the function @xmath21 implies the proper normalization of the initial condition ( [ inigeneral ] ) . this can be checked by applying eq . ( [ integrace ] ) from appendix [ phasespaceint ] where we have summarized the basic rules concerning the integration over the phase space @xmath73 . in the following , we derive also the _ marginal _ pdf for the position of the @xmath79-th particle . at the time @xmath11 , it is obtained by integrating the function ( [ inigeneral ] ) over the coordinates of all other @xmath51 particles . if @xmath80 denotes the marginal pdf in question , we have @xmath81 f^{(n)}(\vec{x}_{n};0)=\\ \notag & = & \frac{n!}{n_{l}!n_{r } ! } f(x_{n})\left [ \int_{0}^{x_{n}}\!\!\!\!\!\!\ ! { \rm d}x \ , f(x ) \right]^{n_{l}}\ ! \left [ \int_{x_{n}}^{+\infty}\!\!\!\!\!\!\!\!\ ! { \rm d}x\ , f(x ) \right]^{n_{r}}\!\ ! , \end{aligned}\ ] ] where @xmath82 ( @xmath83 ) stands for the number of particles located left ( right ) of the @xmath79-th particle . the symbol @xmath84 $ ] is explained in eq . ( [ symbol ] ) from appendix [ phasespaceint ] and the symbol @xmath85 , designating the integration domain , is explained in the paragraph just above eq . ( [ symbol ] ) . the last expression has been written in the form which suggests two important interpretations . first , suppose that we have generated @xmath1 points on the half - line , each of them being independently drawn from the distribution with pdf @xmath21 . then @xmath86 is the pdf for the @xmath79-th rightmost of them ( i.e. , for the @xmath79-th order statistics@xcite ) . second , consider the system of @xmath1 identical , _ indistinguishable , and noninteracting _ particles . let the position of each of them be described by pdf @xmath21 . then @xmath87 equals the probability that there is a particle in @xmath88 and , simultaneously , there are precisely @xmath89 ( @xmath90 ) particles at arbitrary coordinates to the left ( to the right ) of it . in the following , provided we need a further specification of pdf @xmath21 , we always take @xmath91 this expression together with eq . ( [ inigeneral ] ) yields a complete specification of the initial state . the state can be prepared in the following way . up to the time @xmath11 , a ) the pore is closed ( reflecting boundary at the left end of the pore at @xmath92 ) , b ) each particle is pushed towards the reflecting boundary by the external space - homogeneous force ( e.g. the particles are charged and we assume an external electric field ) , c ) the @xmath1-particle system has reached the state of thermal equilibrium . at the time @xmath11 instantaneously ( adiabatically ) a ) the pore becomes opened , i.e. , we replace the reflecting boundary by the partially absorbing one , b ) the external field is switched off . is the absorbing boundary . whenever the particles collide , their trajectories are mutually reflected . one such event occurs roughly at the time @xmath93 . the second particle leaves the pore approximately at the time @xmath94 . at the moment , the coordinate of the first particle is roughly @xmath95 . the lower panel presents the diffusion of the compound particle within the wedge domain bounded by the reflecting boundary ( the blue line ) and by the absorbing boundary ( the red line ) . the point @xmath96 $ ] shows the initial position of the compound particle . whenever its trajectory hits the blue line it is reflected . the reflection corresponds to the collisions of the two particles . at the point @xmath97\approx[4.1,0]$ ] , the trajectory of the compound particle sticks to the absorbing boundary . this represents the exit of the second particle from the pore at the time @xmath94 . afterwards , the compound particle continues to diffuse along the line @xmath98 . its final position at the time @xmath99 is shown by the point @xmath100 $ ] . ] the dynamics described in the previous subsection possess a noteworthy geometric interpretation . it resides in mapping of the @xmath1 interacting diffusing particles onto a single `` compound '' particle in @xmath1 dimensions . at @xmath11 there are @xmath1 particles inside the pore . until the exit of the @xmath1-th particle from the pore , the situation corresponds to the diffusion of the compound particle in the @xmath1 dimensional wedge domain @xmath101 bounded by @xmath51 reflecting hyperplanes @xmath102 @xmath47 , and by the absorbing hyperplane @xmath103 the diffusion within this wedge is described by the partial pdf @xmath42 and it is governed by the @xmath1-dimensional diffusion equation ( [ fneq ] ) . in this picture , the non - crossing boundary conditions ( [ nnc ] ) describe the reflection of the compound particle on @xmath51 reflecting hyperplanes . they guarantee the zero probability currents in the directions perpendicular to these hyperplanes . the exit of the left - most particle from the pore corresponds to `` sticking '' of the compound particle to the absorbing hyperplane and it is incorporated by the requirement ( [ nrc ] ) . the exit of the @xmath1-th particle translates to the further diffusion of the compound particle on the above absorbing hyperplane . equivalently , it diffuses within the @xmath50-dimensional wedge domain @xmath104 bounded by @xmath105 reflecting hyperplanes @xmath106 @xmath107 , and by the absorbing hyperplane @xmath108 the diffusion within this domain is described by the partial pdf @xmath49 , etc . eventually , after the exit of the @xmath105 particles , there are two last particles left inside the pore . this case is illustrated in fig . [ fig : wedgedomain ] where the compound particle diffuses in 2d wedge domain @xmath109 bounded by just one reflecting boundary @xmath110 and by the absorbing half - line @xmath111 . its motion is described by the partial pdf @xmath112 . after this event , the diffusion of the compound particle is described by partial pdf @xmath113 . the exit of the left particle corresponds to the sticking of the compound particle to the half - line @xmath114 . the exit of the last particle simply means the sticking of the compound particle to the origin . the probability of finding the compound particle at the origin at @xmath24 is given by the function @xmath41 . for a further discussion of the 2d case cf . [ fig : wedgedomain ] . in our recent work we have shown that the green function ( gf ) for the diffusion equation of @xmath1 hard - core interacting particles diffusing in an _ arbitrary _ external potential can be constructed from the gf @xmath115 of the corresponding single - particle problem ( see eq . ( 6 ) in ref . ) . in the present context , the same construction yields gf that solves eq . ( [ fneq ] ) with the non - crossing boundary condition ( [ nnc ] ) , with the radiation boundary condition ( [ nrc ] ) , and with the initial condition @xmath116 . the explicit form of this gf is given by the permanent@xcite @xmath117 if @xmath118 , and it vanishes otherwise . the summation runs over all @xmath119 permutations of initial positions . having the gf , the initial condition ( [ inigeneral ] ) evolves as @xmath120 in the present paper we always assume the initial condition ( [ inigeneral ] ) and it is obvious that this special form simplifies the analytical expressions . as a matter of fact , using ( [ inigeneral ] ) , the above function reduces to the simple product ( cf . appendix [ app : permanent ] ) @xmath121 where @xmath28 is the known solution of the corresponding single - particle problem ( cf . ( [ pdef ] ) ) . notice that the product yields the solution just within the domain @xmath73 . it turns out that the products of this type will play an important role in the following . hence we define @xmath122 0 & \,\ , \textrm{for } \,\ , \vec{x}_{n } \notin \mathcal{r}_{n } \,\ , , \end{array } \right.\ ] ] we are now prepared to formulate the exact solution of our diffusion problem . _ suppose that the initial pdf @xmath33 possess the form ( [ inigeneral ] ) . then the hierarchy of coupled evolution equations as formulated in subsec . [ subsec : evolutioneqs ] possesses the solution @xmath123^{k}\ ! , \ ] ] for @xmath124 , and @xmath125^{n}.\ ] ] _ turning to the proof , the solution of the first element of the hierarchy ( the case @xmath126 ) has already been derived above . actually , provided there are still @xmath1 particles in the pore , the solution ( [ theorem1 ] ) coincides with eq . ( [ pnxtproduct ] ) . for an arbitrary fixed @xmath127 , we again first consider the @xmath128-particle gf that solves eq . ( [ fn - keq ] ) with the non - crossing bc ( [ n - knc ] ) , with the radiation bc ( [ n - krc ] ) , and with the initial condition @xmath129 . it reads @xmath130 if @xmath131 , and it vanishes otherwise . in order to derive the partial pdf @xmath132 we first use the above gf ( [ perminitialn - k ] ) to evolve the initial condition @xmath133 this yields the first term on the right - hand side of the following equation . secondly , we take into account the source term in eq . ( [ fn - keq ] ) which gives the second term on the right - hand side of the following equation . altogether , we obtain @xmath134 the first term on the right - hand side vanishes because @xmath135 ( initially , there are @xmath1 particles in the pore ) . as for the second term , we start with @xmath136 and we invoke the same reasoning which enables to rewrite the eq . ( [ pnxt ] ) in the simple product form ( [ pnxtproduct ] ) . more explicitly , inserting the product form ( [ pnxtproduct ] ) with @xmath137 into eq . ( [ soln - k ] ) and repeating the steps as described in appendix [ app : permanent ] , we carry out the required integration over the space variables . after these steps we get @xmath138 this is just eq . ( [ theorem1 ] ) for @xmath136 . the procedure can be simply repeated for @xmath139 . after introducing eq . ( [ n-1pdfprooff ] ) into eq . ( [ soln - k ] ) we have @xmath140 which equals ( cf . eqs . ( [ integraceg ] , [ integrace ] ) ) @xmath141^{2}\,\ , . \label{n-2pdfproofiif}\ ] ] this proves the statement ( [ theorem1 ] ) for @xmath142 . the proof is completed by repeating the procedure for @xmath143 . in the preceding section , we have derived the probabilities @xmath39 of the compound event that , at the time @xmath24 , the pore contains @xmath144 particles _ and _ that they are found in @xmath145 . we now deduce the properties of the single , say @xmath79-th particle ( we shall call it the @xmath79-th tagged particle ) . we start from the partial pdfs @xmath36 , we integrate out the coordinates of all other particles _ and _ we sum over all @xmath146 . the probability that , at the time @xmath24 , the pore contains @xmath0 particles and the @xmath79-th particle is found in the infinitesimal vicinity of the coordinate @xmath147 is @xmath148 , where ( for the definition of the symbols used cf . the text after eq . ( [ inipsi ] ) and the last paragraph in the appendix [ phasespaceint ] ) @xmath149 f^{(n - k)}(\vec{x}_{n - k};t)\,\,.\ ] ] to find the @xmath79-th particle in the pore , the pore must contain at least @xmath79 particles . hence the marginal pdf of the @xmath79-th particle s position regardless the positions of all other particles _ and _ regardless the number of the particles in the pore is given by @xmath150 we now insert the partial pdfs as given by ( [ theorem1 ] ) into eq . ( [ tagged ] ) . skipping out a considerable amount of purely algebraic steps , the pdf for the @xmath79-th tagged particle emerges in the form @xmath151^{n-1 } \left[1-s(t)+f(x , t ) \right]^{n - n}. \label{marginalf}\ ] ] notice that , as promised above , the result is formulated solely by means of the single - particle functions @xmath28 , @xmath30 , and @xmath29 , as defined in eqs . ( [ pdef ] ) , ( [ fdef ] ) , and ( [ survprob ] ) , respectively . in closing the calculation we would like to emphasize the relation @xmath152 which can proved by the direct summation of the expressions ( [ marginalf ] ) . the result is also plausible if we apply the reasoning elaborated in the following paragraph . in the text following eq . ( [ inipsi ] ) we have emphasized the analogies of our sfd model with a ) the system of @xmath1 noninteracting indistinguishable particles , and with b ) the distribution of the @xmath79-th order statistics based on the sample of @xmath1 independent , identically distributed random variables . however , in subsec . [ subsec : initialconditions ] , the discussion refers to the initial distribution of the particles . ( [ marginalf ] ) testifies that the analogies are valid for an arbitrary time if we only supplement them with the necessary modifications stemming from the escape process . indeed , @xmath153 gives the simultaneous probability that one of the @xmath1 non - interacting indistinguishable particles is found in @xmath88 , @xmath154 particles are located in @xmath155 , and each of the remaining @xmath156 particles is either already removed from the pore ( with the probability @xmath157 ) or it is still diffusing in the domain in @xmath25 ( with the probability @xmath29 ) . the indistinguishability is behind the factorials . they account for all possible sequences of particles to the right and to the left of the tagged particle . on the other hand , consider @xmath1 independent , identically distributed random variables each one possessing the probability density @xmath158 . then eq . ( [ marginalf ] ) is just the probability density for the @xmath79-th biggest among them . in this second analogy , the time enters as a parameter . if we use the initial condition ( [ definicef ] ) and if we carry out the steps as given in subsec . [ subsec : singleparticle ] , the single - particle survival probability ( [ survprob ] ) reads @xmath159 \,\ , . \label{s}\end{aligned}\ ] ] at @xmath11 , the survival probability equals to one . it approaches zero as @xmath160 , i.e. , the particle will certainly exit the pore . the survival probability ( [ s ] ) decays with time as the power law@xcite @xmath161 this asymptotic time dependence is determined solely by the geometry of the problem ( 1d semi - infinite interval with the absorbing boundary ) . the constant factor @xmath162 includes the parameters @xmath163 . it reads @xmath164 we shall demonstrate that the parameters @xmath165 , @xmath4 , @xmath7 enter the time - asymptotic behavior of the interacting particles only through this combination . for the tagged particles ( eq . ( [ survn ] ) , solid blue lines ) , and the single - particle survival probability @xmath30 ( eq . ( [ s ] ) , the dashed red line ) as the functions of time . the parameters used : @xmath166 , @xmath167 , @xmath168 , @xmath169 . the number @xmath170 on the right near the blue lines denotes the order of the corresponding particle , cf . fig . 1 . ] having prepared the single - particle survival probability @xmath30 we now turn to the system of interacting particles . the survival probability @xmath171 of the @xmath79-th tagged particle is defined as @xmath172 where @xmath173 is the @xmath79-th particle s pdf as given by eq . ( [ marginalf ] ) . the main steps of the emerging calculation are summarized in appendix [ app : spc ] . the resulting expression includes only the single - particle survival probability : @xmath174 this is the main formula of the present section . to get a better insight into the escape process in question , let us examine the difference between the survival probabilities of the adjacent particles . we have @xmath175 the difference is simply the probability that the particle no . @xmath176 has already exited the pore and , simultaneously , the particle no . @xmath79 is still diffusing inside the pore . at the same time , the right - hand side by itself suggests an interpretation in terms of a system of _ noninteracting and indistinguishable particles _ ( the survival properties of @xmath1 noninteracting particles are discussed e.g. in refs . ) . ( [ rozdils ] ) tells us that the following two events have the same probability : ( i ) exactly @xmath156 of the initial number @xmath1 of interacting particles have already exited the pore by the time @xmath24 , and ( ii ) exactly @xmath156 of the initial number @xmath1 of noninteracting and indistinguishable particles have already exited the pore by the time @xmath24 . differently speaking , the mass transport out of the pore is not affected by the hard - core interaction . in particular , in the probabilistic sense , it will take the same time until all @xmath1 particles escape from the pore regardless they interact or not . [ fig : survival ] illustrates the tagged particle survival probability @xmath171 for different @xmath170 , together with the single - particle survival probability @xmath30 . several observations are worth emphasizing . first of all , it follows from eq . ( [ rozdils ] ) that the function @xmath171 are ordered as @xmath177 where the equalities hold at @xmath11 ( all @xmath1 particles are initially inside the pore , thus all @xmath178 ) and in the limit @xmath179 . each hard - core particle acts on the adjacent ones as a moving ( fluctuating ) reflecting boundary . for example , the exit of the rightmost particle is hindered by the remaining @xmath50 particles which greatly increases its survival probability @xmath180 . effectively , the collisions between the particles induce _ entropic repulsive forces_. the leftmost particle is pushed by the remaining ones towards the pore s boundary which significantly reduces its lifetime inside the pore ; its survival probability @xmath181 rapidly decreases to zero . as a direct consequence of eq . ( [ sumdens ] ) we obtain @xmath182 which relates the arithmetic mean of tagged particles survival probabilities to the survival probability of the single - diffusing particle . hence @xmath180 always exceeds @xmath30 but their difference @xmath183 vanishes as @xmath184 . the above consideration manifest themselves most pronouncedly if we consider the time - asymptotic behavior of the survival probabilities . each @xmath171 tends to zero , i.e. , each particle will certainly exit the pore . the long - time asymptotics of the individual @xmath171 can be obtained directly from eq . ( [ survn ] ) . we have @xmath185 where @xmath162 has the same meaning as in eq . ( [ sdecay ] ) . in words , each survival probabilities exhibits again a power - law decay . however , the decay exponent depends on the particle s order @xmath79 and it _ does not _ depend on the total number of particles . the parameter @xmath1 enters just through the constant prefactor of the power law . this can be understood on physical grounds . notice that the survival probability of the rightmost particle @xmath180 decays as @xmath186 , i.e. , with the same dynamical exponent as @xmath30 ( cf . ( [ sdecay ] ) ) . indeed , in the long - time limit it is highly probable that all other particles have already escaped and thus the initially rightmost particle behaves as a free one . this is also why the total number of particles @xmath1 does not enter the exponents of @xmath171 , for an arbitrary @xmath79 . after a `` long enough '' time , the @xmath187 particles which were initially to the left of the @xmath79-th one have already escaped . thus , irrespective of @xmath1 , the @xmath79-th particle behaves as if it were the leftmost one in the system of @xmath79 particles . the total number of particles @xmath1 specifies only the expression `` long enough '' in the above reasoning . finally , let us return to the mapping which has been developed in subsec . [ subsec : mapping ] where we have discussed the analogy between our sfd problem and the diffusion of a single compound particle in the @xmath1-dimensional space . initially , the compound particle departs from a general interior point in the @xmath1-dimensional wedge domain . the exit of the leftmost particle has been translated to the adsorption of the compound particle onto the @xmath188-dimensional absorbtion hyperplane . then the compound particle continues to diffuse within this hyperplane until its motion is further restricted onto the @xmath189-dimensional absorbtion hyperplane , and so on . the function @xmath171 equals the probability that , at the time @xmath24 , the motion of the compound particle has not been restricted onto the @xmath190-dimensional hyperplane , yet . that is , it still moves in some @xmath146-dimensional wedge , where @xmath191 . similarly , the difference @xmath192 as given in eq . ( [ rozdils ] ) yields the probability that , at the time @xmath24 , the compound particle diffuses in the interior of the @xmath79-dimensional wedge domain . on the whole , as a byproduct , we have solved a nontrivial problem concerning the geometrically restricted @xmath1-dimensional diffusion . the survival probability @xmath171 ( eq . ( [ survn ] ) ) provides complete information about the escape process of the @xmath79-th particle . the pdf @xmath193 of the @xmath79-th particle s _ exit time _ is given by@xcite @xmath194 hence all the moments of the exit time can be obtained from @xmath171 . it follows from the long - time properties of @xmath171 ( cf . ( [ snasymptotics ] ) ) that @xmath195 consequently , the mean exit time of the @xmath79-th particle , @xmath196 is infinite for @xmath197 . the integral ( [ escapetime ] ) becomes finite for @xmath198 and its convergence does not depend on the total number of particles initially located in the pore . @xmath1 only modifies the magnitude of the mean exit time ( if the latter exists ) . similarly , the second moment of the exit time @xmath199 only exists for @xmath200 . the above analysis brings us to an interesting comparison between the escape process confined by the static and by the fluctuating reflecting boundaries , respectively . considering the semi - infinite interval with the absorbing boundary at the origin , the survival probability @xmath30 of the single - diffusing particle decays to zero as the power law ( [ sdecay ] ) and the mean exit time is infinite . if we add the _ static _ reflecting boundary on the right of the single - diffusing particle , the diffusion will be confined to an interval of a finite length . then the survival probability decays exponentially and , consequently , the mean exit time becomes finite@xcite . consider now our sfd model with @xmath201 . then , for the left particle , the right one plays the role of a moving reflection boundary . that is , the left particle diffuses within a finite interval of a fluctuating length . contrary to the case of the static boundary , the survival probability of the left particle decays as @xmath202 , and its mean exit time is infinite . it is interesting that the case @xmath203 brings us to still another behavior of the leftmost particle . for this particle , the central particle again represents a moving boundary . this boundary itself diffuses and , moreover , it feels another moving boundary to the right of it . as a result of such right - hand confinement the escape process of the leftmost particle is accelerated , its mean exit time is finite , but the variance of the exit time still diverges . for a general @xmath1 , the exit time of any @xmath79-th tagged particle with @xmath204 possesses both a finite mean value and a finite variance . in leaving the subject , notice that the limit @xmath9 alters only the prefactor @xmath162 but not the long - time decay exponent of @xmath171 . this limit corresponds to perfect absorption ( particle is absorbed immediately when it hits the absorbing boundary ) . consequently , @xmath205 gives the distribution of the @xmath79-th particle s _ first - passage time _ and @xmath206 equals the mean first - passage time . this paper provides a simple and general formalism for 1d sfd problems with absorbing boundaries . our main message concerns the relation of the physically motivated sfd problem and a broadly developed probabilistic field of order statistics and it can be summarized as follows . if the initial condition in the physical sfd problems is assumed in the form of a joint pdf for the order statistics based on the system of identical and independent parent random variables , then this form is preserved during the subsequent time evolution . implicitly , the observation has been already contained in the previous theoretical sfd studies in problems without boundaries . it can be easily read from the permanent - like structure of the green function . our work elaborates the connection between the sfd problem and the order - statistics point of view into new directions . first of all , we have proven that the relation continues to be valid in the problems with boundaries . in these problems , the arbitrary - time joint pdf for the positions of the particles has again the form of the joint pdf for the order statistics , provided one simply admits that the pdf for a single parent random variable has an atom at the origin . secondly , specifically in the problems with boundaries , the joint pdf for the order statistics at an arbitrary time includes , in a mixed form , both the information on the particles remaining still in the pore and on their exit times . we have shown that these two pieces of information can be separated thereby yielding new exact results on the tagged particle diffusion and on the escape process , respectively . the robustness of the relation is easily understood as it lies in both cases ( with and without the boundaries ) in the hard - core inter - particle interaction . it is therefore not surprising that our results are independent on a detailed form of the single - particle dynamics . they hold true , for example , if the single particle is acted upon by a general space - dependent or even a space - and - time - dependent external force . the overall structure of our solution remains unchanged if we only change the details of the escape process and switch , for example , from the radiating boundary to the totally absorbing one . physically motivated calculations in these directions are in progress and will be reported elsewhere . eventually , let us comment on our choice of the initial condition as given by eq . ( [ inigeneral ] ) . obviously , it is _ not _ the most general option . for example , what happens if the particles are initially placed at specific set of coordinates @xmath207 ? taking a general initial condition , the partial pdf as defined by eq . ( [ pnxt ] ) _ does not _ reduce to the simple product form ( [ pnxtproduct ] ) . instead , it assumes a rather involved permanent - like form similar to the rhs of eq . ( [ perminitial ] ) . with the necessary changes , one can carry out all the steps which give the partial pdfs @xmath208 , the tagged particle pdf @xmath173 , and the survival probabilities @xmath171 . but again , all the final expressions contain permanents . in spite of these more complicated finite - time expressions , the long - time dynamical exponents coincide with those derived in the preceding sections . again , the parameters which specify the initial condition ( together with @xmath4 and @xmath7 ) appear in the prefactors of the power laws ( [ snasymptotics ] ) , ( [ exitpdf ] ) . support of this work by the ministry of education of the czech republic ( project no . msm 0021620835 ) , by the charles university in prague ( project ssv : 110 - 09/265305 ) and by the charles university grant agency ( projects no . 301311 , and no . 251228 ) is gratefully acknowledged . let @xmath209 be a symmetric function of its arguments , i.e. , let @xmath210 holds for any of @xmath119 permutations @xmath211 of the subscripts @xmath212 . then the integration of @xmath213 with respect to the coordinates @xmath214 over the phase space @xmath215 ( defined in sec . [ subsec : initialconditions ] ) extends to the integration with respect to the components of @xmath214 over the half - lines as follows , @xmath216 the first equality introduces just another notation for the integration over @xmath73 , the second equality follows from the symmetry of @xmath213 . for a further discussion see , e.g. , appendix c in ref . . in particular , if @xmath213 stands for a product of identical functions , i.e. , @xmath217 , then we have @xmath218^{n}.\ ] ] if we are interested in properties of a tagged particle , say of the @xmath79-th one , we should carry out another type of the integration over the phase space @xmath73 . in this case we have to integrate over the variables @xmath219 , @xmath220 . let us denote the domain of such integration as @xmath221 . further , let us define the symbol @xmath222={\rm d}x_{1 } ... \ , { \rm d}x_{n-1 } { \rm d}x_{n+1 } ... \ , { \rm d}x_{n}\,\,.\ ] ] the integration of @xmath217 over @xmath221 runs as follows @xmath223\,\ , g(x_{1})g(x_{2 } ) ... \,g(x_{n } ) & = & g(x_{n } ) \int_{x_{n}}^{+\infty } \!\!\!\!\!\!\!\!\!{\rm d}x_{1}\ , g(x_{1})\!\ ! \int_{x_{n}}^{x_{1 } } \!\!\!\ ! { \rm d}x_{2}\ , g(x_{2 } ) \ , ... \int_{x_{n}}^{x_{n-2 } } \!\!\!\!\!\!\!\!\!\!{\rm d}x_{n-1}\,g(x_{n-1})\times \\ \notag & & \times \int_{0}^{x_{n } } \!\!\!\!\!\!{\rm d}x_{n+1}\,g(x_{n+1 } ) \ , \int_{0}^{x_{n+1 } } \!\!\!\!\!\!\!\!\!\!{\rm d}x_{n+2}\,g(x_{n+2 } ) \ , ... \int_{0}^{x_{n-1 } } \!\!\!\!\!\!\!\!\!\!{\rm d}x_{n}\,g(x_{n } ) \\ \label{marginalintegrace } & = & \frac{g(x_{n})}{n_{l}!n_{r } ! } \left [ \int_{0}^{x_{n } } \!\!\!\!\!\!\!{\rm d}x\ , g(x)\right]^{n_{l } } \left [ \int_{x_{n}}^{+\infty } \!\!\!\!\!\!\!\!\!{\rm d}x\ , g(x)\right]^{n_{r } } , \label{tpintegral}\end{aligned}\ ] ] where @xmath224 ( @xmath83 ) stands for the number of particles located left ( right ) from the @xmath79-th particle ( cf . fig . [ fig : singlefile ] ) . for a more comprehensive discussion of this integration technique , see sec . iii b. in ref . . first , notice that the sum on the rhs of eq . ( [ perminitial ] ) can be rearranged as @xmath225 further , notice that @xmath226 is symmetric under the permutations of @xmath227 . inserting the initial condition ( [ inigeneral ] ) into eq . ( [ pnxt ] ) gives @xmath228 we now insert @xmath226 as given by eq . ( [ permfinal ] ) , interchange the summation and integration , and use the symmetry of @xmath226 ( cf . ( [ integraceg ] ) ) . we obtain @xmath229 where the last equality follows from the definition ( [ pdef ] ) . the last sum comprises @xmath119 identical summands and hence we arrive at eq . ( [ pnxtproduct ] ) . let us define the auxiliary function @xmath230 with the properties : @xmath231 , @xmath232 , @xmath233 . then we can rewrite eq . ( [ sndefin ] ) as @xmath234 using the binomial theorem we expand @xmath235 and we insert the unity in the form @xmath236 . then we get @xmath237 where the definite integral equals @xmath238 . on the whole , we have proven eq . ( [ survn ] ) from the main text . moreover , the sum in eq . ( [ survn ] ) can be represented by the definite integral@xcite @xmath239 the integration by parts directly yields eq . ( [ rozdils ] ) . 36ifxundefined [ 1 ] ifx#1 ifnum [ 1 ] # 1firstoftwo secondoftwo ifx [ 1 ] # 1firstoftwo secondoftwo `` `` # 1''''@noop [ 0]secondoftwosanitize@url [ 0 ] + 12$12 & 12#1212_12%12@startlink[1]@endlink[0]@bib@innerbibempty @noop * * , ( ) @noop * * , ( ) @noop _ _ ( , , ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop _ _ ( , ) and , eds . , `` , '' ( , , ) chap . , p. @noop _ _ ( , ) @noop _ _ ( , , ) @noop _ _ , , vol . ( , , ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop _ _ ( , )

we investigate a diffusive motion of a system of interacting brownian particles in quasi - one - dimensional micropores . in particular , we consider a semi - infinite 1d geometry with a partially absorbing boundary and the hard - core inter - particle interaction . due to the absorbing boundary the number of particles in the pore gradually decreases . we present the exact analytical solution of the problem . our procedure merely requires the knowledge of the corresponding single - particle problem . first , we calculate the simultaneous probability density of having still a definite number @xmath0 of surviving particles at definite coordinates . focusing on an arbitrary tagged particle , we derive the exact probability density of its coordinate . secondly , we present a complete probabilistic description of the emerging escape process . the survival probabilities for the individual particles are calculated , the first and the second moments of the exit times are discussed . generally speaking , although the original inter - particle interaction possesses a point - like character , it induces entropic repulsive forces which , e.g. , push the leftmost ( rightmost ) particle towards ( opposite ) the absorbing boundary thereby accelerating ( decelerating ) its escape . more importantly , as compared to the reference problem for the non - interacting particles , the interaction changes the dynamical exponents which characterize the long - time asymptotic dynamics . interesting new insights emerge after we interpret our model in terms of a ) diffusion of a single particle in a @xmath1-dimensional space , and b ) order statistics defined on a system of @xmath1 independent , identically distributed random variables .

-amyloid ( a ) peptide is the main cause of alzheimer 's disease ( ad ) [ 1 , 2 ] . a has two major types , a40 and a42 , which are derived from a ubiquitous type i transmembrane protein amyloid precursor protein ( app ) by a two - step secretase ( - and -secretase ) pathway [ 35 ] . the amyloid cascade hypothesis predicts that the aggregated a peptides in the brain have an early and essential role in the neuronal degeneration that leads to dementia [ 1 , 2 , 6 ] . the aggregation of a occurs following a conformational conversion from either -helix or random coil to -sheet in a time - dependent manner , indicating that the formation of -sheet structure is the key step for the peptide aggregation [ 7 , 8 ] . the formation of a aggregates is modulated by several factors , including metal ions [ 9 , 10 ] . in amyloid plaques of ad - affected brain , remarkably high concentration of metals , such as cu ( 400 m ) , zn ( 1 mm ) and fe ( 1 mm ) , has been found [ 11 , 12 ] . in vitro studies , micromolar levels of cu , zn and fe have been shown to sufficiently induce protease - resistant aggregation and precipitation of a . copper ions are bound to the three his residues of a located at the n - terminus , which forms a 3n1o square - planar motif as verified by epr spectroscopy . copper - selective chelators can dissolve a deposits extracted from ad postmortem brain specimens and reduce the level of free radical . curtain and his colleagues previously reported that the addition of cu to oligomeric a40 in a negatively charged lipid membrane can induce a peptides reinserted into lipid membranes , convert a conformation from -strand into -helix , and cause the lipid peroxidation . their result is the first study to show that instead of -sheet , a in -helical form can also generate free radicals in the presence of cu ions . recently , our group has characterized the conformation of a in the presence of cu ions into three structural states , stable helix , unstable helix , and random coil , in 40% , 25% , and 5% tfe , respectively , . therefore , this provides us a possibility to re - examine the relationship between a conformation , and cu - driven free radical generation . in the present study , we examined the correlation between cu binding affinity , h2o2 formation , and a40 conformation . it was found that both cu binding affinity and h2o2 formation are well correlated with the conformation of a40 . in general , cu ions can be bound to the different structural forms of a40 . the copper - binding affinity of a40 in random coiled form is about 3-fold higher than that of a40 in stable helical form . for h2o2 formation , our result shows in the first time that the generation of h2o2 can also be induced by cu and the stable helical form of a40 . in contrast , in random coiled form , the formation of h2o2 is inhibited by a40 . the synthesis of full - length a40 peptide was performed in an abi-433a solid - phase peptide synthesizer using the fmoc protocol . cleavage and deprotection of the synthesized peptide were performed by treatment with a mixture of trifluoroacetic acid / distilled water / phenol / thioanisole / ethanedithiol . then the peptide was extracted with 1 : 1 ( v : v ) ether : h2o containing 0.1% 2-mercaptoethanol . the synthesized a peptides were purified on a reverse - phase c-18 hplc with a linear gradient from 0% to 100% acetonitrile , and the molecular weight of a40 peptides and purity was verified by an maldi - tof mass spectroscopy . one mg of purified monomeric a40 peptide was dissolved in 1 ml 100% trifluoroethanol ( tfe ) as stock solution . a final a peptide concentration of 30 m in either 5% or 40% tfe was prepared from fresh peptide stock solution diluted in phosphate buffer , ph 7.4 , with or without the same concentration of cu . a thousand m of cu stock solution was prepared by dissolved cucl2 salt in distilled h2o purged by n2 in a sealed flask and freshly diluted into the designed concentration before it was used . all measurements were performed in quartz cells with a path length of 0.1 cm . data were collected at wavelengths from 190 to 260 nm in 0.2 nm increments . the reported cd spectra were corrected using phosphate buffer , ph 7.4 for the baseline . an equal molar 300 m of a and cu in 30% glycerol phosphate buffer , ph 7.4 , and 5% and 40% of tfe was employed for spin counting purposes . epr spectra were obtained at x - band using a bruker emx er073 spectrometer equipped with a bruker te102 cavity and an advanced research system continuous - flow cryostat ( 4.2300 k ) . during epr experiments , the sample temperature was maintained at 10 k. the microwave frequency was measured with a hewlett - packard 5246l electronic counter . tyrosine fluorescence spectroscopy was used to investigate the binding affinity for copper bound to a. a peptide stock solution was diluted in phosphate buffer , ph 7.4 to a final peptide concentration of 10 m with designed concentration of cu . all measurements were performed in a 96-well plate using a microplate reader ( flexstation 3 , md ) . the excitation and emission wavelengths were selected at 278 and 305 nm , respectively . reported data were the average obtained from three individual samples and three repeated measurements of each sample . the binding affinity was calculated using the following equation : ( 1)fxf0=ixii0i=11+ka[cu2+]n , where i0 and ix are the fluorescence intensity for free and a/cucomplex , respectively , i is the fluorescence intensity at saturation state , [ cu ] is the copper concentration , and n is the copper binding number . the related parameters were fitted using nonlinear curve fitting program micro - origin v6.0 ( microcal software , inc . , nothampton , ma ) . in the initial fitting stage , the simplex method , which was set to 100 cycle runs , the final fitting parameters were obtained when the value of was less than 0.05 and the parameters and errors for the parameters reached the convergent and steady state . the production of h2o2 was analyzed using the dichlorofluorescein diacetate ( dcfh - da ) assay . dichlorofluorescein diacetate was dissolved in 100% dimethyl sulfoxide , deacetylated with 50% v / v 0.05 m naoh for 30 min , and then neutralized ( ph 7.4 ) to a final concentration of 200 m as stock solution . the reactions were carried out in dulbecco 's pbs , ph 7.4 , in a 96-well plate ( 100 l / well ) containing different concentration of a40 , 30 m cucl2 , tfe ( 5% and 40% ) , deacylated dcf ( 20 m ) , and horseradish peroxidase ( 5 m ) at 37c . for negative control , an extra of 1.0 mm catalase ( aspergillus niger ) was used to quench h2o2 . fluorescence readings were recorded on a microplate reader ( md , flexstation 3 ) , with the excitation and emission wavelengths selected at 485 and 530 nm , respectively . uv / vis turbidity assay was used to detect the aggregation process of a. 200 l of 30 m a40 in phosphate buffer , ph 7.4 containing either 5% or 40% tfe was freshly prepared from stock solution . fresh prepared samples with or without 30 m cu placed in a 96-well plate were incubated at 37c . turbidity was measured using a microplate reader ( md , flexstation 3 ) at a wavelength of 450 nm . the aim of this study is to examine the relationship between a40 conformation and other physical and chemical properties such as aggregation , cu - binding affinity , and free radical formation . in the present study , we applied 5% and 40% tfe to mimic the conformation of a40 in random coil and stable helix , respectively , . therefore , the effect of tfe on cu binding affinity and free radical generation has to be evaluated . as depicted in supplemental data ( see supplementary material available online at doi:10.4061/2011/607861 ) , the main effect of tfe on the system is only to quench the dcf fluorescence intensity . neither was the solubility of cu ions nor the formation of h2o2 affected by tfe . first of all , we characterized the structural state of a40 with and without cu in either 5% or 40% tfe using circular dichroism ( cd ) spectroscopy . figures 1(a ) and 1(b ) show the cd spectra for a40 and a40/cu in 5% and 40% tfe , respectively . it can be seen that , in 5% tfe , the pattern of cd spectrum for a40 in the presence of cu showed a dramatic change compared to that for a40 only , while the cd spectra of a40 with or without cu in 40% tfe did not show any significant change . the secondary structure of a40 in 5% tfe changes from 63% random coil , 34% -sheet and 3% helix in cu - free state to 45% random coil , 50% -sheet and 5% helix in cu - bound state , representing that there is a structural conversion from random coil into -sheet . on the other hand , the conformation of a40 with or without cu in 40% tfe remains stable in which the secondary structure is 74% helix , 14% -sheet , and 12% random coil in cu - free state and 73% helix , 15% -sheet , and 12% random coil in cu - bound state , indicating that there is no conformational conversion of a40 in 40% tfe while adding cu ions . it has been shown that cu ions are able to accelerate the aggregation of a40 [ 9 , 15 , 18 , 20 ] . hence , we characterized the aggregation process of a40/cu and a40 in 5% and 40% tfe . the aggregation process of a40/cu and a40 in 5% and 40% tfe was analyzed by turbidity assay as shown in figure 2 . in general , in both 5% and 40% tfe , a40 in the presence of cu was aggregated much faster than that in the absence of cu furthermore , the aggregation rate in 5% tfe for both a40/cu and a40 was much faster than that in 40% tfe . the aggregation process in 5% tfe for a40/cu and a40 showed a typical sigmoidal profile . on the other hand , the aggregation process in 40% tfe for a40 with and without cu mostly stayed in the nucleation or the early elongating stage within 24 hrs . the aggregation process for a40 and a40/cu in 5% and 40% tfe echoes with the result obtained in the analyses of secondary structure in which the aggregation ability is correlated with the ability of conformational formation of -sheet . in the present study , we showed that the conformational states for a40/cu and a40 in 5% are dramatically different , while no such conformational change can be observed between a40/cu and a40 in 40% tfe . although cu ions have been shown to be bound to a in aqueous solution , then , whether cu ions are bound to a40 in 40% tfe is needed to be investigated since the structural state for a40/cu and a40 in 40% tfe shows no difference . to address this issue , epr spectroscopy was applied to explore the interaction between cu and a40 in 40% tfe . as shown in figure 3 , the epr spectra of a/cu both in 5% and 40% tfe showed two major groups of hyperfine peaks , while no hyperfine peak could be observed in the epr spectrum for cu alone , indicating that cu ions were bound to a40 in both 5% and 40% tfe . the pattern of hyperfine peaks for a40/cu in 5% and 40% tfe is similar , but the position of hyperfine peaks in 40% tfe shifts to low magnetic field . the related epr parameters of g , a , and g are 2.28 , 156.8 , and 2.06 for a40/cu in 5% tfe , respectively . the g and g values in 5% tfe are very close to those in the literature measured in aqueous condition , representing that the binding geometry of a40/cu in 5% tfe should adopt a similar 3n1o coordination . on the other hand , the related epr parameters of g , a , and g are 2.40 , 119.6 , and 2.09 for a40/cu in 40% tfe , indicating that the copper - binding geometry is different from the 3n1o mode and this further indicates that the binding affinity of cu to a40 in random coiled form may be stronger than that to a40 in stable helical form . as shown in epr studies , cu can be bound to different structural forms of a40 with a different binding affinity . in order to further elucidate the binding property of cu , we applied the tyrosine fluorescence spectroscopy to determine the cu - binding constant , since tyrosine 10 is the only fluorophore in a amino acid sequence and locates at the binding pocket , in which the binding of cuto a40 may cause the change of tyrosine fluorescence . the titration curves of cu concentration versus tyrosine fluorescence intensity in 5% and 40% tfe are shown in figures 4(a ) and 4(b ) , respectively . the binding constants , ka , were estimated using the equation as described in the experimental section with molar ratio of a : cu = 1 : 1 , that is , n = 1 . the calculated ka values are 0.14 m ( r > 0.97 ) and 0.05 m ( r > 0.96 ) for a/cu in 5% and 40% tfe , respectively . the ka of a40/cu in 5% tfe is around 3-fold higher than that in 40% tfe , suggesting that cu is bound to random coiled form of a40 more strongly than to stable helical form of a40 which is consistent with the epr studies . it has been demonstrated that a40 coordinated with cu can cause the reduction of cu and then induce the formation of h2o2 from o2 in a catalytic manner [ 15 , 20 ] . to examine the relationship between free radical formation and a40 conformation , figures 5(a ) and 5(b ) show the plots of dcf fluorescence intensity versus a concentration in 5% and 40% tfe as incubated at 37c for 1 hr . in general , results clearly show that the formation of h2o2 is also correlated with a40 conformation . in 5% tfe , the level of h2o2 was reduced to zero when the a40/cu molar ratio 1 , indicating that the formation of h2o2 is inhibited when a40 adopts the random coiled form . unexpectedly but interestingly , unlike the formation of h2o2 which was inhibited in 5% tfe , the level of h2o2 in 40% tfe was increased with an increase of a40 concentration and was much higher than those of either cu or a40 alone , suggesting that the formation of h2o2 was induced when a40 was in the stable helical form . according to amyloid cascade hypothesis , aggregated a is the main toxic species to cause the alzheimer 's disease . the various forms of a aggregate have been shown to coordinate with redox active transition metals , such as cu and fe , and induce the generation of reactive oxygen species [ 15 , 20 ] . however , the correlation of copper - binding affinity , copper - driven aggregation , and free radical formation with a40 conformation still needs to be elucidated . for ion interaction , our results demonstrate for the first time that cu ions can interact with both random coiled and stable helical forms of a40 . as a larger a value and binding constant obtained for a40 in 5% tfe , the cu - binding affinity for random coiled form of a40 is much stronger than that for stable helical form of a40 . the possible explanation may be attributed to the different flexibility of a40 conformation in 5% and 40% tfe . as shown in cd spectra , the conformation of a40 in 5% tfe is relatively flexible and can easily convert structure from random coil into -sheet while coordinating with cu . on the other hand , the overall conformation of a40 with or without cu is relatively rigid and remains in stable helix in 40% tfe , and only the local geometry of cu - binding site is distorted while interacting with cu ions as indicated by the shift of g value . therefore , the interaction between cu and a40 is strong in 5% tfe and relatively weak in 40% tfe . the binding affinity for stable helical form of a40 is almost 3-fold lower than that for random coiled form of a40 . the cu - binding affinity can further be used to account for the differences for cu - driven aggregation between random coiled and stable helical forms of a40 . it is well known that the formation of -sheet plays a key step for the aggregation of a40 . as shown in the present study , the conformation of a40 in 5% tfe is much easier than that in 40% tfe to convert into -strand structure by cu ions . thus , in the presence of cu , the random coiled form of a40 ( in 5% tfe ) aggregates faster and more severe than the stable helical form of a40 ( in 40% tfe ) . unlike the cascade hypothesis that only -sheet form of aggregated a can produce free radical , we demonstrate that helical form of a40 can also induce the formation of h2o2 . from the aggregation assay , this helical form of a40 may possibly exist as a monomer during the early incubation period . then , this further implies that monomeric a40 in stable helical form by coordinating with cu can induce the formation of h2o2 . in contrast , a40 in random coiled form shows to inhibit the formation of h2o2 during the early incubation period . the inhibition of h2o2 formation becomes more significant with an increase of a40 concentration , and the formation of h2o2 further is completely inhibited when the molar ratio of a/cu molar ratio 1 . our observation is consistent with a recent study by viles and his colleagues , in which they showed that , at a/cu molar ratio = 1 , the formation of h2o2 is inhibited by both monomeric and fibrillar a peptides . taken together , it may suggest that helical structure may play a key factor for the generation of h2o2 by a40/cu . in summary , our present results demonstrate that both ion interaction and copper - driven free radical formation are well correlated with a40 conformation . when a40 adopts a stable helical structure , the cu binding affinity is weaker , and the free radical is produced . on the other hand , when a40 adopts a random coil in 5% tfe , the cu binding affinity is stronger , and the formation of h2o2 is inhibited .

the neurotoxicity of a is associated with the formation of free radical by interacting with redox active metals such as cu2 + . however , the relationship between ion - interaction , ion - driven free radical formation , and a conformation remains to be further elucidated . in the present study , we investigated the correlation of cu2 + interaction and cu2 + -driven free radical formation with a40 conformation . the cu2 + -binding affinity for a40 in random coiled form is 3-fold higher than that in stable helical form . unexpectedly but interestingly , we demonstrate in the first time that the stable helical form of a40 can induce the formation of h2o2 by interacting with cu2 + . on the other hand , the h2o2 generation is repressed at a/cu2 + molar ratio 1 when a40 adopts random coiled structure . taken together , our result demonstrates that a40 adopted a helical structure that may play a key factor for the formation of free radical with cu2 + ions .

Tweet with a location You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| The big picture: Graff — one of the most astute Mueller-watchers , and author of a book focused on his dozen years as FBI director — sees six signs that a Mueller climax may be accelerating. Evidence is mounting that Special Counsel Robert Mueller is moving toward further indictments — and perhaps some big ones, with an end-of-year flurry of activity. Mueller is tightening the screws on Jerome Corsi, a friend of former Trump adviser Roger Stone. A plea deal — or charges — appear imminent. Ecuador may be moving toward turning over WikiLeaks founder Julian Assange. The government removed its Assange-backing U.K. ambassador last week, and has prohibited his lawyers from meeting with him. The report yesterday by The Guardian that Assange and former Trump campaign chairman Paul Manafort may have met repeatedly — denied by Manafort and Assange — raises the stakes dramatically. Russian spy and NRA superfan Maria Butina is reported to be in talks for a plea deal. A number of Mueller’s prosecutors were hard at work on Veterans Day — when Michael Cohen took the train to Washington to talk to Mueller's team. ABC News reported an "unusually high" number — nearly three dozen, in fact — of sealed indictments filed over the course of the year in D.C. Fourteen of those have been added since August, a period when Mueller’s investigation was publicly quiet. And this big one: President Trump last week finally turned in long-awaited written answers to Mueller’s investigators. His story — or at least a version of it — is now locked in. By doing so, Trump tacitly acknowledged Mueller's authority, despite tweeting last night: "The Mueller Witch Hunt is a total disgrace." Since Mueller laid low while waiting for Trump’s responses, the special counsel may have wanted to avoid taking any action that might spook the president. Mueller appears to have been thinking this through carefully — not rocking the boat while he waited out Trump. His team delayed a mid-November hearing, where prosecutors were supposed to discuss Paul Manafort’s "lack of cooperation." They made that accusation Monday, after Trump’s answers were in hand. So the timeline looks like it's speeding up, after four months of near silence from Mueller. Manafort's lack of cooperation might be the opening needed to file Mueller's most explosive findings in public shortly. That could include new information about that mysterious 2016 Trump Tower meeting, or details about a possible Assange connection. include new information about that mysterious 2016 Trump Tower meeting, or details about a possible Assange connection. Based on Monday's court filing, Mueller apparently hopes to quickly issue a "report" on Manafort’s activities to the court, one that — if it’s anything like other documents Mueller has filed thus far — will be more informed, more knowledgeable and more detailed than we can imagine. Be smart: We've been surprised at every turn by how much Mueller knows. Go deeper: ||||| ....Foundation be listed at the top of the Report? Will the scathing document written about Lyin’ James Comey, by the man in charge of the case, Rod Rosenstein (who also signed the FISA Warrant), be a big part of the Report? Isn’t Rod therefore totally conflicted? Will all of.... ||||| .....overturned, 9-0, in the United States Supreme Court. Doing same thing to people now. Will all of the substantial & many contributions made by the 17 Angry Democrats to the Campaign of Crooked Hillary be listed in top of Report. Will the people that worked for the Clinton.... ||||| Tweet with a location You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| ....Will Robert Mueller’s big time conflicts of interest be listed at the top of his Republicans only Report. Will Andrew Weissman’s horrible and vicious prosecutorial past be listed in the Report. He wrongly destroyed people’s lives, took down great companies, only to be........ ||||| Special counsel Robert Mueller Robert Swan MuellerSasse: US should applaud choice of Mueller to lead Russia probe MORE on Friday is expected to file a bombshell report that describes how former Trump campaign chairman Paul Manafort Paul John ManafortDems have new moniker for Trump: ‘Unindicted co-conspirator' Bernstein: Trump ‘is boxed in by Mueller’ Maine senator calls impeachment 'last resort': 'We may get there, but we’re not there now' MORE eviscerated his plea agreement with federal prosecutors. The highly anticipated memo, slated for release as a court filing, will likely shed more light on Mueller’s investigation into whether President Trump Donald John TrumpCorsi sues Mueller for alleged leaks and illegal surveillance Comey: Trump 'certainly close' to being unindicted co-conspirator Trump pushes back on reports that Ayers was first pick for chief of staff MORE’s campaign colluded with Russia's efforts to interfere in the 2016 presidential election. But just how much new information will be made public remains to be seen. ADVERTISEMENT The court document, which federal prosecutors said last week would offer a “detailed” account of how Manafort committed crimes by lying to the FBI, is likely to be heavily redacted in areas that concern the overarching, ongoing probe. Still, whatever information is disclosed is expected to be revelatory in terms of the content and nature of Manafort’s remarks to the special counsel’s office and other FBI investigators. In order to demonstrate that Manafort lied, Mueller will need to refer to evidence or reasons he has for believing Manafort did not tell the truth. “In laying out Manafort’s lies and how they know they’re lies, we’re going to learn a lot about the investigation,” said Elie Honig, a former assistant U.S. attorney for the Southern District of New York. “There will be plenty of clues and indicators about where Mueller has gone and will go.” Any information that could compromise Mueller’s investigation or other probes is likely to be redacted, so the federal judge overseeing Manafort’s case in Washington, D.C., District Judge Amy Berman Jackson, and Manafort’s attorneys would be permitted to view the document in full but the public will not. Earlier this week, Mueller filed a sentencing memo laying out the cooperation of former national security adviser Michael Flynn. That document was heavily redacted to conceal information Flynn has provided in the probe and to at least two other matters under investigation by the Justice Department. Glenn Kirschner, a former federal prosecutor with the U.S. Attorney’s Office in D.C., said he expects the public memo on Manafort to include specifics about the defendant’s lies, unless those details touch on subjects central to the Russia investigation. “It may be that we see an equal number of redactions in the Manafort memo,” Kirschner said, comparing it to the Flynn filing. ADVERTISEMENT Still, Friday’s deadline offers Mueller a fresh opportunity to put facts about the Manafort case and the broader investigation into the public realm. While Mueller and his team of prosecutors have refrained from speaking publicly or commenting on developments in their cases, the special counsel has notably put forth detailed court filings that illuminate an investigation that has captured intense public interest. “The prosecutor has an awful lot of discretion,” Honig said. “It could be a very terse, one- or two-page conclusory statement, or it could be a narrative-style submission.” It remains unclear exactly what Manafort lied about. He was initially ensnared in the Russia investigation on charges related to his foreign lobbying for a pro-Russia political party in Ukraine. Manafort was viewed as a key cooperator with U.S. government investigators because of his visibility into the Trump campaign and information he could offer in related foreign lobbying investigations. The Wall Street Journal reported last week that Manafort allegedly misled investigators about his lobbying work and contacts with Konstantin Kilimnik, a Russian who worked for the offshoot of Manafort’s firm in Ukraine. Kilimnik, suspected of ties to Russian intelligence, was charged alongside Manafort with witness tampering earlier this year but has remained out of the reach of U.S. prosecutors. Mueller first revealed last week that Manafort allegedly lied to the special counsel’s office and other FBI investigators “on a variety of subject matters,” noting that a forthcoming submission would explain “the nature of the defendant’s crimes and lies, including those after signing the plea agreement herein.” Manafort has denied that he misled investigators in breach of his plea agreement. Mueller’s disclosure came days after Trump submitted written answers to the special counsel’s questions about collusion, raising questions among some legal experts about the timing of the two developments. If prosecutors accuse Manafort of lying about something that Trump has said publicly, it could signal the president also lied in his written answers to Mueller, according to former federal prosecutor Shanlon Wu. Wu said that the Manafort memo, in addition to testimony from Trump’s former personal attorney Michael Cohen, could be very dangerous for the president if they contradict the written answers Trump provided on Nov. 20. Cohen has pleaded guilty to several federal crimes in New York and formally agreed last week to cooperate with Mueller, reportedly sitting for interviews with the special counsel’s office that have totaled 70 hours. Legal experts say it’s possible Manafort lied about others in the campaign who have had contact with Russian officials, but they noted it’s unlikely any of those names would be revealed in Friday’s memo. “If he’s disclosing information about somebody who ultimately won’t be prosecuted because Mueller has fallen out of bed with Manafort, there’s more reason to be less clear about it,” said Joel Cohen, a white collar defense attorney and former federal and state prosecutor. “It’s unfair to identify someone as having done wrong if they won’t ultimately be prosecuted for it.” If Manafort lied by omission, that would suggest he might be trying to protect individuals or avoid retribution from someone. “I’ve dealt with dozens of cooperators in my time as a prosecutor, and the reason they go off the rails, as it appears Manafort has, is they are omitting — they are protecting themselves or others,” said Honig. “I think it’s likely that Manafort withheld info from Mueller here. The question, then, is going to be what information was he holding back, who was he protecting, and why?” Berman Jackson, an Obama appointee, is giving Manafort’s defense team until Wednesday to file a preliminary response to the prosecution’s report. Manafort’s attorney, Kevin Downing, said in court last week that he might request further investigation to prove Mueller’s allegations that his client lied to the FBI. While Berman Jackson set March 5 as Manafort’s target sentencing date, she said she will hold a hearing in mid- to late January to determine whether Manafort breached his plea deal. As part of the deal, Manafort had agreed to plead guilty to two felony charges — conspiracy against the U.S. and conspiracy to launder money — and fully cooperate with Mueller’s probe. In return, prosecutors agreed to drop five other charges, including failure to register as a foreign lobbyists, making false statements and tampering with witnesses. But prosecutors said in court last week they are considering bringing new charges against Manafort for lying to the FBI in breach of the agreement. Even if he’s not charged, Joel Cohen said the judge can choose to give Manafort more time if it turns out he sent Mueller on a wild goose chase. The Manafort filing is one of several Mueller will file this week in his sprawling Russia investigation. The special counsel is also slated to submit details Friday on Michael Cohen’s cooperation ahead of his sentencing on eight federal charges in New York. ||||| Breaking News Emails Get breaking news alerts and special reports. The news and stories that matter, delivered weekday mornings. / Updated By Ken Dilanian WASHINGTON — Three new court documents are scheduled to emerge Friday that could shed new light on what Donald Trump's former top aides have been telling — or not telling — federal investigators. A federal judge in New York has ordered that prosecutors for the Southern District of New York and the Special Counsel's Office have until 5 p.m. Friday to deliver sentencing memos designed to detail former Trump lawyer Michael Cohen's cooperation in their ongoing investigations. And special counsel Robert Mueller is also due to file a document spelling out what his team previously referred to as the "crimes and lies" that led them to cancel a cooperation agreement with former Trump campaign chairman Paul Manafort. Legal experts say it's likely that both documents will contain sections that are blacked out, as was the case with the sentencing memo Mueller filed Tuesday in the case of former national security adviser Michael Flynn. The theory that Mueller would use these documents to inform the public about the progress of his ongoing investigation into Russian election interference and related matters did not pan out in the case of the Flynn memo. Key sections of that memo were redacted, including crucial questions about what Trump knew and when about Flynn's lies to the FBI — and a whole page describing a separate criminal investigation. Mueller's decision to withhold that information shows, some experts say, that the former FBI director does not feel that his investigation is at risk of being derailed by Acting Attorney General Matthew Whitaker, who had expressed open hostility toward it before his appointment. "He disclosed so little in the Flynn memo that it led me to conclude two things," said former federal prosecutor Glenn Kirschner, an NBC News legal analyst. "One, he doesn't have a sense of urgency, and two, he probably has a lot more investigating to do. If he was ready to show his cards, he wouldn't have redacted all this stuff." Former federal prosecutor Peter Zeidenberg says there may be something else at play: "As usual, Mueller may be thinking two steps ahead of the rest of us." Zeidenberg noted that Trump has not tweeted or uttered a word about Flynn since the sentencing memo on Flynn was filed, in contrast to Trump's immediate attack on Cohen after Cohen pleaded guilty last week to lying about a Trump Tower project in Moscow. "Trump's been quite quiet since that filing," Zeidenberg said. "He hasn't attacked Flynn. If those blanks had been filled in, Trump's head would have exploded — he'd be going crazy." "If Mueller waits and does his big reveal all at once, everything's done. It's too late" for Trump to engineer his firing, Zeidenberg said. "If he were to have revealed everything on those redactions now, it could jeopardize ongoing matters, and it wouldn't have been smart politically for his continued survival. I think it probably makes a lot of sense. Trump doesn't want to attack Flynn because he doesn't know whether Flynn is coming at him." As for the Southern District’s sentencing memo for Cohen, he is also cooperating in separate ongoing investigations that district prosecutors would likely want to keep secret, so that document may also be redacted. Chuck Rosenberg, a former federal prosecutor and NBC News legal analyst who once worked with Mueller, said Mueller — a by-the-book former Marine combat leader — likely never considered making public anything to do with ongoing criminal matters. The rule of thumb, he said, is "if it's public it won't be sensitive and if it's sensitive it won't be public." Rosenberg believes Friday's filings will be "mildly interesting," in that they may further describe in general terms how helpful prosecutors believe Cohen to have been, and also what sort of lies they allege Manafort told that blew up his plea deal. But if Manafort's lies were about Trump and Russian election interference, Rosenberg said, "We won't see them."

– Those paying attention to the particulars of the Robert Mueller investigation are keeping an eye on two big court filings Friday, developments that might shed important light on where he's at. In the bigger one, Mueller must explain to a judge why he believes former Trump campaign manager Paul Manafort lied to investigators in violation of his plea deal, reports the Hill. In the other, federal prosecutors in New York will file memos spelling out how former Trump attorney Michael Cohen cooperated with them, reports the AP. Expect lots of redacted material, but on Manafort in particular, "there will be plenty of clues and indicators about where Mueller has gone and will go," says Elie Honig, former assistant US attorney for the Southern District of New York. President Trump, meanwhile, has unleashed a fresh storm of criticism, with five anti-Mueller tweets Friday morning alone. "Will Robert Mueller's big time conflicts of interest be listed at the top of his Republicans only Report," he wrote in one. In that and others, here, here, here, and here, the president makes the case that Mueller and "Leakin' Lyin' James Comey" have unfairly gone after Trump and his allies while letting Hillary Clinton and her allies off the hook. And those tweets follow three from Thursday night on the subject, culminating with, "FAKE NEWS - THE ENEMY OF THE PEOPLE!" Friday's court filings come after Mueller filed a sentencing memo Tuesday in the case of former national security adviser Michael Flynn, notes NBC News. That one had many blacked-out details, but it stated that Flynn provided "substantial assistance" to Mueller's team. Axios, for one, thinks the Mueller "endgame" is near.

one of the striking consequences of the quantum nature of physical systems is the impossibility to discriminate perfectly their states that are non - orthogonal in terms of the scalar product between the corresponding state vectors . this fact has profound implications for secret communication in the form of quantum key distribution protocols , but it also leads to non - trivial effects when transmission of classical information is considered . in optical communication , standard schemes to encode a stream of bits employ a pair of coherent states , e.g. the vacuum state and a coherent state with a non - zero amplitude in the case of on off keying ( ook ) , or two coherent states with equal amplitudes but opposite phases in binary phase shift keying ( bpsk ) . when an energy constraint is imposed in the above schemes , the error rate grows with the decreasing signal power , as the two coherent states encoding the bit value become less and less distinguishable in the quantum mechanical sense . an intriguing strategy to boost throughput in such a case is to employ collective detection of the received signal , which for very weak signals can even qualitatively enhance the scaling of the attainable transmission rate with the mean power . the fundamental reason behind this enhancement is that a quantum measurement provides in general only partial knowledge about the state of the measured system and collective detection of multiple elementary systems can be designed to reveal more relevant information . an elegant scheme to achieve superadditivity for binary phase shift keyed signals has been recently described by guha . the basic idea is to prepare sequences of bpsk symbols that can be mapped using a linear optical circuit onto the pulse position modulation ( ppm ) format . this format can be read out using direct detection . moreover , with the right choice of the sequence length [ 811 ] this strategy approaches in the leading order the capacity of a narrowband bosonic channel for low signal powers . the purpose of the present contribution is to propose an implementation of the linear circuit processing bpsk sequences in a multimode quantum memory interface [ 1315 ] . the proposal is motivated by recent demonstrations of fully controllable linear transformations between atomic spin coherences and optical fields . this approach would be well suited to process sequences transmitted in a single spatial mode and encompassing multiple time bins . the presented scheme points to possible applications of quantum memories not only in quantum information processing , but also in future optical communication systems operated at the quantum limit . first , in section 2 we review the principle of bpsk and the attainable transmission rates in the low power regime . the strategy to achieve superadditivity using sequences of bpsk symbols is summarized in section 3 . the proposal for the quantum memory interface to process bpsk sequences is described in section 4 . for short sequence lengths , we analyze in section 5 possible gains from the application of a minimum - error dolinar receiver at one of the output ports . finally , section 6 concludes the paper . any two coherent states can be mapped via a unitary linear optical transformation onto a pair with the same mean photon number but opposite phases . this transformation can be realized using a beam splitter with transmission approaching one and an auxiliary coherent field . moreover , if both the states are equiprobable such a pair minimizes the mean energy for a fixed separation between the complex amplitudes of the coherent states , characterizing their distinguishability . therefore in the following we will restrict our attention to this special case , commonly known in optical communication under the acronym bpsk . in simple terms , bits are encoded in the sign of the complex amplitude of coherent pulses , prepared with the same mean photon number n=||2 in each use of the channel . for large mean photon numbers n , the two coherent states | and |- describing the pulses are almost orthogonal and the bit value can be read out with a negligible error using e.g. homodyne detection . readout becomes less trivial in the regime of low mean photon numbers , when n1 , as the quantum mechanical scalar product between the two coherent states used for communication is then substantially nonzero , ||-|=e-2n , and therefore they can not be distinguished with certainty . the usefulness of a communication scheme for classical information transmission can be characterized with mutual information , which describes the strength of correlations between system preparations at the channel input and measurement results at the channel output . importantly , mutual information provides the upper limit on the attainable transmission rate for a given communication scheme . when two equiprobable quantum states are used as preparations and the physical systems transmitted in consecutive channel uses are measured individually , the optimal detection strategy is to apply the minimum - error measurement described by helstrom . from the information theoretic point of view , such a scheme is described by a binary symmetric channel with the error rate given by(1 ) (n)=121 - 1-||-|2=121 - 1-e-4n. in the above expression we explicitly used the two coherent states constituting the bpsk alphabet . for a binary symmetric channel representing individual detection mutual information reads:(2 ) the second approximate expression in equation ( 2 ) results from expanding mutual information up to the linear term in n and is valid in the regime n1 , with the proportionality constant equal to =2/ln22.885 . in the case of two coherent states , the minimum - error measurement has a feasible implementation of the form of the dolinar receiver comprising an auxiliary coherent reference beam , linear optics , photon counting and fast feedback loop to modulate the auxiliary beam . the sender prepares sequences of bpsk symbols with signs defined by rows of a hadamard matrix . at the receiver side , the symbols are interfered using a linear circuit described by a hadamard matrix rescaled by 1/l . this maps the bpsk sequences onto the pulse position format where only one bin contains a pulse carrying the energy of the entire sequence . the position of the pulse identifies unambiguously the received sequence . for general measurement strategies on received systems , including collective detection , an upper bound on mutual information is given by the holevo quantity , which is defined mathematically as the difference between the von neumann entropy s( ) of the average state emerging from the channel and the average entropy of individual output states . in the case of bpsk modulation , because individual states remain pure after transmission , the holevo quantity is equal to the entropy of the statistical mixture of the two coherent states:(3 ) =s12||+12|--|=h12(1-||-|)nlog21n. the last expression , specifying the leading term in the expansion when n1 , shows that compared to individual measurements , collective detection enables a qualitative change in the scaling of attainable information with n. furthermore , the holevo quantity calculated in equation ( 3 ) approaches asymptotically for n0 in the leading order the classical capacity of a single - mode bosonic channel . these results point to substantial benefits of collective detection in the regime of low mean photon number . although general strategies to construct collective measurements approaching the holevo quantity have been given theoretically , the challenge is to design joint detection schemes that could be implemented in practice using viable components . for bpsk modulation , a very elegant scalable scheme for sequence lengths the basic idea , shown schematically in figure 1 , is to select from all 2l combinations of bpsk symbols only l sequences that correspond to rows of a hadamard matrix of dimension l. hadamard matrices are symmetric with binary entries 1 , and their rows ( or equivalently columns ) form mutually orthogonal vectors . collective detection of such hadamard words is facilitated by an observation that rescaling a hadamard matrix by 1/l yields an orthogonal matrix which can be in principle implemented as a linear optical circuit . because of the orthogonality property , each hadamard word fed into the circuit will generate a non - zero pulse only in one output port of the circuit , different for each sequence , while all other ports will remain dark . the above scheme effectively converts hadamard bpsk words into the well known ppm format , in which information is encoded in the position of a single pulse in the total number of l otherwise empty bins . the most obvious strategy to read out the position of the pulse is to employ direct detection . assuming ideal , unit - efficiency photon counting detectors without dark counts , either the position of the pulse is identified unambiguously , or this information is erased if no count is generated for any bin . from the information theoretic perspective such a communication scheme corresponds to the well - known erasure channel , for which mutual information per one bin reads:(4 ) ippm = pllog2l . where p is the probability of detecting the position of the pulse . in our case , because all l bpsk states interfere constructively at one output port of the hadamard circuit producing a pulse with the mean photon number ln , the probability p is given by(5 ) p=1-e - ln. expanding the above expression up to the first order yields pln , which implies that(6 ) ippmnlog2l . therefore in the case of very weak pulses superadditivity is obtained for the minimum sequence length l=8 . it is worth to emphasize that the simple formula in equation ( 6 ) is valid only for ln1 , as for larger mean photon numbers the probability p saturates at one . the exact expression given in equation ( 4 ) has a well defined maximum as a function of l , which can be approximately identified by expanding p up to the second order in ln. mutual information ippm evaluated at this maximum has the expansion in n1 of the form [ 811](7 ) ippmnlog21n-nlog2ln1n. on the other hand , the capacity of a narrowband bosonic channel is given up to the second order as nlog2(1/n)+n/ln2 for low signal powers and it coincides with the holevo quantity for bpsk modulation found in equation ( 3 ) . it is seen that although the leading orders of both expressions are the same , the first order corrections exhibit different behaviour . a quantum memory interface for converting hadamard sequences of bpsk symbols into the ppm format shown schematically for l=8 sequence length . black diagonal bars indicate beamsplitter - type interactions with the phase shift introduced for transmissions in both directions and reflections from upper - right sides . the case when one of the detectors is replaced by the dolinar receiver is discussed in section 5 . in many commonly used optical communication links , e.g. fibres operating at telecom wavelengths , pulse sequences are transmitted in a single spatial mode . in this case , collective measurements described in the preceding section need to be implemented over multiple time bins . this requires synchronization of individual incoming pulses at the receiver while retaining mutual phase relations . one possible solution would be to employ fast optical switches and delay lines to equalize pulse arrival times before the hadamard circuit . an alternative is to use quantum memories to transform coherently the incoming pulses into the ppm format . within this approach the hadamard circuit can be implemented piecewise with the incoming pulses using beamsplitter - type operations between light pulses and quantum memory modes . a natural decomposition of the hadamard circuit in this implementation is the triangular form of a general linear optical transformation discussed by reck et al . . its explicit form is shown schematically in figure 2 in the case of l=8 time bins . ,l , goes through l quantum memory modes , as symbolized by vertical lines in figure 2 . in each memory mode a transformation combining the incoming light with the already stored excitation is driven by suitable control fields . the final lth memory , empty so far , is driven so as to store all incoming light . at the end , detection of the excitations stored in the memories can be achieved for example by mapping their contents back onto light and counting optical photons in the standard manner . using hadamard words constructed from bpsk symbols as described in section 3 , superadditivity in mutual information can be demonstrated for at least l=8 time bins . on the other hand , a very simple hybrid scheme has been proposed for l=2 bins , where two consecutive pulses are interfered on a 50/50 beam splitter with output ports monitored by a dolinar receiver and a photon counting detector . with the right choice of probabilities of input sequences , the relative enhancement in mutual information is nearly 2.5% , which is close to the approximate value 2.8% found numerically by optimizing joint two - system measurements . we will now discuss generalization of the hybrid scheme to more than two pulses . the basic idea is to supplement the set of hadamard words by a sequence -- - . this sequence provides a non - zero pulse at the same output port of the hadamard circuit as + + + , but with the opposite phase . we will assume that this port is monitored by a dolinar receiver , and both sequences are prepared with equal probabilities ( 1-)/2 , where 01 . the hadamard circuit directs them to other output ports , each monitored with a photon counting detector . a click on a photon counting detector unambiguously identifies the input hadamard word . if none of the photon counting detectors clicks , information from the dolinar receiver is used . in this case , sequences + + + and -- - are identified with an error (ln ) , because the mean total photon number in the entire sequence is ln. any other hadamard word generates either measurement result on the dolinar receiver with the same probability 1/2 , i.e. no information is obtained . mutual information for the above communication scheme can be cast in the following form:(8 ) i=1l{(1-)[1-h((ln))]+plog2(l-1)+h(p)-h(p)}. the overall multiplicative factor 1 / l stems from rescaling mutual information per one time bin . within curly brackets , three contributions can be identified . the first one , given by 1-h((ln ) ) is mutual information for a binary symmetric channel with the error rate (ln ) corresponding to a minimum - error measurement on sequences + + + and -- - . this contribution enters with the weight 1- , which is the overall probability of preparing either sequence . the second term , plog2(l-1 ) , specifies mutual information for an ( l-1)-ary erasure channel with the non - erasure probability p. this channel describes situation when any other hadamard sequence is used , which occurs with the overall probability . finally , the combination of the last two terms , h(p)-h(p ) , specifies mutual information for the so - called z channel with a binary set of input symbols , when one symbol used with probability is identified correctly with the probability p , whereas in the remaining 1-p fraction of cases it gives the same result as the second symbol , used with the probability 1-. in optical communication , such a channel describes ook where either a pulse or an empty bin are sent in each channel use , and an ideal photon counting detector without dark counts is used at the output . the ratio i / iind of mutual information per bin for collective detection compared to the optimal individual detection case evaluated in equation ( 2 ) . solid lines depict asymptotic results given in equation ( 6 ) for direct detection ( gray solid line , red online ) and in equation ( 10 ) for hybrid detection ( light gray solid line , orange online ) , with l treated as a continuous parameter . numerical results based on the exact expressions for the error probability in equation ( 1 ) and the count probability in equation ( 5 ) are shown for n=210 - 4 ( filled symbols ) and n=210 - 2 ( empty symbols ) in the case of direct detection ( squares ) and hybrid detection ( circles ) . all sequence lengths l32 for which hadamard matrices exist have been included in the calculations . in our case assuming that p1 we can approximate(9 ) h(p)-h(p)plog21. it is worth noting that the formula on the right hand side is formally equivalent to mutual information for the ppm format with 1/ input words specified in equation ( 4 ) . in order to simplify calculations , in equation ( 8) we will expand up to linear terms in n the expressions for pln and 1-h((ln))ln. after applying these approximations it is easy to find the optimal value of , which taking into account the constraint 01 gives the following asymptotic expression for mutual information in the case of hybrid detection when n1:(10 ) i = n+l-1e2ln2,ifl < e2+1nlog2(l-1),ifle2+1 it is seen that for large l we recover the expression for ( l-1)-ary ppm , as then the optimal strategy is not to use words + + + and -- - at all . in these cases direct detection scheme yields higher mutual information . however , enhancement is possible for short sequence lengths , as shown in figure 3 depicting the ratio i / iind . in the plots , we used two values of the mean photon number : n=210 - 4 when the asymptotic expression given in equation ( 10 ) is hardly distinguishable within the resolution of the graph from numerical results , and n=210 - 2 , which allows us to identify deviations from the asymptotics with the increasing mean photon number . it is seen that for larger n the superadditivity effect diminishes . in the case of direct detection one can notice that mutual information ippm approaches a maximum with the increasing sequence length l , which is simply a result of the saturation of the count probability p defined in equation ( 5 ) . we described theoretically a construction of a collective receiver for bpsk signal based on beam - splitter type transformations between incoming light pulses and quantum memory modes . such a receiver can be used to demonstrate the superadditivity effect in classical communication over a quantum channel , with enhancement most strongly pronounced in the low - power limit . an interesting extension of the presented work may be to go beyond a sequence of time bins and to consider mixed time - frequency encodings within the available spectral bandwidth which could also be handled by architectures based on quantum memories . multimode interference underlying the superadditivity of the presented receiver relies on perfect phase and amplitude matching between interfering pulses . a recent study suggests that the collective bpsk detection scheme based on hadamard words may be robust against moderate levels of phase noise . one should also take into account unequal losses induced by beam splitter operations and finite lifetime of excitations stored in memory modes . the simplest strategy to mitigate this would be to introduce additional attenuation in order to ensure proper contributions from individual input pulses to the output ports of the receiver . in this case , attainable mutual information calculated in equations ( 6 ) and ( 10 ) would need to be multiplied by the overall power transmission coefficient , which diminishes the superadditivity effect .

we propose a simple architecture based on multimode quantum memories for collective readout of classical information keyed using a pair coherent states , exemplified by the well - known binary phase shift keying format . such a configuration enables demonstration of the superadditivity effect in classical communication over quantum channels , where the transmission rate becomes enhanced through joint detection applied to multiple channel uses . the proposed scheme relies on the recently introduced idea to prepare hadamard sequences of input symbols that are mapped by a linear optical transformation onto the pulse position modulation format [ guha , s. phys . rev . lett . 2011 , 106 , 240502 ] . we analyze two versions of readout based on direct detection and an optional dolinar receiver which implements the minimum - error measurement for individual detection of a binary coherent state alphabet .

radio observations measure the total intensity , polarized intensity and rotation measure ( rm ) . sky maps of these quantities are all related to the magnetic fields in our galaxy . because the milky way is the largest edge - on galaxy in the sky , the synchrotron emission from relativistic electrons gyrating in the galactic magnetic field is dominant in the radio sky . the stronger radio emission is observed nearer the galactic plane , and strongest towards the galactic central regions . the galactic radio emission is polarized ( @xcite ) , if it is not depolarized , best shown at tens of ghz ( @xcite ) . the polarized emission undergoes faraday rotation due to the galactic magnetic fields and ionized electrons . the faraday sky , i.e. the rm sky , is strikingly antisymmetric to the galactic coordinate ( @xcite , see fig . [ rmsky ] ) . the magnetic field of our galaxy is more important in astrophysics and astroparticle physics than the fields in other galaxies . magnetic fields are certainly one of key ingredients of the interstellar medium . large - scale magnetic fields contribute to the hydrostatic balance and stability of the interstellar medium ( @xcite ) , and even disk dynamics ( @xcite ) . magnetic fields in molecular clouds , which are closely related to the galactic fields ( @xcite ) , play an important role in the star formation process ( see a review by @xcite ) . more important is that the magnetic fields of our galaxy are the main agent for transport of charged cosmic - rays ( e.g. @xcite ) . it is impossible to understand the origin and propagation of cosmic rays without adequate knowledge of galactic magnetic fields . the galactic radio emission and its polarization , which result from the galactic magnetic fields , is found to heavily ( up to 95% in polarization ) `` pollute '' the measurements of the cosmological microwave background ( cmb , e.g. @xcite ) . galactic magnetic fields have suddenly become very important in the cmb studies of cosmology ! to understand magnetic fields , we have first to measure them and learn their properties . the galactic scale is in the middle between the stellar scale and the cosmological scale . it is on this scale that the magnetic fields can be well _ measured _ at present , at least from our galaxy . observations of galactic - scale magnetic fields provide the most important hints for and constraints on the origin and maintenance of the magnetic fields of galactic objects and the fields in the universe . in the following , i will review the observed magnetic structures in the galactic disk , the galactic center and the galactic halo . magnetic fields pervade the diffuse interstellar medium , molecular clouds , and very dense cloud cores or hii regions . when interstellar gas contracts to form a cloud or a cloud core the field is enhanced . therefore , the observed field strength in clouds increases with gas density ( @xcite ) . here , i review the observational results of large - scale magnetic fields in the galactic disk which are related to the diffuse medium and spiral structure and have a scale greater than 1 kpc . magnetic fields on smaller scales will be mentioned only if they are related to the large - scale fields . there are five observational tracers of the galactic magnetic fields : polarization of starlight , polarized thermal dust emission from clouds , zeeman splitting of lines , diffuse synchrotron radio emission , and faraday rotation of polarized sources . * polarization of starlight * starlight becomes polarized when it passes through the interstellar medium and is absorbed or scattered by interstellar dust grains preferentially aligned by magnetic fields . the observed polarization is the integrated effect of scattering between the star and the sun , and the `` polarization vectors '' show the averaged field orientation ( weighted by the unknown local dust content ) . starlight polarization data have been obtained for about 10,000 stars , mostly within 2 or 3 kpc of the sun ( see @xcite ) . analysis of these data show that the local field is parallel to the galactic plane and follows the local spiral arms ( @xcite ) . starlight polarization data are difficult to use for detection of galactic magnetic fields in a much larger region than 2 or 3 kpc . however , recent developments in instruments help to get a lot of new starlight polarization data for revealing magnetic fields in given objects ( e.g. @xcite ) . * polarized thermal dust emission from clouds * in recent years , with development of instruments and backend technology ( e.g. @xcite ) , observations of polarized thermal dust emission at mm , sub - mm and infrared bands have been used to detect the transverse orientation of magnetic fields in molecular clouds ( see review by @xcite ) on scales from 1 pc to tens of pc . the observed magnetic fields always have an hourglass shape , which indicates that the fields were enhanced when the clouds were formed by compressing the diffuse interstellar medium . recently , li et al . ( 2006 ) found that magnetic fields in molecular clouds seem to be preferentially parallel to the galactic plane , indicating that the magnetic fields in the clouds preserve the fields frozen into the diffuse medium . * zeeman splitting of lines * zeeman splitting of spectral lines can measure _ in situ _ field strength of the line - of - sight component in molecular clouds or maser spots with a scale size @xmath1 au . to date , zeeman splitting of emission or absorption lines has been detected from about 20 clouds ( see a list in @xcite ) and in oh masers associated with 140 hii or star - formation regions using single dishes ( e.g. @xcite ) or interferometers ( e.g. @xcite ) . from collected zeeman splitting data of oh masers of hii regions and oh or hi absorption or emission lines of molecular clouds themselves , han & zhang ( 2007 ) found large - scale reversals in the sign of the line - of - sight component of the median field , indicating field reversals in a pattern similar to reversals revealed from pulsar rm data ( see below ) . evidently , magnetic fields on such a small scale are related to the large - scale galactic magnetic fields to a very surprising extent ( @xcite ) . interstellar magnetic fields are apparently preserved as fossil fields through the cloud formation and star formation process , and even in stars ( see g. wade s talk in this volume ) . how can such coherent magnetic field directions be preserved from the low density medium ( @xmath2 ) to higher density clouds ( @xmath3 ) , even to the highest density in maser regions ( @xmath4 ) , with compression of 3 or even 10 orders of magnitude ? it is a puzzle . the turbulent and violent processes in molecular clouds apparently can not significantly alter the mean magnetic field . * diffuse synchrotron radio emission * the total and polarized intensities of synchrotron emission are usually used to estimate the total and _ ordered _ field strength . for nearby galaxies , the strength of the _ regular _ large - scale field is probably much overestimated from the polarization percentage , because the so - called _ ordered _ fields consist of the regular large - scale fields and anisotropic random fields ( @xcite ) which both produce polarized emission . we can not have a face - on view of the global magnetic field structure in our galaxy through polarized synchrotron emission , as is possible for nearby spiral galaxies ( see r. beck s talk in this volume ) . polarization surveys of the galactic plane have been comprehensively reviewed by reich ( 2007 ) . the observed polarized emission from the galactic plane is the sum of all contributions with different polarization properties ( i.e. polarization angles and polarization percentages ) coming from various regions at different distances along a line of sight . emission from more distant regions suffers from more faraday effect produced by the foreground interstellar medium . polarized emissions from different regions should `` depolarize '' each other when they are summed , which is more obvious at lower frequencies . observations at higher frequencies ( e.g. at 6 cm by @xcite ) show polarized structures at larger distances because depolarization is less severe . the polarized structures are closely related to the magnetic field structure where the emission is generated . some large - angular - scale polarized features are seen emerging from the galactic disk , for example , the north polar spur ( e.g. @xcite ) . * faraday rotation of pulsars and radio sources * faraday rotation of linearly polarized radiation from pulsars and extragalactic radio sources ( egrs ) is the most powerful probe of the diffuse magnetic field in the galaxy ( e.g. @xcite ) . magnetic fields in a large part of the galactic disk have been revealed by rm data of pulsars , which gives a measure of the line - of - sight component of the field . egrs have the advantage of large numbers but pulsars have the advantage of being spread through the galaxy at approximately known distances , allowing direct three - dimensional mapping of the magnetic fields . for a pulsar at distance @xmath5 ( in pc ) , the rm ( in radians m@xmath6 ) is given by @xmath7 where @xmath8 is the electron density in @xmath9 , @xmath10 is the vector magnetic field in @xmath0 g and @xmath11 is an elemental vector along the line of sight toward us ( positive rms correspond to fields directed toward us ) in pc . with the pulsar dispersion measure , @xmath12 we obtain a direct estimate of the field strength weighted by the local free electron density @xmath13 where rm and dm are in their usual units of rad m@xmath6 and @xmath9 pc and @xmath14 is in @xmath0 g . previous analyses of pulsar rm data have often used the model - fitting method ( @xcite ) , i.e. , to model magnetic field structures in all of the paths from the pulsars to us ( observer ) and fit them , together with the electron density model , to the observed rm data . _ significant improvement _ can be obtained when both rm and dm data are available for many pulsars in a given region with similar lines of sight . measuring the gradient of rm with distance or dm is the most powerful method of determining both the direction and magnitude of the large - scale field local to that particular region of the galaxy ( @xcite ) . field strengths in the region can be _ directly derived _ from the slope of trends in plots of rm versus dm . based on eq . ( [ eq - b ] ) , we get @xmath15 where @xmath16 is the mean line - of - sight field component in @xmath0 g for the region between distances @xmath17 and @xmath18 , @xmath19 and @xmath20 . field structure : * so far , rms of 1021 pulsars have been observed ( @xcite ) , if new rms of 477 pulsars by han , van straten , manchester & demorest ( 2009 , in preparation ) are included ( see fig . [ rm_psr_egr ] ) . this enables us to investigate the structure of the galactic magnetic field over a larger region than that previously possible . we have detected counterclockwise magnetic fields in the innermost arm , the norma arm ( @xcite ) . a more complete analysis for the fields of our galaxy ( @xcite and han et al . 2009 , in preparation ) from both rms of pulsars and egrs gives a picture for the coherent large - scale fields aligned with the spiral - arm structure , as shown in fig.1 : magnetic fields in all inner spiral arms are counterclockwise when viewed from the north galactic pole . on the other hand , at least in the local region and in the inner galaxy in the fourth quadrant , there is good evidence that the fields in interarm regions are similarly coherent , but reversed to be clockwise . there are at least four or five reversals in the fourth quadrant , probably occurring near the boundary of the spiral arms . in the galactic central region interior to the norma arm , new rm data of pulsars indicate that the fields are clockwise , reversed again from the counterclockwise field in the norma arm . in the first galactic quadrant , because the separations between spiral arms are so small , the rm data are dominated by counterclockwise fields in the arm regions though some ( not many ) negative pulsar rms indicate clockwise fields in the interarm regions . the magnetic field in the perseus arm can not be determined well . the averaged rm of egrs in a given sky region reflect the common foreground galactic rm contribution , which is the integration of @xmath21 from the sun to the outskirts of the galactic disk . comparison of the mean of rms of background egrs with rms of foreground pulsars can reveal the magnetic fields behind the pulsars ( see fig . [ rm_psr_egr ] ) . however , the dominant contribution of rms of egrs behind the galactic disk comes from the interstellar medium mostly in tangential regions . the fluctuations in the rm distribution of extragalactic radio sources ( @xcite ) with galactic longitude , especially these of the fourth galactic quadrant , are consistent with magnetic field directions derived from pulsar data ( see fig . 1 ) . the negative rms of egrs in the 2nd quadrant suggest that the interarm fields both between the sagittarius and perseus arms and beyond the perseus arm are predominantly clockwise . , width=234 ] fitting various models to the new rm dataset shows different results ( e.g. @xcite ) . the most important is to have a model consistent with the detected field reversals . looking at table 2 of men et al . ( 2008 ) , one can see that any single - mode model is not enough to fit rm data though the bisymmetrical spiral model with field reversals is the best and gives the smallest @xmath22 . field strength : * with much more pulsar rm data , for the first time , han et al . ( 2006 ) were able to _ measure _ the regular azimuthal field strength of near the tangential regions in the 1st and 4th galactic quadrants , and then plot the dependence of regular field strength as a function of galactocentric radius ( fig . [ br ] ) . although the `` uncertainties '' , which in fact reflect the random fields , are large , the tendency is clear that fields get stronger at smaller galactocentric radius and weaker in interarm regions . to parameterize the radial variation , an exponential function was chosen to give the smallest @xmath22 value and to avoid a singularity at @xmath23 ( for @xmath24 ) and unphysical values at large r ( for the linear gradient ) . that is , @xmath25 , $ ] with the strength of the large - scale field at the sun , @xmath26 @xmath0 g , and the scale radius @xmath27 kpc . in addition , the vertical field in the solar vicinity @xmath28 is estimated to be @xmath29 g ( @xcite ) . using rms of egrs , simard - normandin & kronberg ( 1980 ) and han & qiao ( 1994 ) estimated the scale - height of galactic magnetoionic disk about 1.4 kpc . * field statistics on small scales and spatial b - energy spectrum : * magnetic fields in our galaxy exist on all scales . for the large - scale field , we can determine the field structure and field strength . to study small - scale magnetic fields , the only approach is to make statistics and have a description of their statistical properties . pulsar rms have been used to study the small - scale random magnetic fields in the galaxy . some pairs of pulsars close in sky position have similar dms but very different rms , indicating an irregular field structure on scales of about 100 pc ( @xcite ) . some of these irregularities may result from hii regions in the line of sight to a pulsar ( @xcite ) . it has been found from pulsar rms that the random field has a strength of @xmath30 g independent of cell - size in the scale range of 10 100 pc ( @xcite , @xcite ) . from pulsar rms in a very large region of the galactic disk , han et al . ( 2004 ) obtained a power law distribution for magnetic field fluctuations of @xmath31 at scales from @xmath32 0.5 kpc to 15 kpc , with @xmath33 , corresponding to an rms field of @xmath34 g in the scale range . some results of magnetic field statistics were also obtained from rms of egrs . armstrong et al . ( 1995 ) showed that the spatial power spectrum of electron density fluctuations from small scales up to a few pc could be approximated by a single power law with a 3d spectral index @xmath353.7 , very close to the kolmogorov spectrum . magnetic fields on such small scales should follow the same power - law , since magnetic fields are frozen into the ionized interstellar medium . minter & spangler ( 1996 ) found that structure functions of rotation measure and emission measure were consistent with a 3d - turbulence kolmogorov spectrum of magnetic fields up to 4 pc , but with a 2d turbulence between 4 pc and 80 pc . haverkorn et al . ( 2006 ) found that the structure functions of rms in the directions tangential to the arms have much larger slopes than those in the interarm directions , indicating that the arm regions are more turbulent . sun & han ( 2004 ) found that the structure function for rms at the two galactic poles is flat , but at lower latitudes it becomes inclined with different slopes at different galactic longitudes . combining the above information , one can get the spatial energy spectrum of galactic magnetic fields ( see @xcite ) which should constrain the theoretical simulations ( e.g. @xcite ) of the generation and maintenance of galactic magnetic fields . evidently , on small scales , the distribution follows the kolmogorov power - law spectrum , but at larger scales , it becomes flat and probably has two breaks at a scale of few pc and several tens of pc ( fig . the interstellar magnetic fields probably become strongest at the scales of energy injection by supernova explosions and stellar winds ( e.g. 1 to 10 pc ) . 90 cm data from @xcite ) and the polarized thermal dust emission detected in the molecular cloud zone ( bars in the right panel , see details in @xcite ) . [ gc],width=510 ] within a few hundred pc of the galactic center , both poloidal and toroidal magnetic fields have been observed . the non - thermal radio filaments ( fig . [ gc ] ) discovered within @xmath36 from the galactic center ( @xcite , @xcite , @xcite , @xcite , @xcite ) indicate poloidal magnetic fields in the region within a few hundred parsecs of the center of the galaxy . these filaments are highly polarized ( @xcite ) and almost perpendicular to the galactic plane , although some newly found examples are not so perpendicular to the galactic plane ( @xcite ) . rm studies show that the magnetic field is aligned along the filaments ( @xcite ) . the filaments are probably illuminated flux tubes , with a field strength of about 1 mg ( @xcite ) . larosa et al . ( 2005 ) detected diffuse radio emission of extent 400 pc and on this basis argued for a weak pervasive field of tens of @xmath0 g in the central region . however , this is the volume - averaged field strength in such a large region . the poloidal fields are possibly limited to a smaller central region . the newly discovered `` double helix '' nebula ( @xcite ) , with an estimated field strength of order 100 @xmath0 g , reinforces the presence of strong poloidal magnetic fields in tube format merging from the rotating circumnuclear gas disk near the galactic center . polarized thermal dust emission has been detected in the molecular cloud zone at sub - mm wavelength ( see fig . [ gc ] , @xcite ) , which is probably related to the toroidal fields parallel to the galactic plane and complements the poloidal fields shown by the vertical filaments . the observed molecular cloud zone has a size of a few hundred pc , and is possibly a ring - like cloud outside the central region with poloidal field ( see fig.1 of @xcite ) . the sub - mm polarization observations of the cloud zone offer information only about the field orientations . zeeman splitting measurements of hi absorption against sgr a ( e.g. @xcite ) or of the oh maser in the sgr a region ( @xcite ) give a line - of - sight field strength of a few mg in the clouds . it is possible that toroidal fields in the clouds are sheared from the poloidal fields , so that the rm distribution of radio sources in this very central region could be antisymmetric ( @xcite ) . outside the central region of a few hundred pc to a few kpc , the structure in the stellar and gas distributions and the magnetic structure are all mysterious . there probably is a bar . the large - scale magnetic fields should be closely related to the material structure but have not been revealed yet . the large positive rms of background radio sources within @xmath37 of the galactic center ( @xcite ) are probably related to magnetic fields following the bar ( @xcite ) . comparison of the rms of these background radio sources with rms of foreground pulsars ( see fig . [ rm_psr_egr ] ) should be helpful in delineating the field structure . , width=170 ] , width=170 ] magnetic field structure in the galactic halo can be revealed from rms of egrs if allowance can be made for sources with outstanding intrinsic rms . the foreground galactic rm is the common contribution to the observed rms of all egrs within a small patch of sky . after `` anomalous '' rms are eliminated , the pattern for the galactic rm can be obtained . han et al . ( 1997 ) discarded any source if its rm deviated from the average rm of neighbouring sources by more than 3@xmath38 , and obtained a `` cleaned '' rm sky . a striking antisymmetry in the inner galaxy with respect to galactic coordinates ( see fig . [ rmsky ] ) has been identified from the cleaned rm sky ( @xcite ) . the antisymmetry must result from azimuthal magnetic fields in the galactic halo with reversed field directions below and above the galactic plane . such a field can be produced by an ` a0 ' dynamo mode . the observed filaments near the galactic center should result from the dipole field in this dynamo scenario . the local vertical field component @xmath39 g ( @xcite ) may be a part of this dipole field in the solar vicinity . han ( 2004 ) has shown that the rm amplitudes of extragalactic radio sources in the mid - latitudes of the inner galaxy are systematically larger than those of pulsars , indicating that the antisymmetric magnetic fields are not local but are extended towards the galactic center , far beyond the pulsars . model - fitting by sun et al . ( 2008 ) has confirmed this conclusion . the antisymmetry has been shown more clearly after adding newly observed rms of more mid- or high latitude egrs . only after the magnetic field , @xmath40 , is known at all positions in our galaxy will we have a complete picture of the magnetic structure of the milky way . with only a small number of measurements we must rely on fitting models to the data . `` partial '' measurements in a greater number of regions , including quite large regions , are now available and we are able to `` connect '' the available measurements ( pulsar rms , maps of the rm sky ) and outline some basic features of the galactic magnetic field . however , as seen from the above observational review , many regions of our galaxy have not been observed very well for magnetic fields . for example , the farther half of the galactic disk and the rm sky are not well known . data in these regions are still scarce , either because of lack of field probes or limited capability of current instruments . in addition , when we try to get the large - scale field structure , the small - scale `` random '' fields , which are equally strong or even stronger , `` interfere '' with our measurements to a large extent . in the first galactic quadrant , we obtained a large sample of pulsar rms recently for the galactic magnetic fields , but the spiral structure and pulsar distances are very uncertain . statistical properties of fields on the energy - injection scales are not yet available , but are crucial for theoretical studies of magnetic field origin and maintenance . magnetic fields in the disk - halo interface regions are certainly complex but few observations are available . to fully observe and understand the galactic magnetic fields , there is a long way to go . thanks to drs . tom landecker and a. nelson for reading the manuscript . i am very grateful to colleagues who have collaborated with me for a long time on work on galactic magnetic fields : dr . manchester from the australia telescope national facility , csiro , prof . qiao from peking university ( china ) , dr . willem van straten from swinburne university ( au ) . the author is supported by the national natural science foundation ( nnsf ) of china ( 10521001 , 10773016 and 10833003 ) and the national key basic research science foundation of china ( 2007cb815403 ) . han : * hard . from pulsar rms , we can determine the field strength up to @xmath41 kpc . for the outer galaxy , the rms of extragalactic radio sources have to be fitted with a model of @xmath42 and a model of @xmath8 . given the many uncertainties in these models for the outer disk , it is really hard to determine the field strength . nevertheless , from the determined variation of the field strength with the galactocentric radius , you can extrapolate the field strength to the outer galaxy . han : * for this purpose , one needs to map the polarization in a large field - of - view around the galactic center . at present , the available good maps with a field - of - view of 1 or 2 degrees were made with the vla , and show the non - thermal filaments indicating the poloidal fields . it is impossible to restore the absolute level of @xmath43 and @xmath44 in these maps . therefore we can not map it now even if there may be such an x - shaped field structure . it is possible that the double helix nebula seen by morris et al . ( 2006 ) and the filaments observed in the galactic center region are somehow the foot or leg part of such a structure . * t. landecker : * i am concerned that the interpretation of rms of pulsar and extragalactic radio sources is heavily dependent on the models of electron density distribution of taylor & cordes ( 1993 ) or cordes & lazio ( 2002 ) . these models incorporate implicitly a spiral pattern for the galaxy , going back to the work of georgelin & georgelin ( 1976 ) whose basic assumption is that there is a neat spiral pattern in the structure of the milky way . please comment . han : * you are right on the electron density model . for interpretation for pulsar rms , we work on the rm variations against not only the pulsar distances but also the observed dm . considering that the relative positions of pulsars are more closely related to the dm rather than the electron density model , we believe that the magnetic structure derived from pulsar rms and dms are less model - dependent . for interpretation for rms of extragalactic radio sources , yes , it is very heavily dependent on the electron density model and non `` dm '' to use . from all observations available , evidence for spiral arms is so strong , therefore it is a correct idea to incorporate the spiral structure into any electron density model . now , the spiral arms in the fourth galactic quadrant have been better determined , while in the first quadrant , it is much less clear . also , the electron density within a few kpc from the galactic center is not clear at all . the electron density model and hence the pulsar distances therefore have a large uncertainty in these regions . future electron density models will be probably improved there .

the magnetic structure in the galactic disk , the galactic center and the galactic halo can be delineated more clearly than ever before . in the galactic disk , the magnetic structure has been revealed by starlight polarization within 2 or 3 kpc of the solar vicinity , by the distribution of the zeeman splitting of oh masers in two or three nearby spiral arms , and by pulsar dispersion measures and rotation measures in nearly half of the disk . the polarized thermal dust emission of clouds at infrared , mm and submm wavelengths and the diffuse synchrotron emission are also related to the large - scale magnetic field in the disk . the rotation measures of extragalactic radio sources at low galactic latitudes can be modeled by electron distributions and large - scale magnetic fields . the statistical properties of the magnetized interstellar medium at various scales have been studied using rotation measure data and polarization data . in the galactic center , the non - thermal filaments indicate poloidal fields . there is no consensus on the field strength , maybe mg , maybe tens of @xmath0 g . the polarized dust emission and much enhanced rotation measures of background radio sources are probably related to toroidal fields . in the galactic halo , the antisymmetric rm sky reveals large - scale toroidal fields with reversed directions above and below the galactic plane . magnetic fields from all parts of our galaxy are connected to form a global field structure . more observations are needed to explore the untouched regions and delineate how fields in different parts are connected .

SECTION 1. SHORT TITLE. This Act may be cited as the ``FHA-Insured Hospital Conversion and Reinvestment Act of 2001''. SEC. 2. GRANTS FOR FHA-INSURED HOSPITALS. Section 242 of the National Housing Act (12 U.S.C. 1715z-7) is amended by adding at the end the following: ``(i) Grants for FHA-Insured Hospitals.-- ``(1) Authority and use.--To the extent that amounts for use under this subsection are made available pursuant to section 519(g), the Secretary may make grants to eligible FHA- insured hospitals for use only for purposes that the Secretary determines will reduce the risk of default and loss on mortgages for those hospitals, which purposes shall include-- ``(A) carrying out activities to convert the excess capacity of an eligible FHA-insured hospital to facilities that provide health care and supportive housing for elderly persons and families, including assisted living facilities, nursing homes, and supportive housing for the elderly; and ``(B) assisting in paying debt service for an eligible FHA-insured hospital, including service on debt insured under this section. ``(2) Treatment of mortgage insurance.-- ``(A) In general.--Notwithstanding any provision of this section or of any contract for mortgage insurance provided pursuant to this section, an eligible FHA- insured hospital (or a portion of an eligible FHA- insured hospital) may be converted in accordance with paragraph (1)(A), using grant amounts under this subsection. ``(B) Continuing coverage.--The Secretary shall provide for the uninterrupted continuation of the mortgage insurance coverage for a hospital that is converted in accordance with paragraph (1)(A), for the duration of the original term of the mortgage insurance contract. ``(3) Definitions.--As used in this subsection: ``(A) Assisted living facility; nursing home.--The terms `assisted living facility' and `nursing home' have the same meanings as in section 232 (12 U.S.C. 1715w). ``(B) Elderly person.--The term `elderly person' has the same meaning as in section 202(k) of the Housing Act of 1959 (12 U.S.C. 1701q(k)). ``(C) Eligible fha-insured hospitals.--The term `eligible FHA-insured hospital' means a hospital that-- ``(i) is subject to a mortgage that is insured under this section; ``(ii) would, in the determination of the Secretary, after consultation with the Secretary of Health and Human Services, improve its financial soundness as a result of the proposed activities or costs to be funded with grant amounts under this subsection; and ``(iii) has submitted an application to the Secretary for a grant under this subsection, in accordance with such requirements as the Secretary shall establish. ``(D) Supportive housing for the elderly.--The term `supportive housing for the elderly' has the same meaning as in section 202(k) of the Housing Act of 1959 (12 U.S.C. 1701q(k)). ``(4) Funding.--In addition to any amounts made available under section 519(g), there are authorized to be appropriated for grants under this subsection, such sums as may be necessary for each of fiscal years 2002 through 2006.''. SEC. 3. FUNDING OF GRANTS FROM SURPLUS AMOUNTS IN FHA INSURANCE FUNDS. (a) General Insurance Fund Surplus.--Section 519 of the National Housing Act (12 U.S.C. 1735c) is amended by adding at the end the following: ``(g) Availability of Surplus Amounts for Grants for FHA-Insured Hospitals.-- ``(1) In general.--The amount of any negative credit subsidy that is determined for any fiscal year for purposes of title V of the Congressional Budget Act of 1974 (2 U.S.C. 661 et seq.), and is attributable to the programs referred to in paragraph (2) shall be considered to be new budget authority and shall be available, without fiscal year limitation, for grants under section 242(i). ``(2) Covered programs.--The programs referred to in this paragraph are the programs under this Act for insurance of mortgages and loans that are classified under budget account number 86-0200-0-1-371 and are referred to as `FHA Full Insurance for Health Care Facilities (plus 241/232)', `Health Care Refinances', and `Hospitals' on page 515 of the Appendix to the Budget of the United States Government, Fiscal Year 2001 (H. Doc. 106-162, Vol. II), in the table entitled `Summary of Loan Levels, Subsidy Budget Authority and Outlays by Program'.''. SEC. 4. REGULATIONS. Not later than 120 days after the date of enactment of this Act, pursuant to the authority in section 211 of the National Housing Act (12 U.S.C. 1715b), the Secretary shall issue such rules and regulations as may be necessary to carry out the amendments made by this Act.

FHA-Insured Hospital Conversion and Reinvestment Act of 2001 - Amends the National Housing Act to authorize the Secretary of Housing and Urban Development to make grants to eligible FHA-insured hospitals for use only for purposes that the Secretary determines will reduce the risk of default and loss on mortgages for those hospitals. Includes among such purposes: (1) carrying out activities to convert the excess capacity of an eligible FHA-insured hospital to facilities that provide health care and supportive housing for elderly persons and families, including assisted living facilities, nursing homes, and supportive housing for the elderly; and (2) assisting in paying debt service for an eligible FHA-insured hospital, including service on debt insured under this Act.Authorizes such hospital conversions, and requires the Secretary to provide for uninterrupted continuation of a converted hospital's mortgage insurance coverage for the duration of the original term of the mortgage insurance contract.Makes available to fund conversion grants any negative credit subsidies (surplus amounts) attributable to FHA programs for full insurance for health care facilities.

SECTION 1. SHORT TITLE. This Act may be cited as the ``American Missile Protection Act of 1998''. SEC. 2. FINDINGS. Congress makes the following findings: (1) The threat of weapons of mass destruction delivered by long-range ballistic missiles is among the most serious security issues facing the United States. (A) In a 1994 Executive Order, President Clinton certified, that ``I ... find that the proliferation of nuclear, biological, and chemical weapons (`weapons of mass destruction') and the means of delivering such weapons, constitute an unusual and extraordinary threat to the national security, foreign policy, and economy of the United States, and hereby declare a national emergency to deal with that threat.'' This state of emergency was reaffirmed in 1995, 1996, and 1997. (B) In 1994 the President stated, that ``there is nothing more important to our security and the world's stability than preventing the spread of nuclear weapons and ballistic missiles''. (C) Several countries hostile to the United States have been particularly determined to acquire missiles and weapons of mass destruction. President Clinton observed in January of 1998, for example, that ``Saddam Hussein has spent the better part of this decade, and much of his nation's wealth, not on providing for the Iraqi people, but on developing nuclear, chemical and biological weapons and the missiles to deliver them''. (D) In 1996, the Senate affirmed that, ``it is in the supreme interest of the United States to defend itself from the threat of limited ballistic missile attack, whatever the source.'' (2) The long-range ballistic missile threat to the United States is increasing. (A) Several adversaries of the United States have stated their intention to acquire intercontinental ballistic missiles capable of attacking the United States. (i) Libyan leader Muammar Qaddafi has stated, ``If they know that you have a deterrent force capable of hitting the United States, they would not be able to hit you. If we had possessed a deterrent--missiles that could reach New York--we would have hit it at the same moment. Consequently, we should build this force so that they and others will no longer think about an attack.'' (ii) Abu Abbas, the head of the Palestine Liberation Front, has stated, ``I would love to be able to reach the American shore, but this is very difficult. Someday an Arab country will have ballistic missiles. Someday an Arab country will have a nuclear bomb. It is better for the United States and for Israel to reach peace with the Palestinians before that day.'' (iii) Saddam Hussein has stated, ``Our missiles cannot reach Washington. If we could reach Washington, we would strike if the need arose.'' (iv) Iranian actions speak for themselves. Iran's aggressive pursuit of medium-range ballistic missiles capable of striking Central Europe--aided by the continuing collaboration of outside agents--demonstrates Tehran's intent to acquire ballistic missiles of ever- increasing range. (B) Over 30 non-NATO countries possess ballistic missiles, with at least 10 of those countries developing over 20 new types of ballistic missiles. (C) From the end of World War II until 1980, ballistic missiles were used in one conflict. Since 1980, thousands of ballistic missiles have been fired in at least six different conflicts. (D) The clear trend among countries hostile to the United States is toward having ballistic missiles of greater range. (i) North Korea first acquired 300- kilometer range Scud Bs, then developed and deployed 500-kilometer range Scud Cs, is currently deploying the 1000-kilometer range No-Dong, and is developing the 2000-kilometer range Taepo-Dong 1 and 6000-kilometer range Taepo-Dong 2, which would be capable of striking Alaska and Hawaii. (ii) Iran acquired 150-kilometer range CSS- 8s, progressed through the Scud B and Scud C, and is developing the 1300-kilometer range Shahab-3 and 2000-kilometer range Shahab-4, which would allow Iran to strike Central Europe. (iii) Iraq, in a two-year crash program, produced a new missile, the Al-Hussein, with twice the range of its Scud Bs. (iv) Experience gained from extending the range of short- and medium-range ballistic missiles facilitates the development of intercontinental ballistic missiles. (E) The technical information, hardware, and other resources necessary to build ballistic missiles are increasingly available and accessible worldwide. (i) Due to advances in information technology, a vast amount of technical information relating to ballistic missile design, much of it formerly classified, has become widely available and is increasingly accessible through the Internet and other distribution avenues. (ii) Components, tools, and materials to support ballistic missile development are increasingly available in the commercial aerospace industry. (iii) Increasing demand for satellite-based telecommunications is adding to the demand for commercial Space Launch Vehicles, which employ technology that is essentially identical to that of intercontinental ballistic missiles. As this increasing demand is met, the technology and expertise associated with space launch vehicles also proliferate. (F) Russia and China have provided significant technical assistance to rogue nation ballistic missile programs, accelerating the pace of those efforts. In June of 1997, the Director of Central Intelligence, reporting to Congress on weapons of mass destruction- related equipment, materials, and technology, stated that ``China and Russia continued to be the primary suppliers, and are key to any future efforts to stem the flow of dual-use goods and modern weapons to countries of concern.'' (G) Russia and China continue to engage in missile proliferation. (i) Despite numerous Russian assurances not to assist Iran with its ballistic missile program, the Deputy Assistant Secretary of State for Nonproliferation testified to the Senate, that ``the problem is this: there is a disconnect between those reassurances, which we welcome, and what we believe is actually occurring.'' (ii) Regarding China's actions to demonstrate the sincerity of its commitment to nonproliferation, the Director of Central Intelligence testified to the Senate on January 28, 1998, that, ``the jury is still out on whether the recent changes are broad enough in scope and whether they will hold over the longer term. As such, Chinese activities in this area will require continued close watching.'' (H) The inability of the United States to defend itself against weapons of mass destruction delivered by long-range ballistic missile provides additional incentive for hostile nations to develop long-range ballistic missiles with which to threaten the United States. Missiles are widely viewed as valuable tools for deterring and coercing a vulnerable United States. (3) The ability of the United States to anticipate future ballistic missile threats is questionable. (A) The Intelligence Community has failed to anticipate many past technical innovations (for example, Iraq's extended-range Al-Hussein missiles and its development of a space launch vehicle) and outside assistance enables rogue states to surmount traditional technological obstacles to obtaining or developing ballistic missiles of increasing range. (B) In June of 1997, the Director of Central Intelligence reported to Congress that ``many Third World countries--with Iran being the most prominent example--are responding to Western counter- proliferation efforts by relying more on legitimate commercial firms as procurement fronts and by developing more convoluted procurement networks.'' (C) In June of 1997, the Director of Central Intelligence stated to Congress that ``gaps and uncertainties preclude a good projection of exactly when `rest of the world' countries will deploy ICBMs.'' (D) In 1997, the Director of Central Intelligence testified that Iran would have a medium-range missile by 2007. One year later the Director stated, ``since I testified, Iran's success in getting technology and materials from Russian companies, combined with recent indigenous Iranian advances, means that it could have a medium-range missile much sooner than I assessed last year.'' Department of State officials have testified that Iran could be prepared to deploy such a missile as early as late 1998, nine years earlier than had been predicted one year before by the Director of Central Intelligence. (4) The failure to prepare adequately for long-range ballistic missile threats could have severe national security and foreign policy consequences for the United States. (A) An attack on the United States by a ballistic missile equipped with a weapon of mass destruction could inflict catastrophic death or injury to citizens of the United States and severe damage to their property. (B) A rogue state's ability to threaten the United States with an intercontinental ballistic missile may constrain the United States' options in dealing with regional threats to its interests, deter the United States from taking appropriate action, or prompt allies to question United States security guarantees, thereby weakening alliances of the United States and the United States' world leadership position. (5) The United States must be prepared for rogue nations acquiring long-range ballistic missiles armed with weapons of mass destruction. (A) In its resolution of ratification for the START II Treaty, the United States Senate declared that ``because deterrence may be inadequate to protect the United States against long-range ballistic missile threats, missile defenses are a necessary part of new deterrent strategies.'' (B) In September of 1994, Secretary of Defense Perry stated that in the post-Cold War era, ``we now have opportunity to create a new relationship based not on MAD, not on Mutual Assured Destruction, but rather on another acronym, MAS, or Mutual Assured Safety.'' (C) On February 12, 1997, the Under Secretary of Defense for Policy testified to the Senate that ``I and the administration are quite willing to acknowledge that if we saw a rogue state, a potential proliferant, beginning to develop a long-range ICBM capable of reaching the United States, we would have to give very, very serious attention to deploying a limited national missile defense.'' (6) The United States has no defense deployed against weapons of mass destruction delivered by long-range ballistic missiles and no policy to deploy such a national missile defense system. SEC. 3. NATIONAL MISSILE DEFENSE POLICY. It is the policy of the United States to deploy as soon as is technologically possible an effective National Missile Defense system capable of defending the territory of the United States against limited ballistic missile attack (whether accidental, unauthorized, or deliberate).

American Missile Protection Act of 1998 - States as U.S. policy to deploy as soon as technologically possible an effective National Missile Defense system capable of defending U.S. territory against limited ballistic missile attack (whether accidental, unauthorized, or deliberate).

This morning was “Jobs Friday,” that ever-so-brief moment when the interests of Wall Street, Washington and Main Street are all aligned on one thing: jobs. And this one’s an even bigger deal that usual. Here at MoneyBeat HQ, we crunched the data, tracked the markets and compiled the commentary in real time. Here’s how it all went down. ||||| WASHINGTON (AP) — The unemployment rate tumbled to a seven-year low in August as employers added a modest 173,000 jobs, complicating the U.S. Federal Reserve's decision whether to raise rates in two weeks. The Labor Department says the unemployment rate fell to 5.1 percent from 5.3 percent, the lowest since April 2008. Hiring in August was the weakest in five months, but the government revised up the June and July figures by a combined 44,000 jobs. The economy generated 221,000 jobs a month from June through August, up from an average 189,000 in March through May. Steady hiring could encourage the Fed to raise rates for the first time in a decade. Still, stock market turbulence, a persistently low inflation rate and a sharp slowdown in China could weigh on officials.

– Hiring was relatively weak in August, but the 173,000 jobs added by US employers were enough to bring the nation's unemployment rate down to its lowest level in seven years, reports AP. The Labor Department said today the rate dropped from 5.3% to 5.1%, a level it hasn't reached since April 2008. That's lower than expected and, combined with upward revisions for previous months, provides further evidence that the "labor market is firming," notes the Wall Street Journal. The big question: Will that sway the Fed to raise interest rates later this month?

SECTION 1. SHORT TITLE. This Act may be cited as the ``Realtime Investor Protection Act''. SEC. 2. CONSTITUTIONAL AUTHORITY. The constitutional authority on which this Act rests is the power of Congress to regulate commerce as enumerated in article I, section 8 of the United States Constitution. SEC. 3. METHOD OF MAINTAINING BROKER/DEALER REGISTRATION, DISCIPLINARY, AND OTHER DATA. Subsection (i) of section 15A of the Securities Exchange Act of 1934 (15 U.S.C. 78o-3(i)) is amended to read as follows: ``(i) Obligation to Maintain Registration, Disciplinary and Other Data.-- ``(1) Maintenance of system to respond to inquiries.--A registered securities association shall-- ``(A) establish and maintain a system for collecting and retaining registration information; ``(B) establish and maintain a toll-free telephone listing, and a readily accessible electronic or other process, to receive and promptly respond to inquiries regarding-- ``(i) registration information on its members and their associated persons; and ``(ii) registration information on the members and their associated persons of any registered national securities exchange that uses the system described in subparagraph (A) for the registration of its members and their associated persons; and ``(C) adopt rules governing the process for making inquiries and the type, scope, and presentation of information to be provided in response to such inquiries in consultation with any registered national securities exchange providing information pursuant to subparagraph (B)(ii). ``(2) Recovery of costs.--Such an association may charge persons making inquiries, other than individual investors, reasonable fees for responses to such inquiries. ``(3) Process for disputed information.--Such an association shall adopt rules establishing an administrative process for disputing the accuracy of information provided in response to inquiries under this subsection in consultation with any registered national securities exchange providing information pursuant to paragraph (1)(B)(ii). ``(4) Limitation of liability.--Such an association, or exchange reporting information to such an association, shall not have any liability to any person for any actions taken or omitted in good faith under this subsection. ``(5) Definition.--For purposes of this subsection, the term `registration information' means the information reported in connection with the registration or licensing of brokers and dealers and their associated persons, including disciplinary actions, regulatory, judicial, and arbitration proceedings, and other information required by law, or exchange or association rule, and the source and status of such information.''. SEC. 4. FILING DEPOSITORIES FOR INVESTMENT ADVISERS. (a) Amendment.--Section 204 of the Investment Advisers Act of 1940 (15 U.S.C. 80b-4) is amended-- (1) by striking ``Every investment'' and inserting the following: ``(a) In General.--Every investment''; and (2) by adding at the end the following: ``(b) Filing Depositories.--The Commission may, by rule, require an investment adviser-- ``(1) to file with the Commission any fee, application, report, or notice required to be filed by this title or the rules issued under this title through any entity designated by the Commission for that purpose; and ``(2) to pay the reasonable costs associated with such filing and the establishment and maintenance of the systems required by subsection (c). ``(c) Access to Disciplinary and Other Information.-- ``(1) Maintenance of system to respond to inquiries.--The Commission shall require the entity designated by the Commission under subsection (b)(1) to establish and maintain a toll-free telephone listing, and a readily accessible electronic or other process, to receive and promptly respond to inquiries regarding registration information (including disciplinary actions, regulatory, judicial, and arbitration proceedings, and other information required by law or rule to be reported) involving investment advisers and persons associated with investment advisers. ``(2) Recovery of costs.--An entity designated by the Commission under subsection (b)(1) may charge persons making inquiries, other than individual investors, reasonable fees for responses to inquiries made under paragraph (1). ``(3) Limitation on liability.--An entity designated by the Commission under subsection (b)(1) shall not have any liability to any person for any actions taken or omitted in good faith under this subsection.''. (b) Conforming Amendments.-- (1) Section 203A of the Investment Advisers Act of 1940 (15 U.S.C. 80b-3a) is amended-- (A) by striking subsection (d); and (B) by redesignating subsection (e) as subsection (d). (2) Section 306 of the National Securities Markets Improvement Act of 1996 (15 U.S.C. 80b-10, note; Public Law 104-290; 110 Stat. 3439) is repealed.

Realtime Investor Protection Act - Amends the Securities Exchange Act of 1934 to require a registered securities association to: (1) establish and maintain a registration information system on its members and their associated persons; and (2) establish and maintain a toll-free telephone listing, and a readily accessible electronic or other process, to receive and promptly respond to inquiries regarding that information. (Currently such an association is required to maintain a toll-free telephone listing to receive inquiries regarding disciplinary actions involving its members and their associated persons.) Amends the Investment Advisers Act of 1940 to authorize the Securities and Exchange Commission (SEC) to require an investment adviser to: (1) file with the SEC any fee, application, report, or notice required to be filed through any entity designated by the SEC for that purpose; and (2) pay the reasonable costs associated with such filing and the establishment and maintenance of the telephone and electronic systems required by this Act. Directs the SEC to require the designated entity to establish and maintain a toll-free telephone listing, and a readily accessible electronic or other process, to receive and promptly respond to inquiries regarding registration information (including disciplinary actions, regulatory, judicial, and arbitration proceedings, involving investment advisers and persons associated with investment advisers).

uhl 's anomaly is a rare cardiac anomaly with absent myocardial layer of the right ventricle ( rv ) , with apposition of the right ventricular endocardium and epicardium . it is associated with high mortality and is typically diagnosed in the prenatal period or in children . we describe a case of uhl 's anomaly who presented to us with unrelated symptoms of gastrointestinal bleeding which were subsequently diagnosed to be due to portal hypertension secondary to cardiac cause . the patient was managed conservatively . in this article , we review the literature associated with this condition and highlight a rare presentation of a rare disease . a 27-year - old male patient presented to the medicine inpatient department with progressive distention of the legs and abdomen for 2 years . later , he had had multiple episodes of upper gastrointestinal bleeding in the form of melena . he had no history of alcohol intake and was sexually inactive . clinical examination was significant for mild pallor , mild icterus , bipedal pitting edema , and engorged neck veins . abdominal examination revealed marked ascites with moderate splenomegaly and a firm enlarged liver with palpable left lobe . cardiac examination revealed a laterally shifted diffuse apical impulse with soft first heart sound and pansystolic murmur of tricuspid regurgitation . routine investigations revealed : hemoglobin 8.7 g / dl , total leukocyte count 6700/cumm ( neutrophils 65% , lymphocytes 27% , monocytes 3% ) , and platelet count 80,000/cumm . liver function tests revealed : bilirubin 4 g / dl ( direct fraction 2.4 g / dl ) , aspartate aminotransferase 120 u / l , alanine aminotransferase 208 u / l , serum albumin 3.7 g / dl , and serum globulin 4 g / dl . renal function tests revealed : serum urea 48 mg / dl creatinine 0.9 mg / dl . serum markers for hepatitis b surface antigen , hepatitis c antibody , and hiv antibodies were negative . ascitic fluid analysis revealed ascitic fluid albumin 2.6 g / dl ( serum ascites albumin gradient : 1.1 ) and total cell count 240 cells / cumm with 70% mononuclear cells . an ultrasonography of the abdomen revealed splenomegaly , enlarged liver with coarse echotexture and dilated hepatic vein [ figure 1 ] , and 3 + ascites . ultrasonography of the abdomen showing hepatomegaly with coarse echotexture and dilated hepatic vein a chest x - ray revealed cardiomegaly [ figure 2 ] . echocardiography revealed massively dilated right atrium ( ra ) and rv with spontaneous echo contrast in ra . chest x - ray posteroanterior view showing cardiomegaly a cardiac magnetic resonance imaging ( mri ) revealed : free flow of blood between rv and ra in systole , an unduly dilated and akinetic right ventricular outflow tract , an ironed out rv and ra were massively dilated with akinesia / dyskinesia of rv wall , except the apex [ figures 3 and 4 ] . . the patient did not give consent for a liver or endomyocardial biopsy . magnetic resonance imaging showing absent right ventricular myocardium magnetic resonance imaging consistent with uhl 's anomaly the patient was managed conservatively with salt restricted diet and diuretics . uhl 's anomaly is a rare form of congenital heart disease ( chd ) characterized by a partial or complete absence of the right ventricular myocardium , a normal tricuspid valve , and preserved septal and left ventricular myocardium . probably first described by osler as parchment heart in 1905 , the anomaly is named after henry uhl , who reported a case in 1952 . lack of proper literature and the rarity of the condition have led to many different names for the disease including right ventricular ectasia , congenital right ventricular myocardial aplasia , fat infiltration or lipomatosis , right ventricular idiopathic myocardial dysplasia , and right ventricular myocardial absence . the exact incidence of this exceedingly rare condition is not known , but 84 reported cases were identified till 1993 . median age of death at 15 years equal affection of both sexes has been reported . case presentations have varied from prenatal diagnoses to nonparoxysmal atrioventricular junctional tachycardia with mobitz i block in adults to asymptomatic presentations . the exact cause of uhl 's anomaly is unknown , but primary nondevelopment of myocytes , selective apoptosis , and overexpression of vascular endothelial growth factor by cardiomyocytes have been reported . traditionally , the diagnosis has been established postmortem on autopsy specimens . however , with advancing medical technology , diagnosis can be made on the basis of clinical findings and imaging studies , most commonly a cardiac mri . there are several unique aspects to our case : first , uhl 's anomaly in itself is a rare anomaly . second , portal hypertension secondary to uhl 's anomaly has so far not been reported in literature . third , despite the high mortality of the condition , our patient was considerably stable for years with the disease . fourth , the role of imaging for the diagnosis of uhl 's anomaly has been reiterated . and finally , cardiac cirrhosis though rare may be a pointer toward this rare disease .

uhl 's anomaly is a rare congenital heart disease characterized by partial or complete absence of the right ventricular myocardium and high early mortality rates . we describe a case of uhl 's anomaly in a 27-year - old young male patient presenting with portal hypertension and esophageal varices . in this article , we review the literature associated with this condition and highlight a rare presentation of a rare disease . this report adds to our current knowledge of this exceedingly rare disorder .

a long - standing problem in the dynamics of galactic globular clusters is the observed dichotomy in their surface brightness profiles . while most clusters exhibit a profile similar to a classic king profile @xcite , about one quarter of the clusters exhibit a more cuspy profile @xcite . the second class of objects are usually described as post - core collapse clusters , as the phenomenon of core collapse leads to an object with high central density and small core radius ( * ? ? ? * ; * ? ? ? * ; * ? ? ? * etc . ) . by a statistical study of stellar luminosity functions , however , @xcite suggested that some clusters with a king - like profile might , in fact , be post - core collapse clusters . independently , @xcite used a monte carlo code for star cluster evolution to construct a dynamic , evolutionary model of the king - like globular cluster m4 , and were surprised to find that their model was in the post collapse phase of its evolution at the present day . they suggested that the reason it exhibited a finite core radius is that the core was sustained by heating from a population of primordial binary stars . ( many studies had shown that such a population , certainly in the case of idealised models with stars of equal mass , was sufficient to sustain the core in this way after core collapse ; see , for example , @xcite . ) the case of the globular cluster ngc 6397 casts serious doubt on this interpretation . this cluster has a very similar mass to m4 , and , if anything , a larger population of primordial boundaries , and yet it exhibits a non - king surface brightness profile . if primordial binaries sustain the finite core in m4 , then ngc 6397 should exhibit a finite core in the same way . this conundrum was considered by @xcite , who constructed a dynamic evolutionary model for ngc 6397 , just as they had previously done for m4 . not surprisingly , this model was also in its post - collapse evolution . despite having an appropriate primordial binary fraction , however , it exhibited a non - king surface brightness profile that was a fair match to that of ngc 6397 . they concluded that primordial binaries and core collapse were insufficient to explain the surface brightness profiles of these two clusters . by considering and also eliminating other alternatives , they concluded that the best explanation for the difference between these clusters was one based on fluctuations . they found that , if they constructed the surface brightness profile from a single model at different times , or from different models started from the same initial conditions , but simply with a different seed for the random number generator , then the variety of surface brightness profiles exhibited differences comparable to the difference between the surface brightness profiles of m4 and ngc 6397 . in effect , their conclusion was the following : that a single cluster could sometimes look like m4 , and sometimes look like ngc 6397 . unfortunately it is not clear that a monte carlo code , such as the one used for these clusters , simulates fluctuations correctly . @xcite did their best to ensure that the monte carlo model behaves similarly to an @xmath0-body model , at least in the range of @xmath0 where @xmath0-body models are commonly carried out , but their investigation was restricted to global quantities , such as the evolution of the total mass , and the half - mass radius ; they did not even consider the question of fluctuations . the nature of the fluctuations is also difficult to investigate with a monte carlo code , which does not follow the orbital motions of the particles . these considerations motivate the @xmath0-body simulations which we report in this letter . the initial conditions we use are generated from our monte carlo model of ngc 6397 evolved to the present day , which we took to be 12gyr . we placed the model in a tidal field with a tidal radius equal to that of the monte carlo model ( which used a tidal cut - off ) , but switched off stellar evolution . one of the runs was continued for a simulation time of one gyr . details and results of the runs are given in the following two sections , and the final section of the letter summarises our conclusions . it is unfortunately impossible to specify the initial conditions without access to the complete snapshot of the monte carlo model of ngc 6397 at 12 gyr , but table 1 gives some summary parameters . the monte carlo code stores the mass of every star , including binary components . the only positional information on a star ( or the barycentre of a binary ) which is held by the monte carlo code is its radius , and the full position was generated with the assumption of spherical symmetry . for the velocity of each star ( or barycentre ) the radial and transverse components are available , and the full velocity vector was generated by assuming symmetry about the radial vector . for a binary , the only internal information ( apart from the binary masses ) is for the semi - major axis and eccentricity . the full relative position and velocity were generated assuming a random value of the mean anomaly , and symmetric distributions of the orbital plane and the line of apsides . .data on the initial @xmath0-body model ( from a monte carlo model at 12gyr ) [ cols= " < , < " , ] note : masses are given in @xmath2 , radii in pc . the `` core radius '' is determined as in the @xmath0-body code ( aarseth 2003 , pp.265 - 266 ) . the simulation was run with nbody6 on a pc equipped with a gpu . the cpu was a quad - core intel xeon e5410 at 2.33ghz , and the gpu a geforce 9800 gtx . as usual , the code uses @xmath0-body units @xcite , but the initial virial radius of the model ( the @xmath0-body unit of length ) was 3.43pc , and its crossing time 1.08 myr ( @xmath3 @xmath0-body time units ) . the half - mass relaxation time is of order 700myr . we actually carried out two runs . one was an exploratory ( but scientifically informative ) run with dynamically `` inert '' binaries , i.e. each binary was replaced by a single particle with a mass equal to the combined mass of the components . this was run for an equivalent of almost 260myr . the main run used dynamically `` active '' binaries , as described above . we refer to these two runs as `` i '' and `` a '' respectively . both simulations proceeded at a rate of about 1myr / hr , and the entire run with dynamically active binaries took about 1 month for 1gyr . in the context set out in the introduction , most of our interest is focused on the inner parts of the models , and information on their spatial structure is given in figs.[fig : radii - active ] and [ fig : radii - inert ] for the models with dynamically active and inert binaries , respectively . the core radius is as defined in nbody6 @xcite , and all radii are referred to the density centre . we note immediately substantial variations in 1 ( defined here to be the 1% lagrangian radius ) . since the crossing time at this radius is of order @xmath4yr , it is clear that these are not the kind of fluctuations caused simply by the motion of stars in and out of the core , but take place on a much longer time scale . by comparing the density within the half - mass radius and 1 , and the above estimate of the half - mass relaxation time , we may estimate that the relaxation time at 1 is under 1 myr ( the unit of time in these figures ) , and the variations of largest amplitude ( e.g. the rise between 500 and 700 myr in fig.[fig : radii - active ] ) take place on a much longer time scale . the next obvious observation is that the long - term fluctuations have a comparable amplitude for the two runs . but the maximum and minimum radii are lower in run i. in particular , the deep minima in run i are not found in run a. it is natural to attribute these facts to the presence of primordial binaries : run i has to make its own binaries , which requires higher density than the burning of an existing binary . the amplitude of the fluctuations in the inner lagrangian radii is smaller than that of the core radius , but not inconsiderable , resulting in variations in the mean density within the 1% lagrangian radius by a factor of around 3:1 . though we have not shown data on the outer lagrangian radii , we find that the variations we observe are largely confined to the inner few percent of the mass . in fact the 10% lagrangian radius fluctuates with a relative amplitude of order 7% , and the oscillations are approximately @xmath5 out of phase with those of the core . the relative amplitude of oscillations drops to less than 1% at the half - mass radius . the initial decrease in both runs is an interesting feature . one might suspect that it is due to some property of the monte carlo code , which perhaps maintains thermal equilibrium in a structure which would not be in thermal equilibrium in an @xmath0-body model . another possibility is a response of the system to the cessation of mass loss by stellar evolution . and yet , in the overall range of data in these figures , the structure at the start is not unusual . furthermore , it must be remembered that this model was selected because , at 12 gyr , it yielded a surface brightness profile resembling that of ngc6397 , and this happens only intermittently , even in the monte carlo model . fig.[fig : mc - radii ] , when considered in conjunction with figs.[fig : radii - active ] and [ fig : radii - inert ] , allows a direct qualitative comparison between the monte carlo and @xmath0-body models in respect of the fluctuations in the inner radii , though the definition of the core radius adopted in the monte carlo model is different ( see caption ) . this figure shows oscillations of a similar amplitude and range of time scales to those exhibited by run a ( fig.[fig : radii - active ] ) . is defined by @xmath6 where the mass - weighted mean square three - dimensional velocity @xmath7 and the central density @xmath8 are calculated for the innermost 20 stars . , title="fig:",width=340,height=453 ] in an attempt to make this statement more quantitative we show in fig.[fig : auto ] the autocorrelation of the core radius for run a and the monte carlo model , though it should be borne in mind that these correspond to different time intervals . in both cases we have restricted the offset @xmath9 in the autocorrelation ( defined to be @xmath10 for a zero - mean normalised signal @xmath11 ) to be less than half the duration of the measurements . the result for the @xmath0-body model is striking , and confirms the visual impression from fig.[fig : radii - active ] of fairly regular oscillations with a period of about 400myr . there is a faint suggestion of similar structure in the autocorrelation function of the monte carlo model . is defined in the text . , title="fig:",width=340,height=453 ] another structural quantity of interest is , of course , the total mass , and the @xmath0-body run provides a check on this aspect of the monte carlo model . in the @xmath0-body model the rate of mass loss increases for the first few tens of myr , presumably because escapers take some time to reach the boundary ( at 2 tidal radii ) where escapers are removed . for the period after 200 to 400myr , however , the rate of mass loss is virtually constant , and yields @xmath12 , where the unit of time is 1myr . for the monte carlo model discussed above , we do not have data extending beyond 12gyr . for another model differing only in the initial seed , however , in the same period the corresponding result is @xmath13 . this difference of 13% should be corrected for the fact that there is no mass loss through stellar evolution in the @xmath0-body model . in the monte carlo model this contributes only about 3% of the total , but the direct loss of this mass also induces further loss of stars ( by tidal overflow ) because it make the potential well more shallow . it is difficult to quantify this induced mass loss , but it appears that the discrepancy in the total rate of mass loss between the two models is less than 10% . since so much of the mass at small radii is in the form of degenerate remnants , the influence of the fluctuations shown in fig.[fig : radii - active ] on the surface brightness profile is not obvious . insufficient data were collected from run i , but fig.[fig : profiles ] provides a useful comparison of two snapshots from run a. these are taken at times of 200 and 340 myr , which correspond , respectively , to low and high values of the radii plotted in fig.[fig : radii - active ] ( though not the extreme values ) . as expected , the central surface densities are lower at the time when the lagrangian and core radii are larger . let us consider these profiles in more detail . neutron stars and white dwarfs are the dominant components at the centre , each contributing about half of the projected number density . ( note that the surface density of neutron stars in fig.[fig : profiles ] is divided by 10 , to avoid overlap with the white dwarfs . ) beyond the core , however , the projected density of neutron stars decreases more strongly , as is expected from their greater mass . indeed they are actually the dominant central component in terms of _ spatial _ mass density . the component which contributes least to the projected central density , by a factor of order 10 , are the non - degenerate stars , though they begin to dominate at radii beyond those shown in the figure . all three components show a lower surface density and a larger core at the later epoch ( 340 myr ) compared to the earlier epoch ( 200 myr ) . it is interesting to attempt to quantify this in terms as close as possible to observational procedures , by considering the radius at which the projected density of the non - degenerate component drops below its central value by a factor of two . despite the spatial fluctuations , it is clear that this radius is about 15 at the later epoch , and about 5 at the earlier one . actually , it would also be reasonable to describe the latter profile as a shallow cusp . indeed , in view of the very small number of stars within 1 arcsec , this is a more robust description . at radii beyond about 4 arcsec the changes in the surface density are much smaller but go in the opposite direction , at least for the degenerate components . at the epoch when the core and lagrangian radii are larger , the number density at these radii is higher , the total mass of each component being conserved ( except for escape ) . this discussion still does not necessarily correspond to an observational description , which is usually expressed in terms of surface brightness , i.e. weighted by luminosity . in particular , the most luminous stars are centrally concentrated relative to most non - degenerate stars . because stellar evolution is absent from the @xmath0-body simulation , however , it is not an entirely appropriate model for considering how fluctuations affect the surface brightness . the discussion of our monte carlo model in @xcite is more complete in this respect . run a contains over 3000 binaries , and it is best to begin with run i , where the effects of individual binaries are clearer ( fig.[fig : binaries - i ] ) . by comparing with fig.[fig : radii - inert ] , we can surmise that one or two binaries were responsible for terminating the core collapse at about 70myr and initiating the subsequent expansion . for a period beginning at 125myr , however , no binaries were present , suggesting that the continuing modest expansion was powered gravothermally @xcite . a second phase of core collapse and binary formation appears to have started at about 225myr , but is incomplete by the end of the run . -body units @xcite . , title="fig:",width=340,height=453 ] fig.[fig : binaries - a ] shows similar data for run a. the numbers are not included , but the binaries are separated into two groups . those labelled `` new '' _ exclude _ binaries which have evolved from primordial binaries by exchange . if , however , two binaries collide , resulting in a hierarchical triple system , the outer motion of the hierarchy is regarded as a `` new '' binary . in any event we see that both types of binary have an active role to play . the correlation with the evolution of the radii ( fig.[fig : radii - active ] ) is less clear than for run i , though the initial contraction seems to be associated with a period of relatively sluggish binary activity . while neither run shows the kind of gravothermal oscillations which are so evident in simulations of systems with equal masses , it should not be surprising to find evidence of gravothermal effects in a multi - mass system of the kind which we are studying ( see the discussion in @xcite ) . the rate of change of the binary fraction in run a is @xmath14 , where the unit of time is 1myr . for the monte carlo model the corresponding value is @xmath15 , and these results are pretty consistent within the errors . we have carried out an @xmath0-body simulation of the globular cluster ngc6397 , in order to study the evolution of its central structure over a period of 1gyr starting at the present day . the simulation was initialised using the results of a monte carlo model @xcite which approximately fits the present - day profiles of surface brightness and velocity dispersion , and the mass function at two radii . the main limitation of the @xmath0-body model is that there is no stellar evolution . this apart , it is in many respects the most realistic @xmath0-body simulation of a specific globular cluster of which we are aware . the model provides a new check on the reliability of the monte carlo code , and suggests that the evolution of the binary fraction is satisfactory , while the rate of escape of mass appears to be in agreement to better than 10% . the results show that the population of primordial binaries in the cluster ( about 3% ) suppresses the deepest collapses of the core , which nevertheless still exhibits substantial fluctuations on a time scale of many core relaxation times . their amplitude is sufficient to change the mean density of the innermost 1% of the mass by a factor of order 3:1 . these changes are reflected in variations in the core radius , whether measured in terms of the spatial density , as in an @xmath0-body model , or by the radius at which the surface density decreases to half its central value . these changes manifest themselves in all components that we have studied : neutron stars ( the dominant component in the central density ) , white dwarfs , and non - degenerate stars , which are the least dominant . in view of our results , it is interesting to think of globular clusters as _ variable stellar systems _ , in much the same way that many stars are variable . the time scales and mechanisms are vastly different , and the variations in globular clusters are confined to the vicinity of the core . but it is another demonstration of the deep physical resemblance between these two types of thermal , self - gravitating objects . we are indebted to s. aarseth and k. nitadori for making publicly available their version of nbody6 adapted for use with a gpu . s. aarseth also helped specifically with aspects of input and output . our hardware was purchased using a small project grant awarded to dch and dr m. ruffert ( school of mathematics ) by the university of edinburgh development trust , and we are most grateful for it . we thank s. law and d. marsh for installing and maintaining it . we are grateful to the referee for his expeditious report . this work was partly supported by polish ministry of science and higher education through the grant 92/n astrosim/2008/0 .

m4 and ngc 6397 are two very similar galactic globular clusters , which differ mainly in their surface brightness profile . m4 has a classic king - like profile , whereas ngc 6397 has a more concentrated profile , which is often interpreted as that of a post - core collapse cluster . @xcite , however , found that m4 is also a post - core collapse cluster , and @xcite concluded that the main reason for the difference between the two surface brightness profiles is fluctuations . this conclusion was reached on the basis of monte carlo models , however , and in the present letter we verify that similar fluctuations occur in @xmath0-body models . the models were initialised by generating initial conditions from the monte carlo model of ngc6397 at the simulated age of 12gyr , and one was followed for 1gyr . the new models help to clarify the nature of the fluctuations , which have the nature of semi - regular oscillations with a time scale of order @xmath1yr . they are influenced by the dynamical role which is played by primordial binaries in the evolution of the core . [ firstpage ] stellar dynamics methods : numerical globular clusters : individual : ngc 6397

ultra - relativistic heavy - ion collisions at the relativistic heavy - ion collider ( rhic ) are thought to have created a high temperature and pressure state of qcd matter termed the quark - gluon - plasma ( qgp ) @xcite : two major discoveries stand out : ( 1 ) the emission of hadrons with a transverse momentum @xmath0 of several gev / c or more is strongly suppressed ( jet - quenching ) , implying the presence of matter with a very large color opacity , and ( 2 ) the anisotropic ( `` elliptic '' ) flow in non - central collisions is near the ideal hydrodynamic limit , requiring an early onset of the period during which the expansion is governed by fluid dynamics ( earlier than 1 fm / c after the initial impact ) as well as nearly ideal fluid properties with a viscosity - to - entropy density ratio @xmath1 . the matter created at rhic has been thus called the strongly interacting quark - gluon plasma ( sqgp ) @xcite and quantifying its properties in terms of its transport coefficients is one of the major tasks of the current experimental and theoretical research program . one should note that qcd matter created in relativistic heavy - ion collisions may possess a very rich set of features , reflecting the fundamental symmetries ( and violations thereof ) of qcd , well beyond the above noted characteristics of large opacity and near - ideal fluidity . among the more intriguing features which are currently being searched for is the presence of the chiral magnetic effect ( cme ) @xcite : as was pointed out in @xcite , non - central heavy - ion collisions create a coherent magnetic field that may convert topological charge fluctuations in the qcd vacuum into global electric charge fluctuations with respect to the reaction plane . while the magnitude of the charge fluctuations which can be attributed to the cme is still a matter of ongoing debate @xcite , the star collaboration has recently reported that charge fluctuations with respect to the reaction plane have indeed been seen @xcite . in order to confirm the discovery of the cme in relativistic heavy - ion collisions , one first needs to verify that experimental measurements can not be understood in terms of `` conventional '' , well - established , phenomena observed at rhic . it has recently been pointed out that correlations from charge and momentum conservation at freeze - out overlaid with elliptic flow may very well be able to describe the observed phenomena @xcite . in addition , the experimental observable suggested to measure the cme has been argued to be predominantly sensitive to other effects @xcite . in this paper we focus on estimating various conventional physics mechanisms that lead to charge particle number asymmetry within a realistic model , namely medium - modified jets as well as initial state fluctuations , combined with well - known bulk physics such as momentum conservation , resonance decays and elliptic flow . in section [ observables ] the different observables that have been proposed are introduced . these observables are surely sensitive to fluctuations of multiplicity ( and charge ) if these fluctuations are correlated with the reaction plane . both of the two szenarios that we are studying here , in - medium jets ( in section [ jets ] ) and initial state granularity ( in section [ granularity ] ) give a particular mechanism to generate multiplicity fluctuations correlated in a peculiar way with the reaction plane . only once all possible contributions to the observed charged particle fluctuations with respect to the reaction plane are accounted for , can we quantify the possible contribution of the cme to the measurements . the standard observable used to look for the cme is the angular correlation coefficient @xmath2 where @xmath3 and @xmath4 represent positive and negative charges , @xmath5 measures the angle with respect to the reaction plane orientation and @xmath6 are the measured multiplicities . as argued in @xcite , this observable is ( contrary to initial expectations ) dominated by a strong in - plane like - sign correlation which has no obvious relation with charge separation as proposed as signal of the cme . in the present study we consider two other newly developed observables to quantify the correlations of charged particles with the reaction plane for which a computation using a detailed framework is feasible with a reasonable amount of cpu time . in addition , these observables seem to have a clearer relation to out - of - plane charge separation . the first observable we focus on for measuring the event - by - event charged particle asymmetry has been developed by the purdue group within the star collaboration @xcite . the measurement is based on counting charged particles that are emitted into different hemispheres with respect to the reaction plane . the different hemispheres are defined as follows : up = u means @xmath7 , down = d refers to @xmath8 , left = l stands for @xmath9 and right = r for @xmath10 . the ud - direction reflects the out - of - plane direction whereas the lr - direction represents the in - plane direction . the charged particle asymmetry coefficients are defined in the following way @xmath11 @xmath12 @xmath13 and correspondingly for the lr - direction where @xmath14 and @xmath15 are the numbers of positively and negatively charged particles in one event . the opposite charge correlation ( @xmath16 and @xmath17 ) are positive , if the particles tend to be aligned and negative for a charge separation scenario . without any correlation this observable would be consistent with zero . the @xmath18 and @xmath19 are a measure of the overall charged particle fluctuation . the preliminary star results seem to be positive ( on the order of @xmath20 ) in the out - of - plane as well as the in - plane direction for mid - central au+au collisions at @xmath21 gev . the main difference of this observable compared to the original angular correlation measurement @xcite is that each particle contributes with the same weight independent of its position in the respective hemisphere . the phenix collaboration has recently proposed a different observable that is sensitive to a charge separation with respect to the reaction plane as it is predicted from the chiral magnetic effect @xcite . this multi - particle correlation coefficient relies on an event - by - event measurement technique and is defined as follows @xmath22 where @xmath23 here , the first sum runs over all positively charged particles in one event whereas @xmath6 is the number of negatively charged particles in one event and @xmath5 is the azimuthal angle in the transverse plane in momentum space . @xmath24 is the analogous quantity where the @xmath25th particle is randomly chosen from the event . this observable is a multi - particle correlation that has to be measured event by event . the ratio of the charge sensitive distribution to the one for all charged particles is flat at 1 , if there is no charge specific correlation ( e.g. elliptic flow ) . a concave shape indicates charge separation out of plane ( e.g. the presence of the cme ) and a convex shape arises , if positively and negatively charged particles are preferably emitted in the same direction ( e.g. resonance decays ) . the idea of jets as a mechanism to generate asymmetries in the charged multiplicity distribution is based on the notion that in - medium energy loss from a leading parton is dominated by induced gluon radiation @xcite , giving rise to additional multiplicity production . moreover , this mechanism is predominantly active out of plane : while radiative energy loss asymptotically has an @xmath26 dependence in a constant medium , the actual scaling of lost energy and produced multiplicity in a real situation is complicated and has no simple functional shape for a number of reasons , among them the spacetime evolution of the bulk medium which reduces the density as a function of space and time and the re - interaction of radiated gluons with the medium , leading to a cascade of induced radiation till finite energy corrections become manifest @xcite . however , the multiplicity of medium - induced hadron production is a monotonously rising function of both pathlength and medium density . the basic idea how medium modified jets may generate an asymmetry in the charged hadron multiplicity correlated out of the reaction plane is shown in fig . [ f - jets ] . let us start with a random initial hard vertex position in the transverse plane : if the vertex position is such that one jet is close to the surface and escapes unmodified whereas the other jet propagates a long distance through the medium , the average multiplicity of charged hadrons for both jets is expected to be very different . furthermore , this effect can be estimated to be stronger in the up - down direction than in the left - right direction , simply because the maximum variation in pathlength is larger for out of plane emission than for in - plane emission . note that jets lead to an asymmetry in charged hadron production event by event even without a medium modification , simply because the fragmentation of a hard parton to a hadron jet is a probabilistic process , and also because jets in hadronic collisions may be due to a pqcd subprocess like @xmath27 in which the fragmentation of the gluon in the out state is much softer from the fragmentation of the quark . however , in the presence of a medium , the medium - induced radiation is expected to dominate multiplicity production , and the vacuum case has no mechanism to account for a correlation with the reaction plane . in the following , we use the in - medium shower evolution code yajem ( yet another jet energy - loss model ) in the rad ( radiative energy loss ) scenario to estimate the jet - induced event by event charged hadron multiplicity asymmetry . yajem is a monte carlo code to simulate the medium - modified evolution of a parton shower . it is based on the pyshow algorithm @xcite for shower evolution in vacuum , to which it reduces in the absence of a medium . a detailed description of the model is given in @xcite , here we just summarize the essential physics underlying the model . in yajem , the evolution from the initial parton to a final state parton shower is modelled as a series of branching processes @xmath28 where @xmath29 is called the parent parton and @xmath30 and @xmath31 are referred to as daughters . in qcd , the allowed branching processes are @xmath32 , @xmath33 and @xmath34 . the kinematics of a branching is described in terms of the virtuality scale @xmath35 and of the energy fraction @xmath36 , where the energy of daughter @xmath30 is given by @xmath37 and of the daughter @xmath31 by @xmath38 . it is convenient to introduce @xmath39 where @xmath40 is the scale parameter of qcd . @xmath41 takes a role similar to a time in the evolution equations , as it describes the evolution from some high initial virtuality @xmath42 ( @xmath43 ) to a lower virtuality @xmath44 ( @xmath45 ) at which the next branching occurs . in terms of the two variables , the differential probability @xmath46 for a parton @xmath29 to branch is @xmath47 where the splitting kernels @xmath48 read @xmath49 we do not consider electromagnetic branchings . @xmath50 counts the number of active quark flavours for given virtuality . the resulting system of equations describing the branching processes in vacuum is solved numerically using mc techniques utilizing the pyshow code @xcite . in order to make the link from momentum space where the shower evolution takes place to position space where the medium perturbations evolve , we assume that the average formation time of a shower parton with virtuality @xmath51 is developed on the timescale @xmath52 , i.e. the average lifetime of a virtual parton with virtuality @xmath53 coming from a parent parton with virtuality @xmath54 is in the rest frame of the original hard collision ( the local rest frame of the medium may be different by a flow boost as the medium may not be static ) given by @xmath55 we assume that the actual formation time can then be obtained from a probability distribution @xmath56\ ] ] which we sample to determine the actual formation time of the fluctuation in each branching . the medium modification in the rad scenario appears as a change of parton virtuality @xmath57 dependent on a medium parameter @xmath58 where @xmath59 here , the time @xmath60 is given by eq . ( [ e - rlifetime ] ) , the time @xmath61 is known in the simulation as the endpoint of the previous branching process and the integration @xmath62 is along the eikonal trajectory of the shower - initiating parton . if the parton is a gluon , the virtuality transfer from the medium is increased by the ratio of their casimir color factors , @xmath63 . @xmath58 is a function of medium energy density @xmath64 with the relation chosen such that the single pion suppression observed in 200 agev central au - au collisions at rhic is described @xcite . as a result of the medium - induced change in virtuality , additional gluon radiation occurs which after hadronization leads to an increased multiplicity in the shower . in order to estimate the event by event charged hadron asymmetry , we embed back - to - back jet pairs of three different energies ( 10 , 20 and 40 gev per jet ) into a 3 + 1 d hydrodynamical simulation @xcite on a random position sampled from the binary collision profile . the jet pair then gets a random orientation with respect to the reaction plane . we then propagate both jets through the medium and evaluate eq . ( [ e - qgain ] ) to determine the medium modification . after hadronizing the jets , we count the charged hadron content in the four different quadrants and compute the asymmetry coefficients @xmath65 and @xmath66 . the results are shown in fig . [ fig_only_jet ] . the result indicates that jets are in principle capable of creating substantial charge correlations . in this scenario the charge correlation arises because of an asymmetry in the particle production . the correlation shown in fig . [ fig_only_jet ] shows that in a developing shower the balancing charges are preferably emitted in the same hemisphere , so positively and negativley charged particles tend to align . however , somewhat surprisingly , no pronounced difference between up - down and left - right is visible . this can be traced back to a number of reasons . first , eq . ( [ e - qgain ] ) evaluated in an expanding medium leads to small modifications at late times , i.e. for long paths , as @xmath58 becomes very small when the energy density of the system is low . this means that in an expanding medium , partons do not actually probe the full length difference between in - plane and out - of - plane emission , but rather probe pathlength difference during the time period when modifications are significant only , i.e. the first @xmath67 3 - 5 fm / c . given this filter , the differences between in - plane and out - of - plane emission are considerably smaller than estimated naively based on geometry . furthermore , especially for low @xmath0 hadron production , the angular distribution of hadrons around the jet axis is wide @xcite . note that this can happen even if the jet shape itself is rather narrow , as the jet shape traces the flow of momentum and not multiplicity . the fact that there can be significant multiplicity created also in the down hemisphere even from a shower initiating parton travelling into the up hemisphere further weakens the difference between in - plane and out - of - plane emission . so far , we have investigated the charge correlation coefficients created by a single jet only . this is not a very realistic situation : first , high momentum jets of e.g. 40 gev are very rare events , so even if they create sizeable asymmetries in charged multiplicity , such events may not have much weight in an average over many events . second , for low momentum jets , one can not assume that only a single jet per event contributes . however , it is immediately clear that embedding multiple jets in an event weakens the asymmetry significantly . when we account for these effects by mixing jets with the probability of a jet with given energy being in the event determined from a lo pqcd calculation into a urqmd background @xcite , the picture changes considerably : in fig . [ fig_jet_full ] the contribution of jets appears as an insignificant correction to the background result . in hindsight , this could have been anticipated : while truly hard jets are too rare to influence the result , low @xmath0 jets ( below 5 gev ) tend to be created frequently , but the presence of multiple jets in an event tends to cancel their effect . clearly , a bulk mechanism creating charge asymmetries is more efficient than a rare probe . note also that it is apparent from fig . [ fig_jet_full ] that urqmd background results show that a pure hadronic transport approach is not capable of translating initial state fluctuations to the final state distributions effectively enough to lead to a significant signal as the @xmath68 coefficients are on the order of @xmath69 . in fig . [ fig_jet_phenix ] the calculation of the multi - particle correlation coefficient is shown . medium - modified jets , embedded in a urqmd background lead to a convex shape of the ratio of the distributions in @xmath70 . the result for jets alone leads to the same shape as the combined events . but again , the probability for jet production is very low and therefore the results resemble very much the urqmd results that are shown in fig . [ fig_hybrid_phenix ] . furthermore , the influence of a @xmath71gev cut has been explored , since the preliminary measurements have been made in a limited @xmath72 range and the chiral magnetic effect is mostly expected in the bulk low transverse momentum region . the low @xmath72 result and the result for all charged particles are the same within error bars and especially the shape does not change . since the distribution of the charge sensitive averaged sine differences has a higher peak around zero and lower flanks than the distribution that is not charge specific this result indicates that particles with opposite charges are preferably emitted in the same direction than in different directions . the underlying physics mechanism in both cases is correlated particle production from clusters - in one case jets , in the other decaying resonances . in the second part of this article the charged particle asymmetry that arises from well - known bulk medium effects is investigated . the basic idea is that energy density clusters produced by the initial binary scatterings in heavy ion reactions might lead to asymmetry correlations in the particle production in different hemispheres . due to the development of radial flow during the medium evolution the initial coordinate space granularity is translated to a resulting momentum space anisotropy . these clusters are expected to enhance the multiplicity in a specific hemisphere which results in alignment of the charged particle production instead of separation . in this picture , resonance decays might explicitly introduce a charge correlation of the outgoing particles , if e.g. a @xmath73 meson decays into @xmath74 and there is enough collective flow , both of the pions will preferably be have a momentum in a similar direction . s. pratt recently estimated the effects of elliptic flow , momentum and charge conservation on the observable charged particle correlation measurement @xcite . our approach follows a similar spirit but the effect of initial state fluctuations is emphasized in addition . this kind of event - by - event fluctuations has been found to be crucial also for other two - particle correlation measurements ( the ridge ) at the highest rhic energies @xcite . the charged particle asymmetry that is generated by clusters in the initial energy density distribution is quantified by using a hybrid approach based on the urqmd hadronic transport approach including a ( 3 + 1)-dimensional one fluid ideal hydrodynamic evolution @xcite for the hot and dense stage of the reaction while the early non - equilibrium stage and the final decoupling is treated in the hadronic cascade @xcite . the event - by - event - setup that is naturally employed in this approach is crucial for the observation of charged particle asymmetries . for au+au collisions at the highest rhic energy the starting time for the hydrodynamic evolution has been chosen to be @xmath75 fm depending on the amount of fluctuations to fit the final pion multiplicity at midrapidity , since this is crucial for the present study and allows us to investigate the effect of the initial state granularity on the charge correlations . how the change in the starting time affects other bulk observables like spectra and elliptic flow will be discussed in a further publication @xcite . only the matter around midrapidity ( @xmath76 ) is considered to be locally thermalized and takes part in the ideal hydrodynamic evolution . the more dilute spectator / corona regions are treated in the hadronic cascade approach . to map the point particles from the urqmd initial state to energy , momentum and net baryon density distributions three - dimensional gaussian distributions are used that represent one particle each @xcite . @xmath77 where @xmath78 provides the proper normalisation , @xmath79 and @xmath80 are the energy density and total energy of the particle in the computational frame , while @xmath81 is the position vector of the particle . summing over all single particle distribution functions leads to distributions of energy- , momentum- and baryon number - densities in each cell . the transition from the hydrodynamic evolution to the transport approach when the matter is diluted in the late stage is treated as a gradual transition on an approximated iso - eigentime hyper - surface ( see @xcite for details ) . the final rescatterings and resonance decays are taken into account in the hadronic cascade . to investigate the effect of different initial state granularities the width of the gaussian distribution ( [ eq_gauss ] ) is varied from @xmath82 fm . please note that this is still an event - by - event setup and in this respect different from averging over many fluctuating initial conditions as has been done in @xcite . in a hydrodynamic calculation starting from smooth initial profiles the correlation observable would be zero , since there are no event - by - event fluctuations included . [ fig_ini_sig0.8]-[fig_ini_sig2.0 ] show the initial energy density distribution as it is obtained from urqmd for three different values of the gaussian width @xmath83 , 1.0 and 2.0 fm . a smaller width leads to entropy production during the ideal hydrodynamic evolution indicating that the solution of the differential equation is not stable anymore . therefore , the highest fluctuations are generated with the smallest width of 0.8 fm , while for larger widths the initial fluctuations are more and more smeared out . smaller characteristic sizes could be physically motivated by a color flux tube picture where structures in the transverse plane on the order of @xmath84 fm would be expected . our parameter choices stay in a regime where the implementation is technically stable and the characteristic sizes correspond to typical sizes of a proton . the hybrid approach provides the opportunity to study the influence of initial state fluctuations that can be varied in size without adjusting any other parameter on event - by - event particle production in different hemispheres . initial state clusters and a coordinate space -momentum space correlation due to radial flow leads to observable differences in the charged particle production in different parts of the system ( see fig . [ fig_nch_corr_sigdep ] ) . the ud and lr charged particle asymmetry coefficients have been calculated for four different initial granularities in the hybrid approach . the open symbols depict the results for central ( @xmath85 fm ) au+au collisions at @xmath86 gev and the filled symbols represent mid - central ( @xmath87 fm ) au+au collisions . the overall fluctuations of charged particles are larger in non - central collisions than in central collisions because the overall multiplicity is smaller . the opposite charge asymmetry is positive and similar in the out - of - plane and the in - plane direction . this confirms the expectations that in this scenario the particles tend to align independent of their charge . within our limited statistics , the absolute value of the difference between ud and lr can be constrained to be smaller than @xmath88 . higher granularity in the initial state leads to higher opposite charge asymmetry coefficients that are on the order of the preliminary star data @xcite . this physics mechanism will contribute to the background of a potential measurement of the chiral magnetic effect and needs to be taken into account , before trying to look for a potentially much smaller signal . on the other hand , the comparison of hybrid calculation with different initial state granularities to event - by - event correlation and fluctuation measurements might be helpful to constrain the structure of the initial state of relativistic heavy ion reactions . [ fig_hybrid_phenix ] shows the result for the multi - particle correlation coefficient that has been defined in section [ sec_phenix_def ] from the urqmd hadronic transport approach ( open symbols ) and the hybrid approach ( filled symbols ) . it has been checked that the results for this observable do not depend on the choice of @xmath89 . the low transverse momentum region shows the same behaviour as without @xmath72 cut . if one reduces the number of particles by acceptance ( or other ) cuts , the distribution broadens , however does not change qualitatively in shape . again the correlations induced by these approaches lead to a convex shape and can be attributed to resonance decays whereas a charge separation scenario as expected from the chiral magnetic effect leads to a concave shape in this observable . the initial state fluctuations have to be considered as a non - trivial source of correlations of the particles emitted in a heavy ion reaction . it is likely that any measurement of the observable is dominated by resonance decay effects which are known to be present in nature . in order to observe a different mechanism ( like the cme ) at work , this distribution has to be subtracted . in order to get an idea of the sensitivity of the results to the subtraction , we have tried to isolate the effect of initial state fluctuations by subtracting the urqmd distributions in @xmath70 from the hybrid model distributions . it turns out that the procedure is very sensitive to the subtraction - we were able to observe even qualitative differences in shape which could potentially mock up the cme signal . we have investigated charge asymmetry and multi - particle correlations with the reaction plane generated in relativistic heavy - ion collisions at rhic within a realistic transport approach containing a full medium evolution and medium - modified jets . while jets are in principle capable of generating the aforementioned multi - particle correlations , we were able to rule them out as a significant contributor to such correlations due to the low jet production rate . however , we find that initial state fluctuations can generate values for the charge asymmetry coefficients on the same order of magnitude as seen by experiment . our results were obtained within a hybrid transport approach , based on an event - by - event hydrodynamic evolution , with fluctuating initial conditions and microscopic hadronic afterburner for the realistic treatment of hadronic final state effects , including resonance decays . the precision of our calculation was not sufficient to quantify the difference between in - plane and out - of - plane , due to the very large computational effort involved . however , the coefficients themselves show no sign of charge separation . the multi - particle correlation measurement proposed by the phenix collaboration appears to be potentially the most suitable of the studied observables for differentiating a cme from other mechanisms . however , due to the need of subtracting known background effects like resonance decays , it is currently unclear whether the predicted concave shape as a signal for the cme can be robustly established . we are grateful to the open science grid and the center for the scientific computing ( csc ) at frankfurt for the computing resources . the authors thank fuqiang wang , roy lacey and berndt mller for helpful discussions and dirk rischke for providing the 1 fluid hydrodynamics code . h.p . acknowledges a feodor lynen fellowship of the alexander von humboldt foundation . this work was supported in part by u.s . department of energy grant de - fg02 - 05er41367 and by project 133005 of the academy of finland . is supported by an academy research fellowship of the academy of finland . 99 arsene i _ et al . _ ( brahms ) 2005 _ nucl . phys . _ * a757 * 127 adcox k _ et al . _ ( phenix ) 2005 _ nucl . phys . _ * a757 * 184283 back b b _ et al . _ 2005 _ nucl . phys . _ * a757 * 28101 adams j _ et al . _ ( star ) 2005 _ nucl . _ * a757 * 102183 muller b and nagle j l 2006 _ ann . nucl . part . sci . _ * 56 * 93135 gyulassy m and mclerran l 2005 _ nucl . phys . _ * a750 * 3063 d. e. kharzeev , l. d. mclerran and h. j. warringa , nucl . a * 803 * , 227 ( 2008 ) k. fukushima , d. e. kharzeev and h. j. warringa , phys . d * 78 * , 074033 ( 2008 ) k. fukushima , d. e. kharzeev and h. j. warringa , phys . * 104 * , 212001 ( 2010 ) m. asakawa , a. majumder and b. muller , phys . c * 81 * , 064912 ( 2010 ) b. i. abelev _ et al . _ [ star collaboration ] , phys . lett . * 103 * , 251601 ( 2009 ) s. schlichting and s. pratt , arxiv:1005.5341 [ nucl - th ] . s. pratt , arxiv:1002.1758 [ nucl - th ] . f. wang , phys . c * 81 * , 064902 ( 2010 ) a. bzdak , v. koch and j. liao , phys . rev . c * 81 * , 031901 ( 2010 ) f. wang , talk given at p- and cp- odd effects in hot and dense matter on behalf of the star collaboration , april 2010 . r. baier , y. l. dokshitzer , a. h. mueller , s. peigne and d. schiff , nucl . b * 484 * , 265 ( 1997 ) b. g. zakharov , jetp lett . * 65 * , 615 ( 1997 ) r. b. neufeld and t. renk , phys . c * 82 * , 044903 ( 2010 ) m. bengtsson and t. sjostrand , phys . b * 185 * , 435 ( 1987 ) . m. bengtsson and t. sjostrand , nucl . b * 289 * , 810 ( 1987 ) . t. renk , phys . c * 78 * , 034908 ( 2008 ) t. renk , phys . rev . c * 79 * , 054906 ( 2009 ) c. nonaka and s. a. bass , phys . c * 75 * , 014902 ( 2007 ) t. renk , phys . rev . c * 80 * , 044904 ( 2009 ) s. a. bass _ et al . _ , prog . part . nucl . * 41 * , 255 ( 1998 ) [ prog . phys . * 41 * , 225 ( 1998 ) ] m. bleicher _ et al . _ , j. phys . g * 25 * , 1859 ( 1999 ) j. takahashi , b. m. tavares , w. l. qian , f. grassi , y. hama , t. kodama and n. xu , phys . lett . * 103 * , 242301 ( 2009 ) d. h. rischke , s. bernard and j. a. maruhn , nucl . phys . a * 595 * , 346 ( 1995 ) d. h. rischke , y. pursun and j. a. maruhn , nucl . a * 595 * , 383 ( 1995 ) [ erratum - ibid . a * 596 * , 717 ( 1996 ) ] h. petersen , j. steinheimer , g. burau , m. bleicher and h. stocker , phys . c * 78 * , 044901 ( 2008 ) h. petersen and m. bleicher , phys . c * 79 * , 054904 ( 2009 ) h. petersen , c. coleman - smith , s. a. bass and r. wolpert , arxiv:1012.4629 [ nucl - th ] . j. steinheimer , m. bleicher , h. petersen , s. schramm , h. stocker and d. zschiesche , phys . c * 77 * , 034901 ( 2008 ) q. f. li , j. steinheimer , h. petersen , m. bleicher and h. stocker , phys . b * 674 * , 111 ( 2009 ) j. steinheimer , v. dexheimer , h. petersen , m. bleicher , s. schramm and h. stoecker , phys . c * 81 * , 044913 ( 2010 )

we investigate the contribution of medium - modified jets and initial state fluctuations to the asymmetry in charged particle production with respect to the reaction plane . this asymmetry has been suggested as a compelling signature of the chiral magnetic effect in qcd and make a study of `` conventional '' scenarios for the creation of such charged particle multiplicity fluctuations a timely endeavor . the different pathlength combinations of jets through the medium in non - central heavy ion collisions result in finite correlations of like and different charged particles emitted in the different hemispheres . our calculation is based on combining jet events from yajem ( yet another jet energy loss model ) and a bulk medium evolution . it is found that the jet production probabilities are too small to observe this effect . the influence of initial state fluctuations on this observable is explored using an event - by - event ( 3 + 1)d hybrid approach that is based on urqmd ( ultra - relativistic quantum molecular dynamics ) with an ideal hydrodynamic evolution . in this calculation momentum conservation and elliptic flow are explicitly taken into account . the asymmetries in the initial state are translated to a final state momentum asymmetry by the hydrodynamic flow profile . dependent on the size of the initial state fluctuations the resulting charged particle asymmetries are in qualitative agreement with the preliminary star results . the multi - particle correlation as proposed by the phenix collaboration can in principle be used to disentangle the different contributions , however is in practice substantially affected by the procedure to subtract trivial resonance decay contributions .

Analysis of police audio synced with video raises further questions about whether officers performed any CPR on Walter Scott after he was shot eight times The police officer who shot Walter Scott radioed in to claim that Scott had “grabbed my Taser”, six seconds after firing his final shot, despite video suggesting the unarmed man was not in possession of the stun gun at any point, a Guardian analysis has shown. Syncing police scanner audio with a shocking video – the eyewitness footage out of South Carolina which led to officer Michael Slager being charged with murder – raises further questions about whether either of two officers on the video performed any CPR on Scott as was previously claimed by police. Analysis of the police radio shows Slager, the officer who shot at Scott eight times, making the radio call announcing the shots and alleging the Taser seizure, sounding frantic and breathless at the same time as he walks slowly towards Scott’s body. “Shots fired. Subject is down. He grabbed my Taser,” the scanner audio from Slager states. Officer Michael Slager dispatch audio from the Walter Scott shooting. He reaches the body, handcuffs Scott who has his head down to the floor and walks back to the area where it appears an object was dropped and picks up an item from the ground. At this point a second officer, now identified as Clarence Habersham, arrives on the scene and radios in. Slager then walks back towards the body and radios in stating: “I need to secure my vehicle”. At this point – over a minute after the last shot is fired – neither officer appears to have performed CPR on Scott. Slager then walks and drops the item, which some have speculated is a Taser, next to Scott’s body. At this point Habersham radios in to say he has detected gunshots to Scott’s chest on the right side. He then radios to say he has detected a gunshot wound to the buttocks. He appears to be pulling Scott’s T-shirt up at this point. At a press conference on Wednesday North Charleston police chief Eddie Driggers said after watching the video he believed an officer had lifted Scott’s T-shirt to perform “some sort of life-saving procedure”. But analysis of the video and audio suggests Habersham is actually identifying the gunshot wounds rather than performing any such procedure. At the end of the video, over two minutes after the last shot is fired, Slager stands over Scott’s body and takes a pulse. The combination of the video and audio footage shows that the encounter between Slager and Scott started about four and a half minutes before the scenes now seen on televisions around the world. As Slager began stopping Scott at the intersection of Remount Road and Craig Road at about 9.35am, he radioed the dispatcher to say he was “coming up on a grey ... Mercedes”. Bystander who filmed Walter Scott shooting: officer 'made a bad decision' Read more Exactly three minutes later, Slager radioed again to announce he was chasing on foot down Craig, giving his dispatcher a basic description of Scott. “Black male, green shirt, blue pants,” he said. About 25 seconds later a colleague radioed to say he was “en route” to assist. Ten seconds on, there was another message – possibly from the same officer – asking Slager (“223”) “What’s your direction of travel there?” After he received no response, this officer asked Slager again: “Where you at now?” Eight seconds later, however, there was a clue to why Slager may not have been responding. In a burst of confused radio chatter, an officer can be heard shouting “on the ground!” The dispatcher had asked all officers to ensure radio silence for matters apart from the Slager-Scott chase. Feidin Santana, a bystander who filmed the shooting on his cellphone, told NBC on Wednesday evening that the pair were struggling on the ground before he began recording. Another 47 seconds pass before the supporting officer radioed again: “I’m at the pawn shop,” he said. “Where you at now?” Just three seconds later – at 9.38am, almost five minutes after Slager announced that he was stopping Scott in his car – Slager was back on the radio. “223, shots fired,” he said. “Subject is down. He grabbed my Taser.” ||||| The brother of South Carolina police shooting victim Walter Scott says the white cop “was using my brother for target practice." "It was totally senseless," Rodney Scott told the Daily News on Wednesday. "I mean, eight shots? That was totally cold-hearted murder as far as I'm concerned." Scott's brother spoke out after Officer Michael Slager was fired by the North Charleston Police Department for fatally shooting the unarmed black man in the back on Saturday. Slager was charged with murder on Tuesday after a sickening cellphone video of him killing Scott surfaced. “We were shocked, definitely shocked" by the video, Rodney Scott said. "I'm angry, but he's going to have to give an account for what he did, that was just a horrible thing that he did." Rodney Scott, 48, said he will bury his brother — a father of four and a U.S. Coast Guard veteran — on Saturday. He said he doesn’t believe Slager’s claim that he stopped his brother because of a broken brake light. Walter Scott had been a member of the U.S. Coast Guard. (U.s. coast guard ) “I knew my brother was always on the run for child support,” he said. “He made sure in every vehicle that all the lights were working. He would say, ‘I don't want to get stopped by police’.” S.C. COP MICHAEL SLAGER CHARGED WITH MURDER OF WALTER SCOTT But the grieving Scott brother said he would pray for Slager. "I hope he can make his peace with God knowing he hurt a family," he said. "He made a bad choice. All I can say is he has to get it right with God and I hope he can." Scott, 50, was engaged to the mother of University of Mississippi defensive end Fadol Brown, who considered him a father figure. “Walter Scott was my step dad,” Brown tweeted. “I loved him to death that cop didn't have to shoot him down like a dog like that ... gone miss you man.” Slager, 33, was arrested Tuesday after the telltale video was released by the Scott family's lawyer and contradicted the account he gave his superiors, including his claim that he "feared for his life." The FBI and U.S. Department of Justice's Civil Rights division are now investigating the killing of Scott, who was shot five times — four times in the back, once in the ear. Also, the North Charleston Police Department has turned over its investigation to the South Carolina Law Enforcement Division, or SLED. Investigators on Thursday are expected to release the dash-cam video from Slager’s police car that could shed new light on what happened just before shooting when the officer stopped Scott for a broken brake light. Rodney Scott (l.) and his brother Anthony Scott appear at a news conference in Charleston, S.C., on Tuesday. "That was totally cold-hearted murder as far as I'm concerned," Rodney Scott told the Daily News about his brother Walter's death. (Bruce Smith/AP) Slager, who faces 30 years to life in prison if convicted, remains jailed without bond. Like Scott, he too is a Coast Guard vet. The cellphone video was taken by a young man NBC identified as Feidin Santana, who said he saw Scott and the officer struggling “on the ground” and the sound of a Taser before he recorded the fatal shooting. “They would have swept it under the rug like they have with many others," Walter Scott Sr. told NBC's "Today" show earlier Wednesday. "And I thank God that this young man, whoever it was, had the video ... When I saw it, I just fell off my feet and my heart was broken." The dead man's mom called the disturbing footage "the most horrible thing I've ever seen." "I almost couldn't look at it to see my son running defenselessly, being shot," Judy Scott said on ABC's "Good Morning America." "It just tore my heart to pieces." The scene where police-shooting victim Walter Scott, 50, was killed on Wednesday in North Charleston, S.C. North Charleston police officer Michael Slager was charged Tuesday with murder after shooting and killing Scott during a traffic stop last Saturday. (James Keivom/New York Daily News) In New York City, Mayor de Blasio said the footage was horrific. "It's difficult to look at something like that and watch someone's life taken away before your very eyes," he said. Despite the footage, an Indiegogo campaign supporting Slager has raised $300 out of a $5,000 goal. But what happened in North Charleston points out the need for body cameras for police officers. "If the citizen has done something wrong, that's captured on film," he said. "If the officer's done something wrong, it creates accountability." The NYPD is in the midst of a pilot program to test out the technology. Judy and Walter Scott Sr., Walter Scott's parents, speak on the "Today" show Wednesday about their son's death and the arrest of police officer Michael Slager. (Today Show) Meanwhile, protesters demanding justice for Scott briefly stopped traffic outside City Hall in North Charleston while dozens of demonstrators carrying signs that read "Black Lives Matter" rallied. But there was no outbreak of the kind of violence that rocked Ferguson, Mo., after black teenager Michael Brown was killed by a white officer. Charleston County Sheriff Al Cannon waded into the midst of the protesters to calm tensions and keep the peace. "We have to take a stand on stuff like this," said 23-year-old Lance Braye. "We can't just shake our heads at our computer screens." "It was just a traffic stop," said Nicole King, who said she was a friend of Scott's fiancée. "It could have been any of us." An Indiegogo campaign set up to support Officer Michael Slager has been set up, having earned $300 as of the time of writing. (www.indiegogo.com) Others streamed to the empty lot where Scott was killed. “You change your attitude immediately if you’re coming here from downtown Charleston,” said 48-year-old P. Crable Washington. “It’s a different vibe here and it isn’t good.” EDITORIAL: THE CRIMINAL KILLING OF WALTER SCOTT Earlier, North Charleston Mayor Keith Summey and Police Chief Eddie Driggers paid condolences to Scott's distraught parents. "I got to meet a daddy who is in mourning, a momma who is in mourning," Driggers said afterward at a press conference that was interrupted at times by angry outbursts. "We're gonna continue to strive to do what's right. I have been praying for peace, peace for the family and peace for this community." Walter Scott, 50, was running away when he was shot by a police officer. (Facebook) Michael Slager, 33, faces a murder charge and is held without bond. (NCPD) Driggers added that he was "sickened" by what he saw on the video. But neither he nor Summey delved into the details of the investigation. “We’re still waiting for all the information to come back to us," said Summey, who has issued an order requiring all of his city’s cops to start wearing body cameras. Summey added that Slager’s wife is eight months pregnant and the city will cover her insurance until after the baby is born. The couple also have two step-children. The fatal encounter began at 9:30 a.m. Saturday when Slager pulled over Scott. Slager claimed he opened fire after he struggled with Scott and the victim ran off with his Taser. Anthony Scott, left, hugs visitors outside his home near North Charleston, S.C., on Wednesday. His brother Walter Scott was killed by a North Charleston police officer after a traffic stop Saturday. (Chuck Burton/AP) The video, however, told a different tale. In it, Scott — dressed in a green shirt and jeans — was seen running away and at least 15 feet from Slager when the officer fired the first of eight shots. "Shots fired!" Slager said into his radio as he closed in on Scott. Then, as Slager circled Scott, who was lying facedown and not moving, he shouted, "Put your hands behind your back!" Slager then cuffed the Scott's hands before jogging back to where he had been before and picking something off the ground. Walter Scott lies facedown at the feet of North Charleston cop Michael Slager, who was charged with murder Tuesday. Video shows Officer Michael Slager unleash a hail of bullets at the fleeing 50-year-old Walter Scott. (HANDOUT) This image from a video shows Officer Michael Slager shooting Walter Scott in the back as he ran away. Slager appears to pick something up. Officer Michael Slager appears to be holding something. Officer Michael Slager fatally appears to drop the item he was previously holding. By then another cop had arrived at the scene and when Slager returned to Scott he dropped an object — apparently the stun gun — by his body. The police report stated responding officers performed CPR on Scott. There was no sign of anybody performing CPR on Scott in the video. Scott had been arrested 10 times in the past, mostly for not paying child support. Back in 1987, he was busted on an assault and battery charge and convicted in 1991 of possession of a bludgeon, The Post & Courier newspaper In Charleston, S.C., reported. Scott's kin said he was not a violent man. And his killing stirred memories of the fatal Brown shooting and the chokehold death of Eric Garner on Staten Island at the hands of an NYPD officer. Roughly 80% of North Charleston’s police officers are white in a city where blacks account for 47% of the more than 100,000 residents, according to the most recent DOJ figures. Many Scott supporters complained Wednesday that North Charleston's mostly white police force routinely harasses the city's black residents for minor traffic offenses. WALTER SCOTT VIDEO: CELEBS SHARE OUTRAGE ONLINE Those claims were buttressed by a report in The Post & Courier which found that in 2010 that black drivers in North Charleston were involved in 65% of all traffic stops that didn't involve a ticket or an arrest. That's about 25,000 stops, the paper reported. “I am not surprised at the shooting,” Rep. James Clyburn, the state’s only Democrat on Capitol Hill, said on MSNBC. Riffing off Driggers’ statement that his cops are like his children, Clyburn added: "There comes a time in dealing with our children when we have to have some tough love and I think that this calls for some tough love in this instance.” Ed Bryant, president of the North Charleston chapter of the NAACP, said relations with the police have improved since Driggers took over two years ago but problems still remain with the beat cops. “There has been a good conversation at the top,” Bryant said. “But nothing has changed at the bottom level.” Slager is the third South Carolina cop to be hit in recent years with a criminal charge for killing an unarmed black man. One of those cases in ongoing and the charge against that officer was reduced on Tuesday to shooting into an occupied vehicle — a misdemeanor. Scott, left, appears to be running away from Slager, right. The officer in the other case was cleared by the feds of criminal wrongdoing but his department agreed to pay a $400,000 settlement to the victim’s family. Over the past five years, Palmetto State police officers shot at 209 suspects — less than half of them black, according to an analysis from The State, a newspaper based in the state capital of Columbia. But only “a few” police officers were accused of shooting illegally and none were convicted, the paper reported. In 2014, state prosecutors brought excessive force charges against three white officers who were involved in the shooting of black drivers. But only one case went to trial, and it ended with a hung jury, The State reported. The Rev. Al Sharpton commended the North Charleston police for arresting Slager but said more needs to be done. “When a black man is stopped for a broken taillight and ends up being shot multiple times in the back, it is yet another reminder that we need a national strategy to implement real and meaningful police reform now," he said. "We simply can't rely on citizens with video cameras to make sure justice is served.” The tragedy found Sharpton on the same page with both of South Carolina’s conservative Republican senators. “The horrific video is very difficult to watch and deeply troubling on many fronts,” Sen. Lindsey Graham said, who added that it did not “accurately reflect” the actions of most cops. Earlier, Sen. Tim Scott called it a “senseless” shooting that was “absolutely unnecessary and avoidable.” ON A MOBILE DEVICE? WATCH THE VIDEO HERE. With Celeste Katz, Rocco Parascandola, Matthew Lysiak ||||| Breaking News Emails Get breaking news alerts and special reports. The news and stories that matter, delivered weekday mornings. / Updated / Source: NBC News By Phil Helsel The bystander who captured on video a white police officer shooting an apparently unarmed black man in the back in South Carolina thought about erasing the recording over fears of retaliation. The video recorded by Feidin Santana shocked the nation when it was released this week. The footage resulted in Officer Michael Slager, 33, being arrested and charged with murder Tuesday for the shooting death of Walter Scott, 50, after a traffic stop in North Charleston Saturday. "I won’t deny that I knew the magnitude of this, and I even thought about erasing the video," Santana said in an interview on MSNBC’s "All In With Chris Hayes" Wednesday. "I felt that my life, with this information, might be in danger. I thought about erasing the video and just getting out of the community, you know Charleston, and living some place else," the 23-year-old said. "I knew the cop didn't do the right thing." In an interview with TODAY's Matt Lauer on Thursday, Santana said: "I'm still scared." "I say life changed in a matter of seconds. I never thought this would happen, that I would be a witness," he told TODAY's Matt Lauer in an exclusive interview Thursday. "I'm still scared." Earlier Wednesday, Santana revealed himself as the videographer to "NBC Nightly News" anchor Lester Holt in his first interview since the shooting, and said Slager and Scott did struggle before the encounter turned deadly. But he said the officer did not appear to be in danger when he opened fire. "Before I started recording, they were down on the floor. I remember the police [officer] had control of the situation," Santana said. "He had control of Scott. And Scott was trying just to get away from the Taser. But like I said, he never used the Taser against the cop." "As you can see in the video, the police officer just shot him in the back," Santana said. "I knew right away, I had something on my hands." Slager claimed Scott grabbed his Taser and that he feared for his life. The video shows an object being thrown to the ground and Scott running away, and a delay before the officer fires seven times, pauses, and fires an eighth time. Scott's parents told TODAY on Wednesday they believe Scott fled from Slager because he owed child support and didn't want to go to jail again. Santana said he turned over the video after reading the police report and hearing about it on the news. "It wasn’t like that, the way they were saying," Santana said on MSNBC. "I said, 'No ... this is not what happened.'" Santana told NBC News that when he turned over the video to Scott's family, "they were very emotional when that happened, including me also." "I thought about his position, their situation ... If I were to have a family member that would happen [to], I would like to know the truth," Santana said. He has been called a "hero" by attorneys for the family, but Santana said there are no winners in the situation. "It’s not something that no one can feel happy about. He has his family, Mr. Scott also has his family," Santana told NBC News. "But I think, you know, he [the officer] made a bad decision, and you pay for your decisions in this life." "Mr. Scott didn’t deserve this, and there were other ways that can be used to get him arrested, and that wasn’t the proper way to do that." Police Chief Eddie Driggers said when he watched the video of the encounter, "I was sickened by what I saw." North Charleston Mayor Keith Summey announced Wednesday that Slager was fired. He also ordered body cameras for the police force. Every officer on the street will wear one after a policy is established and the force is trained, Summey said. Slager is being held without bond at Charleston County Jail.

– The disturbing video that resulted in murder charges for a North Charleston, SC, police officer almost never saw the light of day. In an MSNBC interview, Feiden Santana says he feared for his life after taking video of Michael Slager shooting Walter Scott in the back as the 50-year-old Scott ran away. "I thought about erasing the video and just getting out of the community, you know Charleston, and living someplace else," the 23-year-old says. "I knew the cop didn't do the right thing." Instead of deleting the video or leaving town, Santana turned it over to Scott's family. "I wanted them to have this and do something about it," he says. "Because I knew if I didn't give it to them, nothing would happen." In an earlier NBC News interview, Santana said the pair were struggling on the ground before he started filming. Slager "had control of Scott, and Scott was trying just to get away from the Taser," he said. According to a Guardian analysis of the video and police scanner audio, Slager made a radio call saying Scott had "grabbed my Taser" just six seconds after firing the final shot. The officer was fired yesterday, and Scott's brother tells the New York Daily News he will pray for him, even though he "was using my brother for target practice." The brother says he doesn't believe Scott, who owed child support, was really stopped for a broken brake light. "He made sure in every vehicle that all the lights were working," he says. "He would say, 'I don't want to get stopped by police.'"

the mechanical response of most cells arises from the mechanics of its cytoskeleton , a polymeric scaffold that spans the interior of these cells , and its interaction with the extra - cellular environment . the cytoskeleton is made up of complex assemblies of protein filaments crosslinked and bundled together by a variety of accessory proteins . for example , there are approximately 23 distinct classes of accessory proteins such as fascin , @xmath0-actinin , and filamin a @xcite that crosslink filamentous - actin ( f - actin ) , a major component of the cytoskeleton that is resposible for the mechanical integrity and motility of cells . given the multitude of crosslinkers , several natural questions arise : are the different types of crosslinkers redundant , or do they each serve specific functions ? do they act independently or cooperatively ? what are the consequences of their mechanics for the mechanical integrity and response of the cell ? a mutation study of _ dictyostelium discoideum _ cells lacking a particular actin crosslinking can still grow , locomote , and develop , though with some defects , thereby suggesting at least partial redundancy in the crosslinker s mechanical function @xcite . on the other hand , two types of crosslinkers working cooperatively may produce enhanced mechanical response . this cooperativity has been demonstrated in stress fibers crosslinked with the actin binding proteins ( abp ) @xmath0-actinin and fascin , where stress fibers containing both @xmath0-actinin and fascin were more mechanically stable than stress fibers containing only @xmath0 -actinin or fascin @xcite . in addition , it has been found that two different crosslinkers are required for actin bundle formation _ in vivo _ @xcite . it could also be the case that different crosslinkers work independently of one another such that the dominant crosslinker dictates the mechanical response of the network @xcite . given these various possibilities , how the cell uses different crosslinking proteins to optimize for certain mechanical characteristics is an important open issue in cytoskeletal mechanics . here , we address this redundancy versus cooperativity issue by studying a model network of semiflexible filaments crosslinked with two types of crosslinkers . we first study the mechanical properties of the model network with one type of crosslinker and then add the second type of crosslinker and look for mechanical similarities and differences with the original model network . in addition , we also address the redundancy versus cooperativity issue of two types of crosslinkers for networks made of flexible filaments . as for the two types of crosslinkers , we consider crosslinkers that allow the crossing filaments to rotate freely ( freely - rotating crosslinks ) and crosslinkers that constrain the angle between two filaments . the abp @xmath0-actinin is a candidate for the former type of crosslinking mechanics : optical trapping studies demonstrate that two filaments bound by @xmath0-actinin can rotate easily @xcite . as an example of the latter , we consider filamin a ( flna ) , which binds two actin filaments at a reasonably regular angle of ninety degrees , suggesting that flna constrains the angular degrees of freedom between two filaments @xcite . here , we do not take into account the possible unfolding of flna since the energy to unfold filamin a is large @xcite , nor do we take into account the kinetics of flna since we seek to understand fully the mechanics in the static regime first . there exist other possible examples of angle - constraining crosslinkers such as arp2/3 that serves a dual role as an f - actin nucleator and a crosslinker @xcite . while its role as a nucleator has been emphasized in lamellipodia formation @xcite , its role constraining the angle between the mother and daughter filaments is presumably also important for lamellipodia mechanics . better understanding of the mechanical role of arp2/3 in lamellipodia may also help to distinguish between the dendritic nucleation model for lamellipodia formation and a new model where arp2/3 only nucleates new filaments but does not produce branches @xcite . in studying the mechanical properties of compositely crosslinked filamentous networks , we focus on the onset of mechanical rigidity as the filament concentration is increased above some critical threshold . this onset is otherwise known as rigidity percolation @xcite . above this critical threshold , both experiments and theoretical studies of f - actin networks have observed distinct mechanical regimes . for dense , stiff networks the mechanical response is uniform or affine and the strain energy is stored predominantly in filament stretching modes . while for sparse , floppy networks one finds a non - affine response dominated by filament bending where the observed mechanical response of the network is inhomogeneous and highly sensitive to the lengthscale being probed @xcite . it has been recently reported that there exists a _ bend - stretch _ coupled regime for intermediate crosslinking densities and filament stiffnesses @xcite . while considerable progress has been made in understanding the mechanics of cytoskeletal networks that are crosslinked by one type of crosslinkers , compositely crosslinked networks are only beginning to be explored experimentally @xcite as are composite filament networks with one type of crosslinker theoretically @xcite . here we investigate the mechanics of such networks as a function of the concentration and elasticity of the crosslinkers and the filaments . we arrange infinitely long filaments in the plane of a two - dimensional triangular lattice . the filaments are given an extensional spring constant @xmath0 , and a filament bending modulus @xmath1 . we introduce finite filament length @xmath2 into the system by cutting bonds with probability @xmath3 , where @xmath4 , with no spatial correlations between these cutting points . the cutting generates a disordered network with a broad distribution of filament lengths . when two filaments intersect , there exists a freely - rotating crosslink preventing the two filaments from sliding with respect to one another . next , we introduce angular springs with strength @xmath5 between filaments crossing at @xmath6 angles with a probability @xmath7 , where @xmath8 denotes non - collinear . these angular springs model the second type of crosslinker . see fig.[fig0 ] for a schematic . we study the mechanical response of this disordered network under an externally applied strain in the linear response regime . for simplicity we set the rest length of the bonds to unity . let @xmath9 be the unit vector along bonds and @xmath10 the strain on the bond @xmath11 . for small deformation @xmath12 , the deformation energy is [ energies ] e & = & _ ij p_ij ( _ ij . _ ij ) ^2 + _ = p_ij p_jk ( ( _ ji + _ jk ) _ ji ) ^2 + & + & _ p_ij p_jk p_nc ^2 where @xmath13 is the probability that a bond is occupied , @xmath14 represents sum over all bonds and @xmath15 represents sum over pairs of bonds sharing a node . the first term in the deformation energy corresponds to the cost of extension or compression of the bonds , the second term to the penalty for the bending of filament segments made of pairs of adjacent collinear bonds , and the last term to the energy cost of change in the angles between crossing filaments that meet at @xmath6 angle . furthermore , for small deformations @xmath16 . it is straightforward to see that the angular spring @xmath17 between @xmath11 and @xmath18 will contribute to an effective spring in parallel with @xmath19 , giving rise to an enhanced effective spring constant @xmath20 . we study the effective medium mechanical response for such disordered networks following the mean field theory developed in @xcite for central force networks and @xcite for filament bending networks . the aim of the theory is to construct an effective medium , or ordered network , that has the same mechanical response to a given deformation field as the depleted network under consideration . the effective elastic constants are determined by requiring that strain fluctuations produced in the original , ordered network by randomly cutting filaments and removing angular springs vanish when averaged over the entire network . let us consider an ordered network with each bond having a spring constant @xmath21 , a filament bending constant for adjacent collinear bond pairs @xmath22 , and an angular bending constant @xmath23 between bonds making @xmath6 angles . under small applied strain , the filament stretching and filament bending modes are orthogonal , with stretching forces contributing only to deformations along filaments ( @xmath24 ) and bending forces contributing only to deformations perpendicular to filaments ( @xmath25 ) , and hence we can treat them separately . the angular forces due to the angular ( non - collinear ) springs , when present , contribute to stretching of filaments as discussed earlier , where we only consider three body interactions . for these springs to contribute to bending one needs to consider four - body interactions which is outside the scope of this paper and will be addressed in future work . we start with the deformed network and replace a pair of adjacent collinear bonds with bending rigidity @xmath22 by one with a rigidity @xmath1 , and a bond spring with extensional elastic constant @xmath21 by a spring with an elastic constant @xmath26 and the facing @xmath6 angular spring by @xmath5 . this will lead to additional deformation of the above filament segments and the angle which we calculate as follows . the virtual force that needs to be applied to restore the nodes to their original positions before the replacement of the bonds will have a stretching , a bending and an angular contribution : @xmath27 , @xmath28 , and @xmath29 . the virtual stretching force is given by @xmath30 , the virtual filament bending force is @xmath31 , while the virtual force to restore the angle is @xmath32 , where @xmath33 , @xmath34 and @xmath35 are the corresponding deformations in the ordered network under the applied deformation field . by the superposition principle , the strain fluctuations introduced by replacing the above bending hinges and bonds in the strained network are the same as the extra deformations that result when we apply the above virtual forces on respective hinges and segments in the unstrained network . the components of this `` fluctuation '' are , therefore , given by : d _ & = & + d _ & = & + d&= & the effective medium spring and bending constants , @xmath21 , @xmath22 and @xmath23 , respectively , can be calculated by demanding that the disordered - averaged deformations @xmath36 , @xmath36 , and @xmath37 vanish , i.e. @xmath38 , @xmath39 , and @xmath40 . to perform the disorder averaging , since the stretching of filaments is defined in terms of spring elasticity of single bonds @xmath0 , the disorder in filament stretching is given by @xmath41 . filament bending , however , is defined on pairs of adjacent collinear bonds with the normalized probability distribution @xmath42 . similarly , for the angular springs , the normalized probability distribution is given by @xmath43 . this disorder averaging gives the effective medium elastic constants as a function of @xmath44 and @xmath7 as @xmath45 the constants @xmath46 , @xmath47 and @xmath48 for the network contribution to the effective spring constant @xmath49 of bonds , to the filament bending rigidity @xmath50 , and the bending rigidity @xmath51 of angular springs making @xmath6 angles respectively , are given by @xmath52 $ ] . the sum is over the first brillouin zone and @xmath53 is the coordination number . the stretching , filament bending and non - collinear bending contributions , @xmath54 respectively , to the full dynamical matrix @xmath55 , are given by : @xmath56 \rbold_{ij } \rbold_{ij } \nonumber \\ { \dbold_b}(q ) & = & \kappa_m \sum_{\langle ij \rangle } \left [ 4(1 - \cos(\qbold.\rbold_{ij } ) ) \right . \nonumber \\ & & \left . - ( 1 - \cos(2 \qbold.\rbold_{ij } ) ) \right ] \left(\itens-\rbold_{ij } \rbold_{ij } \right ) \nonumber \\ \dbold_{nc } ( q ) & = & \frac{3}{2 } \kappa_{nc , m } \sum \left [ 2 ( 1 - \cos(\qbold.\rbold_{ij } ) ) + 2 ( 1 - \cos(\qbold.\rbold_{ik } ) ) \right . \nonumber \\ & & \left . - 2 ( 1 - \cos(\qbold.\rbold_{jk } ) ) \right ] \rbold_{ij } \rbold_{ik}\label{dnc}\end{aligned}\ ] ] with @xmath57 the unit tensor and the sums are over nearest neighbors @xcite . note that for small @xmath58 , @xmath59 and @xmath60 have the expected wavenumber dependencies for bending and stretching . by definition , @xmath61 , where @xmath62 is the dimensionality of the system . at the rigidity percolation threshold @xmath63 , @xmath21 , @xmath22 and @xmath23 vanish , giving @xmath64 , @xmath65 and @xmath66 . for semiflexible filament networks with only freely - rotating crosslinks i.e. filament stretching and bending interactions only , the rigidity percolation threshold is given by @xmath67 . for networks with angle - constraining crosslinks , at @xmath68 , we obtain rigidity percolation thresholds @xmath69 for the case of flexible filament networks , and @xmath70 for semiflexible filament networks . we also calculate how @xmath71 changes on continuously increasing @xmath7 from @xmath72 to @xmath73 . simulations were carried out on a triangular lattice with half periodic boundary conditions along the shear direction for the energetic terms whose small deformation limit is given in eq . . networks were constructed by adding bonds between lattice sites with probability @xmath44 . next , a shear deformation was applied to the two fixed boundaries of magnitude @xmath74 . the lattice was then relaxed by minimizing its energy using the conjugate gradient method @xcite allowing the deformation to propagate into the bulk of the lattice . once the minimized energetic state was found within the tolerance specified , in this case the square root of the machine precision @xmath75 , the shear modulus was then measured using the relation , @xmath76 , using small strains @xmath77 , with @xmath2 denoting the system length and @xmath78 denoting the area of the unit cell for a triangular lattice which is equal to @xmath79 in our units . system size @xmath80 was studied , unless otherwise specified , and sufficient averaging was performed . * mechanical integrity as measured by the shear modulus : * on a triangular lattice , networks made solely of hookean springs lose rigidity at a bond occupation probability around @xmath81 @xcite . this result corresponds to the central force isostatic point at which the number of constraints is equal to the number of degrees of freedom on average . in contrast , networks made of semiflexible filaments become rigid at a smaller @xmath44 due to extra constraints placed on the system via filament bending . for semiflexible networks with freely - rotating crosslinks , our effective medium theory shows that the shear modulus , @xmath82 , approaches zero at @xmath67 as shown in fig.[fig1 ] @xmath83 . this result is in good agreement with our simulation results yielding @xmath84 and previous numerical results @xcite . see fig.[fig1 ] @xmath85 . a different formulation of the emt yields @xmath86 @xcite . by introducing additional crosslinks that constrain angles between filaments at @xmath6 , the rigidity percolation threshold is lowered . our emt yields @xmath70 and our simulations yield @xmath87 for @xmath68 ( fig.[fig1 ] @xmath88 and @xmath89 ) . the cooperative mechanical interplay between these crosslinks and their interaction with filaments allows the network to form a rigid stress - bearing structure at remarkably low crosslinking densities , almost immediately after it attains geometric percolation , @xmath90 , which agrees with a calculation by kantor and webman @xcite . for flexible filament networks , introducing angle - constraining crosslinkers also lowers the rigidity percolation threshold as compared to the isostatic point with the network attaining rigidity at @xmath69 for our emt and @xmath91 in the simulations ( ( fig.[fig1 ] @xmath92 and @xmath93 ) . incidentally , our result agrees very well with a previous simulation @xcite . we also compute analytically and numerically how @xmath71 changes with @xmath7 . see fig.[fig2]@xmath83 , @xmath92 and @xmath88 . note that @xmath71 is lowered continuously as the concentration of angle - constraining crosslinks is increased . just above the rigidity percolation threshold , for a semiflexible network with freely - rotating crosslinks , we find a bending - dominated regime for sparse networks with the shear modulus eventually crossing over to a stretch dominated affine regime at higher filament densities . the purely stretch dominated regime is represented by the macroscopic shear modulus @xmath82 staying almost constant with increasing @xmath44 , while in the purely bend dominated regime the network is highly floppy and @xmath82 is a sensitive function of @xmath44 , decreasing rapidly as @xmath44 is lowered . this behavior has been observed previously in @xcite . for @xmath94 , both the effective medium theory and the simulations yield a bend - stretch coupled regime , which is characterized by an inflection in @xmath82 as a function of @xmath44 as observed most clearly for @xmath95 ( with @xmath96 ) . we find a similar non - affine to affine crossover for the compositely crosslinked flexible filament networks and semflexible filament networks as @xmath44 is increased . for the flexible filament networks , however , the bend - stretch coupling regime occurs for @xmath97 , i.e. @xmath5 replaces @xmath1 . for semiflexible filament networks , as long as @xmath98 , the bend - stretch coupled regime is robust ( for fixed @xmath7 ) . in contrast , for @xmath99 , the angle - constraining crosslinker suppresses the bend - stretch coupled regime and enhances the shear modulus to that of an affinely deforming network ( for fixed @xmath7 ) . the mechanics of the network has been altered with the introduction of the second type of crosslinker . * non - affinity parameter : * to further investigate how the interaction of the crosslinkers affects the affine and non - affine mechanical regimes , we numerically study a measure for the degree of non - affinity in the mechanical response , @xmath100 , defined in ref.@xcite as : = _ i^n(_i-_aff)^2 . [ na ] the non - affinity parameter can be interpreted as a measure of the proximity to criticality , diverging at a critical point as we approach infinite system size . we find that @xmath100 develops a peak at the rigidity percolation threshold , which progressively moves to smaller values of @xmath44 as the concentration of angular crosslinkers @xmath7 is increased ( fig.[fig3 ] @xmath83 ) . a second peak develops near the isostatic point for @xmath98 as seen in fig.[fig3 ] @xmath92 . as both the collinear and non - collinear bending stiffnesses tend to zero , the network mechanics approaches that of a central force network , and the second peak in @xmath100 at the isostatic point becomes increasingly more pronounced . on the other hand , this second peak can be suppressed by increasing @xmath101 ( fig.[fig3 ] @xmath92 ) , or by increasing the concentration @xmath7 ( fig.[fig3 ] @xmath83 ) even for very small values of @xmath102 . this further corroborates that adding angle - constraining crosslinkers to non - affine networks can suppress non - affine fluctuations , provided they energetically dominate over filament bending . the reason for this suppression can be understood by considering the effect of adding a constraint which prohibits the free rotation of crossing filaments . as the concentration of these non - collinear crosslinks @xmath7 is increased ( at fixed avg . filament length ) microscopic deformations will become correlated . the lengthscale associated with this correlation will increase on increasing either @xmath44 or @xmath7 , and will eventually reach a lengthscale comparable to system size even at @xmath103 at large enough concentration and/or stiffness of the angular springs . as a result the mechanical response of the network will approach that of an affinely deforming network . upon decreasing the value of @xmath104 relative to @xmath102 we again recover the second peak because energetically the system can afford to bend collectively near the isostatic point . * scaling near the isostatic point : * finally , using scaling analysis we quantify the similarity in mechanics between freely - rotating crosslinked semiflexible networks and compositely crosslinked flexible networks . to do this , we examine the scaling of the shear modulus @xmath82 near the isostatic point with @xmath105 . for @xmath106 ( or @xmath107 ) , the shear modulus scales as @xmath108 ( or @xmath109 ) @xcite . for both @xmath110,@xmath111 and @xmath112 , @xmath113 , the emt predicts @xmath114 and @xmath115 as shown in fig.[fig4](a ) and ( b ) , indicating that both types of networks demonstrate redundant , or generic , mechanics . to compare the emt results with the simulations , we use the position in the second peak in @xmath100 to determine the central force percolation threshold , @xmath116 , and then vary @xmath117 and @xmath118 to obtain the best scaling collapse . for case ( a ) , @xmath119 , @xmath120 and @xmath121 . for case ( b ) , @xmath122 , @xmath120 and @xmath123 . both sets of exponents are reasonably consistent with those found in ref . @xcite for a semiflexible network with freely - rotating crosslinks only . preliminary simulations for compositely crosslinked semiflexible networks indicate that the shear modulus scales as @xmath124 also with a similar @xmath117 and a similar @xmath118 with @xmath125 . in the limit of small strain , we conclude that the presence of multiple crosslinkers in living cells can be simultaneously cooperative and redundant in response to mechanical cues , with important implications for cell mechanics . redundant functionality helps the cytokeleton be robust to a wide range of mechanical cues . on the other hand , different crosslinkers can also act cooperatively allowing the system to vary the critical filament concentration above which the cytoskeleton can transmit mechanical forces . this may enable the cytoskeleton to easily remodel in response to mechanical cues via the binding / unbinding of crosslinkers ( tuning concentration ) or their folding / unfolding ( tuning stiffness and type of crosslinker ) . since the cytoskeleton consists of a finite amount of material , the ability to alter mechanics without introducing major morphological changes or motifs may play important role in processes such as cell motility and shape change . * cooperativity : * in our study of two types of crosslinkers , crosslinkers that allow free rotations of filaments and crosslinkers that do not , we find two types of cooperative effects in the mechanics of such compositely crosslinked networks . the first cooperative effect depends on the relative concentration of the two types of crosslinkers and second depends on the relative stiffness of the angle - constraining crosslinkers to the bending stiffness of the individual filaments . the first cooperative effect can be most strikingly observed beginning with an actin/@xmath0-actinin network and increasing the concentration of flna , with @xmath0-actinin representing the freely - rotating crosslinker @xcite and flna representing the angle - constraining crosslinker @xcite . by tuning the concentration of flna , the cell can modulate the minimum concentration of actin filaments necessary to attain mechanical rigidity , which can be essentially as low as the filament concentration required to form a geometrically percolating structure . this is in good agreement with the experimental observation that flna creates an f - actin network at filament concentrations lower than any other known crosslinker @xcite . increasing the flna concentration also suppresses the non - affine fluctuations near the rigidity percolation threshold by increasing the shear modulus of the network and giving rise to a more affine mechanical response while keeping the filament concentration fixed . moreover , the cooperativity of @xmath0-actinin and flna working to ehance the mechanical stiffness of actin networks has recently been observed in experiments @xcite . the addition of angle - constraining crosslinkers to flexible filament networks also decreases the concentration threshold required for mechanical rigidity , though the lower bound on the threshold is not as close as to geometric percolation as it is for semiflexible filaments . the lowering of the rigidity percolation threshold is independent of the energy scale of the crosslinker . it depends purely on the number of degrees of freedom the crosslinker can freeze out between two filaments , i.e. the structure of the crosslinker . the second cooperative interplay between the two crosslinkers depends on the energy scale of the angle - constraining crosslinker to the filament bending energy . for @xmath126 , the freely - rotating semiflexible filament system exhibits large non - affine fluctuations near the isostatic point . upon addition of the angle - constraining crosslinkers , for @xmath127 , the non - affine fluctuations near this point become suppressed and the mechanics of the angle - constraining crosslinker dominates the system . once again , with a small change in concentration of the second crosslinker , the mechanical response of the network is changed dramatically . * redundancy : * we observe two redundant effects in these compositely crosslinked networks , the first of which depends on energy scales . for @xmath128 with @xmath126 , the non - affine fluctuations near the isostatic point in the freely - rotating crosslinker semiflexible filament network remain large even with the addition of the angle - constraining crosslinker . in other words , the angle - constraining crosslinkers are redundant near the isostatic point . their purpose is to decrease the amount of material needed for mechanical rigidity as opposed to alter mechanical properties at higher filament concentrations . redundancy is also evident in the mechanics of these networks sharing some important , generic properties . all three networks studied here ( free - rotating crosslinked semibflexible networks and compositely crosslinked semiflexible and flexible networks ) have three distinct mechanical regimes : a regime dominated by the stretching elasticity of filaments , a regime dominated by the bending elasticity of filaments and/or stiffness of angle - constraining crosslinkers , and an intermediate regime which depends on the interplay between these interactions . the extent of these regimes can be controlled by tuning the relative strength of the above mechanical interactions . in particular , the ratio of bending rigidity to extensional modulus of an individual actin filament is @xmath129 @xcite . since the bend - stretch coupled regime has not been observed in prior experiments on _ in - vitro _ actin networks crosslinked with flna only , we conjecture that the energy cost of deformation of angles between filaments crosslinked with flna is larger than the bending energy of filaments . the qualitative redundancy becomes quantitative , for example , near the isostatic point where we obtain the same scaling exponents for @xmath82 as a function of @xmath130 and @xmath1(or @xmath5 ) for the free - rotating crosslinked semiflexible network and the compositely crosslinked flexible network . preliminary data suggests the same scaling extends to compositely crosslinked semiflexible networks . this result is an indication of the robustness of these networks and should not be considered as a weakness . whether or not this robustness extends to systems experiencing higher strains such that nonlinearities emerge is not yet known . * lamellipodia mechanics : * the interplay between cooperative and redundant mechanical properties may be particularly important for the mechanics of branched f - actin networks in lamellipodia . within lamellipodia , there exist some filament branches occuring at an angle of around @xmath131 with respect to the plus end of the mother filament ( referred to as @xmath132 junctions ) . these branches are due to the abp arp2/3 @xcite . during lamellipodia formation , these branches are presumed to be the dominant channel for filament nucleation . the mechanics of arp2/3 can be modeled as an angular spring between the mother and daughter filament with an angular spring constant of approximately @xmath133 @xcite . in other words , arp2/3 is an angle - constraining crosslinker for @xmath132junctions ( as opposed to @xmath134junctions ) , and thereby plays an important role in lamellipodia mechanics as demonstrated in this work . the mechanical role of arp2/3 in lamellipodia has not been investigated previously and may help to discriminate between the dendritic nucleation model @xcite and a new model @xcite by predicting the force transmitted in lamellipodia as a function of the arp2/3 concentration . in addition to arp2/3 , flna localizes at @xmath134junctions in the lamellipodia and is thought to stabilize the dendritic network @xcite . both angle - constraining crosslinkers lower the filament concentration threshold required for mechanical rigidity in the system . depending on the energy scale of flna as compared to the energy scale of arp2/3 , addition of the flna may or may not modulate , for example , the bend - stretch coupling regime at intermediate filament concentrations . again , at times mechanical redundancy is needed and at times not . with three crosslinkers , the system can maximize the redundancy and the cooperativity . of course , lamellipodia are dynamic in nature and are anisotropic since the arp2/3 is activated from the leading edge of a cell . both attributes will modulate the mechanical response . * outlook : * we have demonstrated both cooperativity and redundancy in the mechanics of compositely crosslinked filamentous networks . we have done so while maintaining the structure of an isotropic , unbundled filament network . of course , crosslinkers can alter the morphology of the network via bundling , for example . in other words , different crosslinkers serve specific functions . this specificity results in a change in microstructure . this will presumably affect the mechanics such that the cooperative and redundant interactions between multiple crosslinkers may differ from the above analysis . for example , the crosslinker that dominates in terms of creating the morphology will presumably dominate the mechanics . schmoller and collaborators @xcite suggest that crosslinker with the higher concentration determines the structure and , therefore , the mechanics . instead of redundancy or cooperativity , the specificity leads to the simple additivity of two types of crosslinkers in that different crosslinkers act independently of one another . in this study , however , we find both cooperativity and redundancy in the network mechanics even in the absence of such structural changes @xcite , which , is arguably less intuitive and , therefore , more remarkable . finally , while our focus here has been on the actin cytoskeleton as an example of a filamentous network , our results can be extended to collagen networks as well @xcite . daq would like to thank silke henkes and xavier illa for useful discussions regarding lattice simulations . md would like to thank alex j. levine , f. c. mackintosh , c. broedersz , t.c . lubensky , c. heussinger and a zippelius for discussions on the mechanics of semiflexible networks . md and jms also acknowledge the hospitality of the aspen center for physics where some of the early discussions took place . jms is supported by nsf - dmr-0654373 . md is supported by a veni fellowship from nwo , the netherlands . rivero f , furukawa r , fechheimer m , noegel aa ( 1999 ) three actin cross - linking proteins , the 34 kda actin - bundling protein , alpha - actinin and gelation factor ( abp-120 ) have both unique and redundant roles in the growth and development of _ dictyostelium_. _ j. cell sci . _ 112:2737 - 2751 . tseng y , kole tp , lee jsh , fedorov e , almo sc , schafer bw , wirtz d ( 2005 ) how actin crosslinking and bundling proteins cooperate to generate an enhanced mechanical response . _ _ 334 : 183 - 192 . tilney lg , connelly ka , vranich mk , shaw mk , guild gm ( 1998 ) why are two different cross - linkers necessary for actin bundle formation in vivo and what does each cross - link contribute ? _ j. cell biol . _ 143 : 121 - 133 . nakamura f , osborn tm , hartemink ca , hartwig jh , stossel tp ( 2007 ) structural basis of filamin a functions _ j. cell biol _ 179 : 1011 - 1025 ; stossel tp , condeelis j , cooley l , hartwig jh , noegel a , schleicher m , shapiro ss ( 2001 ) filamins as integrators of cell mechanics and signalling _ nat rev mol cell biol _ 2:138 - 45 . gardel ml , nakamura f , hartwig jh , stossel tp , weitz da ( 2006 ) prestressed f - actin networks cross - linked by hinged filamins replicate mechanical properties of cells _ _ 103:1762 - 1767 . blanchoin l , amann kj , higgs hn , marchand j - b , kaiser da , pollard td ( 2000 ) direct observation of dendritic actin filament networks nucleated by arp2/3 complex and wasp / scar proteins _ nature _ 404 : 1007 - 1011 . latva - kokko m , timonen j ( 2001 ) rigidity of random networks of stiff fibers in the low - density limit _ phys . 64:066117 , 5 pgs ; latva - kokko m , mkinen j , timonen j , rigidity transition in two - dimensional random fiber networks _ phys . 63:046113 , 10 pages . head da , levine aj , mackintosh fc ( 2003 ) deformation of cross - linked semiflexible polymer networks _ phys . lett . _ 91:108102 , 4 pgs . ; head da , mackintosh fc , levine aj ( 2003 ) distinct regimes of elastic response and deformation modes of cross - linked cytoskeletal and semiflexible polymer networks _ phys . 68 : 061907 , 15 pgs . ; head , f.c . mackintosh and a.j . levine ( 2003 ) nonuniversality of elastic exponents in random bond - bending networks _ phys . 68:025101(r ) , 4 pgs . gardel ml , shin jh , mackintosh fc , mahadevan l , matsudaira pa , weitz da scaling of f - actin network rheology to probe single filament elasticity and dynamics ( 2004 ) _ phys . _ 93 : 188102 , 4 pgs . ; gardel ml , shin jh , mackintosh fc , mahadevan l , matsudaira pa , weitz da , elastic behavior of cross - linked and bundled actin networks _ science _ 304:1301 - 1305 . wagner b , tharmann r , haase i , fischer m , bausch a r ( 2006 ) cytoskeletal polymer networks : the molecular structure of cross - linkers determines macroscopic properties _ proc . _ 103:13974 - 13978 . , and angle - constraining crosslinker occupation probability @xmath135 the purple lines denote semiflexible filaments , the red arcs denote angle - constraining crosslinks , the black circles represent nodes where all crossing filaments are free to rotate , while the grey circles denote nodes where some of the crossing filaments are free to rotate . the filament bending stiffness relative to stretching stiffness @xmath136 and the stiffness of angular crosslinks relative to stretching stiffness @xmath137 . ] for semiflexible networks with freely - rotating crosslinks ( ( a ) and ( d ) ) , flexible networks with freely - rotating and angle - constraning crosslinks ( ( b ) and ( e ) ) , and semiflexible networks with both crosslinkers ( ( c ) and ( f)).the top panels show results from the effective medium theory and bottom panels show results from the simulations.,scaledwidth=100.0% ] for the semiflexible filaments and @xmath80 for the flexible filaments . figures ( b ) and ( c ) show the shear modulus ( in logarithmic scale described by the colorbar ) as a function of @xmath44 and @xmath7 for flexible networks ( b ) and semiflexible networks ( c ) . the parameter values studied are ( b ) @xmath138 and ( c ) @xmath139 , @xmath140 . the black dashed lines in ( b ) and ( c ) correspond to the effective medium theory prediction of the rigidity percolation threshold . , scaledwidth=100.0% ] as a function of @xmath44 for semiflexible networks with both types of crosslinkers . in ( a ) we show the effect of changing the concentration @xmath7 of the angle - constraining crosslinkers for @xmath139 , @xmath140 and @xmath141 , while in ( b ) we show the effect of changing their stiffness @xmath5 for @xmath80 . ] scales with @xmath142 and @xmath1 ( @xmath5 ) as @xmath143 . the effective medium theory predicts mean field exponents @xmath114 and @xmath115 for both semiflexible networks with freely - rotating crosslinkers ( a ) and compositely crosslinked flexible networks ( b ) , while simulations predict @xmath120 and @xmath123 for semiflexible networks with freely - rotating crosslinkers ( c ) and @xmath120 and @xmath121 for compositely crosslinked flexible networks ( d ) . ]

the actin cytoskeleton in living cells has many types of crosslinkers . the mechanical interplay between these different crosslinker types is an open issue in cytoskeletal mechanics . we develop a framework to study the cooperativity and redundancy in the mechanics of filamentous networks with two types of crosslinkers : crosslinkers that allow free rotations of filaments and crosslinkers that do not . the framework consists of numerical simulations and an effective medium theory on a percolating triangular lattice . we find that the introduction of angle - constraining crosslinkers significantly lowers the filament concentrations required for these networks to attain mechanical integrity . this cooperative effect also enhances the stiffness of the network and suppresses non - affine deformations at a fixed filament concentration . we further find that semiflexible networks with only freely - rotating crosslinks are mechanically very similar to compositely crosslinked flexible networks with both networks exhibiting the same scaling behavior . we show that the network mechanics can either be redundant or cooperative depending on the relative energy scale of filament bending to the energy stored in the angle - constraining crosslinkers , and the relative concentration of crosslinkers . our results may have implications for understanding the role of multiple crosslinkers even in a system without bundle formation or other structural motifs .

the online version of this article ( doi:10.1007/s11605 - 014 - 2485 - 5 ) contains supplementary material , which is available to authorized users . while peptic ulcer disease has decreased in incidence over the past decades , the epidemiological pattern of the complications , including haemorrhage and perforation , have changed little.1 although outcomes from bleeding ulcers have improved with modern endoscopic and interventional radiological strategies,2 the outcomes of perforations have remained fairly unchanged.3 even in recent reports , the mortality from perforated peptic ulcer ( ppu ) remains up to 27 % 46 and complications are reported in 2050 % of the patients.6,7 a number of scoring systems for outcome prediction have been reported , yet none appear to be superior and most are investigated in isolation.8 among the most frequently used are the american society of anesthesiologists ( asa ) physical status classification system,7 the boey score9 and the more recently introduced peptic ulcer perforation ( pulp ) score.5 however , only the boey and pulp scores are designed specifically for the prediction of mortality for ppu patients . the boey score is the most frequently used score , but with varying degree of accuracy.7,10,11 the pulp score appears more accurate , yet it is more complex and has not been validated outside the original cohort . consequently , contemporary risk prediction in ppu patients is less well investigated with no universally agreed standard , and an optimal way of outcome prediction in this patient group is not known . thus , the aim of this study was to compare known risk scores and clinical and laboratory factors for the prediction of 30-day mortality in a consecutive cohort of patients surgically treated for perforated ulcer . the study was approved as a quality control assurance project according to the regional ethics committee ( rek vest # 2011/713 ) . the study was reported to comply with the strengthening the reporting of observational studies in epidemiology ( strobe ) statement as best applicable.12 the stavanger university hospital ( suh ) serves as the only hospital in the greater stavanger area and has a catchment area of about 340,000 inhabitants . all consecutive patients diagnosed with and operated for a perforated gastric or duodenal ulcer admitted between january 2001 and december 2010 were identified from the hospital administrative electronic database using icd-10 diagnostic codes ( k25 and k26 ) and relevant codes for surgical procedures ( i.e. jda 60 gastroraphy , jda 61 laparoscopic gastroraphy , jdh 70 duodenoraphy , jdh 71 laparoscopic duodenoraphy ) . patient demographics , including laboratory values and clinical data , were retrieved from hospital records and surgical notes . five patients with a malignant ulcer , three patients with ppu identified at autopsy , seven patients conservatively treated without operation and two patients operated on suspicion of ppu without finding any perforation were excluded . diagnosis was based on clinical symptoms and signs ( i.e presence of peritonitis ) supported by imaging ( mainly with abdominal computed tomography ( ct ) ) . a standard predefined set of laboratory values was obtained on admission for all patients with a suspected acute abdomen , including , among others , haemoglobin , c - reactive protein ( crp ) , liver enzymes , bilirubin , albumin and creatinine . the preferred surgical procedure in our institution is an open or laparoscopic primary closure of the perforation by interrupted sutures covered with a pedicled omentoplasty.3 in rare cases with no omentum ( or falciform ligament ) available , primary closure without omentoplasty was done . the primary endpoint of the study was mortality defined as death within 30 days of surgery . delay of treatment was measured as time from admittance to hospital until the start of surgery . sepsis was defined as the presence of two or more of the sepsis criteria ( i.e. temperature > 38.0 , pulse rate > 90 beats per minute , respiration rate > 20 per minute ) and in addition to infection being proved or likely . shock on admission was defined as a systolic blood pressure of < 100 mmhg and a heart rate of > 90 beats per minute . complications were graded using the clavien - dindo score.13 this classification separates complications into five categories : grades 1 and 2 are mild complications that can be medically treated ( e.g. pneumonia or urinary tract infections ) ; grade 3 complications require surgical , endoscopic or radiologic intervention ; and grade 4 complications are life - threatening complications . the boey score9 was calculated based upon the presence of shock , delay from admission to surgery of > 24 h and a high degree of co - morbidity , such as chronic obstructive pulmonary disease , heart failure and active cancer ( defined as current cancer under curative treatment or incurable cancer ) . the asa score14 was based on the patients pre - existing co - morbidity with present clinical condition at admission taken into consideration . accordingly , any acute deterioration of the patient at admission ( e.g. fulfilling the sepsis criteria or the presence of peritonitis or shock ) was incorporated in the asa score evaluation . the pulp score5 was based on age of > 65 years , co - morbidity including liver failure , aids and active cancer , concomitant use of steroids , shock on admission , time from admission to surgery of > 24 h , serum creatinine of > 130 ( mol / l ) and the above - mentioned asa score . the boey score originally measures delay of > 24 h from perforation to surgery , while the pulp score originally measures time from perforation to admission . since we measured time from admission to surgery , this time delay is used for the calculation of both the boey score and the pulp score . this means that a delay of > 24 h in this study , represents at least 24 h from perforation to surgery . optimal cut - off for each continuous variable and risk scores were calculated by the receiver operating characteristics ( roc ) curve analysis with assessment of the area under the curve ( auc ) and its 95 % confidence interval ( 95 % ci).15 an auc value of > 0.8 is considered excellent ( i.e. correctly classifies 80 % of , or four out of five , patients ) , while an auc of 0.700.80 is considered acceptable , and a value of 0.5 equals the flip of a coin.16 sensitivity and specificity with 95 % ci are given for the optimal cut - off value as defined by the roc analysis , and in addition , the corresponding positive or negative likelihood ratio ( lr+ or lr ) is given . data were analysed using the statistical package for social sciences ( v. 21 , spss inc . ) . roc analysis was performed by medcalc ( v. 12.7.5 , http://www.medcalc.org , medcalc software , ostend , belgium ) . a non - parametric distribution of data was assumed , and appropriate statistical tests were used for descriptive data . optimal cut - off values ( based on roc analyses ) were used for dichotomization of the variables for use in the binary regression analyses . clinical judgement was used for the cut - off for age , where a clinically defined cut - off was set to 60 years . logistic binary regression analysis was performed for mortality as the outcome to identify univariate risk factors . factors with a p value of < 0.20 in the univariate analyses were included in the multivariable logistic regression model , and all multivariable analyses were adjusted for gender . included factors were tested both for their continuous values and for the dichotomized variable , where applicable , to test the robustness of the model . for the final multivariable model , the corresponding predicted probability value given for each patient was tested by roc analysis to estimate the performance of the model by the auc . in addition , the same was run for each of the asa , pulp and boey scores in order to compare the accuracy performance across the models . in addition , the hosmer and lemeshow goodness - of - fit test was performed for the final multivariable regression model . for internal validation , boostrapping by 1,000 samples was performed on the final multivariable regression model . all tests are two - sided and p values of < 0.05 were regarded as statistically significant . the stavanger university hospital ( suh ) serves as the only hospital in the greater stavanger area and has a catchment area of about 340,000 inhabitants . all consecutive patients diagnosed with and operated for a perforated gastric or duodenal ulcer admitted between january 2001 and december 2010 were identified from the hospital administrative electronic database using icd-10 diagnostic codes ( k25 and k26 ) and relevant codes for surgical procedures ( i.e. jda 60 gastroraphy , jda 61 laparoscopic gastroraphy , jdh 70 duodenoraphy , jdh 71 laparoscopic duodenoraphy ) . patient demographics , including laboratory values and clinical data , were retrieved from hospital records and surgical notes . five patients with a malignant ulcer , three patients with ppu identified at autopsy , seven patients conservatively treated without operation and two patients operated on suspicion of ppu without finding any perforation were excluded . diagnosis was based on clinical symptoms and signs ( i.e presence of peritonitis ) supported by imaging ( mainly with abdominal computed tomography ( ct ) ) . a standard predefined set of laboratory values was obtained on admission for all patients with a suspected acute abdomen , including , among others , haemoglobin , c - reactive protein ( crp ) , liver enzymes , bilirubin , albumin and creatinine . the preferred surgical procedure in our institution is an open or laparoscopic primary closure of the perforation by interrupted sutures covered with a pedicled omentoplasty.3 in rare cases with no omentum ( or falciform ligament ) available , primary closure without omentoplasty was done . the primary endpoint of the study was mortality defined as death within 30 days of surgery . delay of treatment was measured as time from admittance to hospital until the start of surgery . sepsis was defined as the presence of two or more of the sepsis criteria ( i.e. temperature > 38.0 , pulse rate > 90 beats per minute , respiration rate > 20 per minute ) and in addition to infection being proved or likely . shock on admission was defined as a systolic blood pressure of < 100 mmhg and a heart rate of > 90 beats per minute . complications were graded using the clavien - dindo score.13 this classification separates complications into five categories : grades 1 and 2 are mild complications that can be medically treated ( e.g. pneumonia or urinary tract infections ) ; grade 3 complications require surgical , endoscopic or radiologic intervention ; and grade 4 complications are life - threatening complications . the boey score9 was calculated based upon the presence of shock , delay from admission to surgery of > 24 h and a high degree of co - morbidity , such as chronic obstructive pulmonary disease , heart failure and active cancer ( defined as current cancer under curative treatment or incurable cancer ) . the asa score14 was based on the patients pre - existing co - morbidity with present clinical condition at admission taken into consideration . accordingly , any acute deterioration of the patient at admission ( e.g. fulfilling the sepsis criteria or the presence of peritonitis or shock ) was incorporated in the asa score evaluation . the pulp score5 was based on age of > 65 years , co - morbidity including liver failure , aids and active cancer , concomitant use of steroids , shock on admission , time from admission to surgery of > 24 h , serum creatinine of > 130 ( mol / l ) and the above - mentioned asa score . the boey score originally measures delay of > 24 h from perforation to surgery , while the pulp score originally measures time from perforation to admission . since we measured time from admission to surgery , this time delay is used for the calculation of both the boey score and the pulp score . this means that a delay of > 24 h in this study , represents at least 24 h from perforation to surgery . optimal cut - off for each continuous variable and risk scores were calculated by the receiver operating characteristics ( roc ) curve analysis with assessment of the area under the curve ( auc ) and its 95 % confidence interval ( 95 % ci).15 an auc value of > 0.8 is considered excellent ( i.e. correctly classifies 80 % of , or four out of five , patients ) , while an auc of 0.700.80 is considered acceptable , and a value of 0.5 equals the flip of a coin.16 sensitivity and specificity with 95 % ci are given for the optimal cut - off value as defined by the roc analysis , and in addition , the corresponding positive or negative likelihood ratio ( lr+ or lr ) is given . the boey score9 was calculated based upon the presence of shock , delay from admission to surgery of > 24 h and a high degree of co - morbidity , such as chronic obstructive pulmonary disease , heart failure and active cancer ( defined as current cancer under curative treatment or incurable cancer ) . the asa score14 was based on the patients pre - existing co - morbidity with present clinical condition at admission taken into consideration . accordingly , any acute deterioration of the patient at admission ( e.g. fulfilling the sepsis criteria or the presence of peritonitis or shock ) was incorporated in the asa score evaluation . the pulp score5 was based on age of > 65 years , co - morbidity including liver failure , aids and active cancer , concomitant use of steroids , shock on admission , time from admission to surgery of > 24 h , serum creatinine of > 130 ( mol / l ) and the above - mentioned asa score . the boey score originally measures delay of > 24 h from perforation to surgery , while the pulp score originally measures time from perforation to admission . since we measured time from admission to surgery , this time delay is used for the calculation of both the boey score and the pulp score . this means that a delay of > 24 h in this study , represents at least 24 h from perforation to surgery . optimal cut - off for each continuous variable and risk scores were calculated by the receiver operating characteristics ( roc ) curve analysis with assessment of the area under the curve ( auc ) and its 95 % confidence interval ( 95 % ci).15 an auc value of > 0.8 is considered excellent ( i.e. correctly classifies 80 % of , or four out of five , patients ) , while an auc of 0.700.80 is considered acceptable , and a value of 0.5 equals the flip of a coin.16 sensitivity and specificity with 95 % ci are given for the optimal cut - off value as defined by the roc analysis , and in addition , the corresponding positive or negative likelihood ratio ( lr+ or lr ) is given . data were analysed using the statistical package for social sciences ( v. 21 , spss inc . ) . roc analysis was performed by medcalc ( v. 12.7.5 , http://www.medcalc.org , medcalc software , ostend , belgium ) . a non - parametric distribution of data was assumed , and appropriate statistical tests were used for descriptive data . optimal cut - off values ( based on roc analyses ) were used for dichotomization of the variables for use in the binary regression analyses . clinical judgement was used for the cut - off for age , where a clinically defined cut - off was set to 60 years . logistic binary regression analysis was performed for mortality as the outcome to identify univariate risk factors . factors with a p value of < 0.20 in the univariate analyses were included in the multivariable logistic regression model , and all multivariable analyses were adjusted for gender . included factors were tested both for their continuous values and for the dichotomized variable , where applicable , to test the robustness of the model . for the final multivariable model , the corresponding predicted probability value given for each patient was tested by roc analysis to estimate the performance of the model by the auc . in addition , the same was run for each of the asa , pulp and boey scores in order to compare the accuracy performance across the models . in addition , the hosmer and lemeshow goodness - of - fit test was performed for the final multivariable regression model . for internal validation , boostrapping by 1,000 samples was performed on the final multivariable regression model . all tests are two - sided and p values of < 0.05 were regarded as statistically significant . the study population comprised 172 patients with a median age of 68 ( range 18101 ) years . the 30-day mortality was 16.3 % ( 28/172 ) , and complications were encountered in 52 % ( 89/172 ) of the patients ( fig . 1 ) . there were no grade 1 complications recorded . among the complications recorded were ten suture leakages from the ulcer site , five in the laparotomy and five in the laparoscopy group ( p = 0.13 ) suture leaks were not associated with mortality ( p = 0.585).table 1clinicopathological characteristics of patients operated for perforated peptic ulcercharacteristics ( n = 172)age < 60 years ( n = 55)age 60 years ( n = 117 ) p value for differencegender , n ( % ) female20 ( 36)69 ( 59)0.006 male35 ( 64)48 ( 41)location of ulcer , n ( % ) duodenal18 ( 33)42 ( 36)0.606 gastric37 ( 67)75 ( 64)delay to surgery ( h ) , median ( range)6.3 ( 0.552.4)6.2 ( 1.1116.2)0.463operation time in min , median ( range)78 ( 41210)79 ( 34291)0.890laparoscopy16 ( 29)34 ( 29)0.997laparotomy39 ( 71)83 ( 71)asa score 1247 ( 85)52 ( 44)<0.001 38 ( 15)65 ( 56)boey score 147 ( 85)69 ( 59)0.001 > 18 ( 15)48 ( 41)pulp score < 648 ( 87)38 ( 32)<0.001 67 ( 13)79 ( 68)median ( range)3 ( 110)8 ( 114)albumin ( g / l ) median ( range)42 ( 2048)37 ( 1448)<0.001 hypoalbuminaemia ( 37 g / l ) , n ( % ) 9 ( 5)63 ( 37)<0.001bilirubin ( mol / l ) median ( range)8 ( 3197)12 ( 2481)0.004 hyperbilirubinaemia , n ( % ) 6 ( 4)18 ( 11)0.418creatinine ( mol / l ) median ( range)78 ( 27583)88 ( 34507)0.124 creatinine>1186 ( 4)32 ( 19)0.015 p value was calculated by chi - square test for categorical data and mann - whitney u test for continuous data p value represents differance between pulp scores < 6 and 6fig . 1distribution of complications according to the clavien - dindo complication grading systems clinicopathological characteristics of patients operated for perforated peptic ulcer p value was calculated by chi - square test for categorical data and mann - whitney u test for continuous data p value represents differance between pulp scores < 6 and 6 distribution of complications according to the clavien - dindo complication grading systems optimal cut - off values for each continuous variable based on roc are given in table 2 . a large variability in discrimination is shown , and none of the variables scored an auc over 0.8 . the lr + was consistently low , with none having a value over 4.table 2optimal cut - off based on receiver operating characteristics ( roc ) curve analysis for 30-day mortalityfactorcut - offsensitivity ( 95 % ci)specificity ( 95 % ci)auc p value of auclr+lrage ( years)>7953.6 ( 33.972.5)83.3 ( 76.289.0)0.74<0.0013.20.6delay ( h)>1448.2 ( 28.768.1)75.5 ( 67.682.3)0.580.222.00.7operation time ( min)8675.0 ( 55.189.3)41.6 ( 33.350.1)0.520.741.30.6asa score>385.7 ( 67.396.0)66.0 ( 57.673.7)0.79<0.0012.50.2boey score>164.3 ( 44.181.4)94.4 ( 89.397.6)0.75<0.0012.50.5pulp score>692.9 ( 76.599.1)58.3 ( 49.866.5)0.79<0.0012.30.1albumin ( g / l)3782.1 ( 63.193.9)65.5 ( 57.173.3)0.78<0.0012.40.3bilirubin ( mol / l)>1935.7 ( 18.655.9)90.2 ( 84.194.5)0.610.0963.70.7creatinine ( mol / l)>11842.9 ( 24.562.8)81.9 ( 74.787.9)0.520.782.40.7crp ( mg / l)>2178.6 ( 59.091.7)52.8 ( 44.361.1)0.69<0.0011.70.4 auc area under the curve , lr+ positive likelihood ratio , lr negative likelihood ratio , asa score american society of anesthesiologists score , pulp score peptic ulcer perforation score optimal cut - off based on receiver operating characteristics ( roc ) curve analysis for 30-day mortality auc area under the curve , lr+ positive likelihood ratio , lr negative likelihood ratio , asa score american society of anesthesiologists score , pulp score peptic ulcer perforation score univariate risk factors associated with mortality are displayed in table 3 . in addition , we analysed for ulcer site , method of operation , presence of cardiovascular disease , prednisolone use , smoking , sepsis , autoimmune disease and nsaid use , but none were statistically significantly associated with mortality . absence of peritonitis on admission was significantly associated with mortality ( p = 0.038 ) by univariate analysis , but not after multivariable regression analysis.table 3univariate regression analysis of factors associated with 30-day mortalityfactorsdeceasedalive p valueodds ratio ( 95 % ci)gendermale11720.2990.6 ( 0.31.5)female1772age ( years)>602592<0.0014.7 ( 1.416.4)60352delay ( h)>249220.0272.8 ( 1.16.9)2418121preoperative shockyes10270.0342.6 ( 1.16.2)no17117active canceryes910<0.0016.4 ( 2.317.6)no19134peritonitisyes13990.0340.4 ( 0.21.0)no1444asa score>32449<0.00111.6 ( 3.835.4)3495boey score>11838<0.0015.0 ( 2.111.8)110106pulp score>62660<0.00118.2 ( 4.279.6)6284albumin ( g / l)>37593<0.0018.7 ( 3.124.4)372349bilirubin ( mol / l)>191014<0.0015.1 ( 2.013.2)1918129creatinine ( mol / l)>11812260.0043.4 ( 1.48.1)11816118crp ( mg / l)>2122680.0024.1 ( 1.610.7)21676haemoglobin ( g / dl)>12.5141060.0132.8 ( 1.26.4)12.51438 asa score american society of anesthesiologists score , pulp score peptic ulcer perforation score univariate regression analysis of factors associated with 30-day mortality asa score american society of anesthesiologists score , pulp score peptic ulcer perforation score during multivariable modelling , non - significant variables were taken out of the regression model for optimization . adding or leaving the asa score out of the model only changed the model minimally , and the asa score was thus left out . the final multivariable regression model for mortality is presented in table 4 . the hosmer and lemeshow goodness - of - fit test ( p = 0.948 ) indicated a good model fit , and roc analyses of the predicted probability value gave an auc of 0.89 ( fig . the model was internally validated by bootstrapping , changing the p values only marginally , thus confirming the validity of the model ( see supplementary info , table 5).table 4multivariable regression analysis of factors associated with 30-day mortalityfactorswald p valueodds ratio ( 95 % ci)age10.20.0011.1 ( 1.01.1)delay > 24 h4.40.0353.5 ( 1.111.3)active cancer7.80.0057.6 ( 1.831.7)albumin 37 g / l5.60.0184.1 ( 1.313.8)bilirubin > 19 mol / l6.50.0115.1 ( 1.518.2)creatinine > 118 mol / l4.40.0363.5 ( 1.111.1)adjusted for genderfig . 2roc analysis of scores and current model in mortality prediction : a current model from the predictive probabilities of the multivariable regression model , b the pulp score , c the boey score and d the asa score multivariable regression analysis of factors associated with 30-day mortality roc analysis of scores and current model in mortality prediction : a current model from the predictive probabilities of the multivariable regression model , b the pulp score , c the boey score and d the asa score the predicted probability of each of the clinical scores , as well as the predicted probability used for variables included in the final model ( table 4 ) , is presented for comparison in fig . the final model had a better auc and more consistent 95 % ci ( fig . in addition , we analysed for ulcer site , method of operation , presence of cardiovascular disease , prednisolone use , smoking , sepsis , autoimmune disease and nsaid use , but none were statistically significantly associated with mortality . absence of peritonitis on admission was significantly associated with mortality ( p = 0.038 ) by univariate analysis , but not after multivariable regression analysis.table 3univariate regression analysis of factors associated with 30-day mortalityfactorsdeceasedalive p valueodds ratio ( 95 % ci)gendermale11720.2990.6 ( 0.31.5)female1772age ( years)>602592<0.0014.7 ( 1.416.4)60352delay ( h)>249220.0272.8 ( 1.16.9)2418121preoperative shockyes10270.0342.6 ( 1.16.2)no17117active canceryes910<0.0016.4 ( 2.317.6)no19134peritonitisyes13990.0340.4 ( 0.21.0)no1444asa score>32449<0.00111.6 ( 3.835.4)3495boey score>11838<0.0015.0 ( 2.111.8)110106pulp score>62660<0.00118.2 ( 4.279.6)6284albumin ( g / l)>37593<0.0018.7 ( 3.124.4)372349bilirubin ( mol / l)>191014<0.0015.1 ( 2.013.2)1918129creatinine ( mol / l)>11812260.0043.4 ( 1.48.1)11816118crp ( mg / l)>2122680.0024.1 ( 1.610.7)21676haemoglobin ( g / dl)>12.5141060.0132.8 ( 1.26.4)12.51438 asa score american society of anesthesiologists score , pulp score peptic ulcer perforation score univariate regression analysis of factors associated with 30-day mortality asa score american society of anesthesiologists score , pulp score peptic ulcer perforation score during multivariable modelling , non - significant variables were taken out of the regression model for optimization . adding or leaving the asa score out of the model only changed the model minimally , and the asa score was thus left out . the final multivariable regression model for mortality the hosmer and lemeshow goodness - of - fit test ( p = 0.948 ) indicated a good model fit , and roc analyses of the predicted probability value gave an auc of 0.89 ( fig . the model was internally validated by bootstrapping , changing the p values only marginally , thus confirming the validity of the model ( see supplementary info , table 5).table 4multivariable regression analysis of factors associated with 30-day mortalityfactorswald p valueodds ratio ( 95 % ci)age10.20.0011.1 ( 1.01.1)delay > 24 h4.40.0353.5 ( 1.111.3)active cancer7.80.0057.6 ( 1.831.7)albumin 37 g / l5.60.0184.1 ( 1.313.8)bilirubin > 19 mol / l6.50.0115.1 ( 1.518.2)creatinine > 118 mol / l4.40.0363.5 ( 1.111.1)adjusted for genderfig . 2roc analysis of scores and current model in mortality prediction : a current model from the predictive probabilities of the multivariable regression model , b the pulp score , c the boey score and d the asa score multivariable regression analysis of factors associated with 30-day mortality roc analysis of scores and current model in mortality prediction : a current model from the predictive probabilities of the multivariable regression model , b the pulp score , c the boey score and d the asa score the predicted probability of each of the clinical scores , as well as the predicted probability used for variables included in the final model ( table 4 ) , is presented for comparison in fig . the final model had a better auc and more consistent 95 % ci ( fig . in the current study , several clinical factors were predictive of 30-day post - operative mortality , of which the combination of increasing age , the presence of active cancer , the state of hypoalbuminaemia , presence of hyperbilirubinaemia , delay to surgery of > 24 h and increased creatinine represented the best predictive model . indicated by an auc of 0.89 , this model would correctly classify nine out of ten patients . notably , the included factors are all objective measures that are obtainable before surgery and could thus be used for improved risk prediction . while all clinical risk scores evaluated had reasonably accurate ability to predict mortality , none were excellent as deemed by the auc . moreover , the single most important factor , the state of hypoalbuminaemia , is not included in any of the three existing risk scores . an improved risk prediction model may be used for better communication with patients and next - of - kin before surgery for this disease with known high mortality . obviously , a single predictor can not be attributed to any individual patient , but the presence of several or all of the most detrimental factors may pose a much greater mortality risk compared to patients with few or none of these attributes . also , for clinical resource allocation and planning ( e.g. risk for prolonged icu or hospital stay , or need of prolonged care ) , the combined set of variables may be useful . finally , the combined score may better allow comparison of patients between studies and allow for case mix adjustments and , importantly , may also allow for potential risk stratification for future clinical trails . comparison between different patient cohorts from different regions may be valid , as all variables are objective and not influenced by subjective interpretation . hypoalbuminaemia was strongly associated with increased mortality , and this is in line with previous reports on perforated peptic ulcer.17 indeed , several past studies found a relation between preoperative hypoalbuminaemia and poor post - operative outcomes across several surgical disciplines.1820 this association may be due to the fact that a low serum albumin is closely correlated to a poor preoperative status of the patient , due to chronic disease , presence of underlying cancer , state of cachexia or other causes of malnutrition . hyperbilirubinaemia has been found to be associated with perforation in acute appendicitis , and this has been partly explained by a decrease in bile secretion as a consequence of bacteraemia.21 since similar mechanisms may apply for a perforated ulcer , hyperbilirubinaemia may also be of relevance in the management of ppu patients . mller et al . found a decrease in mortality from 27 to 17 % after initiating a care bundle protocol.22 in the current cohort , the mortality is 16 % , and the two cohorts appear comparable in most aspects . also , the mortality in our study is in the range of 1027 % as reported by recent studies from a number of countries , including the usa , denmark , scotland , israel , nigeria and ethiopia.8,2328 as our study includes all comers in a defined population with no selection in referral , we believe that the mortality rate is as would be expected for this group of patients . most of the deaths in the cohort were attributed to sepsis and multiorgane failure,6 which corroborates previous findings in ppu.29 however , the presence of sepsis preoperatively was not found to be significantly associated with mortality in the current study . notably , several other factors may likely be related to the sepsis syndrome and act as surrogates for the presence of sepsis , such as hyperbilirubinaemia and increased creatinine . increased creatinine levels may be an indicator of several conditions , including chronic renal failure ( known or unknown before diagnosis ) , the expression of pending renal failure ( due to the current disease ) , but may also be due to dehydration or reflect shock or sepsis per se . nevertheless , increased creatinine is a well - recognized risk factor for mortality both in ppu patients and in other patient groups.5,20 indeed , we recognize that several of the factors deemed to be of importance ( e.g. albumin , bilirubin and creatinine levels ) may be surrogates or indicators for other underlying factors , most likely attributed to pre - existing disease ( such as presence of cancer or severe chronic illness ) or the state of the acute disease ( e.g. reflecting dehydration , state of infection or sepsis , or altered physiology or pending organ failure ) . we did not attempt to define or investigate causality from the findings in this study . further investigation into the cause and consequence interactions for the better understanding of the nature of this disease is clearly warranted . incorporating delay as a risk factor is controversial and inconsistent across studies . the boey score originally measures delay as the time from perforation to surgery , which may be prone to error based on recall bias by the patient or record bias when prehospital data are to be obtained in retrospect . on the other side , the pulp score measures delay as the time from perforation to admission , thus not including the potential diagnostic delay that may occur in some patients prior to an established diagnosis and start of treatment . in the current study , we have obtained delay as the time interval from admission to surgery , as we believe this to be a more robust predictor , as admission to hospital and start of surgery are consistently recorded . hence , this was applied as the time delay variable for both the pulp score and the boey score . this means that a delay of > 24 h ( from admission ) represents at least 24 h of delay ( since symptom debut ) . notably , as our institution covers a region with fairly short travelling distances , the time from perforation to admission should not be considerable for most patients . however , we can not rule out an influence of this on the score parameters . even though the pulp score achieved both higher or and auc values , the boey score is a much simpler score with higher clinical usefulness than the more complex pulp score , ranging from 0 to 18 points . the asa score and the pulp score performed equally well by most aspects in our cohort . the reason for this can to some extent be attributed to our patients receiving higher asa grading . the asa grading is known to have interobserver variability , since it is not an objective system.30 the asa grade also varies according to whether or not the acute state is taken into consideration for the asa grading.31 most of the factors in the pulp score are related to preoperative status and could be included in the asa score alone , except of age and prednisolone use . since we included the acute state when grading asa , it is not so surprising that the pulp score and the asa score performed equally well . however , the asa grading which is only based upon pre - existing illness can also be problematic . clearly , a previous healthy patient presenting with septic shock and acute multiorgane failure is at high risk , but ignoring this in the asa grading can be misleading . the question remains how to best improve outcomes for the patients at high risk of dismal outcomes . as recently discussed , there are several important prognostic factors that are unmodifiable , such as age and the presence of active cancer.3 however , other important prognostic factors for mortality may be modifiable . as already addressed in the pulp study , the adherence to a sepsis - focused protocol could reduce the mortality by one third compared to conventional treatment,22 but when introducing this as a quality - of - care initiative , the factors that improved most were delay to surgery and monitoring of vital parameters , with no significant change in mortality.32 to decrease the time interval from perforation to operation appears particularly important as each hour of delay carries with it a worse prognosis.24 some limitations to this study deserve to be mentioned . however , we had little missing data in the variables obtained , likely due to a fairly consistent hospital system with electronic hospital files available for the majority of the study period . a larger study population may have revealed associations not seen in this study ; however , most of the results are in line with the recent national data from denmark,5 and as such , this study from the greater stavanger area should have a wide external validity . the combination of age , active cancer , hyperbilirubinaemia , hypoalbuminaemia , elevated creatinine and delay from perforation to surgery of > 24 h predicted mortality best . the new pulp score and the asa score predicted mortality equally well and better than the boey score , but none of them were optimal . hypoalbuminaemia was the strongest single predictor of mortality and may be included for improved risk estimation .

backgroundmortality rates in perforated peptic ulcer ( ppu ) have remained unchanged . the aim of this study was to compare known clinical factors and three scoring systems ( american society of anesthesiologists ( asa ) , boey and peptic ulcer perforation ( pulp ) ) in the ability to predict mortality in ppu.material and methodsthis is a consecutive , observational cohort study of patients surgically treated for perforated peptic ulcer over a decade ( january 2001 through december 2010 ) . primary outcome was 30-day mortality.resultsa total of 172 patients were included , of whom 28 ( 16 % ) died within 30 days . among the factors associated with mortality , the pulp score had an odds ratio ( or ) of 18.6 and the asa score had an or of 11.6 , both with an area under the curve ( auc ) of 0.79 . the boey score had an or of 5.0 and an auc of 0.75 . hypoalbuminaemia alone ( 37 g / l ) achieved an or of 8.7 and an auc of 0.78 . in multivariable regression , mortality was best predicted by a combination of increasing age , presence of active cancer and delay from admission to surgery of > 24 h , together with hypoalbuminaemia , hyperbilirubinaemia and increased creatinine values , for a model auc of 0.89.conclusionsix clinical factors predicted 30-day mortality better than available risk scores . hypoalbuminaemia was the strongest single predictor of mortality and may be included for improved risk estimation.electronic supplementary materialthe online version of this article ( doi:10.1007/s11605 - 014 - 2485 - 5 ) contains supplementary material , which is available to authorized users .

quantum cryptography , also called quantum key distribution ( qkd ) , allows two remote parties , usually called alice and bob , to establish a secret key that can be used to transmit secret message with a classical one - time pad scheme . after the pioneering work presented by bennett and brassard in 1984 ( bb84 ) , the unconditional security of the bb84 protocol was proven with the assumption of ideal settings @xcite . in practice , the devices of qkd are imperfect , the eavesdropper , called eve , can exploit the imperfections of the devices to gain partial or full information about the key bits @xcite . it has been shown that eve may take advantage of the nonzero multiphoton emission probability of alice s laser source and the loss of quantum channel , by using the photon - number - splitting ( pns ) attack @xcite . decoy state qkd has been proposed to beat eve s pns attacks , which can substantially increase the secure key distribution distance @xcite . an important part of qkd system is the measurement devices . in experiments , the detection efficiency of the practical single - photon detectors ( spds ) is low and in most cases , the two detectors are asymmetric , which may be exploited by the eve to steal information on the final key . for example , attacks that exploit the efficiency mismatch between two spds in qkd system have been proposed , demonstrated , and analyzed ; they include the time - shift attack @xcite , and the faked states attack @xcite . also , it has been demonstrated experimentally that eve can tracelessly acquire the full secret key bits using specially tailored bright illumination @xcite . recently , a measurement - device - independent ( mdi ) qkd scheme was proposed to remove detector side channel attacks @xcite . the advantage is that security can be guaranteed without regard to the experimental details of the measurement device . in this scheme , alice and bob send signal pulses to a bell - state measurement device which may be owned by eve and it is proven that they can distill some secure key bits based on the bell measurement results . recently , the security of four - state deterministic quantum key distribution ( dqkd ) with a two - way quantum channel against the most general attacks has been proven by us @xcite under the ideal - device setting , while it is widely believed that two - way dqkd is vulnerable under eve s practical attacks because eve can attack the travel photon in both forward and backward lines . in this paper , we prove that two variations of the dqkd protocol are immune to all detector side channel attacks at bob s side in the backward line . we do not analyze the mdi security of alice s detectors and assume that they are ideal and non - blinded . in most qkd protocols , after distributing all signal qubits , alice and bob should communicate through public channel for basis reconciliation . in the bb84 protocol , about half of bob s measurement results are discarded due to the inconsistent bases alice and bob used . but , in two - way dqkd protocols @xcite , bob can decode alice s key bits after measuring the returned qubits directly , without basis reconciliation . this means that all measurement results will be used for key distillation . the two - way dqkd was first proposed by using entanglement @xcite . later , single - photon two - state protocol @xcite was proposed for improving the experimental performance and then single - photon four - state protocol was proposed independently in refs . @xcite . after that , the security of two - way dqkd against some special attacks were studied @xcite . recently , the security of the four - state protocol against the most general attacks under the ideal - device setting was proved by us @xcite . let us start with a brief review of the four - state two - way dqkd protocol with two encoding operations [ see fig . [ fig : protocols](a ) ] . ( 1 ) bob prepares @xmath0 qubits randomly in one of the four states , @xmath1 , @xmath2 , @xmath3 , and @xmath4 , where @xmath5 and sends them to alice . ( 2 ) alice randomly switches the communication to the check mode or the encoding mode . ( 3 ) in check mode , alice randomly measures part of the received states in the @xmath6 basis or @xmath7 basis . ( 4 ) in the encoding mode , alice randomly perform unitary operations @xmath8 to encode bit 0 or @xmath9 to encode bit 1 . ( 5 ) alice sends the encoded qubits back to bob . since alice s encoding operations do not change the bases of bob s states , _ i.e. _ , @xmath10 and @xmath11 , bob measures each qubit in the same basis as the one he used for preparation to get alice s key bit deterministically , without basis reconciliation . ( 6 ) after bob measured all returned qubits , alice announces her measurement results in the check mode to compute the fidelity of the forward states in the b - to - a channel for the consistent - basis measurements . they can get the fidelity @xmath12 , @xmath13 , @xmath14 , and @xmath15 of @xmath1 , @xmath2 , @xmath3 , and @xmath16 , respectively . ( 7 ) alice announces part of her key bits in encoding mode to compute the error - rate @xmath17 in the a - to - b channel . ( 8) alice and bob perform error - correction ( ec ) and privacy amplification ( pa ) to generate the final key bits . in the asymptotic scenario , after verifying @xmath18 , alice and bob can get the secure final key against general attacks with the generation rate , @xmath19 where @xmath20 is the binary entropy function , and @xmath21 and @xmath22 are the amounts of key bits alice and bob should sacrifice for ec and pa . with the idea of delaying pa , the security of a two - way dqkd protocol that uses four states and four encoding operations was proven @xcite [ see fig . [ fig : protocols](b ) ] . it has been shown that the idea of delaying pa can simplify the security proof of two - way dqkd protocols , with the same key generation rate as that derived in @xcite . the security of two - way dqkd can also be proved against most general attacks with the entropic uncertainty relation , and a higher final key generation rate may be achieved @xcite . we prove that the four - state dqkd protocols with two encoding operations ( a ) and four encoding operations ( b ) are mdi secure in line a - to - b . protocol ( b ) was shown to be equivalent to protocol ( c ) where the forward channel runs the bb84 protocol and the backward channel runs a classical one - time pad ( otp ) @xcite . here , @xmath23 , @xmath24 , and @xmath25 represent a raw secret key bit in all three protocols randomly chosen by alice . in protocol ( b ) , either @xmath24 or @xmath25 will be used as the key bit depending on the basis chosen by bob which he will inform alice after his measurement . here , @xmath26 represents eigenstate @xmath27 of basis @xmath28 and @xmath29 represents a measurement in basis @xmath28 . , width=480 ] we prove in this section the mdi security of line a - to - b for the original four - state protocol with two encoding operations proposed by refs . @xcite , and the four - state protocol with four encoding operations proposed by ref . our proof relies on the use of equivalent protocols . in order to prove the security of the mdi version of the protocol in line a - to - b , we modify the protocol by moving bob s measurement to the hands of eve in line a - to - b . the modified protocol is the same as the original protocol in sec . [ sec - security of the four - state protocol ] except with step ( 5 ) replaced as follows : ( 5 ) alice sends the encoded qubit to eve . bob tells eve the measurement basis . eve makes a measurement on alice s qubit using bob s basis , and returns the measurement result to bob . note that bob tells eve the basis only after the alice has received the qubit on line b - to - a . this ensures that eve can not determine the initial qubit bob sent out . intuitively , we can understand the security of the modified protocol as follows . since bob randomly prepares the signal qubit in one of the four states , eve can not know alice s encoding operations even if she gets bob s measurement result . to know alice s encoding , eve has to know bob s initial state as well . to prove security of the modified protocol rigorously , we consider the pa term in the key rate formula . the secure key rate @xmath30 from pa for secret key generation is given by renner and knig s result @xcite : @xmath31 , where @xmath32 is the overall state of alice s encoding ( @xmath33 ) , the qubit emitted to line b - to - a ( @xmath34 ) , and eve s ancillas ( @xmath35 ) , and @xmath36 . note that system @xmath34 is released by bob , encoded by alice , and returned to eve . this pa formula reflects that eve , in order to learn about the key bit , uses the entire qubit from alice and her own ancillas which include those used in her attack on line b - to - a . this is consistent with the modified protocol where eve measures @xmath37 . we now show that @xmath38 , i.e. , the overall state is not changed due to the knowledge of the basis . bob initially prepares the qubit @xmath39 in one of the four states . when the basis is @xmath40 or @xmath41 , bob prepares @xmath42 or @xmath43 , respectively . since @xmath44 , further evolution of this state will be independent of the basis . thus , @xmath45 for completeness , we describe @xmath32 in more detailed as follows . eve s most general attack on b - to - a channel can be described as a joint unitary operation together with ancilla . after eve s attack on b - to - a channel , the joint state of the forward qubit and eve s ancilla becomes @xmath46 , where @xmath47 is the initial state of eve s ancilla . after alice s encoding operations , the joint state of backward qubit and eve s ancilla becomes @xmath48 , where @xmath49 and @xmath50 . therefore , eq . reduces @xmath30 to @xmath51 for the modified protocol ; and also @xmath32 in the modified protocol is the same as in the original protocol because @xmath39 undergoes the same evolution in both protocols . therefore , we can directly apply the calculation of @xmath30 of the original protocol and its result to the modified protocol here . in summary , the modified protocol has the same key rate formula eq . . the four - state protocol is secure independent of the measurement and is immune against all detector side channel attacks in line a - to - b . .key bit value dependence on the basis used by bob ( @xmath41 or @xmath40 ) and alice s encoding operation ( @xmath52 , @xmath6 , @xmath53 , or @xmath7 ) . for instance , when bob uses basis @xmath41 , bit @xmath54 is encoded by alice if she applies @xmath7 or @xmath53 on the qubit emitted by bob . [ table - encoded - value ] [ cols="^,^,^ " , ] here , we also show the mdi security in line a - to - b of the four - state protocol with four encoding operations of ref . @xcite [ see fig . [ fig : protocols](b ) ] . in this protocol , the steps are the same as the protocol given in sec . [ sec - security of the four - state protocol ] except with steps ( 4 ) and ( 5 ) replaced as follows : ( 4 ) in the encoding mode , alice randomly perform unitary operations @xmath8 , @xmath55 , @xmath56 , or @xmath57 . the actual key bit value is dependent on the basis used ( table [ table - encoded - value ] ) . ( 5 ) alice sends the encoded qubits back to bob . bob measures each qubit in the same basis as the one he used for preparation to get alice s key bit deterministically , without basis reconciliation . bob also tells alice his basis choice so that she knows the key bit value according to table [ table - encoded - value ] . we show that this protocol is mdi secure in line a - to - b . the security proof of this protocol given in ref . @xcite reduces the protocol to an equivalent protocol where the forward channel b - to - a runs the bb84 protocol and the backward channel a - to - b runs a classical one - time pad ( otp ) [ see fig . [ fig : protocols](c ) and fig . 3 of ref . it is argued in ref . @xcite that the classical otp is equivalent to a quantum otp by encoding classical states onto quantum states in some basis . the basis used has no bearing on the security since the security originates from that of the classical otp : eve is allowed to know the otp - encrypted bit value in transit on line a - to - b . it is argued further in ref . @xcite that this basis is the basis used by bob for his initial state . thus , it is irrelevant whether bob announces the basis before or after the otp operation on line a - to - b . using the same modification in sec . [ sec - proof - mdi1 ] for moving the measurement device from bob to eve , this variant of the four - state protocol is mdi secure in line a - to - b . although the two - way dqkd has higher resistance to pns attack - like attacks @xcite , decoy states are necessary to modify the four - state protocol for long - distance key distribution @xcite . another problem is that the two - way qkd is vulnerable to eve s trojan horse attacks , such as the invisible photon attack @xcite . in practice , alice can add a filter to defeat eve s invisible photon attack . all bob s photon pulses should pass through alice s filter first and only wavelengths close to the operating wavelength are allowed to pass through . it has been widely believed that , since eve can attack the travel photons both in line b - to - a and in line a - to - b , qkd with a two - way quantum channel is more vulnerable under eve s practical attacks comparing with one - way qkd protocol , such as the bb84 protocol . in this paper , we have shown that two four - state protocols are mdi secure in line a - to - b , i.e. , when eve instead of bob measures alice s qubit using bob s basis , the modified protocols have the same key generation rate as that of the original protocols . since the line a - to - b is mdi secure , measurement device dependent attacks may only work in line b - to - a . finally , we want to emphasize that we only proved the security of two - way dqkd against detector side channel attacks at bob s side in the backward line a - to - b , while the mdi security of alice s detectors in the check mode should be studied in future work . financial support from nsfc under grant nos . 11104324 and 11074283 of the prc government and rgc under grant 700712p of the hksar government is gratefully acknowledged . secondoftwoauthor secondoftwoauthor c .- h . f. fung , secondoftwoauthor k. tamaki , secondoftwoauthor b. qi , secondoftwoauthor h .- k . lo , and secondoftwoauthor x. ma , secondoftwojournal secondoftwojournal quant . comput . , * * secondoftwovolume 9 * * , secondoftwopages 0131 ( secondoftwoyear 2009 ) v. makarvo , a. anisimov , and j. skaar , phys . a * 74 * , 022313 ( 2006 ) .

in a two - way deterministic quantum key distribution ( dqkd ) protocol , bob randomly prepares qubits in one of four states and sends them to alice . to encode a bit , alice performs an operation on each received qubit and returns it to bob . bob then measures the backward qubits to learn about alice s operations and hence the key bits . recently , we proved the unconditional security of the final key of this protocol in the ideal device setting . in this paper , we prove that two - way dqkd protocols are immune to all detector side channel attacks at bob s side , while we assume ideal detectors at alice s side for error testing . our result represents a step forward in making dqkd protocols secure against general detector side channel attacks .

cellulomonas sp . hzm is a gram positive , rod - shaped bacterium isolated from soil surface plant detritus in pekan tropical peat swamp in pahang , malaysia . the isolate was acquired by culture - plating on sizova 's cellulose minimal salt media preceded by a series of enrichment steps . genomic dna was extracted from 24 hour old cultures using the gf nucleic acid extraction kit ( vivantis , malaysia ) as per manufacturer 's instructions . the genome was sequenced using an illumina miseq sequencer ( 150-bp paired - end reads ) and the raw reads were trimmed and assembled de novo using clc genomics workbench 6 ( clc bio , denmark ) . a total of 78 contigs with an accumulated length of 3,559,280 bp ( 74-fold coverage , n50 = 99,115 bp ) and a g + c content of 73% were obtained . the genome contains 52 trna genes and 3 rrna genes ( 5s23s16s ) as predicted using trnascan 1.2 and rnammer 1.2 , respectively . a total of 3180 coding sequences in 352 subsystems were functionally annotated by rapid annotation using the subsystems technology ( rast ) server fig . a gene sequence putatively encoding endoglucanase ( ec 3.2.1.4 ) , as well as six copies of -glucosidase ( ec 3.2.1.21 ) gene sequences were identified in the starch and sucrose metabolism subsystem using the kyoto encyclopedia of genes and genomes ( kegg ) database available in rast . no sequences for exoglucanases ( ec 3.2.1.91 ) were identified , possibly indicating an incomplete cellulolytic system . of the hemicellulolytic enzymes , only a single copy of the sequence of alpha - l - arabinofuranosidase b ( ec 3.2.1.55 ) and acetyl xylan esterase ( ec 3.2.1.41 ) were identified . these enzymes remove side chains and thus have assistive roles as compared to endoxylanases ( ec 3.2.1.8 ) and -xylosidases ( ec 3.2.1.37 ) which cleave glycosidic bonds between xylose residues . however , no sequence for any xylan - degrading enzymes was annotated within the genome . other gene sequences for hydrolytic enzymes identified include those for -mannosidase ( ec 3.2.1.25 ) and chitinase ( ec 3.2.1.14 ) . both these enzymes may assist in providing nutrient availability for cellulomonas sp . . functional comparison of genome sequences in the rast server revealed the closest neighbors of cellulomonas sp . hzm as sanguibacter keddieii dsm 10,542 ( score 555 ) followed by cellulomonas flavigena dzm 20,109 ( score 336 ) , beutenbergia cavernae dsm 12,333 ( score 293 ) , actinomyces odontolyticus atcc 17,982 ( score 189 ) and xylanimonas cellulosilytica dsm 15,894 ( score 186 ) . analysis using the complete 16s rrna sequence ( performed using eztaxon at http://www.ezbiocloud.net/eztaxon ) is more specific by comparison , with the list of candidates being predominantly cellulomonas , whereby the closest match is cellulomonas uda ( pairwise similarity of 98.20% ) followed by cellulomonas chitinilytica ( 98.15% ) , cellulomonas gelida ( 98.06% ) and cellulomonas iranensis ( 97.89% ) . the whole genome shotgun project has been deposited at ddbj / embl / genbank under the accession no . jeoe00000000 . the authors declare that there is no conflict of interests with respect to the work published in this paper .

we report the draft genome sequence of cellulomonas sp . hzm , isolated from a tropical peat swamp forest . the draft genome size is 3,559,280 bp with a g + c content of 73% and contains 3 rrna sequences ( single copies of 5s , 16s and 23s rrna ) .

the demand for dietary supplements has continually increased in recent years as the concept of ' well being ' widely spread in korea . the market value for dietary supplements in korea was approximately 600 billion won ( 600 million usd ) in year 2005 ( 1 ) , and personal spending was approximately 950,000 won ( 950 usd ) per year in 2005 ( 2 ) . aloe has been purported to have positive effects on wound healing , recovery from burn injury , cell growth , and immune modulation . in particular , there have been one each in germany ( 3 ) , turkey ( 4 ) , and usa ( 5 ) . in switzerland ( 6 ) , 10 cases of hepatotoxicity associated with dietary supplements from herbalife products were reported . although 2 of those 10 cases took aloe preparation , the causality assessment between aloe and toxic hepatitis could not be done due to multiple herbalife products . a 57-yr - old female patient with a 2 month history of dyspepsia was presented to our department . she had taken aloe tablets containing 250 mg of an extract of aloe arborescens and 28.5 mg of an extract of aloe vera ( fig . laboratory abnormalities included aspartate aminotransferase ( ast ) 331 iu / l , alanine aminotransferase ( alt ) 565 anti - hav igm , anti - hcv , hcv pcr , and anti - hev igm were negative . there was no serologic evidence for recent infections with cytomegalovirus ( cmv ) , epstein - barr - virus ( ebv ) , or herpes simplex virus ( hsv ) . iu / l ) on the 12th day of admission and gradually decreased to 452 iu / l on the 25th day of admission . alt as well as total bilirubin gradually returned to normal level over several weeks ( fig . 3 ) . using the roussel uclaf causality assessment method for determining drug hepatotoxicity ( rucam ) scale , this case was scored as ' probable ' ( table 1 ) . the type of liver injury was determined as ' hepatocellular ' since r ratio ( serum activity of alt / serum activity of ap ) was 10 ( 7 ) . a 62-yr - old female patient was presented to our department with a week history of fatigue . she had taken aloe powder containing 420 mg of an extract of aloe vera ( fig . 1b ) for about 3 months prior to the admission . physical examination revealed jaundice on her sclera . anti - hav igm , anti - hcv , hcv pcr , and anti - hev igm were negative . there were bile - stasis and bile stained kupffer cells ( fig . 2b ) . alt gradually decreased to 452 iu / l which was lower than half of the peak value on the 17th day of admission . when she was discharged alt and ast were normal . we explained to her about the aloe - induced hepatotoxity and advised not to take it anymore . however , the patient started taking the same aloe extract again 1 month after her discharge from the hospital . a month later , follow - up liver function test showed ast 477 iu / l , alt 785 iu / l , and ap 165 iu / l ( fig . 4 ) . since a hepatitis recurred after re - challenge of aloe extract , we could confirm her diagnosis as aloe - induced toxic hepatitis . the type of liver injury was determined as ' hepatocellular ' since r ratio was 39 . six months later , the patient was presented to our department with a 2 week history of jaundice . laboratory test showed ast 752 iu / l , alt 1,135 iu / l , ap 243 iu / l and total bilirubin 15.81 mg / dl . we recommended admission , but she refused to be admitted and she never visited our hospital again . a 55-yr - old female patient was presented to our department with a 3 month history of epigastric discomfort . laboratory abnormalities included ast 344 iu / l , alt 666 iu / l , ap 298 iu / l . anti - hav igm , anti - hcv , hcv pcr , and anti - hev igm were negative . alt was 484 iu / l on her discharge ( on the 5th day of admission ) . liver function test was normal at that time ( ast 29 iu / l , alt 11 iu / l , ap 190 the type of liver injury was determined as ' hepatocellular ' since r ratio was 11 . a 57-yr - old female patient with a 2 month history of dyspepsia was presented to our department . she had taken aloe tablets containing 250 mg of an extract of aloe arborescens and 28.5 mg of an extract of aloe vera ( fig . laboratory abnormalities included aspartate aminotransferase ( ast ) 331 iu / l , alanine aminotransferase ( alt ) 565 anti - hav igm , anti - hcv , hcv pcr , and anti - hev igm were negative . there was no serologic evidence for recent infections with cytomegalovirus ( cmv ) , epstein - barr - virus ( ebv ) , or herpes simplex virus ( hsv ) . iu / l ) on the 12th day of admission and gradually decreased to 452 iu / l on the 25th day of admission . alt as well as total bilirubin gradually returned to normal level over several weeks ( fig . 3 ) . using the roussel uclaf causality assessment method for determining drug hepatotoxicity ( rucam ) scale , this case was scored as ' probable ' ( table 1 ) . the type of liver injury was determined as ' hepatocellular ' since r ratio ( serum activity of alt / serum activity of ap ) was 10 ( 7 ) . a 62-yr - old female patient was presented to our department with a week history of fatigue . she had taken aloe powder containing 420 mg of an extract of aloe vera ( fig . 1b ) for about 3 months prior to the admission . physical examination revealed jaundice on her sclera . laboratory abnormalities included ast 1,477 iu / l , alt 1,564 iu / l , total bilirubin 14.64 mg / dl . anti - hav igm , anti - hcv , hcv pcr , and anti - hev igm were negative . alt gradually decreased to 452 iu / l which was lower than half of the peak value on the 17th day of admission . when she was discharged alt and ast were normal . we explained to her about the aloe - induced hepatotoxity and advised not to take it anymore . however , the patient started taking the same aloe extract again 1 month after her discharge from the hospital . a month later , follow - up liver function test showed ast 477 iu / l , alt 785 iu / l , and ap 165 iu / l ( fig . 4 ) . since a hepatitis recurred after re - challenge of aloe extract , we could confirm her diagnosis as aloe - induced toxic hepatitis . the type of liver injury was determined as ' hepatocellular ' since r ratio was 39 . six months later , the patient was presented to our department with a 2 week history of jaundice . laboratory test showed ast 752 iu / l , alt 1,135 iu / l , ap 243 iu / l and total bilirubin 15.81 mg / dl . we recommended admission , but she refused to be admitted and she never visited our hospital again . a 55-yr - old female patient was presented to our department with a 3 month history of epigastric discomfort . past medical history and family history laboratory abnormalities included ast 344 iu / l , alt 666 iu / l , ap 298 iu / l . anti - hav igm , anti - hcv , hcv pcr , and anti - hev igm were negative . alt was 484 iu / l on her discharge ( on the 5th day of admission ) . liver function test was normal at that time ( ast 29 iu / l , alt 11 iu / l , ap 190 the type of liver injury was determined as ' hepatocellular ' since r ratio was 11 . the major driving force for the growth of the dietary supplements market is the perception that ' they are safe because they are natural ' . however , the recently reported cases of hepatotoxicity induced by natural substances ( 8) indicate that natural substances may not be entirely safe . there have been positive reports on aloe vera as anti - inflammatory , anticancer , analgesic , anti - aging as well as liver protective . but , clinical effectiveness of aloe vera was not sufficiently defined because there were no large and randomized studies ( 9 ) . in 1994 , korea 's national institute of safety research conducted an experiment on the efficacy and toxicity of aloe ( 10 ) . there was no difference of natural killer cell activity between the aloe vera gel treated and control animals . to observe the toxicity of aloe gel any adverse effects were not detected in hematological test , serum biochemistry , and histopathological examination . careful history taking , laboratory finding , and histopathology are used to diagnose it . the best way to determine causing agent is re - challenging . patients usually do not regard dietary supplements as ' real ' medicine , they may fail to mention it when physicians query medication history . physicians should keep in mind that dietary supplements can be the cause of hepatotoxicity when querying medication history , and should educate the lay public . there are three types of acute liver injury by drug or herb ( 12 ) : hepatocellular , cholestatic , and mixed type . our cases are characterized as hepatocellular ; there is a predominant initial elevation of the alt level . there are two proposed pathogeneses of drug induced liver disease ( 13 ) : direct toxicity and idiosyncratic mechanism . it is more likely that an idiosyncratic immunological mechanism ( hypersensitivity ) is responsible for the cases . a role for hypersensitivity is further supported by the presence of eosinophilic granulocytes in the periportal fields seen in the biopsy . hypersensitivity to aloe has been described in humans ( 14 ) , and the patch test or allergic skin test showed positive results ( 15 ) . herb induced liver injury is an important problem in clinical setting , because it can be an etiology of undiagnosed acute hepatitis . however , there are few available data about the incidence and clinical manifestation of dietary supplements such as aloe . our cases emphasize that physicians should consider various dietary supplements as causative agents for hepatotoxicity .

aloe has been widely used in phytomedicine . phytomedicine describes aloe as a herb which has anti - inflammatory , anti - proliferative , anti - aging effects . in recent years several cases of aloe - induced hepatotoxicity were reported . but its pharmacokinetics and toxicity are poorly described in the literature . here we report three cases with aloe - induced toxic hepatitis . a 57-yr - old woman , a 62-yr - old woman and a 55-yr - old woman were admitted to the hospital for acute hepatitis . they had taken aloe preparation for months . their clinical manifestation , laboratory findings and histologic findings met diagnostic criteria ( rucam scale ) of toxic hepatitis . upon discontinuation of the oral aloe preparations , liver enzymes returned to normal level . aloe should be considered as a causative agent in hepatotoxicity .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Low Income Taxpayer Protection Act of 2003''. SEC. 2. REGULATION OF INCOME TAX RETURN PREPARERS AND REFUND ANTICIPATION LOAN PROVIDERS. (a) Definitions.--In this Act: (1) Income tax return preparer.-- (A) In general.--The term ``income tax return preparer'' means any individual who is an income tax return preparer (within the meaning of section 7701(a)(36) of the Internal Revenue Code of 1986) who prepares not less than 5 returns of tax imposed by subtitle A of such Code or claims for refunds of tax imposed by such subtitle A per taxable year. (B) Exception.--Such term shall not include a federally authorized tax practitioner within the meaning of section 7526(a)(3) of such Code. (2) Refund anticipation loan provider.--The term ``refund anticipation loan provider'' means a person who makes a loan of money or of any other thing of value to a taxpayer because of the taxpayer's anticipated receipt of a Federal tax refund. (3) Secretary.--The term ``Secretary'' means the Secretary of the Treasury. (b) Regulations.-- (1) Registration required.-- (A) In general.--Not later than 120 days after the date of the enactment of this Act, the Secretary shall promulgate regulations that-- (i) require the registration of income tax return preparers and of refund anticipation loan providers with the Secretary or the designee of the Secretary, and (ii) prohibit the payment of a refund of tax to a refund anticipation loan provider or an income tax return preparer that is the result of a tax return which is prepared by the refund anticipation loan provider or the income tax return preparer which does not include the refund anticipation loan provider's or the income tax return preparer's registration number. (B) No disciplinary action.--The regulations shall require that an applicant for registration must not have demonstrated any conduct that would warrant disciplinary action under part 10 of title 31, Code of Federal Regulations. (C) Burden of registration.--In promulgating the regulations, the Secretary shall minimize the burden and cost on the registrant. (2) Rules of conduct.--All registrants shall be subject to rules of conduct that are consistent with the rules that govern federally authorized tax practitioners. (3) Reasonable fees and interest rates.--The Secretary, after consultation with any expert as the Secretary deems appropriate, shall include in the regulations guidance on reasonable fees and interest rates charged to taxpayers in connection with loans to taxpayers made by refund anticipation loan providers. (4) Renewal of registration.--The regulations shall determine the time frame required for renewal of registration and the manner in which a registered income tax return preparer or a registered refund anticipation loan provider must renew such registration. (5) Fees.-- (A) In general.--The Secretary may require the payment of reasonable fees for registration and for renewal of registration under the regulations. (B) Purpose of fees.--Any fees required under this paragraph shall inure to the Secretary for the purpose of reimbursement of the costs of administering the requirements of the regulations. (c) Prohibition.--Section 6695 of the Internal Revenue Code of 1986 (relating to other assessable penalties with respect to the preparation of income tax returns for other persons) is amended by adding at the end the following new subsection: ``(h) Actions on a Taxpayer's Behalf by a Non-Registered Person.-- Any person not registered pursuant to the regulations promulgated by the Secretary under the Low Income Taxpayer Protection Act of 2003 who-- ``(1) prepares a tax return for another taxpayer for compensation, or ``(2) provides a loan to a taxpayer that is linked to or in anticipation of a tax refund for the taxpayer, shall be subject to a $500 penalty for each incident of noncompliance.''. (d) Coordination With Section 6060(a).--The Secretary shall determine whether the registration required under the regulations issued pursuant to this section should be in lieu of the return requirements of section 6060. (e) Paperwork Reduction.--The Secretary shall minimize the amount of paperwork required of a income tax return preparer or a refund anticipation loan provider to meet the requirements of these regulations. SEC. 3. IMPROVED SERVICES FOR TAXPAYERS. (a) Electronic Filing Efforts.-- (1) In General.--The Secretary shall focus electronic filing efforts on benefiting the taxpayer by-- (A) reducing the time between receipt of an electronically filed return and remitting a refund, if any, (B) reducing the cost of filing a return electronically, (C) improving services provided by the Internal Revenue Service to low and moderate income taxpayers, (D) providing tax-related computer software at no or nominal cost to low and moderate income taxpayers, and (E) providing electronic filing for all taxpayers without the use of an intermediary. (2) Report.--Not later than 120 days after the date of the enactment of this Act, the Secretary shall prepare and submit to Congress a report on the efforts made pursuant to paragraph (1). (b) Volunteer Income Tax Assistance Program.-- (1) Study.--The Secretary shall undertake a study on the expansion of the volunteer income tax assistance program to service more low income taxpayers. (2) Report.--Not later than 120 days after the date of the enactment of this Act, the Secretary shall prepare and submit to Congress a report on the study conducted pursuant to paragraph (1). (c) Tele-Filing.--The Secretary shall ensure that tele-filing is available for all taxpayers for the filing of tax returns with respect to taxable years beginning in 2003. (d) Termination of the Debt Indicator Program.--The Secretary shall terminate the Debt Indicator program announced in Internal Revenue Service Notice 99-58. (e) Direct Deposit Accounts.--The Secretary shall allocate resources to programs to assist low income taxpayers in establishing accounts at financial institutions that receive direct deposits from the United States Treasury. (f) Pilot Program for Mobile Tax Return Filing Offices.-- (1) In general.--The Secretary shall establish a pilot program for the creation of four mobile tax return filing offices with electronic filing capabilities. (2) Location of service.-- (A) In general.--The mobile tax return filing offices shall be located in communities that the Secretary determines have a high incidence of taxpayers claiming the earned income tax credit. (B) Indian reservation.--At least one mobile tax return filing office shall be on or near an Indian reservation (as defined in section 168(j)(6) of the Internal Revenue Code of 1986). SEC. 4. ASSISTANCE PROGRAM TO IMPROVE ACCESS TO FEDERALLY INSURED FINANCIAL INSTITUTIONS FOR TAXPAYERS. (a) Findings and Purpose.-- (1) Findings.--Congress finds the following: (A) Approximately 40,000,000 Americans are unbanked and not utilizing mainstream, insured financial institutions. (B) In 1999, nearly half of the $30,000,000,000 in earned income tax credits (EITC) claimed nationwide was refunded through refund anticipation loans, and an estimated $1,750,000,000 intended to assist low-income families through the EITC was received by commercial tax preparers and affiliated national banks to pay for tax assistance, electronic filing of returns, and high- cost refund loans. (C) Refund anticipation loans carry interest rates in a range between 97.4 percent to more than 2000 percent. (D) An estimated 45 percent of earned income tax credit recipients pay for check cashing services, which reduces EITC benefits by $130,000,000. (E) Individuals with bank accounts can receive their tax refunds faster than waiting for a paper check and without the need to utilize refund anticipation loans or check cashiers. (F) Individuals with federally insured depository accounts have an increased opportunity to access financial services at mainstream financial institutions, which typically have reduced costs for consumers. (2) Purpose.--It is the purpose of this section to establish a grant program to provide unbanked low- and moderate-income taxpayers with tax preparation services and increase their access to financial services by the establishment of an account at a federally insured depository institution or credit union and the provision of financial education. (b) Establishment of Program.--The Secretary is authorized to award demonstration project grants (including multi-year grants) to eligible entities to provide tax preparation services and assistance along with establishing an account in a federally insured depositary institution for individuals that currently do not have such an account. (c) Eligible Entities.-- (1) In general.--An entity is eligible to receive a grant under this section if such an entity is-- (A) an organization described in section 501(c)(3) of the Internal Revenue Code of 1986 and exempt from tax under section 501(a) of such Code, (B) a federally insured depository institution, (C) an agency of a State or local government, (D) a community development financial institution, (E) an Indian tribal organization, (F) an Alaska Native Corporation, (G) a Native Hawaiian organization, (H) a labor organization, or (I) a partnership comprised of 1 or more of the entities described in the preceding subparagraphs. (2) Definitions.--For purposes of this section-- (A) Federally insured depository institution.--The term ``federally insured depository institution'' means any insured depository institution (as defined in section 3 of the Federal Deposit Insurance Act (12 U.S.C. 1813)) and any insured credit union (as defined in section 101 of the Federal Credit Union Act (12 U.S.C. 1752)). (B) Community development financial institution.-- The term ``community development financial institution'' means any organization that has been certified as such pursuant to section 1805.201 of title 12, Code of Federal Regulations. (C) Alaska native corporation.--The term ``Alaska Native Corporation'' has the same meaning as the term ``Native Corporation'' under section 3(m) of the Alaska Native Claims Settlement Act (43 U.S.C. 1602(m)). (D) Native hawaiian organization.--The term ``Native Hawaiian organization'' means any organization that-- (i) serves and represents the interests of Native Hawaiians, and (ii) has as a primary and stated purpose the provision of services to Native Hawaiians. (E) Labor organization.--The term ``labor organization'' means an organization in which employees participate and which exists for the purpose, in whole or in part, of dealing with employers concerning grievances, labor disputes, wages, rates of pay, hours of employment, or conditions of work. (d) Application.--An eligible entity desiring a grant under this section shall submit an application to the Secretary in such form and containing such information as the Secretary may require. (e) Limitation on Administrative Costs.--A recipient of a grant under this section may not use more than 6 percent of the total amount of such grant in any fiscal year for the administrative costs of carrying out the programs funded by such grant in such fiscal year. (f) Evaluation and Report.--For each fiscal year in which a grant is awarded under this section, the Secretary shall submit a report to Congress containing a description of the activities funded, amounts distributed, and measurable results, as appropriate and available. (g) Authorization of Appropriations.--There is authorized to be appropriated to the Secretary, for the grant program described in this section, $10,000,000, or such additional amounts as deemed necessary, to remain available until expended. (h) Regulations.--The Secretary is authorized to promulgate regulations to implement and administer the grant program under this section. SEC. 5. MATCHING GRANTS TO LOW-INCOME TAXPAYER CLINICS FOR RETURN PREPARATION. (a) In General.--Chapter 77 of the Internal Revenue Code of 1986 (relating to miscellaneous provisions) is amended by inserting after section 7526 the following new section: ``SEC. 7526A. RETURN PREPARATION CLINICS FOR LOW-INCOME TAXPAYERS. ``(a) In General.--The Secretary may, subject to the availability of appropriated funds, make grants to provide matching funds for the development, expansion, or continuation of qualified return preparation clinics. ``(b) Definitions.--For purposes of this section-- ``(1) Qualified return preparation clinic.-- ``(A) In general.--The term `qualified return preparation clinic' means a clinic which-- ``(i) does not charge more than a nominal fee for its services (except for reimbursement of actual costs incurred), and ``(ii) operates programs which assist low- income taxpayers in preparing and filing their Federal income tax returns, including schedules reporting sole proprietorship or farm income. ``(B) Assistance to low-income taxpayers.--A clinic is treated as assisting low-income taxpayers under subparagraph (A)(ii) if at least 90 percent of the taxpayers assisted by the clinic have incomes which do not exceed 250 percent of the poverty level, as determined in accordance with criteria established by the Director of the Office of Management and Budget. ``(2) Clinic.--The term `clinic' includes-- ``(A) a clinical program at an eligible educational institution (as defined in section 529(e)(5)) which satisfies the requirements of paragraph (1) through student assistance of taxpayers in return preparation and filing, and ``(B) an organization described in section 501(c) and exempt from tax under section 501(a) which satisfies the requirements of paragraph (1). ``(c) Special Rules and Limitations.-- ``(1) Aggregate limitation.--Unless otherwise provided by specific appropriation, the Secretary shall not allocate more than $10,000,000 per year (exclusive of costs of administering the program) to grants under this section. ``(2) Other applicable rules.--Rules similar to the rules under paragraphs (2) through (5) of section 7526(c) shall apply with respect to the awarding of grants to qualified return preparation clinics.''. (b) Clerical Amendment.--The table of sections for chapter 77 of the Internal Revenue Code of 1986 is amended by inserting after the item relating to section 7526 the following new item: ``Sec. 7526A. Return preparation clinics for low-income taxpayers.''. (c) Effective Date.--The amendments made by this section shall apply to grants made after the date of the enactment of this Act.

Low Income Taxpayer Protection Act of 2003 - Amends the Internal Revenue Code to: (1) require the registration of income tax preparers, including tax refund anticipation loan providers, and subjects unregistered preparers and providers to a $500 per incident violation fine; (2) provide for improved taxpayer services, including, improved electronic filing services, tele-filing, terminating the debt indicator program, assisting low-income taxpayers in receiving direct deposits from the U.S. Treasury, and establishing pilot mobile tax return offices; (3) provide for demonstration grants to eligible entities (federally insured depository institutions, State agencies, Indian tribal organizations, labor organizations, and etc.) to provide tax preparation services and assistance along with establishing an account in a federally insured depository institution for individuals not having such an account; and (4) provide grants for matching funds for the development, expansion, or continuation of qualified tax preparation clinics for low-income tax payers.

OFFICERS. ``The State Administrator shall establish a Problem Resolution Office. Problem Resolution Officers shall have the authority to investigate taxpayer complaints and enjoin collection activity if, in the opinion of the Problem Resolution Officer, said collection activity is reasonably likely to not be in compliance with law. Said administrative injunction may only be reversed by the highest official in the relevant State or Federal taxing authority or by its General Counsel upon a finding that the collection activity is justified by clear and convincing evidence. The authority to reverse this administrative injunction may not be delegated. Problem Resolution Officers shall not be disciplined or adversely affected for the issuance of administrative injunctions unless a pattern or issuing injunctions that are manifestly unreasonable is proven in an administrative hearing. Nothing in this section shall limit the authority of the State Administrators or the taxpayer to pursue any legal remedy in any court with jurisdiction over the dispute at issue. ``SEC. 53. JURISDICTION AND INTERSTATE ALLOCATION. ``(a) Allocation Rules.--For purposes of allocating revenue between or among administering states from taxes imposed by this subtitle, the revenue shall be allocated to those states that are the destination of the taxable property or services. The destination of the purchase of taxable property and services shall be determined in accordance with this section. ``(b) Federal Office of Revenue Allocation.--The Secretary shall establish an Office of Revenue Allocation to arbitrate any claims or disputes among administering states as to the destination of taxable property and services for purposes of allocating revenue between or among the states from taxes imposed by this subtitle. The determination of the Administrator of the Office of Revenue Allocation shall be subject to judicial review in any federal court with competent jurisdiction provided, however, that the standard of review shall be abuse of discretion. ``(c) Tangible Personal Property.--The destination of tangible personal property shall be the state or territory in which the property was first delivered to the purchaser. Tangible personal property shipped by means of the mail or common carrier shall be deemed delivered to the location of the purchaser for purposes of this subsection upon shipment by mail or common carrier. ``(d) Real Property.--The destination of real property or rents or leaseholds on real property shall be state or territory in which the real property is located. ``(e) Other Property.--The destination of other property shall be residence of the purchaser. ``(f) Services.-- ``(1) General rule.--The destination of services shall be state or territory in which the use, consumption or enjoyment of the services occurred. Allocation of service invoices relating to more than one jurisdiction shall be on the basis of time. ``(2) Telecommunications services.--The destination of telecommunications services shall be the residence of the purchaser. Telecommunications services shall include telephone, telegraph, cable television, satellite and computer on-line or network services. ``(3) Domestic transportation services.--For transportation services where all of the final destinations are within the United States, the destination of transportation services shall be the final destination of the trip (in the case of round or multiple trip fares, the services amount shall be equally allocated among the final destinations). ``(4) International transportation services.--For transportation services where the final destination or origin of the trip is without the United States, the service amount shall be deemed 50 percent attributable to the United States destination or origin. ``(g) Financial Intermediation Services.--The destination of financial intermediation services shall be the residence of the purchase. ``(h) A State Tax Administrator shall have jurisdiction over any gross payments made which have a destination (as determined in accordance with this section) within the state of said State Tax Administrator. This grant of jurisdiction is not exclusive of other jurisdiction that said State Tax Administrator may have. ``(i) Rents and Royalties Paid for the Lease of Tangible Property.-- ``(1) General rule.--The destination of rents and royalties paid for the lease of tangible property shall be where the property is located. ``(2) Vehicles.--The destination of rent and lease payments on vehicles shall be-- ``(A) in the case of rentals and leases of a term one month or less, the location where the vehicle was originally delivered to the lessee; and ``(B) in the case of rentals and leases of a term greater than one month, the residence of the lessee. ``SEC. 54. TAX TO BE STATED AND CHARGED SEPARATELY. ``(a) In General.--For each purchase of taxable property or services for which a tax is imposed pursuant to section 1, the sales tax shall be charged separately from the purchase price by the vendor or seller. For purchase of taxable property or services for which a tax is imposed pursuant to section 1, the vendor shall provide to the purchaser a receipt that sets forth at least the following information: ``(1) The property or services price exclusive of tax. ``(2) The amount of tax paid. ``(3) The property or service price inclusive of tax. ``(4) The tax rate (the amount of tax paid (per subparagraph 2) divided by the property or service price inclusive of tax (per subparagraph 3)). ``(5) The date that the good or service was sold. ``(6) The name of the vendor. ``(7) The vendor registration number. ``(b) Vending Machine Exception.--The requirements of subsection (a) shall be inapplicable in the case of sales by vending machines. Vending machines for purposes of this subsection shall mean machines-- ``(1) that dispense taxable property in exchange for coins, one, five, ten or twenty dollar bills, and ``(2) that sell no single item exceeding ten dollars per unit in price. ``SEC. 55. INSTALLMENT AGREEMENTS; COMPROMISES. ``The State Administrator or the Secretary, as the case may be, is authorized to enter into written agreements with any person under which the person is allowed to satisfy liability for payment of any tax in installment payments if he determines that such agreement will facilitate the collection of such liability. The agreement shall remain in effect for the term of the agreement unless the information that the person provided to the Secretary or the State Administrator was materially inaccurate or incomplete. The Secretary and the State Administrator may compromise any amounts alleged to be due. ``SEC. 56. ACCOUNTING. ``(a) Cash Method To Be Used Generally.--Vendors and other persons shall remit taxes and report transactions with respect to the month for which payment was received or the tax imposed by this chapter otherwise becomes due. ``(b) Election To Use Accrual Method.--A person may elect with respect to a calendar year, in a form prescribed by the Secretary, to remit taxes and report transactions with respect to the month where a sale was invoiced and accrued. ``(c) Cross Reference.-- ``For rules relating to bad debts for vendors electing the accrual method, see section 11(g). ``SEC. 57. HOBBY ACTIVITIES. ``(a) The exemption afforded by section 2(a)(1) shall not be available for any taxable property or service used by a trade or business if that trade or business is not engaged in for profit. ``(b) If the trade or business has received gross payments for the sale of taxable property or services that exceed the sum of-- ``(1) taxable property and services purchased, ``(2) wages paid, and ``(3) taxes paid, in 2 or more of the most recent 4 calendar years during which it operated, then the business activity shall be conclusively deemed to be engaged in for profit.''. SEC. 5. PHASE-OUT OF THE INTERNAL REVENUE SERVICE. (a) In General.--Appropriations for any expenses of the Internal Revenue Service including processing income tax returns for years prior to the repeal of the income tax, revenue accounting, management, transfer of payroll tax data to the Social Security Administration and otherwise for years after fiscal year 2007 are not authorized. (b) Excise and Sales Tax Bureaus.--Section 7801 is amended by adding the following new subsections: ``(d) Excise Tax Bureau.--There shall be in the Department of Treasury an Excise Tax Bureau to administer those excise taxes not repealed by this Act. ``(e) Sales Tax Bureau.--There shall be in the Department of Treasury a Sales Tax Bureau to administer the national sales tax in those States where it is required pursuant to section 31(g), and to discharge other Federal duties and powers relating to the national sales tax (including those required by sections 32, 33, and 53(b)). The Office of Revenue Allocation shall be within the Sales Tax Bureau.''. (c) Assistant General Counsels.--Section 7801(b)(2) is amended to read as follows: ``(2) Assistant general counsels.--The Secretary of the Treasury may appoint, without regard to the provisions of the civil service laws, and fix the duties of not more than 5 Assistant General Counsels.''. (d) Short Year.-- (1) For purposes of the Federal income tax, the tax imposed by section 1 and section 11 for taxable years ending June 30, 2006, shall be modified as set forth in this subsection. (2) For calendar year taxpayers, the dollar figures in section 1 and section 11 shall be reduced by dividing by 2 all dollar figures that would be applicable but for this subsection. (3) For fiscal year taxpayers, the dollar figures in section 1 and section 11 shall be equal to the product of-- (A) the dollar amount that would be applicable but for this subsection, and (B) the ratio that has as its numerator the number of months in the taxpayer's taxable year ending June 30, 2006, and as its denominator 12. (4) The Secretary shall publish tax rate schedules in accordance with this subsection. SEC. 6. SOCIAL SECURITY ADMINISTRATION TO COLLECT PAYROLL TAXES. (a) In General.--Commencing January 1, 2006, the Social Security Administration shall collect and administer the taxes imposed pursuant to chapter 2 of subtitle A (relating to self employment income taxes) and subtitle C (relating to employment taxes) of the Internal Revenue Code of 1986. (b) Cross References.-- For revised rules relating to the self- employment tax, see section 7 of this Act. For rules relating to revised withholding tax schedules and family consumption refund, see section 13. SEC. 7. SELF-EMPLOYMENT TAX. (a) In General.--Subsection 1402(a) of the Internal Revenue Code of 1986 is amended to read as follows: ``(a) In General.--`Self employment income' shall mean gross payments received in a calendar year from the sale of taxable property or services (without regard to exemption) less the sum in a calendar year of-- ``(1) purchases of taxable property or services (without regard to exemption) in furtherance of a business purpose, ``(2) any wages paid (whether to the self-employed person or others) in furtherance of a business purpose, ``(3) unused transition amounts, and ``(4) undeducted negative self employment income amounts from prior periods. ``(b) Transition Amounts.-- ``(1) General rule.--The transition amount for the ten calendar years commencing in 2006 shall be the unrecovered basis amount as of the end of December 31, 2005, divided by ten. ``(2) Unrecovered basis amount.--The unrecovered basis amount shall be remaining income tax basis relating to-- ``(A) prior law section 167 property placed in service prior to January 1, 2006, and ``(B) inventory held as of the end of 2005 (including any amounts capitalized in accordance with prior law section 263A).''. (b) Conforming Amendments.--Subsections 1402(b) and 1402(c) are hereby repealed. Subsections 1402(d) et seq. are hereby renumbered as subsections 1402(b) et seq. SEC. 8. SOCIAL SECURITY BENEFITS INDEXED ON SALES TAX INCLUSIVE BASIS. Subparagraph (D) of paragraph (1) of subsection (i) of section 215 of the Social Security Act (42 U.S.C. 415) (relating to cost-of-living increases in Social Security benefits) is amended to read as follows: ``(D)(i) the term `CPI increase percentage', with respect to a base quarter or cost-of-living quarter in any calendar year, means the percentage (rounded to the nearest one-tenth of 1 percent) by which the Consumer Price Index for that quarter (as prepared by the Department of Labor) exceeds such index for the most recent prior calendar quarter which was a base quarter under subparagraph (A)(ii) or, if later, the most recent cost- of-living computation quarter under subparagraph (B); ``(ii) if the Consumer Price Index (as prepared by the Department of Labor) does not include the national sales tax paid, then the term `CPI increase percentage' with respect to a base quarter or cost-of-living quarter in any calendar year, means the percentage (rounded to the nearest one-tenth of 1 percent) by which the product of-- ``(I) the Consumer Price Index for that quarter (as prepared by the Department of Labor); and ``(II) the national sales tax factor, exceeds such index for the most recent prior calendar quarter which was a base quarter under subparagraph (A)(ii) or, if later, the most recent cost-of-living computation quarter under subparagraph (B); and ``(iii) for purposes of clause (ii), the `national sales tax factor' is equal to one plus the quotient that is-- ``(I) the sales tax rate (as defined in section 1 of title 26), divided by ``(II) the quantity that is one minus the sales tax rate.''. SEC. 9. COMPENSATING PAYMENTS TO CERTAIN PERSONS ON FIXED INCOME. (a) Compensating Payment.--Eligible persons (as defined in subsection (c)) shall receive a compensating payment (as defined in subsection (b)) provided that they comply with subsection (g) (relating to applications). (b) Compensating Payment Defined.--The term ``compensating payment'' means the product of the qualified fixed income payment amount (as defined in subsection (e)) and the excess inflation rate (as defined in subsection (f)). (c) Eligible Person Defined.--An eligible person is any person with respect to any calendar year who is entitled to-- (1) Social Security benefits; and (2) qualified fixed income payments (as defined in subsection (d)). (d) Qualified Fixed Income Payment Defined.--A qualified fixed income payment is a payment received by-- (1) a beneficiary under a defined benefit plan (within the meaning of section 414(j) of the Internal Revenue Code as in effect prior to the enactment of this Act) whether sponsored by a private or Government employer; or (2) by an annuitant pursuant to an annuity contract between the annuitant and a bona fide insurance company. A payment pursuant to a plan or annuity contract is not a qualified fixed income payment if the payment varies with investment performance, interest rates, or inflation. Payments pursuant to an annuity contract entered into after June 30, 2006, shall not be qualified fixed income payments. Payments pursuant to a defined benefit plan to a beneficiary that had been a participant in said defined benefit plan (within the meaning of section 410 of the Internal Revenue Code as in effect prior to the enactment of this Act) for less than 5 years shall not be qualified fixed income payments. (e) Qualified Fixed Income Payment Amount.--The qualified fixed income payment amount is \1/12\ of qualified fixed income payments that an eligible person is entitled to receive during the calendar year subsequent to the year for which the compensating payment is calculated, provided, however, that the qualified fixed income payment amount shall not exceed $5,000. (f) Excess Inflation Rate Defined.--The term ``excess inflation rate'' shall mean the excess, if any, of the consumer price index (all urban) during the 18-month period ending December 31, 2006, over the increase projected for the consumer price index (all urban) in the Office of Management and Budget baseline reported in the Budget of the United States for Fiscal Year 2006 for said 18-month period. The baseline assumption for the 6 months in 2006 shall be \1/2\ of the assumed increase for the entire calendar year 2006. (g) Application Required.--In order to receive compensating payments, each eligible person must apply in a form prescribed by the Secretary of Health and Human Services and provide such documentation as the Secretary may reasonably require. (h) Means of Payment.--Each person entitled to a compensating payment shall receive the compensating payment with their Social Security benefit payment. The compensating payment shall be separately indicated but may be included in one check. The funds to make compensating payments shall come from the general fund. (i) The Secretary of Health and Human Services may require insurers that are parties to annuity contracts and defined benefit plan sponsors to issue a statement to annuitants or plan participants including such information as the Secretary may require to determine the qualified fixed income payment amount. SEC. 10. INTEREST. Section 6621 of the Internal Revenue Code of 1986 is amended by striking the last sentence in section 6621(a)(1) and by striking ``3'' in section 6621(a)(2)(B) and substituting in its stead ``2''. SEC. 11. SUPERMAJORITY REQUIRED TO RAISE RATE. (a) In General.--It shall not be in order in the House of Representatives or the Senate to consider any bill, joint resolution, amendment thereto, or conference report thereon that includes any provision that-- (1) increases any federal sales tax rate, and (2) provides any exemption, deduction, credit or other benefit which results in a reduction in federal revenues. (b) Waiver or Suspension.--This section may be waived or suspended in the House of Representatives or the Senate only by the affirmative vote of two-thirds of the Members, duly chosen and sworn.

Individual Tax Freedom Act of 2004 - Amends the Internal Revenue Code to repeal the income tax, estate and gift taxes, certain excise taxes, and certain tax administration provisions of the Internal Revenue Code of 1986 (effective in 2006). Imposes a national sales tax (effective in 2006) equal to 15 percent of the gross payments for the use, consumption or enjoyment in the United States of any taxable property or service, whether produced or rendered within or without the United States. Allows certain exemptions from such tax, including exemptions for property or services purchased for a business purpose in an active trade or business or for export for use or consumption outside the United States. Sets forth provisions for the administration and collection of the tax and for credits and refunds. Allows for: (1) installment payments of tax resulting from the purchase of a principal residence; (2) a sales tax rebate for certain low-income families; and (3) compensating payments to certain persons on fixed incomes. Grants States the authority to administer and collect the sales tax and to remit tax proceeds to the Treasury. Prohibits the funding of the Internal Revenue Service after FY 2007. Establishes in the Department of Treasury: (1) an Excise Tax Bureau to administer any excise taxes not repealed by this Act; and (2) a Sales Tax Bureau to administer the national sales tax established by this Act. Directs the Social Security Administration to collect and administer employment and self-employment payroll taxes. Requires a two-thirds vote of the Members of the House of Representatives or the Senate to consider any legislation that raises any Federal sales tax rate or results in a reduction in Federal revenues.

congenital muscular dystrophy type 1a ( mdc1a ) was first described in 1994 as a variant form of classic congenital muscular dystrophy ( cmd)1 ) . mdc1a is an autosomal recessive disorder , and patients show absent merosin ( laminin 2 ) on skeletal muscle biopsy . a mutation in the laminin 2 ( lama2 ) gene , located on 6q22 - 23 , most patients with mdc1a show absent merosin in muscle immunohistochemistry studies , however , there have been some reports of cases of mdc1a with residual merosin expression3,4,5 ) . mdc1a is very rare in asian countries . comparing with studies conducted in western countries2,3 ) , only a few cases without merosin expression have been reported in the asian population6,7,8 ) . here the patient was born at 38 weeks of gestation with a birth weight of 3,500 gm . she was a second child , with one 4-year - old brother with no medical problems . she was healthy at birth , but her parents noticed that she had a delayed motor milestone at the age of 4 months as indicated by her inability to fully control her head . she was brought to severance children 's hospital for the first time at the age of 4 months and was hypotonic at that time . she was fully examined for muscular disease at the age of 6 months , at which time she could not yet control her head . however the bayley scales of infant development for language and cognitive development were normal . her serum creatine kinase ( ck ) level was elevated to 2,184 iu / l ( 0 - 50 norm ) and her serum aldolase level was also high at 31.6 sigma u / ml ( 0 - 7.6 norm ) . in a nerve conduction study , brain magnetic resonance imaging ( mri ) performed at the age of 6 months showed excessive t2 hyper - intensity at the peritrigone and external capsule ( fig . 1 ) . repeated brain mri at the age of 8 months showed progression of dysmyelination . hematoxylin and eosin staining showed marked muscle fiber size variation , increased endomysial fibrosis , many endomysial inflammatory cell infiltrations , and many necrotic and regenerative muscle fibers ( fig . modified gomori trichrome staining did not show ragged red fibers , nemaline bodies , or rimmed vacuoles . immunohistochemical staining was performed using antibodies against the c - terminal of dystrophin , rod domain of dystrophin , n - terminal of dystrophin , -sarcoglycan , -sarcoglycan , -sarcoglycan , -sarcoglycan , dysferlin , -dystroglycan , caveolin 3 , and laminin 2 . staining against laminin 2 3 ) . to confirm mutation in the lama2 gene , we performed direct sequencing of exons 14 , 25 , 26 , and 27 , all of which are known as common sites of mutation . typical clinical features of mdc1a or merosin deficient congenital muscular dystrophy include severe floppiness at birth , elevated serum ck , delayed motor milestones , white matter changes as seen on brain mri , and normal intelligence2 ) . however , merosin - positive cmd generally presents with less severe clinical features and without any abnormalities on brain mri2,5 ) . initially , mdc1a was thought to be a homogenous disease ; however , case reports of atypical phenotypes and some cases showing only partially reduced merosin expression contributed to classifying the disease as a heterogeneous group3,5 ) . there have been mdc1a patients who show late - onset weakness , mental retardation , seizures , subclinical cardiac involvement , or neuronal migration defects9 ) . in particular , cases with residual merosin expression have more variable phenotypes than cases with absolute merosin deficiency . according to previous reports , patients with residual merosin tend to have milder phenotypes3,5 ) . with regards to ambulation , a previous study showed that eight out of 12 patients with residual merosin achieved independent ambulation , whereas , out of four patients with absent merosin , none could walk independently5 ) . another study presented similar results : five out of 13 patients with residual merosin and two out of 33 patients with absent merosin could walk independently3 ) . in our case , the onset of symptoms was 4 months after birth , rather than during the neonatal period . usually , merosin deficient patients present with symptoms within 7 days of birth , while patients with residual merosin have a later onset of symptoms . the other symptoms of this patient , such as hypotonia , normal intelligence , elevated serum ck , and the absence of seizures , are typical presentations of mdc1a patients . at present , she is 14 months old , and can sit without support but can not get into a sitting position . we estimate that she has about a 50% probability of walking independently later in her life . however , the patient 's site of lesion is in the external capsule , which is an unusual area for this disease . a study of 25 brazilian patients with mdc1a reported that bilateral white matter involvement in the parietal , frontal , and temporal regions was frequent , and brain stem , cerebellum , and internal and external capsules were also affected in a minority of cases10 ) . however , there were no correlations with sites of white matter abnormalities and clinical status or merosin status . to confirm mutation of the lama2 gene , we sequenced exons 14 , 25 , 26 , and 27 . this technique , while able to screen for point mutations in above 4 exons , is limited in its ability to detect large deletions or insertions or point mutations in the other sites . we did not further evaluate other possible mutations in the lama2 gene because of her parents ' refusal . according to a previous report , a majority of mutations in the residual merosin group are splice site mutations , and frameshift mutations are less frequent3 ) . this patient may have mutations in her lama2 gene , although we could not confirm the specific mutations because of incomplete study . mdc1a is very rare in asia , and the cases reported thus far are typically those without merosin , and have mostly been severe forms of mdc1a . in our study , the patient showed a typical phenotype of mdc1a , including features such as hypotonia , elevated serum ck , delayed motor development , and t2 hyperintensity on brain mri . however , immunohistochemical staining of the muscle fibers showed partially decreased merosin levels and some atypical findings , such as a somewhat later age of disease onset and involvement of the external capsule . from our experience , performing immunohistochemical staining to assay the extent of merosin expression is an important procedure , and may be helpful in predicting the clinical course of the disease .

congenital muscular dystrophy type 1a ( mdc1a ) is an autosomal recessive disorder characterized by hypotonia , elevated serum creatine kinase level , delayed motor milestones , white matter changes observed by brain magnetic resonance imaging , and normal intelligence . a mutation in the laminin 2 ( lama2 ) gene , located at 6q22 - 23 , is a genetic cause of mdc1a . patients have merosin ( laminin 2)-deficient skeletal muscles . however , the degree of merosin expression ranges from total absence to partial reduction . patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency . we observed a korean girl with mdc1a with residual merosin expression . clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement . immunohistochemical staining of muscle fibers including merosin , is important to evaluate patients with hypotonia , delayed motor development , and abnormal white matter changes .

all participants received a detailed explanation of the study and signed an informed consent form approved by the partners human research committees ( institutional review board ) , in accordance with the principles embodied in the declaration of helsinki . brillouin sagittal profiles were acquired in 56 eyes of 30 healthy subjects , age 19 to 63 years old ( mean age : 36 13 years ) . exclusion criteria included cataracts , allergy to ophthalmic medications , severe refractive abnormalities , occludable narrow angles or other pathologies that preclude safe dilation , systemic disease , and previous refractive surgery . the system employed a 780-nm tunable laser diode ( dl - pro ; toptica photonics , munich , germany ) with an optical power of 2 mw on the cornea surface . the laser light was focused by a 5 infinity - corrected objective lens ( na = 0.1 ; mitutoyo america , aurora , il , usa ) with a long working distance of 34 mm . the beam size at the focus was approximately 4 m laterally ( x - y ) and 60 m ( z ) axially . the focus was scanned along axial lines by translating the objective with a motorized stage ( t - lsm25 ; zaber technologies , vancouver , bc , canada ) . a wide - field video camera was used to track the pupil and to control the x - y position of the scan axis . a maltese cross fixation target was used on a modified badal optometer to fix the vergence of the eye during axial scans . ( b ) raw emccd output of the vipa spectrometer showing the vitreous humor ( top ) and lens nucleus ( bottom ) at an integration time of 0.2 seconds and a laser power of 2 mw . the two peaks represent the stoke shift and the antistoke shift of the following laser order . ( c ) 2-lorentzian peak fit ( solid line ) of the raw imaging data ( points ) along the brillouin spectral line for vitreous humor ( black ) and lens nucleus ( red ) . the collected brillouin backscattered light was spectrally dispersed by a spectrometer consisting of a two - stage virtually imaged parallel array ( vipa ) device and imaged onto an electron - magnification charged coupled device ( ixon du-897 ; andor technologies , belfast , northern ireland ) . figures 1b and 1c report typical raw brillouin spectra for the human vitreous humor and the lens nucleus , and the 2-lorentzian peak fit used to determine brillouin frequency shifts . the setup used labview ( national instruments , austin , tx , usa ) for real - time operations , including hardware control , laser - to - eye position registration , image processing , and display of raw spectrometer output and brillouin line - scan profiles . during brillouin scans , the visual stimulus was set at a far point ( infinity ) with correction of the vergence to compensate the refractive error of the eye . the axial scanning speed was adjusted between 150 and 850 m / s for an emccd integration time of 0.1 to 0.4 second , taking into account the individual subject 's ability to fixate and stay still . typical axial scan durations ranged between 10 and 20 seconds at a laser power of 2 mw . in initial scans , low - resolution brillouin axial profiles of the whole anterior segment were taken to locate the interface of the posterior cornea , anterior and posterior lens capsule , and anterior and posterior lens nucleus with an accuracy of approximately 120 m . the measured distances were then included in an iterative eye propagation model based on a full gullstrand eye model to determine the actual focal depth within the eye . following this initial procedure , high - resolution scans along the sagittal axis of the lens were performed with a step size of 60 m , the same as the axial resolution of our system . a minimum of 10 scans were performed on each eye to confirm reproducibility of the scan data . scans with significant motion artifact , as determined by the eye registration system , were removed from the analysis . the laser power of 2 mw is 63 times lower than the maximum permissive exposure defined by the american national standards institute for retinal hazard and 16 times lower than the guideline of the international committee on non - ionizing radiation protection standards for the lens and cornea thermal hazards . none of the subjects expressed any discomfort , pain , or vision problems during or after the imaging session . the laser light was seen as a diffuse faint - red color , barely visible on top of the fixation target projection . for the first 10 subjects , comprehensive eye examinations were performed at massachusetts eye and ear infirmary before and 6 months after scan sessions . the brillouin shift was obtained from the spacing between the stokes ( left peak ) and anti - stokes shift ( right peak ) . for accurate calibration , the free spectral range and spectral dispersion of the spectrometer were determined from the measured brillouin spectra of two known materials , water and poly(methyl methacrylate ) plastic , immediately before or after each human imaging session . this calibration step allowed subpixel localization of the peak central position even in the presence of the typical drifts in the laser frequency and spectrometer alignment . the measurement error in brillouin shifts was approximately 16 mhz at a laser power of 2 mw and an integration time of 0.2 second . the long - term frequency stability of the measurement was better than 16 mhz , as estimated from the standard deviation ( sd ) in repetitive measurements of test materials over 30 days . the brillouin longitudinal modulus ( m ) was calculated from the brillouin shift ( ) according to the following relation : where is the mass density , ( 780 nm ) is the optical wavelength in air , n is the refractive index , and ( 180 degrees in our experimental condition ) is the angle between the incident and scattered light . the refractive index and density of the tissue are spatially nonuniform within the lens ; however , the ratio of /n is approximately constant at 0.5636 g / cm with a variation of less than 1% throughout the lens . to quantify the regional variation of lens elasticity , the obtained sagittal profiles were fitted using a general power law model : the central position xc and thickness l were obtained from the brillouin axial profiles , and the peak modulus mmax , the amplitude of variation m , and the exponents were used as fitting parameters . separate fits were performed for the anterior cortex , anterior nucleus , posterior nucleus , and posterior cortex . for the plateau region fit , the inner region of the lens with the top 50% value of m was used to accurately reproduce the flat central region and the transitional region between the nucleus and the cortex ( see fig . 2 ) . in this central region , xc is the lens center , and l is the half lens width of this top 50% region . for the peripheral regions , all points lower than 98% of the peak longitudinal modulus were used in the fit . in these regions , xc was the axial position at the 98% value , and l was the thickness of the anterior or posterior cortical region . the exponent is a geometric factor describing the shape of the lens 's modulus profile ( e.g. , a parabolic profile for = 2 , and bell - shaped profiles at higher values ) . representative brillouin sagittal profiles in 19- , 31- , 43- , and 60-year - old human lenses showing the aqueous humor ( a.h . ) , the vitreous humor ( v.h . ) , the lens cortex , and central plateau . the points and error bars represent the mean and sd of successive scans taken along the sagittal axis . ex vivo measurements were conducted on 14 human eyes obtained from two young donors ( mean age : 24 2 years ) , and five old donors ( mean age : 59 6 years ) . the human donor eyes were obtained from the national disease research interchange ( philadelphia , pa , usa ) , and used in compliance with the guidelines of the declaration of helsinki for research involving the use of human tissue . to limit postmortem swelling , the lens was surgically extracted from the eye at the donor agency and immediately stored in mineral oil at 4c before shipment . on arrival , the ciliary body and lens capsule were carefully removed by making a small incision at the edge of the equatorial plane and by peeling out the capsule with surgical tweezers . eight lenses were dissected into thin disks , and brillouin microscopy and shear rheometry were performed on each disk . for dissection , the lens was cut with a scalpel in 1.5-mm - thick layers with cutting plane perpendicular to the equatorial plane . then , from each layer , 4-mm disks were extracted by using a biopsy punch and then immediately stored in a small petri dish filled with mineral oil . for the other six lenses , the whole lenses were characterized with three - dimensional - scan brillouin imaging and shear rheometer without dissection ; the results of this analysis were consistent with the findings obtained with the dissection approach , but the details will be reported elsewhere . brillouin measurements were performed right after dissection . for each lens piece , a two - dimensional map ( typically 40 40 points ) in the central equatorial / sagittal plane was obtained by moving the sample with a three - axis translation stage ( h117 ; prior scientific , fulbourn , cambridge , uk ) . from the map , the average value of the measured data was calculated , which represents the brillouin longitudinal modulus of the sample . after brillouin measurements , all lens samples were stored at 4c , and allowed to thermalize at room temperature 20 minutes before rheometry measurements . for shear rheometry , a standard stress - controlled rheometer was used ( ar - g2 ; ta instruments , new castle , de , usa ) with 8-mm diameter parallel plates , with a precompression of approximately 100 m , frequency sweeps from 0.1 to 10 hz with 0.1% strain amplitude . the data reported here refer to the shear modulus measured at approximately 0.2 hz . all measurements were completed within 36 hours postmortem . all participants received a detailed explanation of the study and signed an informed consent form approved by the partners human research committees ( institutional review board ) , in accordance with the principles embodied in the declaration of helsinki . brillouin sagittal profiles were acquired in 56 eyes of 30 healthy subjects , age 19 to 63 years old ( mean age : 36 13 years ) . exclusion criteria included cataracts , allergy to ophthalmic medications , severe refractive abnormalities , occludable narrow angles or other pathologies that preclude safe dilation , systemic disease , and previous refractive surgery . figure 1 schematically represents the confocal brillouin microscope used in this study . the system employed a 780-nm tunable laser diode ( dl - pro ; toptica photonics , munich , germany ) with an optical power of 2 mw on the cornea surface . the laser light was focused by a 5 infinity - corrected objective lens ( na = 0.1 ; mitutoyo america , aurora , il , usa ) with a long working distance of 34 mm . the beam size at the focus was approximately 4 m laterally ( x - y ) and 60 m ( z ) axially . the focus was scanned along axial lines by translating the objective with a motorized stage ( t - lsm25 ; zaber technologies , vancouver , bc , canada ) . a wide - field video camera was used to track the pupil and to control the x - y position of the scan axis . a maltese cross fixation target was used on a modified badal optometer to fix the vergence of the eye during axial scans . ( b ) raw emccd output of the vipa spectrometer showing the vitreous humor ( top ) and lens nucleus ( bottom ) at an integration time of 0.2 seconds and a laser power of 2 mw . the two peaks represent the stoke shift and the antistoke shift of the following laser order . ( c ) 2-lorentzian peak fit ( solid line ) of the raw imaging data ( points ) along the brillouin spectral line for vitreous humor ( black ) and lens nucleus ( red ) . the collected brillouin backscattered light was spectrally dispersed by a spectrometer consisting of a two - stage virtually imaged parallel array ( vipa ) device and imaged onto an electron - magnification charged coupled device ( ixon du-897 ; andor technologies , belfast , northern ireland ) . figures 1b and 1c report typical raw brillouin spectra for the human vitreous humor and the lens nucleus , and the 2-lorentzian peak fit used to determine brillouin frequency shifts . the setup used labview ( national instruments , austin , tx , usa ) for real - time operations , including hardware control , laser - to - eye position registration , image processing , and display of raw spectrometer output and brillouin line - scan profiles . during brillouin scans , the subject was asked to stare at the fixation target through the objective lens . the visual stimulus was set at a far point ( infinity ) with correction of the vergence to compensate the refractive error of the eye . the axial scanning speed was adjusted between 150 and 850 m / s for an emccd integration time of 0.1 to 0.4 second , taking into account the individual subject 's ability to fixate and stay still . typical axial scan durations ranged between 10 and 20 seconds at a laser power of 2 mw . in initial scans , low - resolution brillouin axial profiles of the whole anterior segment were taken to locate the interface of the posterior cornea , anterior and posterior lens capsule , and anterior and posterior lens nucleus with an accuracy of approximately 120 m . the measured distances were then included in an iterative eye propagation model based on a full gullstrand eye model to determine the actual focal depth within the eye . following this initial procedure , high - resolution scans along the sagittal axis of the lens were performed with a step size of 60 m , the same as the axial resolution of our system . a minimum of 10 scans were performed on each eye to confirm reproducibility of the scan data . scans with significant motion artifact , as determined by the eye registration system , were removed from the analysis . the laser power of 2 mw is 63 times lower than the maximum permissive exposure defined by the american national standards institute for retinal hazard and 16 times lower than the guideline of the international committee on non - ionizing radiation protection standards for the lens and cornea thermal hazards . none of the subjects expressed any discomfort , pain , or vision problems during or after the imaging session . the laser light was seen as a diffuse faint - red color , barely visible on top of the fixation target projection . for the first 10 subjects , comprehensive eye examinations were performed at massachusetts eye and ear infirmary before and 6 months after scan sessions . the brillouin shift was obtained from the spacing between the stokes ( left peak ) and anti - stokes shift ( right peak ) . for accurate calibration , the free spectral range and spectral dispersion of the spectrometer were determined from the measured brillouin spectra of two known materials , water and poly(methyl methacrylate ) plastic , immediately before or after each human imaging session . this calibration step allowed subpixel localization of the peak central position even in the presence of the typical drifts in the laser frequency and spectrometer alignment . the measurement error in brillouin shifts was approximately 16 mhz at a laser power of 2 mw and an integration time of 0.2 second . the long - term frequency stability of the measurement was better than 16 mhz , as estimated from the standard deviation ( sd ) in repetitive measurements of test materials over 30 days . the brillouin longitudinal modulus ( m ) was calculated from the brillouin shift ( ) according to the following relation : where is the mass density , ( 780 nm ) is the optical wavelength in air , n is the refractive index , and ( 180 degrees in our experimental condition ) is the angle between the incident and scattered light . the refractive index and density of the tissue are spatially nonuniform within the lens ; however , the ratio of /n is approximately constant at 0.5636 g / cm with a variation of less than 1% throughout the lens . to quantify the regional variation of lens elasticity , the obtained sagittal profiles were fitted using a general power law model : the central position xc and thickness l were obtained from the brillouin axial profiles , and the peak modulus mmax , the amplitude of variation m , and the exponents were used as fitting parameters . separate fits were performed for the anterior cortex , anterior nucleus , posterior nucleus , and posterior cortex . for the plateau region fit , the inner region of the lens with the top 50% value of m was used to accurately reproduce the flat central region and the transitional region between the nucleus and the cortex ( see fig . 2 ) . in this central region , xc is the lens center , and l is the half lens width of this top 50% region . for the peripheral regions , all points lower than 98% of the peak longitudinal modulus were used in the fit . in these regions , xc was the axial position at the 98% value , and l was the thickness of the anterior or posterior cortical region . the exponent is a geometric factor describing the shape of the lens 's modulus profile ( e.g. , a parabolic profile for = 2 , and bell - shaped profiles at higher values ) . representative brillouin sagittal profiles in 19- , 31- , 43- , and 60-year - old human lenses showing the aqueous humor ( a.h . ) , the vitreous humor ( v.h . ) , the lens cortex , and central plateau . the points and error bars represent the mean and sd of successive scans taken along the sagittal axis . ex vivo measurements were conducted on 14 human eyes obtained from two young donors ( mean age : 24 2 years ) , and five old donors ( mean age : 59 6 years ) . the human donor eyes were obtained from the national disease research interchange ( philadelphia , pa , usa ) , and used in compliance with the guidelines of the declaration of helsinki for research involving the use of human tissue . to limit postmortem swelling , the lens was surgically extracted from the eye at the donor agency and immediately stored in mineral oil at 4c before shipment . the ciliary body and lens capsule were carefully removed by making a small incision at the edge of the equatorial plane and by peeling out the capsule with surgical tweezers . eight lenses were dissected into thin disks , and brillouin microscopy and shear rheometry were performed on each disk . for dissection , the lens was cut with a scalpel in 1.5-mm - thick layers with cutting plane perpendicular to the equatorial plane . then , from each layer , 4-mm disks were extracted by using a biopsy punch and then immediately stored in a small petri dish filled with mineral oil . for the other six lenses , the whole lenses were characterized with three - dimensional - scan brillouin imaging and shear rheometer without dissection ; the results of this analysis were consistent with the findings obtained with the dissection approach , but the details will be reported elsewhere . brillouin measurements were performed right after dissection . for each lens piece , a two - dimensional map ( typically 40 40 points ) in the central equatorial / sagittal plane was obtained by moving the sample with a three - axis translation stage ( h117 ; prior scientific , fulbourn , cambridge , uk ) . from the map , the average value of the measured data was calculated , which represents the brillouin longitudinal modulus of the sample . after brillouin measurements , all lens samples were stored at 4c , and allowed to thermalize at room temperature 20 minutes before rheometry measurements . for shear rheometry , a standard stress - controlled rheometer was used ( ar - g2 ; ta instruments , new castle , de , usa ) with 8-mm diameter parallel plates , with a precompression of approximately 100 m , frequency sweeps from 0.1 to 10 hz with 0.1% strain amplitude . the data reported here refer to the shear modulus measured at approximately 0.2 hz . all measurements were completed within 36 hours postmortem . figure 2 shows four representative axial profiles of brillouin modulus obtained from 19- , 31- , 43- , and 61-year - old subjects . the brillouin frequency shifts of the aqueous and vitreous humors were equal within the instrument accuracy . brillouin longitudinal modulus increased steeply in the lens periphery but moderately in the lens center . based on the fitted profiles , we defined a central plateau region as the inner portion of the lens with the top 98% value in longitudinal modulus , and a peripheral region as the remaining outside of the central plateau region . the central plateau region corresponds , approximately , to the anatomical lens nucleus ; the peripheral region includes the anterior and posterior lens cortices . figures 3a and 3b show several examples of sagittal brillouin profiles taken from right ( dashed line ) and left ( solid line ) eyes of the same subject in young ( fig . the difference in the mean longitudinal elastic modulus of the central plateau region between the left and right eyes showed no statistically significant difference or the difference was smaller than the instrument accuracy . on the other hand , grouping individuals in age - matched subjects ( 1.5 years ) , we found an intersubject variability of 57 46 mhz , which is approximately three times larger than the system spectral resolution . ( a ) brillouin sagittal profiles of the left and right eyes of three individuals in an age range of 21 1 . ( b ) comparison of the left and right eyes in two 51-year - old subjects . ( c ) the relative difference in the mean longitudinal modulus observed in the central plateau between the left and right eyes in the same subject and between subjects within an age - window of 3 years ( inter ) . figure 4 shows the age - related variations in thickness for the whole lens and for the different regions of the lens as previously identified on the base of their longitudinal modulus . a linear increase of the whole lens thickness at a slope of 32 3 m per year was found , and is consistent with previous measurements by scheimpflug imaging , mri , ultrasonography , and optical coherence tomography ( birkenfeld j , et al . importantly , the increase in the lens size was entirely due to a growth of the stiff central region ( slope of 31 3 m / y ) ; the thickness of the peripheral softer regions being constant with age . the mean thickness of the anterior peripheral region was 1.0 0.2 mm , slightly greater than the mean thickness of the posterior peripheral region of 0.71 0.13 mm . variation of the human lens anterior cortex ( a.c . ) , posterior cortex ( p.c . ) , central plateau , and overall lens thickness with age . the error bars represent the instrument 's thickness accuracy of 120 m , which is a conservative assumption equal to twice the optical resolution of the brillouin microscope and accounting for the accuracy in the two interfaces localization . figure 5 shows the magnitudes of maximal brillouin longitudinal modulus at the center of the lens and the minimal longitudinal modulus at the interfaces with the aqueous humor and vitreous . the minimal longitudinal modulus showed no statistically significant age dependence and had an identical average value of 2.36 0.02 gpa in both the anterior and posterior sides . also , the longitudinal modulus of the central plateau did not show statistically significant age dependence in the age range of 19 to 45 years . beyond age 45 , however , a small decrease in the longitudinal modulus of the central plateau was observed at a rate of 4.5 1.4 mpa per year . variation of the brillouin longitudinal modulus with age in aqueous humor , vitreous humor , and lens plateau . the error bars represent the sd within each eye subregion . for the plateau region , linear regressions for age younger than 45 years ( solid line ) and older than 45 years ( dashed line ) are shown . figure 6 shows the exponent obtained from the fitting of the anterior and posterior plateau regions . the parameter increased with the subject age significantly ( p < 0.001 ) in a linear regression analysis , which is consistent with the observed flattening of the central region and an increase of the gradient at the transition between the central and peripheral regions . variation of the power law exponent for the anterior and posterior region within the slowly varying central region of the lens . ( a ) comparison of the cortical sagittal elasticity gradient between young ( < 25 years old ) , mid ( 3545 years old ) , and old ( > 50 years old ) groups . ( b ) variation of the power law exponent for the cortical anterior and posterior regions . the error bars represent the 95% confidence bound of the fit coefficients . to compare the brillouin longitudinal moduli with traditional shear moduli , we used ex vivo lens tissues cut into small pieces . figure 8 shows the quasistatic shear modulus and the brillouin longitudinal modulus along the equatorial direction . in both young and old lenses , we found an increase of the elastic modulus from the lens periphery toward the lens center . the variability within the same layer represents the intrinsic variations of shear and longitudinal moduli of lens tissues in the equatorial and sagittal axes . in young lenses , the measured quasistatic shear modulus ranged from 0.20 to 10.3 kpa , whereas the brillouin modulus varied from 2.81 to 3.11 gpa . in old lenses , shear moduli ranged from 0.36 to 19.2 kpa , whereas brillouin moduli ranged from 2.91 to 3.27 gpa , respectively . the six to seven orders of magnitude difference between shear and longitudinal moduli is well expected from the incompressibility of water and consistent with previous results . nevertheless , the correlation between brillouin moduli and shear moduli is strong ( p < 0.05 in linear regression analysis for all lenses analyzed ) . spatial variation of the shear and longitudinal elastic moduli of ex vivo human lenses along the equatorial axis . ( a ) young lenses ( n = 2 , 4-mm disks from the left and right eyes of a 26-year - old donor ) . ( b ) old lenses ( n = 48 , 4-mm disks from left and right eyes of three donors at ages of 50 , 60 , and 62 ) . solid dots , measured data from each individual sample ; open squares , average value of the data within each layer ; and error bars , standard variation . figure 2 shows four representative axial profiles of brillouin modulus obtained from 19- , 31- , 43- , and 61-year - old subjects . the brillouin frequency shifts of the aqueous and vitreous humors were equal within the instrument accuracy . brillouin longitudinal modulus increased steeply in the lens periphery but moderately in the lens center . based on the fitted profiles , we defined a central plateau region as the inner portion of the lens with the top 98% value in longitudinal modulus , and a peripheral region as the remaining outside of the central plateau region . the central plateau region corresponds , approximately , to the anatomical lens nucleus ; the peripheral region includes the anterior and posterior lens cortices . figures 3a and 3b show several examples of sagittal brillouin profiles taken from right ( dashed line ) and left ( solid line ) eyes of the same subject in young ( fig . the difference in the mean longitudinal elastic modulus of the central plateau region between the left and right eyes showed no statistically significant difference or the difference was smaller than the instrument accuracy . on the other hand , grouping individuals in age - matched subjects ( 1.5 years ) , we found an intersubject variability of 57 46 mhz , which is approximately three times larger than the system spectral resolution . ( a ) brillouin sagittal profiles of the left and right eyes of three individuals in an age range of 21 1 . ( b ) comparison of the left and right eyes in two 51-year - old subjects . ( c ) the relative difference in the mean longitudinal modulus observed in the central plateau between the left and right eyes in the same subject and between subjects within an age - window of 3 years ( inter ) . figure 4 shows the age - related variations in thickness for the whole lens and for the different regions of the lens as previously identified on the base of their longitudinal modulus . a linear increase of the whole lens thickness at a slope of 32 3 m per year was found , and is consistent with previous measurements by scheimpflug imaging , mri , ultrasonography , and optical coherence tomography ( birkenfeld j , et al . importantly , the increase in the lens size was entirely due to a growth of the stiff central region ( slope of 31 3 m / y ) ; the thickness of the peripheral softer regions being constant with age . the mean thickness of the anterior peripheral region was 1.0 0.2 mm , slightly greater than the mean thickness of the posterior peripheral region of 0.71 0.13 mm . variation of the human lens anterior cortex ( a.c . ) , posterior cortex ( p.c . ) , central plateau , and overall lens thickness with age . the error bars represent the instrument 's thickness accuracy of 120 m , which is a conservative assumption equal to twice the optical resolution of the brillouin microscope and accounting for the accuracy in the two interfaces localization . figure 5 shows the magnitudes of maximal brillouin longitudinal modulus at the center of the lens and the minimal longitudinal modulus at the interfaces with the aqueous humor and vitreous . the minimal longitudinal modulus showed no statistically significant age dependence and had an identical average value of 2.36 0.02 gpa in both the anterior and posterior sides . also , the longitudinal modulus of the central plateau did not show statistically significant age dependence in the age range of 19 to 45 years . beyond age 45 , however , a small decrease in the longitudinal modulus of the central plateau was observed at a rate of 4.5 1.4 mpa per year . variation of the brillouin longitudinal modulus with age in aqueous humor , vitreous humor , and lens plateau . the error bars represent the sd within each eye subregion . for the plateau region , linear regressions for age younger than 45 years ( solid line ) and older than 45 years ( dashed line ) are shown . figure 6 shows the exponent obtained from the fitting of the anterior and posterior plateau regions . the parameter increased with the subject age significantly ( p < 0.001 ) in a linear regression analysis , which is consistent with the observed flattening of the central region and an increase of the gradient at the transition between the central and peripheral regions . variation of the power law exponent for the anterior and posterior region within the slowly varying central region of the lens . ( a ) comparison of the cortical sagittal elasticity gradient between young ( < 25 years old ) , mid ( 3545 years old ) , and old ( > 50 years old ) groups . ( b ) variation of the power law exponent for the cortical anterior and posterior regions . to compare the brillouin longitudinal moduli with traditional shear moduli , we used ex vivo lens tissues cut into small pieces . figure 8 shows the quasistatic shear modulus and the brillouin longitudinal modulus along the equatorial direction . in both young and old lenses , we found an increase of the elastic modulus from the lens periphery toward the lens center . the variability within the same layer represents the intrinsic variations of shear and longitudinal moduli of lens tissues in the equatorial and sagittal axes . in young lenses , the measured quasistatic shear modulus ranged from 0.20 to 10.3 kpa , whereas the brillouin modulus varied from 2.81 to 3.11 gpa . in old lenses , shear moduli ranged from 0.36 to 19.2 kpa , whereas brillouin moduli ranged from 2.91 to 3.27 gpa , respectively . the six to seven orders of magnitude difference between shear and longitudinal moduli is well expected from the incompressibility of water and consistent with previous results . nevertheless , the correlation between brillouin moduli and shear moduli is strong ( p < 0.05 in linear regression analysis for all lenses analyzed ) . spatial variation of the shear and longitudinal elastic moduli of ex vivo human lenses along the equatorial axis . ( a ) young lenses ( n = 2 , 4-mm disks from the left and right eyes of a 26-year - old donor ) . ( b ) old lenses ( n = 48 , 4-mm disks from left and right eyes of three donors at ages of 50 , 60 , and 62 ) . solid dots , measured data from each individual sample ; open squares , average value of the data within each layer ; and error bars , standard variation . in this article , we have reported measurements of the mechanical properties of the aging human crystalline lens in vivo , for the first time to our knowledge . in particular , the high spatial resolution of brillouin microscopy enabled us to characterize the spatial distribution of the longitudinal modulus within the crystalline lens . we found that , throughout all ages , the central portion of the lens is stiffer than the periphery . this result was confirmed by the ex vivo experiments , where we compared brillouin moduli to shear moduli measured by traditional gold - standard shear rheometry . our result is consistent with findings based on previous brillouin scattering experiments , bubble - based acoustic radiation force , and conical probe indentation , in which the elastic modulus in the nucleus was always larger than in the cortex in both animals and human samples . however , these results do not agree with other experiments using spinning platforms and localized small probes in which the nucleus was found to be softer than the cortex in human lenses at ages up to 30 to 50 years old . a softer nucleus at such age is difficult to explain , considering that elastic modulus typically increases with protein concentration . in pre - teenage lenses , furthermore , the maximal compaction , leading to a constant protein concentration with age , is already completed in the center of the lens somewhere in the 20s . in terms of age - related trends , we did not find a statistically significant change of the peak longitudinal modulus with age in the range of 19 to 45 years , a period over which the accommodation power gradually decreases . instead , the most prominent age - related change was the expansion and flattening of the central stiff plateau . by the age of 60 years , the sagittal thickness of the central plateau reached 3.2 0.12 mm , a size in agreement with the four nuclear zones consisting of the embryonic , fetal , juvenile , and adult nuclei isolated by lyophilisation or hydrodissection . interestingly , no statistically significant age - related differences were found in the axial gradient of modulus in the peripheral regions . this may provide insights into the production of new lens fibers and their distribution and compaction . our data do not appear to support a notion that a massive increase of lens modulus is the main contributor to the age - related loss of accommodation . rather , the data point to the existence of other factors , such as the changes in lens shape . to estimate the actual elastic properties of the lens , a more in - depth mechanical analysis of the lens will benefit from a volumetric brillouin image , beyond an axial profile , of the lens . with the given experimental data , we estimate an approximately 2-fold increase in the overall stiffness of the lens from 19 to 45 years , which is consistent with previous ex vivo data . it is also worthwhile to note the apparent similarity between the profiles of longitudinal modulus and typical protein distributions that were previously obtained by optical techniques , and ultrasound . this similarity provides insights into the relationship between the ultrastructure and the mechanical modulus of the lens tissues . in particular , the -crystallins are thought to enhance water expulsion by creating an extended network of alternately charged groups at their surface and creating a large number of molecular electrostatic dipole moments . in humans , the relative protein proportion of the - , - , and -crystallins stays constant with age within the nucleus . in contrast , in rodents , the -crystallins continue to be synthesized throughout life and thus may lead to a more extensive water loss with age . hence , one would expect the maximal compaction to saturate in humans in the nuclear region , whereas it should increase for rodents . this is consistent with our results that the peak longitudinal modulus in human lenses was constant up to the age of 45 to 50 years , whereas our earlier study of the murine lenses showed continually increasing longitudinal modulus over age . finally , the brillouin profiles of the left and right eyes of the same subject were nearly identical to each other . this result is in line with clinical findings that accommodation may be a consensual response , in which both eyes change equally to a change in accommodative stimulus . in contrast , significant differences could be found in terms of lens thickness and elasticity in age - matched subjects within a 3-year window . such differences could potentially explain the very broad range of accommodation amplitude observed at a given age . in this regard , our approach would offer a unique tool to monitor mechanical changes resulting from surgical or pharmacological treatments .

purposeto analyze the age dependence of the longitudinal modulus of the crystalline lens in vivo using brillouin scattering data in healthy subjects.methodsbrillouin scans were performed along the crystalline lens in 56 eyes from 30 healthy subjects aged from 19 to 63 years . longitudinal elastic modulus was acquired along the sagittal axis of the lens with a transverse and axial resolution of 4 and 60 m , respectively . the relative lens stiffness was computed , and correlations with age were analyzed.resultsbrillouin axial profiles revealed nonuniform longitudinal modulus within the lens , increasing from a softer periphery toward a stiffer central plateau at all ages . the longitudinal modulus at the central plateau showed no age dependence in a range of 19 to 45 years and a slight decrease with age from 45 to 63 years . a significant intersubject variability was observed in an age - matched analysis . importantly , the extent of the central stiff plateau region increased steadily over age from 19 to 63 years . the slope of change in brillouin modulus in the peripheral regions were nearly age-invariant.conclusionsthe adult human lens showed no measurable age - related increase in the peak longitudinal modulus . the expansion of the stiff central region of the lens is likely to be the major contributing factor to age - related lens stiffening . brillouin microscopy may be useful in characterizing the crystalline lens for the optimization of surgical or pharmacological treatments aimed at restoring accommodative power .

migraine and tension - type headache prevalence has been determined to be 16 ( 21.8% for women and 10.9% for men ) and 31.7% , respectively , in turkey based on a structured cross - sectional study for headache carried out in 13 centers with 2,007 participants . however , structured studies in certain age and target groups are rather limited in turkey [ 28 ] . migraine prevalence in university students has been reported in a few studies [ 5 , 7 , 8 ] . those studies may be limited when the negative impact of migraine on the quality of life for each age is considered . it is unequivocal that migraine data vary according to the populations and detailed evaluations are much more informative . nonetheless , it is undeniable that a reliable and validated screening test can analyze this widespread disorder in populations quickly . these tests are advantageous and practical for clinicians to provide a preliminary data in large populations . , new york , usa ) , which is a quick and appropriate test , has been used as a screening test in primary health services . sensitivity , specificity and positive predictive value of this test in primary care have been defined as 81 , 75 and 93% , respectively . the turkish version of the i d migraine screening test has already been validated [ 11 , 12 ] . karli et al . reported 91.8% sensitivity , 63.4% specificity , 71.9% positive predictive value and 88.4% negative predictive value for i d migraine in their study . it has rarely been used in large series and primarily for validation purposes [ 9 , 13 , 14 ] . for example , kim et al . used i d migraine for diagnostic purposes in patients with temporomandibular joint disease , whereas karli et al . validated the test in outpatient clinics . in this prospective study , we aimed to determine the prevalence of migraine and non - migraine headaches by using a questionnaire including i d migraine for university students from various academic departments . the study was approved by the hospital ethics committee and consent was received from each subject . a total of 1,310 students were selected randomly among the 20032004 curriculum list ( 16,252 students in total ) recieved from the university administration . the study was designed cross - sectionally and migraine prevalence was accepted as 20% in university students ( worst acceptable 1723% ) and sample size was calculated as 1,100 students with 80% power and 99% reliability range . of the 1,310 students , 26 refused to participate in the study and 28 students were chosen randomly from faculties of medicine , science and social sciences of different terms to ensure standardization . second term includes 3rd year medicine and dentistry students and 2nd year of other faculties . third term comprises 4th year medicine and dentistry students and 3rd year students of other faculties , whereas fourth term includes all seniors of all faculties . the study was performed based on the questionnarie merely , without a face - to - face interview with the students . due to this the questionnarie was first applied to 40 students who were not enrolled in the study and after this , it was revised into its final form . in the first part , questions related to social and demographic aspects of the students such as familial , economic , housing , school life , success levels , loss of term , etc . , were found . the second part comprised questions related to headache . subjects having headache were those who answered yes to the questions : did you ever have headache in your lifetime ? and did you ever have headache in the last 3 months ? the final three - item screening questions of the i d migraine test were as follows ( questions 41 , 42 and 43 in the questionnaire ) : during the last 3 months , ( 1 ) did you feel nauseated or sick in your stomach with your headaches ? ( 2 ) did light bother you when you had a headache ( a lot more than when you do not have headaches ) ? ( 3 ) did your headache limit your ability to work , study or do what you needed to do for at least 1 day ? the cut - off point for a test - diagnosis of migraine headache was at least two positive responses . a total of 1,310 students were selected randomly among the 20032004 curriculum list ( 16,252 students in total ) recieved from the university administration . the study was designed cross - sectionally and migraine prevalence was accepted as 20% in university students ( worst acceptable 1723% ) and sample size was calculated as 1,100 students with 80% power and 99% reliability range . of the 1,310 students , 26 refused to participate in the study and 28 were excluded due to lack of questionnaire or inappropriate internal consistency test . students were chosen randomly from faculties of medicine , science and social sciences of different terms to ensure standardization . second term includes 3rd year medicine and dentistry students and 2nd year of other faculties . third term comprises 4th year medicine and dentistry students and 3rd year students of other faculties , whereas fourth term includes all seniors of all faculties . the study was performed based on the questionnarie merely , without a face - to - face interview with the students . due to this the questionnarie was first applied to 40 students who were not enrolled in the study and after this , it was revised into its final form . questions related to social and demographic aspects of the students such as familial , economic , housing , school life , success levels , loss of term , etc . , were found . the second part comprised questions related to headache . subjects having headache were those who answered yes to the questions : did you ever have headache in your lifetime ? and did you ever have headache in the last 3 months ? the final three - item screening questions of the i d migraine test were as follows ( questions 41 , 42 and 43 in the questionnaire ) : during the last 3 months , ( 1 ) did you feel nauseated or sick in your stomach with your headaches ? ( 2 ) did light bother you when you had a headache ( a lot more than when you do not have headaches ) ? ( 3 ) did your headache limit your ability to work , study or do what you needed to do for at least 1 day ? the cut - off point for a test - diagnosis of migraine headache was at least two positive responses . of the 1,310 subjects , 1,256 students ( 529 female and 727 male ) were enrolled in the study . their mean age was 21.9 2.1 years ( 1731 years ) . different types of headache were identified in 1,129 ( 89.9% ) subjects , whereas 127 were headache - free . migraine - type headache was detected in 265 subjects ( 21.9% ) based on the i d migraine evaluation . table 1 displays social and demographic characteristics of the students . table 1social and demographic characteristics of the studentsmigraine % ( n ) non - migraine % ( n)headache free % ( n)psex females14535762<0.001 males12050765parents parents alive94 ( 249)92.1 ( 796)92.4 ( 73)0.094 parents deceased3.4 ( 9)6.3 ( 54)5.1 ( 4 ) father alive , mother deceased2.7 ( 7)1.6 ( 14)2.5 ( 2 ) live together61.5 ( 163)62.9 ( 544)62.2 ( 79)mother s education illiterate13.6 ( 36)13.7 ( 118)17.7 ( 14)0.539 primary school48.3 ( 128)50.8 ( 439)55.7 ( 44 ) higher education38.1 ( 101)35.6 ( 307)26.6 ( 21)father s education illiterate3.8 ( 10)3.4 ( 26)5.1 ( 4)0.192 primary school34.9 ( 92)40.2 ( 347)49.3 ( 39 ) higher education61.4 ( 162)56.4 ( 487)45.6 ( 36)housing with parents37.9 ( 100)40.3 ( 348)43 ( 34)0.822 alone41.7(110)40.7(352)34.2 ( 27 ) dormitory14 ( 54)15.7(164)21.5 ( 18)academic department medicine46.8 ( 124)52.8 ( 456)41.8 ( 33)0.281 social sciences34.7 ( 92)31.9 ( 276)38 ( 30 ) science18.5 ( 49)15.3 ( 132)20.3 ( 16)satisfaction with school yes 24.5 ( 65)22.8 ( 207)25.1 ( 31)0.116 moderate35.1(92)30.9(267)24.1(19 ) no 40.7 ( 108)45.1 ( 390)36.7 ( 29)term first term31.3 ( 83)24.5 ( 212)29.1(23)0.365 second term23.8(63)23.1 ( 200)27.7 ( 22 ) third term22.6(60)26.3 ( 227)22.8 ( 18 ) last term22.3 ( 59)26.0 ( 225)20.3 ( 16)school success perfect12.8 ( 34)11.9 ( 103)8.9 ( 7)0.693 good77.4 ( 205)81.1 ( 701)81 ( 64 ) poor7.2 ( 18)5.2 ( 41)7.6 ( 4 ) no comment2.6 ( 9)1.7 ( 19)2.5 ( 4)year(s ) lost before university43.7 ( 111)55 ( 308)40 ( 28)0.953 after university6.7 ( 8)8.1(27)6.7 ( 2)income 350 $ > 23.5 ( 60)24.2 ( 198)22.4 ( 17)0.989 3501,000 $ 55.3 ( 141)53.2 ( 436)53.9 ( 41 ) 1,000 $ < 21.2 ( 54)22.6 ( 185)23.7 ( 18)social activities never or rarely2.6 ( 53)2.3 ( 210)26.6 ( 21)0.935 occasionally43.8 ( 95)48.7 ( 442)46.8 ( 37 ) frequently or always27.2 ( 59)28.8 ( 264)26.6 ( 21 ) social and demographic characteristics of the students of these , 145 ( 11.5% ) were female and 120 ( 9.6% ) were male ( female / male ratio : 1.2/1 ) . therefore , migraine was diagnosed in 145 of 529 female subjects ( 28.1% ) and in 120 of 727 male subjects ( 17.3% ) . non - migraine type headache was identified in 864 subjects , 357 female and 507 male ( table 1 ) . a total of 334 students ( 26.6% ) were in the first term , 298 ( 23.3% ) in the second term , 312 ( 24.8% ) in the third term and 312 ( 24.8% ) in the fourth term . migraine frequency was found to be 26.6% in the first term , being relatively higher compared to other terms , though not statistically significant . no significant difference was found in non - migraine - type headaches among different terms . nevertheless , the frequency of non - migraine headaches ( 71.5% ) , and the overall headache frequency ( 93.5% ) in the 4th term were higher than in the other terms . gender only had a significant relation in all groups ( subjects with migraine , subjects with non - migraine headache and headache free ) ( p < 0.005 ) . in 21.9% of 1,256 university students , migraine diagnosis was established based on the data of the questionnaire using i d migraine. female / male ratio was 1.2/1.0 ( 145/120 ) in subjects with migraine in our study . non - migraine - type headache was found in 71.5% of the subjects considering the questionnaire results , whereas 6.5% of the subjects defined no headache . there are few studies on migraine in university students in turkey [ 5 , 7 , 8 ] female / male ratio was 3.4/1.0 ( 99/29 ) and 1.6/1.0 ( 224/138 ) in subjects with migraine in the first two studies , respectively . in a recent study from our department , aimed to determine all types of headache in senior medical students , migraine was found in 24.4% ( n 31/127 ) . it might be speculated that headache in cases who were invited but did not attend the study had a less negative impact on their life . our results using i d migraine were not much different from the other studies using distinct methodologies in the literature . these ratios are higher than the ratios in the above - mentioned study . in a multicenter study for headache prevalence in turkey , migraine prevalence was found to be 20.9% in the mediterranean region and 24.0% in the southeastern region , whereas the prevalence in agean , mid - anatolian , marmara , and karadeniz regions was 20.6 , 11.7 , 11.4 and 14.7% , respectively . in a recent multi - center study ( mira ) , including ours , migraine prevalence was found to be 24.9% in outpatient clinics irrespective of subgroup analysis . migraine prevalence was found to range between 2.4 and 40.2% in various studies based on the questionnaire in the literature . the prevalence in the studies by mitsikostas , muniz , deleu , demirkirkan , kurt , bigal 19 and amayo 20 was 2.4 , 7.58 , 12.2 , 12.4 , 24.9 , 25 and 38% , respectively , whereas sanvito 21 found 40.2% only in medical students of similar age . migraine prevalence found by using i d migraine in our study ( 21.9% ) is quite consistent with the results derived from the multicenter study in turkey . these variations may be due to the study designs as well as the variations in the study groups . however , our own results seem to be consistent with our country s data . on the other hand , in 71.5% of 1,256 subjects however , the high frequency rate of migraine and non - migraine - type headache in a student population is quite interesting . as has been known , tension - type headache is the most common in the age group we have investigated . in the multicenter study for headache prevalence in turkey , frequency of tension - type headache in the mediterranean and southeastern regions were 59 and 36.6% , respectively , being consistent with the rates in our study . regarding the latter , it is not surprising that migraine prevalence in our study is higher than in other turkish university studies since most of the students in cukurova university are from the mediterranean and southeastern regions [ 5 , 8 ] . considering the stress factors for migraine in the population mentioned above in detail , gender had a statistically significant relation with migraine . on the other hand , it was quite interesting that factors such as parental health and their marital status , school success , income and social activites had no significant relation . a limitation of our study is that sensitivity and specificity ratios and predictive values could not be assessed due to its design . as a conclusion ; it is straightforward that a face - to - face verbal interview is the gold standard for migraine diagnosis and specifically designed further studies are necessary . nevertheless , i d migraine , as a valid , reliable and quick screening tool in primary care migraine recognition , may encourage the clinician due to the similarities between the results of face - to - face interview and screening questionnaires in migraine studies . it would be practical and beneficial to the clinician to perform the i d migraine in larger populations for preselection of the patients for further face - to - face interview .

in this prospective study , we aimed to determine the prevalence of migraine and non - migraine headaches using a questionnaire , including i d migraine , for university students . the study was designed cross - sectionally and a questionnaire consisting of 43 questions was applied to 1,256 students . the questionnaire consisted of questions related to demographic , social , curriculum , housing and headache characteristics of the subjects . three - item screening questions of the i d migraine test were included at the end of the questionnaire aimed at migraine diagnosis . the mean age of 1,256 students ( 529 females and 727 males ) enrolled in this study was 21.9 2.1 years ( 1731 years ) . migraine - type headache was detected in 265 subjects ( 21.9% ) based on the i d migraine evaluation . of these , 145 ( 54.7% ) were female and 120 ( 45.3% ) were male ( female / male ratio : 1.2/1 ) . non - migraine - type headache was identified in 864 subjects , with 357 females and 507 males . as a conclusion , i d migraine screening test might be practical and beneficial when a face - to - face interview is not possible or to pre - determine the subjects for a face - to - face interview for migraine diagnosis in larger populations .

tissues were extracted from the area surrounding the chamber angle of an eyeball obtained from the eye bank that had been extracted within six hours of death . the eye had not previously been afflicted with ocular disease nor had it undergone any type of surgery . the trabecular meshwork was stripped away from the anterior chamber angle and the explants were moved to a culture plate coated with poly - l - lysine ( sigma , st . louis , mo , usa ) and cultured in dulbecco 's modified eagle 's medium ( dmem ; gibco , gaithersburg , md , usa ) containing antibiotics ( gibco ) and 10% fetal bovine serum ( gibco ) at 5% co2 . after confirming that the trabecular meshwork cells had grown out into the surroundings of the explanted tissues , the explants were removed and the culture was continued . when the cells were confluent , they were treated with trypsin and subcultured at a ratio of 1:3 with a medium containing 10% fetal bovine serum . fetal bovine serum ( 50 mg / ml ) without endotoxin , 100 mmol / ml glyceraldehyde and 1 mmol / l phenylmethylsulfonyl fluoride ( sigma ) were dissolved in pbs solution . after dialyses with pbs solution , the electrolytes were removed by chromatography ( amersham pd-10 column chromatography ; amersham pharmacia biotech , piscataway , nj , usa ) . to determine the efficiency of glycation , browning of the glycated bovine serum albumin ( g - bsa ) preparation the absorbance of g - bsa increased with time , whereas the absorbance of control bsa ( without glyceraldehydes ) did not . the concentration of g - bsa was measured with the bradford assay and samples were stored in the deep freezer until use . after dividing the cells ( 1 10 cells / well of a 24-well culture plate , 0.6 10 cells / well of a 96-well culture plate ) , they were allowed to attach for 24 hours . the medium was removed and then replaced with dmem medium including 1% fetal bovine serum and a low concentration of glucose ( 5 mm ) to prevent the antioxidant effect of serum protein . the cells were exposed to 0 , 10 , 50 , 100 , and 200 g / ml g - bsa for five days . a culture with 25 mm mannitol the cells in the 24-well and 96-well plates were exposed to 100 m l - arginine ( sigma ) and 100 m sepiapterin ( sigma ) , which are known to promote the no generation . the cells were also exposed to an anti - oxidant of 50 m n - acetylcysteine ( nac , sigma ) to reveal the effects of age on the generation of reactive oxygen species . the effect of age on cell survival was assessed by 3-[4 , 5-dimethylthiazol-2-yl]-2 , 5-diphenyltetrazolium bromide ( mtt , sigma ) assay , a colorimetric test frequently used as a screening tool to determine cell survival and toxicity , and no generation was measured using the griess assay . for the mtt assay , the cultures were incubated for four hours after treatment with 100 l of mtt per well , then washed with pbs solution and transferred to a 96-well culture plate . then , 0.5 ml of dimethylsulfoxide was added to each well to dissolve the mtt formazan crystals . the absorbance was measured at 570 nm with a spectrophotometer ( fluostar optima ; bmg labtech , offenburg , germany ) . cell survival was computed as a percentage by dividing the absorbance values of the experimental group by the absorbance values of the control group , which was not treated . the griess assay was performed to measure the quantity of nitrite , a reactant in no generation . after mixing the medium containing cells with the same quantity of griess reagent ( sigma ) , the absorbance was measured at 540 nm using a spectrophotometer . serial dilutions of sodium nitrite ( sigma ) were used to generate a standard curve . the generation of superoxide was measured with a microplate reader using modified cytochrome c reduction . the reactive solution was prepared by mixing 160 m cytochrome c ( sigma ) and 100 u / ml superoxide dismutase ( sigma ) , and cells were exposed to 100 l of this solution for 20 minutes . the quantity of cytochrome c reduced at 540 nm was measured over the course of an hour . the quantity of superoxide was expressed as nmol/10cell / h , reflecting the quantity of cytochrome c ( in nmol ) reduced by 10 cells per hour with a 2.1 10/m / cm net extinction coefficient . the generation of reactive oxygen species was measured using the dichlorofluorescin diacetate assay . on the fifth day after treatment of cells in a 96-well culture plate , cells were then treated with 5 m dichlorofluorescin diacetate ( sigma ) , after which they were incubated for 30 minutes at 37 in pbs in the dark . the change in fluorescence of oxidized dichlorofluorescin was measured at excitation and emission wavelengths of 488 nm and 527 nm , respectively , using a fluorescence analyzer ( fluostar optima ) . to investigate whether age generates apoptosis , flow cytometry was performed by double staining of fluorescein isothiocyanite - labeled annexin v / propidium iodide ( pi ) with a commercial kit ( tacs annexin v - fitc apoptosis detection kit ; r&d systems , minneapolis , mn , usa ) . after trypsinization and washing , 5 l annexin v and 1 l pi were added to a 100 l cell suspension and incubated at room temperature for 15 minutes , and then a 400 l buffer solution was added and mixed . next , flow cytometric analysis was performed ( cytomics 500fc ; beckman coulter , miami , fl , usa ) at fluorescence emission wavelengths less than 530 nm and greater than 575 nm . a commercial senescence - associated -galactosidase kit ( sa--gal , sigma ) was used to measure -galactosidase activity , which is characteristic of senescent cells . the culture was incubated for two hours after adding staining solution ; -galactosidase in senescent cells stains blue . the proportion of senescent cells was computed as a percentage by dividing the number of senescent cells stained blue by the total number of cells . a round optical glass with a grid dividing the view into five square fields was attached to the eyepiece of an optical microscope and used to count the number of cells in each field over ten fields . the average numbers of stained and total cells were determined for these ten fields ( 100 ) . all experiments were performed with cells between the third and fifth passages and repeated three times . an unpaired t - test was used to compare the experimental group and control group with a significance level of 0.05 . tissues were extracted from the area surrounding the chamber angle of an eyeball obtained from the eye bank that had been extracted within six hours of death . the eye had not previously been afflicted with ocular disease nor had it undergone any type of surgery . the trabecular meshwork was stripped away from the anterior chamber angle and the explants were moved to a culture plate coated with poly - l - lysine ( sigma , st . louis , mo , usa ) and cultured in dulbecco 's modified eagle 's medium ( dmem ; gibco , gaithersburg , md , usa ) containing antibiotics ( gibco ) and 10% fetal bovine serum ( gibco ) at 5% co2 . after confirming that the trabecular meshwork cells had grown out into the surroundings of the explanted tissues , the explants were removed and the culture was continued . when the cells were confluent , they were treated with trypsin and subcultured at a ratio of 1:3 with a medium containing 10% fetal bovine serum . fetal bovine serum ( 50 mg / ml ) without endotoxin , 100 mmol / ml glyceraldehyde and 1 mmol / l phenylmethylsulfonyl fluoride ( sigma ) were dissolved in pbs solution . after dialyses with pbs solution , the electrolytes were removed by chromatography ( amersham pd-10 column chromatography ; amersham pharmacia biotech , piscataway , nj , usa ) . to determine the efficiency of glycation , browning of the glycated bovine serum albumin ( g - bsa ) preparation was determined by measuring the absorbance at 340 nm using a spectrophotometer . the absorbance of g - bsa increased with time , whereas the absorbance of control bsa ( without glyceraldehydes ) did not . the concentration of g - bsa was measured with the bradford assay and samples were stored in the deep freezer until use . after dividing the cells ( 1 10 cells / well of a 24-well culture plate , 0.6 10 cells / well of a 96-well culture plate ) , they were allowed to attach for 24 hours . the medium was removed and then replaced with dmem medium including 1% fetal bovine serum and a low concentration of glucose ( 5 mm ) to prevent the antioxidant effect of serum protein . the cells were exposed to 0 , 10 , 50 , 100 , and 200 g / ml g - bsa for five days . a culture with 25 mm mannitol the cells in the 24-well and 96-well plates were exposed to 100 m l - arginine ( sigma ) and 100 m sepiapterin ( sigma ) , which are known to promote the no generation . the cells were also exposed to an anti - oxidant of 50 m n - acetylcysteine ( nac , sigma ) to reveal the effects of age on the generation of reactive oxygen species . the effect of age on cell survival was assessed by 3-[4 , 5-dimethylthiazol-2-yl]-2 , 5-diphenyltetrazolium bromide ( mtt , sigma ) assay , a colorimetric test frequently used as a screening tool to determine cell survival and toxicity , and no generation was measured using the griess assay . for the mtt assay , the cultures were incubated for four hours after treatment with 100 l of mtt per well , then washed with pbs solution and transferred to a 96-well culture plate . then , 0.5 ml of dimethylsulfoxide was added to each well to dissolve the mtt formazan crystals . the absorbance was measured at 570 nm with a spectrophotometer ( fluostar optima ; bmg labtech , offenburg , germany ) . cell survival was computed as a percentage by dividing the absorbance values of the experimental group by the absorbance values of the control group , which was not treated . the griess assay was performed to measure the quantity of nitrite , a reactant in no generation . after mixing the medium containing cells with the same quantity of griess reagent ( sigma ) , serial dilutions of sodium nitrite ( sigma ) were used to generate a standard curve . the generation of superoxide was measured with a microplate reader using modified cytochrome c reduction . the reactive solution was prepared by mixing 160 m cytochrome c ( sigma ) and 100 u / ml superoxide dismutase ( sigma ) , and cells were exposed to 100 l of this solution for 20 minutes . the quantity of cytochrome c reduced at 540 nm was measured over the course of an hour . the quantity of superoxide was expressed as nmol/10cell / h , reflecting the quantity of cytochrome c ( in nmol ) reduced by 10 cells per hour with a 2.1 10/m / cm net extinction coefficient . the generation of reactive oxygen species was measured using the dichlorofluorescin diacetate assay . on the fifth day after treatment of cells in a 96-well culture plate , cells were then treated with 5 m dichlorofluorescin diacetate ( sigma ) , after which they were incubated for 30 minutes at 37 in pbs in the dark . the change in fluorescence of oxidized dichlorofluorescin was measured at excitation and emission wavelengths of 488 nm and 527 nm , respectively , using a fluorescence analyzer ( fluostar optima ) . to investigate whether age generates apoptosis , flow cytometry was performed by double staining of fluorescein isothiocyanite - labeled annexin v / propidium iodide ( pi ) with a commercial kit ( tacs annexin v - fitc apoptosis detection kit ; r&d systems , minneapolis , mn , usa ) . after trypsinization and washing , 5 l annexin v and 1 l pi were added to a 100 l cell suspension and incubated at room temperature for 15 minutes , and then a 400 l buffer solution was added and mixed . next , flow cytometric analysis was performed ( cytomics 500fc ; beckman coulter , miami , fl , usa ) at fluorescence emission wavelengths less than 530 nm and greater than 575 nm . a commercial senescence - associated -galactosidase kit ( sa--gal , sigma ) was used to measure -galactosidase activity , which is characteristic of senescent cells . the culture was incubated for two hours after adding staining solution ; -galactosidase in senescent cells stains blue . the proportion of senescent cells was computed as a percentage by dividing the number of senescent cells stained blue by the total number of cells . a round optical glass with a grid dividing the view into five square fields was attached to the eyepiece of an optical microscope and used to count the number of cells in each field over ten fields . the average numbers of stained and total cells were determined for these ten fields ( 100 ) . all experiments were performed with cells between the third and fifth passages and repeated three times . an unpaired t - test was used to compare the experimental group and control group with a significance level of 0.05 . the trabecular meshwork cells started to grow out into the surroundings of the tissue explants as a monolayer after two or three weeks of primary culture . the presence of trabecular meshwork cells was confirmed by their characteristic morphology and their characteristic growth pattern as satellite colonies grew distant from the tissue explants . when trabecular meshwork cells were exposed to 100 g / ml g - bsa for five days , cell survival was significantly decreased to 98.5% compared with non - exposed controls ( p < 0.05 ) ( fig . the decreased survival rate induced by g - bsa exposure was abolished by l - arginine and sepiapterin , which increase the generation of no and nac as antioxidants , respectively ( p > 0.05 ) ( fig . 2 ) . mannitol appeared not to have a significant effect on cell survival and thus it was inferred that the effect of age was not due to a change in osmotic pressure ( data not shown ) . age significantly decreased the quantity of no generated in the medium ( p < 0.05 ) ( fig . the decrease in no generation was abolished by l - arginine , sepiapterin and antioxidants ( p > 0.05 ) ( fig . thus , the decrease in the survival of trabecular meshwork cells caused by age could be caused by a decrease in no or induced oxidative stress . treatment with 10 g / ml age significantly increased the generation of superoxide in trabecular meshwork cells ( p < 0.05 ) ( fig . 5 ) . the increased generation of superoxide was abolished by l - arginine , sepiapterin and nac ( p < 0.05 ) ( fig . age increased the generation of reactive oxygen species ( p < 0.05 ) ( fig . 7 ) , and this increase in reactive oxygen species was abolished by nac ( p < 0.05 ) but not by l - arginine or sepiapterin ( p > 0.05 ) ( fig . on fitc - annexin / pi double staining , normal live cells were fitc - negative and pi - positive , early apoptotic cells were fitc - positive and pi - negative , and necrotic cells were fitc - positive and pi - positive . flow cytometric analysis revealed that apoptosis had been induced in cells exposed to 10 mg / ml g - bsa for 5 days ( p < 0.05 ) ( fig . the apoptotic cell population was 7.57 0.5% in the control group ( without age treatment ) . in the experimental group , there was a dose - dependent increase in the apoptotic cell population in the following order : 50 g / ml ( 11.39 2.4% ) , 100 g / ml ( 16.61 1.0% ) , and 200 g / ml ( 26.91 2.0% ) . sa--gal staining was performed to investigate the effect of g - bsa on cell senescence . senescent cells stained blue and began to appear after exposure to 10 g / ml g - bsa ( fig . 10 ) . as the concentration of g - bsa increased , senescent cells were observed more frequently ( fig . 11 ) . when cells were co - exposed to l - arginine , sepiapterin and nac with 50 g / ml and 100 g / ml g - bsa , the number of senescent cells significantly decreased compared to the cells exposed to g - bsa only ( fig . thus , it appears that age induces apoptosis and promotes the senescence of trabecular meshwork cells . the trabecular meshwork cells started to grow out into the surroundings of the tissue explants as a monolayer after two or three weeks of primary culture . the presence of trabecular meshwork cells was confirmed by their characteristic morphology and their characteristic growth pattern as satellite colonies grew distant from the tissue explants . when trabecular meshwork cells were exposed to 100 g / ml g - bsa for five days , cell survival was significantly decreased to 98.5% compared with non - exposed controls ( p < 0.05 ) ( fig . the decreased survival rate induced by g - bsa exposure was abolished by l - arginine and sepiapterin , which increase the generation of no and nac as antioxidants , respectively ( p > 0.05 ) ( fig . 2 ) . mannitol appeared not to have a significant effect on cell survival and thus it was inferred that the effect of age was not due to a change in osmotic pressure ( data not shown ) . age significantly decreased the quantity of no generated in the medium ( p < 0.05 ) ( fig . the decrease in no generation was abolished by l - arginine , sepiapterin and antioxidants ( p > 0.05 ) ( fig . thus , the decrease in the survival of trabecular meshwork cells caused by age could be caused by a decrease in no or induced oxidative stress . treatment with 10 g / ml age significantly increased the generation of superoxide in trabecular meshwork cells ( p < 0.05 ) ( fig . 5 ) . the increased generation of superoxide was abolished by l - arginine , sepiapterin and nac ( p < 0.05 ) ( fig . age increased the generation of reactive oxygen species ( p < 0.05 ) ( fig . 7 ) , and this increase in reactive oxygen species was abolished by nac ( p < 0.05 ) but not by l - arginine or sepiapterin ( p > 0.05 ) ( fig . 8) . on fitc - annexin / pi double staining , normal live cells were fitc - negative and pi - positive , early apoptotic cells were fitc - positive and pi - negative , and necrotic cells were fitc - positive and pi - positive . flow cytometric analysis revealed that apoptosis had been induced in cells exposed to 10 mg / ml g - bsa for 5 days ( p < 0.05 ) ( fig . the apoptotic cell population was 7.57 0.5% in the control group ( without age treatment ) . in the experimental group , there was a dose - dependent increase in the apoptotic cell population in the following order : 50 g / ml ( 11.39 2.4% ) , 100 g / ml ( 16.61 1.0% ) , and 200 g / ml ( 26.91 2.0% ) . sa--gal staining was performed to investigate the effect of g - bsa on cell senescence . senescent cells stained blue and began to appear after exposure to 10 g / ml g - bsa ( fig . 10 ) . as the concentration of g - bsa increased , senescent cells were observed more frequently ( fig . when cells were co - exposed to l - arginine , sepiapterin and nac with 50 g / ml and 100 g / ml g - bsa , the number of senescent cells significantly decreased compared to the cells exposed to g - bsa only ( fig . thus , it appears that age induces apoptosis and promotes the senescence of trabecular meshwork cells . this study shows that age not only decreases cell survival by inducing apoptosis , but also promotes the senescence of trabecular meshwork cells accompanied by increased oxidative stress . age is a composite substance formed by non - enzymatic glycation that changes the structure and the function of proteins . age is known to increase the generation of reactive free radicals by a process similar to lipid peroxidation , generate oxidative stress in cells by activating age membrane receptors , and induce aging , glycosuria , vascular disease and nervous atrophy by promoting the inflammatory response . age is also related to various ocular diseases including diabetic retinopathy [ 39 - 43 ] and it is known to accumulate in the optic nerve head . dysfunction of the trabecular meshwork increases the resistance of the outflow pathway and induces an increase in intraocular pressure . it is important to maintain the normal physiological function of the trabecular meshwork because it functions in regulating outflow . the number of trabecular meshwork cells decreases with aging and the histopathologic findings of primary open - angle glaucoma tissue are similar to those of aged cells [ 46 - 49 ] . although no acts as an important physiological adjusting factor in the human body at low concentrations , it is converted into reactive oxygen species and may induce pathologic damage at either excess or deficient states [ 3 - 5 ] . the decreased efficiency of no in the trabecular meshwork not only decreases outflow as the trabecular meshwork shrinks , but can also cause various pathologic consequences as a result of decreasing physiological activation . when the physiological activation of no decreases , the generation of harmful reactive oxygen species such as superoxide or peroxynitrite increases . these reactive oxygen species not only induce oxidative stress but also bring about the senescence of cells [ 51 - 56 ] . in addition , ascorbic acid , which exists in high concentrations within the aqueous humor , plays a role as an antioxidant by decreasing oxidative stress and , thereby decreasing cellular senescence . in this study , g - bsa was used as an age because glycolaldehyde has previously been reported as the best modifier for fast and reproducible generation of a high - affinity receptor for age binding and age . thus , trabecular outflow may be decreased by contraction or inhibition of the relaxation of the trabecular meshwork . superoxide could possibly be further increased by the uncoupling of no , and promoting the generation of harmful free radicals such as peroxynitrite may cause further damage . thus , if the generation of no is promoted at the physiological level or the synthesis of reactive oxygen species is restrained , it may be helpful to keep the trabecular meshwork functionally intact to prevent further damage . as the results of this experiment demonstrate , l - arginine and sepiapterin , which participate in the generation of no or nac as antioxidants , not only increased the generation of no , but also decreased the generation of reactive oxygen species . these results indicate that no plays a role in keeping the outflow pathway open by relaxing the trabecular meshwork and in preserving the functionality of the trabecular meshwork , which is continually exposed to free radicals in the aqueous humor . the role of no and the importance of oxidative stress as the mechanism underlying glaucoma have been presented in recent studies . although age - induced generation of superoxide is suppressed by either no supplements or antioxidants , age - induced generation of reactive oxygen species is suppressed by antioxidants only . the availability of no is related to superoxide , one of the mitochondrial reactive oxygen species . therefore , the increased availability of no by supplementation of l - arginine and sepiapterin with inhibition by the uncoupling of enos could result in the reduced generation of superoxide . our results are consistent with previous studies that found that age enhanced peroxynitrite formation mediated by no and superoxide in retinal neurons . various reactive oxygen species other than superoxide are formed by age and this could lead to oxidative stress unrelated to no or superoxide . our findings indicate that this age - induced oxidative stress could be reduced by antioxidants . reactive oxygen species not only damage trabecular meshwork cells , but also induce apoptosis and promote cellular aging , and no is known to play a role in delaying cellular senescence [ 10 - 12 ] . trabecular meshwork cells of the human eye have been suggested as the proper model system for the study of the cellular ageing phenomenon . it was reported that the number of trabecular meshwork cells decreases due to tissue damage induced by oxidative stress [ 64 - 67 ] and senescence in glaucoma . in this study , protein glycation appeared to induce functional changes in cells and age appeared to promote the senescence of trabecular meshwork cells . the exacerbation of trabecular meshwork cell senescence by age could be caused by oxidative stress supported by no generation and the restraint of cell senescence by antioxidants . to conclude , age induced the senescence of cultured human trabecular meshwork cell , mediated by an increase in oxidative stress . thus , maintaining no generation at the physiological level or using antioxidants makes the trabecular meshwork competent not only by maintaining the patency of the trabecular meshwork as an outflow pathway , but also by decreasing damage to and senescence of the trabecular meshwork due to oxidative stress . the senescence of trabecular meshwork cells due to oxidative stress could serve as a target for a therapeutic strategy to preventing damage in the management of glaucoma .

purposeto investigate the effect of advanced glycation end products ( age ) on oxidative stress and cellular senescence in cultured human trabecular meshwork cells ( htmc).methodsprimarily cultured htmc were exposed to 0 , 10 , 50 , 100 , 200 g / ml of glycated bovine serum albumin ( g - bsa ) for 5 days . also co - exposed were l - arginine , sepiapterin , and antioxidant n - acetylcysteine ( nac ) . cellular survival and production of nitric oxide ( no ) , superoxide , and reactive oxygen species were assessed by 3-[4 , 5-dimethylthiazol-2-yl]-2 , 5-diphenyltetrazolium bromide assay , griess assay , cytochrome c assay , and dichlorofluorescin diacetate assay , respectively . senescence - associated -galactosidase staining was performed to quantify the degree of cellular senescence.resultsg-bsa decreased cellular survival , no production , and increased superoxide production significantly in a dose - dependent manner . the effects of g - bsa were abolished with co - exposure of l - arginine , sepiapterin , and nac . g - bsa enhanced cellular senescence accompanied by increased production of reactive oxygen species . g - bsa - induced cellular senescence was suppressed by application of l - arginine , sepiapterin , and nac.conclusionsage enhances cellular senescence of htmc accompanied with increased oxidative stress . age - induced oxidative stress and cellular senescence could be delayed by application of anti - oxidants .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Health Benefits Claims Prompt Payment Act of 2002''. SEC. 2. PROMPT PAYMENT OF CLAIMS. (a) Group Health Plans.-- (1) Public health service act amendments.--Subpart 2 of part A of title XXVII of the Public Health Service Act is amended by adding at the end the following new section: ``SEC. 2707. PROMPT PAYMENT OF CLAIMS. ``(a) In General.--A group health plan, and a health insurance issuer offering health insurance coverage in connection with a group health plan, shall provide for prompt payment of claims submitted for health care services or supplies furnished to a participant, beneficiary, or enrollee with respect to benefits covered by the plan or issuer, in a manner that is no less protective than the provisions referred to in subsection (b). ``(b) Provisions.--The provisions referred to in this subsection are the provisions of section 1842(c)(2) of the Social Security Act (42 U.S.C. 1395u(c)(2)), as modified as follows: ``(1) Alternative interest rate.--Instead of applying the interest rate calculated under section 3902(a) of title 31, United States Code, the interest rate shall be 1 percent of the payment amount due plus, in the case of payments not made within 25 days of the due date, an additional 1 percent interest due for every month the payment is past due. ``(2) Coverage of 100 percent of claims.--The reference in such section 1842(c)(2) to `not less than 95 percent of all claims submitted under this part' shall be deemed to be a reference to `100 percent of all claims submitted under the plan or coverage involved'. ``(c) Permitting Additional Penalties.--State Insurance Commissioners may establish and impose monetary penalties or other penalties for failure by a group health plan, and a health insurance issuer offering health insurance coverage in connection with a group health plan, to comply with the provisions referred to in subsection (b).''. (2) ERISA amendments.--(A) Subpart B of part 7 of subtitle B of title I of the Employee Retirement Income Security Act of 1974 is amended by adding at the end the following new section: ``SEC. 714. PROMPT PAYMENT OF CLAIMS. ``(a) In General.--A group health plan, and a health insurance issuer offering health insurance coverage in connection with a group health plan, shall provide for prompt payment of claims submitted for health care services or supplies furnished to a participant or beneficiary with respect to benefits covered by the plan or issuer, in a manner that is no less protective than the provisions referred to in subsection (b). ``(b) Provisions.--The provisions referred to in this subsection are the provisions of section 1842(c)(2) of the Social Security Act (42 U.S.C. 1395u(c)(2)), as modified as follows: ``(1) Alternative interest rate.--Instead of applying the interest rate calculated under section 3902(a) of title 31, United States Code, the interest rate shall be 1 percent of the payment amount due plus, in the case of payments not made within 25 days of the due date, an additional 1 percent interest due for every month the payment is past due. ``(2) Coverage of 100 percent of claims.--The reference in such section 1842(c)(2) to `not less than 95 percent of all claims submitted under this part' shall be deemed to be a reference to `100 percent of all claims submitted under the plan or coverage involved'. ``(c) Permitting Additional Penalties.--State Insurance Commissioners may establish and impose monetary penalties or other penalties for failure by a group health plan, and a health insurance issuer offering health insurance coverage in connection with a group health plan, to comply with the provisions referred to in subsection (b).''. (B) The table of contents in section 1 of such Act is amended by inserting after the item relating to section 713 the following new item: ``Sec. 714. Prompt payment of claims.''. (3) Internal revenue code amendments.-- (A) In general.--Subchapter B of chapter 100 of the Internal Revenue Code of 1986 is amended-- (i) in the table of sections, by inserting after the item relating to section 9812 the following new item: ``Sec. 9813. Prompt payment of claims.''; and (ii) by inserting after section 9812 the following: ``SEC. 9813. PROMPT PAYMENT OF CLAIMS. ``(a) A group health plan shall provide for prompt payment of claims submitted for health care services or supplies furnished to a participant or beneficiary with respect to benefits covered by the plan, in a manner that is no less protective than the provisions referred to in subsection (b). ``(b) Provisions.--The provisions referred to in this subsection are the provisions of section 1842(c)(2) of the Social Security Act (42 U.S.C. 1395u(c)(2)), as modified as follows: ``(1) Alternative interest rate.--Instead of applying the interest rate calculated under section 3902(a) of title 31, United States Code, the interest rate shall be 1 percent of the payment amount due plus, in the case of payments not made within 25 days of the due date, an additional 1 percent interest due for every month the payment is past due. ``(2) Coverage of 100 percent of claims.--The reference in such section 1842(c)(2) to `not less than 95 percent of all claims submitted under this part' shall be deemed to be a reference to `100 percent of all claims submitted under the plan involved'. ``(c) Permitting Additional Penalties.--State Insurance Commissioners may establish and impose monetary penalties or other penalties for failure by a group health plan to comply with the provisions referred to in subsection (b).''. (b) Individual Health Insurance.--Part B of title XXVII of the Public Health Service Act is amended by inserting after section 2752 the following new section: ``SEC. 2753. PROMPT PAYMENT OF CLAIMS. ``The provisions of section 2707 shall apply to health insurance coverage offered by a health insurance issuer in the individual market in the same manner as they apply to health insurance coverage offered by a health insurance issuer in connection with a group health plan in the small or large group market.''. (c) Protection of States' Rights.--Any issue relating to prompt payment for health care services or supplies that is not governed by any provision of law as amended by this section shall be governed by otherwise applicable State or Federal law. This section (and the provisions amended by this section) does not preempt or supercede any law that imposes shorter time frames for payment, greater penalties for non-payment, and, in general, provides greater assurances that group health plans and health insurance issuers provide for prompt payment of claims submitted for health care services or supplies furnished to a participant, beneficiary, or enrollee with respect to benefits covered by the plan or issuer. (d) Effective Dates.-- (1) Group health plans and group health insurance coverage.--The amendments made by subsection (a) apply with respect to group health plans for plan years beginning on or after January 1, 2003. (2) Individual health insurance coverage.--The amendment made by subsection (b) apply with respect to health insurance coverage offered, sold, issued, renewed, in effect, or operated in the individual market on or after such date.

Health Benefits Claims Prompt Payment Act of 2002 - Amends the Employee Retirement Income Security Act of 1974, the Internal Revenue Code, and the Public Health Service Act to require that group and individual health insurance coverage and group health plans provide for prompt payment for health benefits claims.

A woman who was cited along with a man for having sex on a Delta plane last week was highly intoxicated during the activity, which they tried to hide with a blanket, according to a police report released Monday (Photo: Ted S. Warren / AP file) A woman who was cited along with a man for having sex on a plane last week was highly intoxicated during the activity, which they tried to hide with a blanket, according to a police report released Monday. The woman, 48, of Simi Valley, California, had a blood-alcohol content of 0.11, said the Wayne County Airport Police report. The man 28, of Compton, California, had a level of 0.06. The legal limit to drive is 0.08. The two, who didn’t know each other, were flying on Delta Oct. 29 from Los Angeles to Detroit, where they were catching connecting flights. The two couldn’t be reached for comment. The couple had oral sex next to a sleeping passenger, a witness told police, according to the report. Another witness told police the woman wasn’t supposed to be in the seat next to the man, said the report. That was supposed to be the witness’ seat. “Again she was in my seat on accident,” said the witness, whose name was redacted from the report. After they were cited for disorderly conduct, and lewd and lascivious behavior, they were released by police. Officers tried to help the woman get rebooked on her connecting flight to Nashville, but Delta security said she no longer was permitted to fly with the airline, according to the police report. They took her to another airline, where she got a flight for the following morning. The name of the other airline wasn’t mentioned in the report. Several witnesses saw the sex act and reported it to a flight attendant, said the report. The flight attendant told police she also witnessed the act, which the couple tried to hide with a blanket. She asked the woman to sit up, she said. The man apologized for the incident, she told police. Read or Share this story: http://detne.ws/2j4ITQT ||||| CLOSE Prepare to fly in style: Delta's latest Airbus A350 offers onboard beds and privacy doors along with several other high-class upgrades. USA TODAY The woman's seat was not in his row, but she switched her seat so that she could be next to him. (Photo: Jeremy Dwyer-Lindgren, Special for USA TODAY ) A couple caught in a sex act on a Detroit-bound passenger jet last month not only tried to hide their activity with a blanket, but pulled it off while a man was sleeping in the same row next to them, according to a police report obtained by the Free Press. As one passenger wrote in a witness statement: "I felt bad for the guy beside them, but I guess he was sleeping." What he slept through was an incident that triggered an FBI investigation: A "highly intoxicated" woman was performing oral sex on a man in Row 26, triggering complaints from nearby passengers in other rows who caught on to what was going on. The woman in particular was less than cooperative, a police report said, noting she "yelled and screamed" and was "continuously disruptive" after being hauled off to an airport jail cell. More: Airplane sex case lands in FBI's lap; couple likely to avoid charges More: Report: 2 passengers who met on plane accused of sex on flight to Detroit These are some of the details involving the Oct. 29 incident, which was documented in a 9-page police report obtained by the Free Press under the Freedom of Information Act. The Wayne Metro Airport Police Department, which responded to the incident, said both the man and women received citations from the FBI for lewd and lascivious behavior and for disorderly conduct. According to the police report, the 48-year-old California woman and 28-year-old man met on the Delta Air Lines flight between Los Angeles and Detroit. The woman's seat was not in his row, but she switched her seat so that she could be next to him. At about 3:30 pm, the airport police at Detroit Metro received a report about two passengers having intercourse on the plane. "Per dispatch, the female involved was reported to be highly intoxicated," the report said. When the plane landed at Detroit Metro, two police officers entered the plane. One of them spoke with the man, who said that the woman "had fallen asleep in his lap but that they did not have intercourse." He stated that he only "grabbed her breasts on the outside of her clothes." An officer then questioned the woman, whose eyes were "bloodshot and red." Both passengers were handcuffed and led away. The FBI was en route. In the end, both passengers were issued citations based on passengers' witness statements, including one person who wrote that they "went to the row and witnessed the lady in the man's lap performing felatio. ... they had a blanket partially covering the 'act.' I asked for boarding cards and names." The woman sat straight up in her seat. "He tried to apologize." Police allowed both passengers to get their luggage. They tried to help the woman re-book her flight, but Delta said no. Security informed her she was "not permitted to fly Delta." She left the next day, on another flight, without incident. The Free Press is not naming the individuals as they were not charged. As legal expert Peter Henning previously noted: “It’s certainly distasteful, but it was not disruptive or interfering with the operation of the plane. ... The embarrassment is probably the biggest punishment they can receive.” Tresa Baldas can be reached at [email protected] Follow Tresa Baldas on Twitter: @TBaldas Read or Share this story: http://on.freep.com/2hMrE3o

– A male passenger aboard a Detroit-bound Delta flight claimed a woman "had fallen asleep in his lap" after those seated nearby complained that she'd actually been performing oral sex, according to a police report. The pair, strangers who'd booked seats in separate rows on the Oct. 29 flight, had used a single blanket in an attempt to hide the sex act in Row 26 while a man apparently slept beside them, per a police report cited in the Detroit Free Press. Others nearby were conscious of what was happening and complained. The 28-year-old man and 48-year-old woman were removed from the plane when it landed in Detroit. The woman—described as "highly intoxicated" with eyes that were "bloodshot and red"—didn't go quietly, however. The report notes she was "continuously disruptive" and "yelled and screamed" throughout her exit. She was later found to have a blood-alcohol content of 0.11, per the Detroit News. The man—who had a BAC of 0.06—later told an officer that the woman had been taking a nap. And while he admitted he'd "grabbed her breasts on the outside of her clothes," he said they didn't have intercourse, per the report. A witness contradicts that, describing how the woman sat up when addressed, while the man "tried to apologize."

the simplest form of finite - dimensional system capable of exhibiting the fundamental , holistic property of entanglement``that feature of quantum formalism which makes it impossible to simulate quantum correlations within any classical formalism '' @xcite is that composed of a pair of two - level systems ( quantum bits or `` qubits '' ) @xcite . the joint state of two qubits is describable ( @xmath5 ) by a @xmath0 density matrix @xmath1 , that is a hermitian matrix ( its transpose equalling its complex conjugate ) having its four nonnegative diagonal entries ( probabilities)as well as its four nonnegative eigenvalues summing to one @xcite . the entirety of such @xmath0 density matrices with their entries restricted to real values which will be our principal subject of analysis here forms a nine - dimensional convex set . we note that @xmath6 density matrices with real entries have been termed `` rebits '' @xcite . endowing the nine - dimensional set of pairs of rebits with hilbert - schmidt ( hs ) ( euclidean / flat ) measure @xcite @xcite , we arrive at the following trio of computational results @xcite . the three are : ( 1 ) the average value or mean ( first moment ) of the ( necessarily nonnegative ) determinant of @xmath1 , denoted @xmath2 ( @xmath7 ) , is @xmath8 ; ( 2 ) the mean of the determinant @xmath3 of the partial transpose ( pt ) of @xmath1negative values of which , by the celebrated results of peres @xcite and the horodecki family @xcite , are fully equivalent ( for qubit - qubit systems as well as qubit-_qutrit _ systems , representable by @xmath9 density matrices ) to the entanglement / nonseparability of @xmath1is @xmath10 ; and ( 3 ) the mean of the product of these two determinants , that is @xmath11 ( @xmath12 by the cauchy - binet [ gram s ] theorem ) , is zero . ( the partial transpose identifiable with the antiunitary operation of time - reversal @xcite ( cf . @xcite)of a @xmath0 matrix can be obtained simply by transposing in place its four @xmath6 blocks . ) so , by assigning to each generic real @xmath0 density matrix @xmath1 , a value equal to this product of determinants , we find that the total ( but yet undetermined , necessarily negative ) value allotted to the entangled states exactly cancels the ( necessarily nonnegative ) value allotted to the disentangled / separable states . this result appears to be special to the hs measure , as the analogous trio of results using the well - known bures ( minimal monotone ) measure @xcite @xcite is @xmath13 and , numerically , -0.0030959720 and @xmath14 @xcite . it is a natural hypothesis but one apparently presenting substantial computational challenges to test that this zero - mean ( hs ) result extends to the standard 15-dimensional convex set of @xmath0 density matrices with arbitrary _ complex _ off - diagonal entries @xcite . ( from a `` physical point of view one should in general consider the entire set of complex density matrices '' @xcite . we can not , however , unqualifiedly , straightforwardly extend the interpretation of the zero - product - mean hypothesis to bipartite quantum systems describable by density matrices of dimensions greater than four . then , @xmath15 can have more than one negative eigenvalue , with an even number of such eigenvalues yielding a positive value for the determinant @xmath3 ( cf . thus , a nonnegative value of @xmath3 would not necessarily indicate that @xmath1 is separable . ) the zero - product - mean hs result does not hold , in general , however , for arbitrary two - qubit scenarios . this can be seen by slightly modifying in each of three ways , our basic nine - dimensional two - rebit example thereby diminishing its inherent symmetry . firstly , if we set one off - diagonal pair of entries ( @xmath16 , say ) of @xmath1 to zero , giving us an 8-dimensional convex set of density matrices , we obtain a mean of the probability distribution over @xmath2 of @xmath17 , for @xmath3 , a mean of @xmath18 , and for the product of the two determinants , a _ nonzero _ mean of @xmath19 . secondly , if we _ increase _ the dimensionality from nine to ten by letting @xmath20 and @xmath21 be arbitrary complex conjugates of each other , then , the trio of means , numerically , is 0.000412154 , -0.00082468 , and ( small , but apparently nonzero ) @xmath22 . thirdly , for the eight - dimensional set of @xmath23 density matrices with real entries consisting of those minimally degenerate matrices having one eigenvalue zero which constitute the boundary of the basic nine - dimensional set @xcite the mean of the product of the three nonzero eigenvalues is @xmath24 , the mean of @xmath3 is @xmath25 , while the mean of the product of @xmath3 and the three nonzero eigenvalues is also nonzero , that is , @xmath26 . ( of course , in this last minimally degenerate analysis , the determinant @xmath2 , equalling the product of its _ four _ eigenvalues , is zero . so , we replace it , for our purposes , by the product of the three generically nonzero eigenvalues . ) we , additionally , have found that _ no _ pair of principal ( @xmath0 , @xmath27 , @xmath6 ) minors , other than @xmath2 and @xmath3one minor of @xmath1 and the other of @xmath15are orthogonal over the nine - dimensional set with respect to hs measure . since both @xmath2 and @xmath3 in the generic ( two - rebit ) nine - dimensional case are polynomials in nine variables , it is suggestive , at least , to consider these two determinants as a pair of multivariate orthogonal polynomials ( mops)@xcite with respect to the hs measure . griffiths and span have reviewed multivariate orthogonal polynomials with respect to weight measures given by dirichlet distributions over simplices ( such as that to be given below by ( [ andaidirichlet ] ) @xcite over the 3-dimensional simplex formed by the diagonal entries of @xmath0 density matrices @xcite ) . let us also note , in our basic nine - dimensional scenario , that the expected value with respect to the hilbert - schmidt measure of the determinant of the _ commutator _ ( appearing in the von neumann equation for the time evolution of @xmath1 ) , @xmath28 = \rho \rho^{pt}- \rho^{pt } \rho$ ] , is zero too . ( jarlskog found the the determinant of the commutator of mass matrices vanishes `` if and only if there is no _ cp _ nonconservation '' @xcite . ) the analogous result was nonzero , that is @xmath29 , when , once again , we broke the symmetry by setting @xmath30 . the range of possible values of @xmath2 is @xmath31 $ ] , that of @xmath3 is @xmath32 $ ] , while that of the product @xmath11 , in the nine - dimensional scenario , we find , is @xmath33 $ ] . this last upper limit is reached , clearly , by the fully mixed ( classical ) state the diagonal density matrix with diagonal entries ( probabilities ) all equal to @xmath34 . an instance of a density matrix attaining the last lower limit is @xmath35 now , the determinant @xmath2 is @xmath36 and @xmath37 ( their product being the indicated lower limit @xmath38 ) . both @xmath1 and @xmath15 have three identical eigenvalues ( @xmath39 for @xmath1 , and @xmath40 for @xmath15 . the isolated eigenvalue for @xmath1 is @xmath41 , and for @xmath15 , @xmath42 . the purity ( index of coincidence @xcite ) , @xmath43 , of ( [ newmatrix ] ) equals @xmath44 , so its inverse ( the participation ratio @xcite ) is 2 . with the considerable computational ( mathematica ) assistance of michael trott , we investigated the orthogonality hypothesis in the more demanding 15-dimensional generic two - qubit scenario , utilizing the euler - angle parameterization of tilma , byrd and sudarshan @xcite , together with the appropriate formulas of yczkowski and sommers ( * ? ? ? * eq . ( 3.11 ) ) . for the expected value of @xmath11 , we obtained the _ _ value of @xmath45 , and for the mean of @xmath3 , the more negative value , @xmath46 . ( normalizing the two quantitates @xmath2 and @xmath3 to have unit length [ the latter numerically ] , we find that their inner product is approximately -0.07 . this translates into an angle of 94 degrees , close to orthogonality . ) are , since it appears to be even more computationally challenging to normalize @xmath3 so that its average hs length is unity . ) ( however , we are not presently able to evaluate how close to orthogonality the determinants @xmath2 and @xmath3 are , since it appears to be even more computationally challenging to normalize @xmath3 so that its average hs length is unity . ) the mean of @xmath2 is known ( * ? ? ? * eq . ( 3.11 ) ) to be @xmath47 . it has been a relatively long - standing problem of `` philosophical , practical and physical '' significance @xcite ( in the recently - burgeoning field of quantum information @xcite ) to determine the probability ( with respect to a number of measures , such as the hs and bures ) that a pair of qubits is separable @xcite . in this regard , it would be of interest to , in some manner , combine ( to achieve a fuller understanding of the `` geometry of quantum states '' @xcite ) the trio of hs ( first ) moment ( mean ) results given above with two theorems ( apparently the only ones yet developed ) pertaining to entanglement in terms of the hilbert - schmidt measure ( cf . @xcite ) . one of these theorems states that the probability that a generic bipartite state ( of arbitrary dimension ) has a positive partial transpose ( ppt ) is _ twice _ the probability that a generic boundary ( minimally degenerate [ one eigenvalue zero ] ) state has a ppt . ( for the proof , it was established that the convex set of mixed ppt states is `` pyramid - decomposable and hence is a body of constant height '' @xcite . ) the other ( but now dimension - specific ) theorem derived by enforcing the nonnegativity of pairs of principal @xmath27 minors of @xmath15is that the probability that a generic real @xmath0 density matrix has a ppt ( or , equivalently , by the peres - horodecki results , is separable ) is no greater than @xmath48 , nor no less ( using the concept of _ absolute _ separability @xcite and the important verstraete - audenaert - de moor bound @xcite ) than @xmath49 @xcite . ( an absolutely separable state is one that can not be entangled by any unitary transformation . ) from these two theorems together , one easily obtains the corollary that the hs separability probability of a generic two - rebit minimally degenerate state is no greater than @xmath50 . in addition to the trio of hs means ( _ first _ moments ) given above , we have been able to compute exactly several higher - order moments , as well , for the nine - dimensional scenario . the corresponding trio of _ second _ ( raw / non - central ) moments is @xmath51 , @xmath52 , and @xmath53 . from our several results , we can deduce that the generic two - rebit hilbert - schmidt correlation between @xmath2 and @xmath3 is positive , that is @xmath54 . further , making use of the generalized normalization constants ( * ? ? ? * eq . ( 4.3 ) ) , we obtain that the @xmath55-th moment of the probability distribution over @xmath2 is @xmath56 let us also note that the counterpart of this result for the 15-dimensional generic complex two - qubit states is @xmath57 the skewness ( @xmath58 ) of the hilbert - schmidt probability distribution over @xmath3 is negative ( as well as all odd moments [ @xmath59 so far computed ) , that is , -3.13228so , the left tail of the distribution is more pronounced than the right tail while its kurtosis ( @xmath60 ) , a measure of `` peakedness '' is quite high , 17.6316 . ( higher kurtosis indicates that more of the variance is the result of infrequent extreme deviations than frequent modestly sized deviations . ) from the first two moments , we obtain the variance @xmath61 application of the standard - form one - sided chebyshev inequality @xcite ( we perform a linear transformation , so that negative values of @xmath3 are mapped to [ 0,1 ] ) , then , yields an upper bound on the hilbert - schmidt separability probability of the two - rebit density matrices of @xmath62 . this is a substantially weaker upper bound , however , than that of @xmath48 established in @xcite , by enforcing the nonnegativity of pairs of @xmath27 principal minors of the partial transpose , and even weaker than @xmath63 , obtained by requiring the nonnegativity of all six @xmath6 principal minors of the partial transpose @xcite . further , we linearly mapped @xmath64 $ ] to @xmath65 , so that @xmath66 $ ] , and transformed its exact first nine moments accordingly . then we exactly fit the first and second such moments to a basic ( two - parameter ) beta distribution , giving us a probability distribution of the form ( fig . [ fig : goodbetafit ] ) , @xmath67 where @xmath68 is the beta function . the ratios of the next six transformed moments ( @xmath69 ) to the corresponding moments of this beta distribution all rather remarkably lie between 0.99 and 1 ( with the ratio of the ninth moments being 0.986 ) ( fig . [ fig : ratiosofmoments ] ) . integrating the distribution ( [ goodbetafit2 ] ) over the interval @xmath70 $ ] , we obtain an associated separability probability estimate of 0.4183149 . we did similarly linearly transform the product of @xmath2 and @xmath3 to lie in the unit interval [ 0,1 ] , and exactly fit to the so - transformed first two moments , a beta distribution of the form ( cf . ( [ goodbetafit2 ] ) ) @xmath71 the associated probability ( over the separability domain @xmath72 $ ] ) was computed as 0.49331935 . using numerical methods , we found that the ( transformed ) third moment of the distribution of the product @xmath11 was approximately @xmath73 as large as the third moment of ( [ goodbetafit4 ] ) , but the fourth moment was only @xmath74 as large . so , this fit to a beta distribution certainly appears to be inferior to the earlier one ( [ goodbetafit2 ] ) ( figs . [ fig : goodbetafit ] and [ fig : ratiosofmoments ] ) based on fitting the first two moments of @xmath3 . one can use the calculated exact nine moments of @xmath3 in certain formulas for cumulative distribution functions , in order to approximate the desired , specific ( separability ) probability that @xmath3 is greater than zero ( * ? ? ? * ; * ? ? ? * eq . ( 2 ) ) ( cf . @xcite ) . in fig . [ fig : cdfhp ] we display together one such set of nine ( greater ) separability probability estimates based on the nonparametric ( stable approximant ) reconstruction approach of mnatsakanov @xcite , along with the analogous first nine ( lesser ) estimates using the orthogonal - polynomial - based methodology of provost and ha ( * ? ? ? * eq . ( 3.5 ) ) . ( in the latter approach , we used the well - fitting beta distribution ( [ goodbetafit2 ] ) as a `` baseline '' density that is adjusted by associated modified jacobi orthogonal polynomials . ) it is clear that additional ( exact ) moments ( @xmath75 ) are certainly needed to more satisfactorily sharpen the generic two - rebit separability probability estimates in fig . [ fig : cdfhp ] . then , one might be able to obtain convincing evidence in the absence of the desired , but highly challenging exact symbolic computation for the true ( hypothetically exact @xcite ) value of the separability probability . ( perhaps , somewhat relatedly , gurvits has shown " that the weak membership problem for the convex set of separable normalized bipartite density matrices is np - hard @xcite . ) our analysis proceeds in the framework of the bloore ( or correlation coefficient ) parameterization @xcite of the @xmath0 density matrices ( @xmath1 ) which allows us ( in the generic two - rebit case of immediate interest here ) to work primarily in seven dimensions , rather than the nine naively expected . also , in our computations , we still further reparametrize three ( @xmath76 ) of the six correlations @xmath77\ ] ] in terms of _ partial _ correlations @xcite , allowing certain requisite integrations to be performed simply over six - dimensional hypercubes , rather than more complicated domains @xcite . ( alternatively , and reasonably computationally competitively , one may utilize the cylindrical algebraic decomposition @xcite to define the integration limits [ as indicated in @xcite ] that specify the domain of feasible density matrices , directly within the bloore - type framework , without transforming to partial correlations . ) the computation of the @xmath55-th hilbert - schmidt moment over @xmath3 is carried out in two stages . ( the moments of the distribution of purity @xmath78 for quantum states with respect to the _ bures _ measure have recently been determined by osipov , sommers and yczkowski @xcite , while giraud has investigated the hilbert - schmidt counterparts @xcite . ) in the first stage , we perform an integration over the six - dimensional hypercube @xmath79 ^ 6 $ ] of the @xmath55-th power of a ( transformed ) polynomial ( @xmath80)proportional to @xmath3in seven variables ( ( * ? ? ? * eq . ( 7 ) ) ) . ( the proportionality factor is @xmath81 . ) the free ( unintegrated ) variable is of the form @xmath82 where the @xmath83 s are the diagonal entries of @xmath1 . ( in the related study @xcite , @xmath84 was used as the principal variable , and in @xcite , @xmath85 . ) we have that ( before the transformation ( [ transformationjoe ] ) to partial correlations , yielding @xmath80 ) the multivariate polynomial ( proportional to @xmath3 ) @xmath86 where @xmath87 and @xmath88 the transformation of the three correlations @xmath76 to partial correlations ( denoted @xmath89 ) takes the form @xcite @xmath90 @xmath91 @xmath92 the jacobian for this transformation is ( note that one of the six variables [ or three partial correlations]@xmath93is absent ) @xmath94 for the @xmath55-th moment ( @xmath95 ) , the indicated six - dimensional integration of @xmath96 in now reparameterized ( partial correlation ) form @xmath97 over the hypercube defined by @xmath98 $ ] takes the form including a normalization factor of @xmath99the ( `` intermediate function '' ) result @xmath100 @xmath101^m \mbox{d } z_{12 } \mbox{d}z_{23 } \mbox{d } z_{34 } \mbox{d } z_{13,2 } \mbox{d } z_{24,3 } \mbox{d } z_{14,23}.\ ] ] for the first ( @xmath102 ) moment , we have the result ( fig . [ fig : intermediate ] ) @xmath103 for the second moment ( @xmath104 ) , @xmath105 and for the third ( @xmath106 ) , @xmath107 at this point , we omit terms of lower order @xmath108 than @xmath109 , since their coefficients in a symmetrical manner match the coefficients @xmath110 . then , @xmath111 @xmath112 @xmath113 @xmath114 @xmath115 @xmath116 @xmath117 @xmath118 and @xmath119 @xmath120 for the nine cases ( @xmath121 ) we have so far been able with considerable computational expense to explicitly compute , the coefficients of the corresponding @xmath122-degree even polynomials @xmath123 are , as already indicated , symmetric for reasons not immediately apparent around the @xmath124 term . the constant terms ( which equal the coefficients of the @xmath125 term ) of the intermediate functions , used in the computation of the moments of @xmath3 , are expressible as @xmath126 additionally , the coefficients of the second and @xmath127 terms are @xmath128 further , the coefficients of the fourth and @xmath129 terms are @xmath130 these results were obtained using the `` rate '' , guessing program of c. krattenthaler . then further , m. trott was able to obtain the result ( using the findsequencefunction command of mathematica , which searches for a possible rational form ) @xmath131 @xmath132 from the formulas for these coefficients , it is clear that the numerator of the coefficient @xmath133 ) of @xmath134 is a polynomial of degree @xmath135 , and the denominator is a polynomial of degree @xmath136 . ( the denominators are very simple in structure ( [ hammer])as evidenced above . ) . for @xmath137 , the roots are @xmath138 and @xmath139 , and as @xmath140 increases by 1 , an additional root 1 larger in value than the previous smallest is added . thus , _ poles _ occur at the coefficient functions at such half - integers . ) utilizing this observation , we were then able to move on to obtaining the coefficients @xmath141 , @xmath142 @xmath143 , @xmath144 and @xmath145but not yet higher . in studying the ( nontrivial ) roots of these functions , we have detected one quite interesting feature . that is , as @xmath140 increases , the dominant roots of @xmath146 show very strong evidence of converging to @xmath147 , the subdominant roots to @xmath148, ... for instance , for @xmath149 , the dominant roots of @xmath150 are @xmath151 , while for @xmath152 , they are @xmath153 , @xmath154 , @xmath155 . such roots would then come increasingly close to canceling the near - to - matching poles in the denominators in @xmath156 as @xmath140 increases . ( this behavior suggests an intimate connection with the theory of angular momentum and its [ semiclassical ] asymptotics @xcite . ) in the second stage of our procedure to compute the @xmath55-th hilbert - schmidt moment , we reverse the substitution ( [ substitution ] ) in these @xmath157-degree polynomials , multiply the result by the necessarily _ nonnegative _ factor @xmath81 ( the factor @xmath158 had been removed , as previously indicated , in forming the polynomial @xmath159 in seven variables , proportional to @xmath3 ) and also by the jacobian corresponding to the transformation to bloore ( correlation ) variables for the two - rebit density matrices @xcite @xmath160 ( @xmath161 , for the two - qubit case , and @xmath162 for the corresponding quaternionic scenario , in accordance with random matrix theory results . ) the result of the indicated multiplications is , then , integrated over the unit three - dimensional simplex , @xmath163 to obtain the @xmath55-th moment ( @xmath164 ) . in other words ( taking into account the appropriate normalization factor ) , and setting @xmath165 , the computation takes the form @xmath166 @xmath167 we are , in fact , able to perform the indicated _ symbolic _ integration , obtaining thereby ( using an index @xmath168 ) @xmath169 @xmath170 @xmath171 where the @xmath172 s are our previously - indicated rational coefficient functions ( ( [ coefficient0])-([coefficient6 ] ) ) , symmetric about @xmath109 . these ( rational functions ) @xmath173 s themselves as discussed above are the ratios of polynomials in @xmath55 of degree @xmath174 divided by the term ( using the pochhammer symbol , as well as rising factorials for gamma functions with half - integer arguments ) @xmath175 @xmath176 for @xmath177 , by way of example , this gives us the denominator of ( [ coefficient4 ] ) , @xmath178 on the other hand , the _ numerators _ of the @xmath173 s for @xmath179 have zero as a trivial root , and for @xmath180 , trivial roots @xmath181 . again , converting gamma functions with half - integer arguments to rising factorials , we have , equivalently to ( [ momentform1 ] ) , that @xmath182 @xmath183 } \big [ \big((2m+3)!!\big)^2 c_{2 m}(m ) + 2 \sigma_{i=0,2,4 ... }^{2 m-2 } \big((3+i ) ! ! ( 3-i+4 m)!!\big)^2 c_i(m ) \big].\ ] ] pursuant to these formulas , the first moment ( mean ) of the hilbert - schmidt probability distribution of @xmath3 over the interval @xmath184 $ ] was found to be @xmath185 falling within the [ negative ] region ( @xmath186 ) of entanglement . ( we were also able to compute this result using the alternative euler - angle parameterization of the real density matrices @xcite , but only after correcting a typographical error in the associated haar measure ( * ? ? ? * eq . ( 48 ) ) , in which the factor @xmath187 had to be replaced by its square . also , we depart from the standard convention of denoting moments by @xmath188 , since that symbol has been employed in our earlier studies @xcite and above ( [ substitution ] ) . ) then , successively , the ( [ necessarily ] decreasing in absolute value ) raw ( non - central ) moments are @xmath189 @xmath190 @xmath191 @xmath192 @xmath193 @xmath194 @xmath195 @xmath196 @xmath197 and ( requiring four days of mathematica computation on a macmini machine ) @xmath198 @xmath199 ( after four weeks of uninterrupted computation , we did not succeed , however , in determining @xmath200 . ) interestingly , the sequence of denominators immediately above ( in apparent contrast to that of the numerators ) appears to be `` nice '' in that the number of their prime factors do not grow rapidly , but rather linearly . this is a strong indication of the possible existence of a `` closed form '' , that is an expression which is built by forming products and quotients of factorials ( * ? ? ? 12 ) . in fig . [ fig : transposefit ] , we display a ( naive ) fit of a simple power series in @xmath201 of degree nine to the computed first nine moments ( ( [ firstmoment])-([lastmoment ] ) ) ( cf . * figs . 1 , 2 ) ) of the hilbert - schmidt probability distribution over @xmath3 , where @xmath1 is a generic two - rebit density matrix . no nonnegativity constraints were , however , imposed and considerable incursions into negative regions result . ( such negativity can be obviated through the use of maximum - entropy , spline - fitting and other methodologies @xcite , and we do explore such directions . ) the hilbert - schmidt separability probability predicted by the curve in fig . [ fig : transposefit]that is the `` probability mass '' ( the resultant of both positive and negative values ) lying within the interval @xmath202$]is @xmath203 , while our previous studies @xcite , indicate that the actual value is somewhat higher , @xmath204a discrepancy the use of additional higher - order moments should ameliorate . since the plotted distribution ( fig.[fig : transposefit ] ) appears to be _ unimodal _ , one can presumably use the computations of the first and second moments above to isolate the mode of the distribution within the interval ( * ? ? ? * eq . ( 13 ) ) @xmath205 containing the value @xmath206 . narrower intervals containing the mode can be obtained using higher - order moments and the associated hankel determinants ( * ? ? ? 3.2 ) . it is clear that it would be of considerable utility to have available exact values for still higher - order ( than @xmath208 ) moments and for the coefficients @xmath209 of the terms in the intermediate functions / polynomials @xmath123but the associated computational demands seem quite considerable . our only current recourse , in this regard , then , appeared to be a numerical one . we employed a quasi - monte carlo ( tezuka - faure @xcite ) procedure ( using 18,870,000 [ low - discrepancy ] points ) to estimate the values of @xmath146 for @xmath210 and @xmath211 , for @xmath212 . ( actually , by the evident symmetry around the @xmath213-th power of the coefficients of the intermediate functions , we were able to obtain two values [ which we averaged ] for each point . ) coupling these approximate results with the exact formulas for the intermediate functions obtained above for @xmath214 ( sec . [ intersection ] ) , we obtained estimates of the first _ fifty _ moments . ( we investigated the possibility of using these additional numerical results to infer the desired further _ exact _ formulas for the @xmath146 s , but this seemed too demanding a task , given the ordinary machine precision of our quasi - monte carlo simulations and the evident high [ multi - digit ] complexity of the exact coefficients . ) we then used these values ( the first nine moments being exact , and the remaining `` semi - exact '' forty - one , being sums of exact and numerical terms ) in the procedure of mnatsakanov for approximating the `` moment - determinate cumulative distribution function ( cdf ) from its moments '' . the relevant formula for the cdf ( at the separable / nonseparable boundary of principal interest to us ) based on the first @xmath215 moments ( linearly mapping @xmath3 to lie in [ 0,1 ] , and the moments accordingly ) is of the form ( * ? ? ? * eq . ( 2 ) ) ( * ? ? ? * eq . ( 1.3))@xmath216 ( we have to subtract this [ entangled probability estimate ] from 1 to get the [ complementary ] separability probability estimate , to be plotted as a function of the number of moments @xmath217 . ) in fig . [ fig : cdfmnats ] , we show estimates of this value based on increasingly large numbers of moments . ( for more than thirty - six moments , the results turn negative . if we just employ in this same reconstruction procedure , the known exact formulas for the coefficients of the intermediate functions effectively setting the supplementary / corrective numerical terms to zero then the two sets of results are quite close up to twenty moments , but then become considerably more ill - behaved when none of our supplementary numerical results is included [ fig . [ fig : cdfmnats2 ] ] . in a recent interesting study , gzyl and tagliani concluded that thirty - two was `` the maximum allowable moments before incurring numerical instability , unless one conducts the calculation with high accuracy @xcite . they also assert that ' ' the additional information introduced by using the @xmath218-order moment is visible only after the @xmath219-th decimal digit " . in this regard , let us note that the quasi - monte carlo calculations used to complement the exact results here were conducted with only ordinary machine precision . ) it would appear that the wide range and lack of stability of estimates is reflective of the ill - posedness of the hausdorff moment ( inverse ) problem ( stemming ultimately from the lack of orthogonality of the sequence @xmath220 @xcite ) . in fig . [ fig : momentratios ] we show the ratio of the exact ( but incomplete for @xmath75 ) moment computations to that ( semi - exact one ) based on the exact and complementary numerical results . we have explored the use of extensions of the ( two - parameter ) beta distribution @xcite @xcite to better fit the nine exact moments than found , as presented above ( sec . [ betasection ] ) , with the particular distribution ( [ goodbetafit2 ] ) that had been fit to the first two moments of @xmath3 . doing so , we were able to obtain a _ three_-parameter libby - novick ( ln ) distribution of the form @xcite ( * ? ? ? * eq . ( ix.1 ) ) , @xmath221 @xmath222 this gave us a further considerably improved fit over that of ( [ goodbetafit2 ] ) to the first nine exact moments . ( the ninth moment was now predicted within @xmath223as opposed to within @xmath224and the preceding moments better still in a monotonically declining goodness - of - fit manner from the first to the ninth . ) the estimated separability probability now increased to 0.429121 . to arrive at the probability distribution ( [ libbynovick ] ) , we started with the beta distribution fit ( [ goodbetafit2 ] ) that exactly reproduced the first two moments , now trying to fit the first _ three _ moments . this involved a very long ( slowly converging ) iterative process , which at each stage , appealingly , seemed to improve the fit to all our computed fifty ( nine exact and forty - one , `` semi - exact '' ) moments . additionally , the estimated separability probability seemed to increase at each step , which we found to better accord with our earlier extensive numerical investigations ( * ? ? ? * a ) ( * ? ? ? * a.2 ) @xcite . one can employ the libby - novick distribution ( [ libbynovick ] ) as a `` baseline density '' , in the manner below using the beta distribution , following the methodology of ha and provost ( * ? ? ? * eq . ( 3.5 ) ) , to generate estimates of the hs separability probability . a necessary , but not sufficient condition that a two - qubit density matrix be separable is that any @xmath27 principal minor of its partial transpose be nonnegative @xcite so , we can select one such minor , say ( cf . ( [ pt ] ) ) , @xmath225 expressed in terms of the bloore parameterization , and compute the associated moments . ( enforcing the nonnegativity of such a minor yields an _ upper bound _ of @xmath226 on the hilbert - schmidt probability of separability of generic two - rebit systems @xcite . ) we have been able to compute exactly the first forty - five such moments of the probability distribution over the interval @xmath227 $ ] , following very much the same scheme as we pursued for the first nine moments of @xmath3 . the first two moments are @xmath228 and @xmath229 , while remarkably , the ( raw ) third moment is identically zero ( cf . the form the corresponding `` intermediate functions '' now took for these first three cases were ( cf . ( [ inter1])-([inter3 ] ) ) @xmath230 @xmath231 and @xmath232 general formulas could now also be obtained for the coefficients of the @xmath233-th powers of the intermediate functions . these involved the mathematica functions lerchphi or differenceroot ( cf . ( [ coefficient0])-([coefficient6 ] ) ) . however , we were unable to find a general formula for the @xmath55-th moment , even based on the availability of the first fifty - eight moments . the main foci of our initial analyses had been , firstly , the moments of the determinant @xmath3 of the partial transpose of generic two - rebit density matrices , and , secondarily , the moments of the ( necessarily nonnegative ) determinant @xmath2 of the underlying density matrix itself the moments of the latter determinant being more computationally amenable , it is clear , to exact analyses . now , in this context , it is not unnatural to ask the question of the nature of the moments of the _ product _ of these two determinants , @xmath234 ( cf . this approach potentially contributes insight into the separability probability question , since a value of the product less than zero still indicates the presence of an entangled state , and a value greater than zero , a separable state . ( it would appear that the argument in @xcite of augusiak , horodecki and demianowicz could be adapted , so that the value of the product could be construed as that obtainable from a single certain observable measurement . ) in undertaking the associated analysis of moments , we immediately encountered a most interesting result . the first moment or mean of the normalized product @xmath11 is zero , that is @xmath235 the associated `` intermediate function '' being ( cf . ( [ inter1 ] ) ) @xmath236 ( numerically , the first moment of the _ absolute _ value of the normalized product is @xmath237 . this is close to the absolute value , @xmath238 , of the product of the mean of @xmath2 , that is , @xmath239 and the mean of @xmath3 , @xmath240 . ) the second moment ( cf . ( [ momenttwo ] ) ) is @xmath241 ( so , the corresponding standard deviation is the square root of this , that is @xmath242 ) with the associated intermediate function being ( cf . ( [ inter2 ] ) ) @xmath243 ( to compute the @xmath55-th moment of the probability distribution of the product , using the new set of intermediate functions , we employ the same formula as ( [ normfactor ] ) , but for the replacement of the exponent @xmath244 by @xmath245 . ) we see that the coefficients of the constant ( and highest power of @xmath188 ) terms in the first and second intermediate functions immediately above ( ( [ interone ] ) , ( [ intertwo ] ) ) are @xmath246 and @xmath247 . the next four such constant coefficients ( @xmath248 ) have been found to be @xmath249 and @xmath250 . however , we have yet to obtain a general formula , parallel to ( [ coefficient0 ] ) , in light of the increased computational burden , encompassing these six values . the third to the sixth moments are @xmath251 @xmath252 @xmath253 and @xmath254 despite their lengthy digital descriptions , the ratios of these six moments to the hs moments of @xmath255given by ( [ generalformula ] ) are rather remarkably simple , that is , @xmath256 we have only so far been able to compute the two - qubit analogue of the first ( zero ) of the six ratios above it turning out quite remarkably to be @xmath244/ since these ratios are so simple , it suggested to us that we might be more able to progress in our series of analyses , by making our initial goal the computation of these ( unknown ) but apparently well - behaved ratios for higher - order moments rather than the very small values of these moments themselves . we have studied here the moments of probability distributions generated by certain determinantal functions of generic two - qubit density matrices ( @xmath1 ) with real entries ( `` rebits '' ) over the associated nine - dimensional convex domain , assigned hilbert - schmidt measure . it was found that the mean of the ( nonnegative ) determinant @xmath2 is @xmath239 , the mean of the determinant of the partial transpose @xmath3negative values indicating entanglement is @xmath240 , while the mean of the product of these two determinants , @xmath234 , is _ zero_. we determined the exact values also rational numbers of the succeeding eight moments of @xmath3 . at intermediate steps in the derivation of the @xmath55-th moment of @xmath3 , rational functions @xmath156 emerge , yielding the coefficients of the @xmath233-th power of even polynomials ( `` intermediate functions '' @xmath123 ) of total degree @xmath157 . these functions possess poles at finite series of consecutive half - integers ( @xmath257 ) , and certain ( trivial ) roots at finite series of consecutive natural numbers ( @xmath258 ) . the ( nontrivial ) dominant roots of @xmath156 appear to converge , as @xmath140 increases , to the same half - integer values ( @xmath259 ) . if formulas for @xmath146 could be developed for arbitrary @xmath140we do possess them already for @xmath214then , the desired hilbert - schmidt separability probability would be computable to high accuracy . we reproduced the ( linearly transformed ) first nine moments of @xmath3 quite closely by a certain ( two - parameter ) beta distribution , and still more closely by a three - parameter ( libby - novick ) extension of it . the first two moments of @xmath3when employed in the one - sided chebyshev inequality gave an upper bound of @xmath62 on the hilbert - schmidt separability probability of two - rebit density matrices . we ascertained by numerical methods that the orthogonality established of @xmath2 and @xmath3 with respect to hilbert - schmidt measure does not hold with respect to the bures ( minimal monotone ) measure , nor if we slightly distort the symmetry of our basic nine - dimensional generic two - rebit scenario . the ( two - parameter ) beta probability distribution ( [ goodbetafit2 ] ) that closely ( within @xmath224 ) reproduces the ( linearly transformed to the interval [ 0,1 ] ) first exact nine moments of @xmath3 . the vertical axis corresponds to the separable - entangled boundary ( @xmath260 ) , so the mode of the distribution ( located at @xmath261 , corresponding to @xmath262 ) lies within the separable region . ] ratios of the @xmath55-th exact moment of @xmath3 ( linearly transformed to the interval [ 0,1 ] ) to the @xmath55-th moment of the beta probability distribution ( [ goodbetafit2 ] ) fitted to the first and second moments ] separability probability estimates for the generic real @xmath0 density matrices based on differing numbers ( @xmath263 ) of exact moments of @xmath3 , using the nonparametric reconstruction procedures of mnatsakanov @xcite giving the higher ( blue ) set of nine points and the polynomial adjustment of the baseline density methodology of ha and provost @xcite . the horizontal axis is drawn to intercept the vertical at @xmath48 , the least upper bound so far established @xcite . ] fit without nonnegativity constraints imposed of a nine - degree polynomial to the first nine exactly - computed moments of the hilbert - schmidt probability distribution over @xmath3 , where @xmath1 is a generic two - rebit density matrix . the domain of separability is @xmath265 . ] separability probability estimates based on differing numbers ( exact for @xmath266 and `` semi - exact '' for @xmath75 ) of moments , using the reconstruction procedure of mnatsakanov @xcite . the horizontal axis is drawn to intercept the vertical at @xmath48 , the least upper bound so far established @xcite . ] separability probability estimates , without any complementary numerical ( quasi - montecarlo ) input ( for @xmath75 ) , using the reconstruction procedure of mnatsakanov @xcite . the horizontal axis intercepts the vertical at @xmath48 , the least upper bound so far established @xcite . ] i would like to express appreciation to the kavli institute for theoretical physics ( kitp ) for computational support in this research , to michael trott for lending his mathematica expertise , and christian krattenthaler , mihai putinar , robert mnatsakanov , mark coffey and charles dunkl for general discussions and insights .

a complete description of the multitudinous ways in which quantum particles can be entangled requires the use of high - dimensional abstract mathematical spaces . we report here a particularly interesting feature of the nine - dimensional convex set endowed with hilbert - schmidt ( euclidean / flat ) measure composed of two - rebit ( @xmath0 ) density matrices ( @xmath1 ) . to each @xmath1 is assigned the product of its ( nonnegative ) determinant @xmath2 and the determinant of its partial transpose @xmath3negative values of which , by the results of peres and horodecki , signify the entanglement of @xmath1 . integrating this product , @xmath4 , over the nine - dimensional space , using the indicated ( hs ) measure , we obtain the result zero . the two determinants , thus , form a pair of multivariate orthogonal polynomials with respect to hs measure . however , orthogonality does not hold , we find , if the symmetry of the nine - dimensional two - rebit scenario is broken slightly , nor with the use of non - flat measures , such as the prominent bures ( minimal monotone ) measure nor in the full hs extension to the 15-dimensional convex set of two - qubit density matrices . we discuss relations involving the hs moments of @xmath3to the long - standing problem of determining the probability that a generic pair of rebits / qubits is separable .

the cosmic x ray background ( cxrb ) is widely interpreted as the integrated x - ray emission from many discrete sources . active galactic nuclei ( agn ) are expected to contribute the majority of the cxrb , and since the late 1980s the leading ` synthesis models ' have invoked a combination of absorbed and unabsorbed agn to reproduce the overall intensity and broadband spectral shape of the cxrb . typically these synthesis models are based on agn ` unification schemes ' @xcite in which each agn contains an obscuring torus , and the orientation to our line of sight determines the absorption ( e.g. * ? ? ? * ; * ? ? ? * ; * ? ? ? the energy density of the cxrb peaks at @xmath11 kev , but the cxrb has only been substantially resolved into sources at lower energies . in the 0.5 - 2 kev band , the deepest surveys with _ rosat _ resolved 70 - 80% of the x ray background into individual objects , the majority of which are broad - line agn ( e.g. * ? ? ? * ; * ? ? ? * ) . deep surveys performed with _ xmm - newton _ and _ chandra _ have increased the resolved fraction to 80 - 90% in the 0.5 - 2 kev band , and have also resolved a significant fraction ( @xmath12 ) in the 2 - 10 kev band ( e.g. * ? ? ? * ; * ? ? ? * ; * ? ? ? the broadband x - ray spectral properties of the objects detected in the _ xmm - newton _ and _ chandra _ surveys support the hypothesis that the majority of the cxrb is due to agn with a wide range of photoelectric absorption . however , there have been a number of findings that are contrary to the assumptions and predictions of the synthesis models . firstly , the optical and x - ray spectroscopic characteristics of the x - ray sources are sometimes discrepant . there are now many examples of agn which appear to show photoelectric absorption from large column densities ( @xmath13 @xmath4 ) of material , but which exhibit little attenuation to their optical and ultraviolet radiation ( e.g. * ? ? ? * ; * ? ? ? * ) . on the other hand , there are also examples of agn for which the broad optical emission lines are weak or absent , suggesting obscuration of the broad line region by dust , but which show little or no absorption in their x - ray spectra ( e.g. * ? ? ? * ; * ? ? ? secondly the absorbed sources , and those without broad optical emission lines in their optical spectra ( often referred to as ` type 2 ' agn ) , are typically found at lower redshifts than predicted by the synthesis models @xcite . this suggests that the absorption properties of agn have some dependence on either luminosity or redshift , in contrast to the very simple geometric unification schemes employed in the earlier versions of the synthesis models , which were independent of luminosity or redshift . however , this issue is still controversial ( e.g. see * ? ? ? * ; * ? ? ? * ) and determining the absorption characteristics of agn as a function of redshift and luminosity is one of the most important objectives of x - ray survey science . the 13@xmath0 _ xmm - newton _ / _ chandra _ deep field is a project to investigate the astrophysics of the major contributors to the cxrb , particularly sources around the break in the x ray source counts where the contribution to the cxrb per log - flux interval peaks . in order to understand the phenomena , processes and conditions in these sources we combine the high quality x ray spectra of _ xmm - newton_with the precise positions of _ chandra _ and a host of other multi - wavelength data , including a deep 1.4 ghz survey from the vla @xcite . the 13@xmath0 field is centred at @xmath14 , was the location of one of the deepest _ rosat _ surveys @xcite and is a region of extremely low galactic absorption ( @xmath15 @xmath4 ) . in this paper we present the european photon imaging camera ( epic , * ? ? ? * ; * ? ? ? * ) spectra of the 13@xmath0 sources that have been optically identified and which have sufficient x - ray counts to yield a meaningful x - ray spectrum . at present , this amounts to 86 sources . throughout this paper we assume @xmath16 km s@xmath5 mpc@xmath5 , @xmath17 , and @xmath18 . we define a power law spectrum as @xmath19 where @xmath20 is the number of photons , @xmath21 is photon energy , @xmath22 is the photon index and @xmath23 is the normalisation . the source numbering scheme used here is identical to that used in @xcite . the 13@xmath0 field was observed three times with _ xmm - newton _ for a total exposure time of 200ks . when deadtime and periods of high background are excluded , the total live exposure time is 120ks for the pn camera and 130ks for each of the mos cameras . the _ xmm - newton _ observations are fully described in @xcite . the epic spectra were produced from the same event lists , filtered with the same good time intervals , and using the same version of the _ xmm - newton _ science analysis system ( sas 6.0 ) as the source lists presented in @xcite . spectra were produced for all optically - identified sources with @xmath1 source counts . source counts were accumulated in elliptical regions centred on the positions reported by @xcite . the size and ellipticity of each source extraction region was determined by the off - axis angle of the x - ray source , and its countrate . the point spread function is relatively symmetrical near the centre of the _ xmm - newton _ field of view but becomes elongated in the tangential direction at larger off - axis angles . therefore to optimise signal to noise the ellipticity of the source extraction regions increases with off - axis angle , from 0 at the optical axis to 2 near the edge of the field . the minor axes of our source regions vary from 10@xmath24 to 20@xmath24 depending on the overall source countrates . there are several pairs of sources which are close enough together that the nominal extraction regions would overlap . in such cases the two regions were renormalised so that they do not overlap , with the ratio of the minor axes set to the ratio of the countrates of the two sources . all valid event patterns ( pattern 012 ) were used in constructing the mosspectra . for the pn spectra , single and double events ( pattern 04 ) were used for channel energies @xmath25 kev , and only single events were used for lower energy channels . channels close to the energies of the strongest instrumental emission lines ( cu - k at 7.8 kev in pn and al - k at 1.7 kev in mos ) were excluded from the spectra . response matrices and effective area files were constructed for each source region using the sas tasks rmfgen and arfgen respectively . for each source the different epic spectra were combined to form a single spectrum over the 0.212 kev range , using the method of @xcite . spectra were grouped to a minimum of 30 counts per bin . optical spectroscopic observations were carried out in 2002 and 2003 at the william herschel telescope , using the af2/wyffos multi - fibre positioner and spectrograph , and at the w.m . keck observatory , using the lris and deimos multi - object spectrographs . at present , 115 _ xmm - newton _ and _ chandra _ sources have optical spectroscopic identifications and redshifts . full details of the observations and the optical spectra will be presented in loaring et al . ( in prep ) . .power law fits to the _ xmm - newton _ spectra . @xmath23 is the power law normalisation at 1 kev in units of @xmath26 photons @xmath4 s@xmath5 kev@xmath5 . @xmath27 is the redshift of the source . p is the null hypothesis probability corresponding to @xmath28 . [ cols="<,^,^,^,^ , < " , ] we have presented the _ xmm - newton _ epic x - ray spectra of 86 x - ray sources in the 13@xmath0 field which have optical identifications and @xmath29 x - ray counts . more than half of the sources are blagn , and the majority of these ( 42/50 ) have spectra which are consistent with a power law shape . the photon indices are distributed about a mean @xmath30 with an intrinsic dispersion of @xmath31 . of the 8 blagn which have x - ray spectra inconsistent with a power law shape , 3 have curvature with excess emission at the high and low energy ends relative to a power law , and 5 show evidence for absorption at soft x - ray energies . the addition of a cold photoelectric absorber yields an acceptable fit for 3 of these objects , one requires an ionised absorber , and the remaining object can be fitted with either an ionised absorber or with an additional component of scattered or reprocessed soft x - ray emission . of the 25 nelgs , 13 have absorbed x - ray spectra , 9 of which can be fitted with a cold photoelectric absorber , and 4 of which require a more complex model with either an ionised absorber or an additional component of soft x - ray emission . of the 6 absorption line galaxies in the sample , 2 show evidence for x - ray absorption , and both are consistent with a simple cold photoelectric absorber . of the 12 nelgs which do not show evidence for x - ray absorption , 2 have x - ray properties which suggest that their x - ray emission is powered by star formation . the other 14 nelgs and galaxies which are not x - ray absorbed have x - ray properties implying the presence of an agn . at least at @xmath32 , where our r - band imaging probes the rest - frame optical starlight , these objects are luminous galaxies ( @xmath33 ) , containing relatively low x - ray luminosity agn ( @xmath34 erg s@xmath5 ) , and the lack of agn signatures in the optical could be due to the dilution of the agn radiation by the bright host galaxy . these objects are likely to be massive black holes ( @xmath35m@xmath36 ) accreting with low eddington ratios ( @xmath37 ) , rather than vigorous , low mass black holes . finally , the sample contains 5 galactic stars which have x - ray spectra consistent with optically thin thermal emission with a broad distribution of temperature , consistent with active stellar coronal emission . in 4 of the 5 stars , the x - ray spectra alone can distinguish them from agn at similar x - ray flux levels . based on observations obtained with xmm - newton , an esa science mission with instruments and contributions directly funded by esa member states and nasa . the william herschel telescope is operated on the island of la palma by the isaac newton group in the spanish observatorio del roque de los muchachos of the instituto de astrofisica de canarias . keck observatory is operated as a scientific partnership among the california institute of technology , the university of california and the national aeronautics and space administration and was made possible by the generous financial support of the w.m . keck foundation . we thank sergey kuznetsov for helpful comments .

we present the x - ray spectra of 86 optically - identified sources in the 13@xmath0_xmm - newton_/_chandra _ deep field which have @xmath1 x - ray counts . the majority of these sources have 2 - 10 kev fluxes between @xmath2 and @xmath3 erg @xmath4 s@xmath5 . the sample consists of 50 broad line agn , 25 narrow emission line galaxies , 6 absorption line galaxies , and 5 galactic stars . the majority ( 42/50 ) of the broad line agn have x - ray spectra which are consistent with a power law shape . they have a mean photon index @xmath6 and an intrinsic dispersion @xmath7 . three of the broad line agn show curved spectra , with more emission near the high and low energy ends of the spectrum relative to the emission in the 1 - 2 kev range than can be reproduced by the power law model . five blagn show a deficit of soft x - rays , indicating absorption . we consider a source to be significantly absorbed if a power law model fit is rejected with @xmath8 confidence and an absorbed power law model produces an acceptable fit , or if the best - fit power law is abnormally hard ( @xmath9 ) . significant absorption is more common in the narrow emission line galaxies ( 13/25 ) and absorption line galaxies ( 2/6 ) than in the broad line agn ( 5/50 ) , but is not universal in any of these classes of object . the majority of the 20 absorbed sources have x - ray spectra consistent with a simple cold photoelectric absorber , but a significant minority ( 6/20 ) require more complex models with either an additional component of soft x - ray emitting plasma , or an ionised absorber . of the 16 narrow emission line and absorption line galaxies which do not show evidence for x - ray absorption , only 2 objects are likely to be powered by star formation , and both have 210 kev x - ray luminosities of @xmath10 erg s@xmath5 . the x - ray emission in the other 14 unabsorbed nelgs and galaxies is most likely powered by agn , which are not detected in the optical because they are outshone by their luminous host galaxies . the galactic stars show multi - temperature thermal spectra which peak between 0.5 and 1 kev . star / agn discrimination is possible for 4 of the 5 stars solely from their x - ray spectra . surveys x - rays : galaxies galaxies : active quasars : general

SECTION 1. SHORT TITLE. This Act may be cited as the ``Water and Energy Efficient Appliances Act of 2004''. SEC. 2. CREDIT FOR WATER AND ENERGY EFFICIENT APPLIANCES. (a) In General.--Subpart D of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 (relating to business-related credits) is amended by adding at the end the following new section: ``SEC. 45G. WATER AND ENERGY EFFICIENT APPLIANCE CREDIT. ``(a) Allowance of Credit.-- ``(1) In general.--For purposes of section 38, the water and energy efficient appliance credit determined under this section for the taxable year is an amount equal to the sum of the amounts determined under paragraph (2) for qualified water and energy efficient appliances produced by the taxpayer during the calendar year ending with or within the taxable year. ``(2) Amount.--The amount determined under this paragraph for any category described in subsection (b)(2)(B) shall be the product of the applicable amount for appliances in the category and the eligible production for the category. ``(b) Applicable Amount; Eligible Production.--For purposes of subsection (a)-- ``(1) Applicable amount.--The applicable amount is-- ``(A) $25, in the case of a dishwasher manufactured with an EF of at least 0.65, ``(B) $50, in the case of a dishwasher manufactured with an EF of at least 0.69, ``(C) $75, in the case of a clothes washer which is manufactured with an MEF of at least a 1.80 and a WF of no more than 7.5, ``(D) $100, in the case of a refrigerator which consumes at least 30 percent less kilowatt hours per year than the energy conservation standards for refrigerators promulgated by the Department of Energy and effective on July 1, 2001, and ``(E) $150, in the case of a clothes washer which is manufactured with an MEF of at least a 1.80 and a WF of no more than 5.5. ``(2) Eligible production.-- ``(A) In general.--The eligible production of each category of qualified water and energy efficient appliances is the excess of-- ``(i) the number of appliances in such category which are produced by the taxpayer during such calendar year, over ``(ii) the average number of appliances in such category which were produced by the taxpayer during calendar years 2002, 2003, and 2004. ``(B) Categories.--For purposes of subparagraph (A), the categories are-- ``(i) dishwashers described in paragraph (1)(A), ``(ii) dishwashers described in paragraph (1)(B), ``(iii) clothes washers described in paragraph (1)(C), ``(iv) clothes washers described in paragraph (1)(E), and ``(v) refrigerators described in paragraph (1)(D). ``(c) Limitation on Maximum Credit.-- ``(1) In general.--The amount of credit allowed under subsection (a) with respect to a taxpayer for all taxable years shall not exceed $65,000,000, of which not more than $15,000,000 may be allowed with respect to the credit determined by using the applicable amount under subsections (b)(1)(A) and (b)(1)(B). ``(2) Limitation based on gross receipts.--The credit allowed under subsection (a) with respect to a taxpayer for the taxable year shall not exceed an amount equal to 2 percent of the average annual gross receipts of the taxpayer for the 3 taxable years preceding the taxable year in which the credit is determined. ``(3) Gross receipts.--For purposes of this subsection, the rules of paragraphs (2) and (3) of section 448(c) shall apply. ``(d) Definitions.--For purposes of this section-- ``(1) Qualified water and energy efficient appliance.--The term `qualified water and energy efficient appliance' means-- ``(A) a dishwasher described in subparagraph (A) or (B) or subsection (b)(1), ``(B) a clothes washer described in subparagraph (C) or (E) of subsection (b)(1), or ``(C) a refrigerator described in subparagraph (D) of subsection (b)(1). ``(2) Dishwasher.--The term `dishwasher' means a standard residential dishwasher with a capacity of 8 or more place settings plus 6 serving pieces. ``(3) Clothes washer.--The term `clothes washer' means a residential clothes washer, including a residential style coin operated washer. ``(4) Refrigerator.--The term `refrigerator' means an automatic defrost refrigerator-freezer which has an internal volume of at least 16.5 cubic feet. ``(5) EF.--The term `EF' means Energy Factor (as determined by the Secretary of Energy). ``(6) MEF.--The term `MEF' means Modified Energy Factor (as determined by the Secretary of Energy). ``(7) WF.--The term `WF' means Water Factor (as determined by the Secretary of Energy). ``(e) Special Rules.-- ``(1) In general.--Rules similar to the rules of subsections (c), (d), and (e) of section 52 shall apply for purposes of this section. ``(2) Aggregation rules.--All persons treated as a single employer under subsection (a) or (b) of section 52 or subsection (m) or (o) of section 414 shall be treated as 1 person for purposes of subsection (a). ``(f) Verification.--The taxpayer shall submit such information or certification as the Secretary, in consultation with the Secretary of Energy, determines necessary to claim the credit amount under subsection (a). ``(g) Termination.--This section shall not apply to water and energy efficient appliances produced after December 31, 2010.''. (b) Credit Made Part of General Business Credit.--Section 38(b) of such Code (relating to current year business credit) is amended by striking ``plus'' at the end of paragraph (14), by striking the period at the end of paragraph (15) and inserting ``, plus'', and by adding at the end the following new paragraph: ``(16) the water and energy efficient appliance credit determined under section 45G(a).''. (c) Limitation on Carryback.--Section 39(d) of such Code (relating to transition rules) is amended by adding at the end the following new paragraph: ``(11) No carryback of water and energy efficient appliance credit before effective date.--No portion of the unused business credit for any taxable year which is attributable to the water and energy efficient appliance credit determined under section 45G may be carried to a taxable year ending before January 1, 2008.''. (d) Clerical Amendment.--The table of sections for subpart D of part IV of subchapter A of chapter 1 of such Code is amended by adding at the end the following new item: ``Sec. 45G. Water and energy efficient appliance credit.''. (e) Effective Date.--The amendments made by this section shall apply to appliances produced after December 31, 2007, in taxable years ending after such date.

Water and Energy Efficient Appliances Act of 2004 - Amends the Internal Revenue Code to allow a business tax credit for the production of certain water and energy efficient appliances (i.e. dishwashers, clothes washers, and refrigerators). Sets the amount of the credit based upon certain energy and water efficiency ratings. Terminates the credit after 2010.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Protecting Our Children from Sexual Predators Act of 2005''. SEC. 2. ISSUANCE OF DRIVER'S LICENSES OR IDENTIFICATION CARDS TO SEX OFFENDERS. A State or tribal actor that issues driver's licenses or identification cards must have in effect throughout the jurisdiction of the actor laws and policies that ensure the following: (1) The actor does not issue a driver's license, commercial driver's license, or identification card to a sex offender or renew the driver's license, commercial driver's license or identification card of a sex offender until the actor has satisfactory evidence indicating that the sex offender is in compliance with all applicable sex offender registration requirements. (2) A driver's license, commercial driver's license, or identification card issued to a sex offender expires on the first anniversary date of the offender's birthday, measured from the birthday nearest the date of issuance. SEC. 3. IMPLEMENTATION BY STATES AND INDIAN TRIBES. (a) In General.--Each State actor or tribal actor shall have not more than 2 years from the date of the enactment of this Act in which to fully implement this Act. (b) Implementation by Tribes and in Indian Country.--The Attorney General shall coordinate with the Secretary of the Interior to assist tribal actors in fully implementing this Act throughout the jurisdiction of each tribal actor. (c) Ineligibility for Funds.-- (1) In general.--For any fiscal year after the expiration of the period specified in subsection (a), a State actor or tribal actor that fails to fully implement this Act shall not receive 10 percent of the funds that would otherwise be allocated for that fiscal year to the actor under any of the following programs: (A) Byrne.--Subpart 1 of Part E of title I of the Omnibus Crime Control and Safe Streets Act of 1968 (42 U.S.C. 3750 et seq.), whether characterized as the Edward Byrne Memorial State and Local Law Enforcement Assistance Programs, the Edward Byrne Memorial Justice Assistance Grant Program, or otherwise. (B) LLEBG.--The Local Government Law Enforcement Block Grants program. (C) Other law enforcement grants.--Any other program under which the Attorney General provides grants or other financial assistance. (2) Reallocation.--Amounts not allocated under a program referred to in paragraph (1) to an actor for failure to fully implement this Act shall be reallocated under that program to State actors and tribal actors that have not failed to fully implement this Act. SEC. 4. DEFINITIONS. In this Act: (1) State actor.--The term ``State actor'' means any of the following: (A) A State. (B) The District of Columbia, the Commonwealth of Puerto Rico, Guam, American Samoa, the United States Virgin Islands, or any other territory or possession of the United States. (2) Tribal actor.--The term ``tribal actor'' means a federally recognized Indian tribe. (3) Sex offender.--The term ``sex offender'' means an individual who, either before or after the enactment of this Act, was convicted of, or adjudicated a juvenile delinquent for, an offense (other than an offense involving sexual conduct where the victim was at least 13 years old and the offender was not more than 4 years older than the victim and the sexual conduct was consensual, or an offense consisting of consensual sexual conduct with an adult) whether Federal, State, local, tribal, foreign (other than an offense based on conduct that would not be a crime if the conduct took place in the United States), military, juvenile or other, that is-- (A) a specified offense against a minor; (B) a serious sex offense; or (C) a misdemeanor sex offense against a minor. (4) Specified offense against a minor.--The term ``specified offense against a minor'' means an offense against a minor that involves any of the following: (A) Kidnapping (unless committed by a parent). (B) False imprisonment (unless committed by a parent). (C) Solicitation to engage in sexual conduct. (D) Use in a sexual performance. (E) Solicitation to practice prostitution. (F) Possession, production, or distribution of child pornography. (G) Criminal sexual conduct towards a minor. (H) Any conduct that by its nature is a sexual offense against a minor. (I) Any other offense designated by the Attorney General for inclusion in this definition. (J) Any attempt or conspiracy to commit an offense described in this paragraph. (5) Serious sex offense.--The term ``serious sex offense'' means-- (A) a sex offense punishable under the law of a jurisdiction by imprisonment for more than one year; (B) any Federal offense under chapter 109A, 110, 117, or section 1591 of title 18, United States Code; (C) an offense in a category specified by the Secretary of Defense under section 115(a)(8)(C) of title I of Public Law 105-119 (10 U.S.C. 951 note); (D) any other offense designated by the Attorney General for inclusion in this definition. (6) Misdemeanor sex offense against a minor.--The term ``misdemeanor sex offense against a minor'' means a sex offense against a minor punishable by imprisonment for not more than one year. (7) Minor.--The term ``minor'' means an individual who has not attained the age of 18 years.

Protecting Our Children from Sexual Predators Act of 2005 - Requires a state actor (any state, the District of Columbia, or specified U.S. territories and possessions) or federally recognized Indian tribe (tribal actor) that issues driver's licenses or identification cards to have in effect throughout the jurisdiction laws and policies that ensure that: (1) the actor does not issue or renew a driver's license, commercial driver's license, or identification card to a sex offender (offender) without satisfactory evidence that the offender is in compliance with all applicable offender registration requirements; and (2) such license or card expires on the first anniversary date of the offender's birthday, measured from the birthday nearest the date of issuance. Grants each actor two years to implement this Act. Directs the Attorney General to coordinate with the Secretary of the Interior to assist tribal actors in implementing this Act. Provides that for any fiscal year after the expiration of that period a state or tribal actor that fails to fully implement this Act shall not receive 10% of the funds that would otherwise be allocated under the Byrne, Local Government Law Enforcement Block Grants program and any other program under which the Attorney General provides grants or financial assistance.

in many applications of x - ray diffraction ( xrd ) techniques to the study of crystal properties , a key step in the data processing chain is an effective and adaptive noise filtering @xcite . a correct noise removal can facilitate the separation of the useful crystallographic information from the background signal , and the estimation of crystal structure and domain size . important issues of xrd data filtering are performances in noise suppression , capability to preserve the peak position , computational cost and , finally , the possibility of being used as a blackbox tool . different digital filters have been applied to xrd data , in spatial and frequency domains . simple procedures are based on polynomial filtering ( and fitting ) in the spatial domain @xcite . a standard practice when working in frequency domain is to use fourier smoothing . it consists in removing the high - frequency components of the spectrum @xcite . since the truncation of high - frequency components can be problematic in the case of high level noise , a different approach based on the wiener fourier ( wf ) filter has been proposed to clean xrd data @xcite . a different approach , which makes use of the singular value decomposition ( svd ) , has been successfully applied to time - resolved xrd data to reduce noise level @xcite . in this work we describe an application of the hankel lanczos singular value decomposition ( hlsvd ) algorithm to filter xrd intensity data . the proposed filter is based on a subspace - based parameter estimation method , called hankel singular value decomposition ( hsvd ) @xcite , which is currently applied to nuclear magnetic resonance spectroscopy data for solvent suppression @xcite . the hsvd method computes a `` signal '' subspace and a `` noise '' subspace by means of the svd of the hankel matrix @xmath0 , whose entries are the noisy signal data points . its computationally most intensive part consists of the computation of the svd of the matrix @xmath1 recently , several improved versions of the algorithm have been developed in order to reduce the needed computational time @xcite . in this paper , we choose to apply the hsvd method based on the lanczos algorithm with partial reorthogonalization ( hlsvd pro ) , which is proved to be the most accurate and efficient version available in the literature . a comparison in terms of numerical reliability and computational efficiency of hsvd with its lanczos - based variants can be found in ref . @xcite . a criterion is presented to facilitate the separation of noise from the useful crystallographic signal . it enables the design of a blackbox filter to be used in the processing of xrd data . here , the filter is applied to nanocrystalline xrd data . nanocrystals are characterized by chemical and physical properties different from those of the bulk @xcite . at a scale of a few nanometers , metals can crystallize in a structure different from that of bulk . nowadays , different branches of science and engineering are benefiting from the properties of nanocrystalline materials @xcite . in particular , recent xrd experiments have shown that intensities , measured as a function of the scattering angle , could be useful to extract structural and domain size information about nanocrystalline materials . synthetic xrd datasets are generated by computing the x - ray scattered intensity from nanocrystalline samples of different size and properties by using an analytic expression ( see eq . ( [ eq : debye ] ) in section 3 ) . synthetic datasets are processed and filter performance is studied when considering different levels of noise . numerical tests on real xrd data of au nanocrystalline samples of different size and properties show the robustness of the proposed filter and its capability to extract easily and efficiently the useful crystallographic information . these characteristics make this filter an interesting and user friendly tool for the interactive processing of xrd data . the paper has the following structure . section 2 is devoted to the theoretical aspects of the proposed approach . the dataset used to study the filter properties is described in section 3 . numerical results are reported in section 4 . finally , some conclusions are drawn in section 5 . let us denote with @xmath2 the samples of the diffracted intensity signal collected at angles @xmath3 , @xmath4 . they are modelled as the sum of @xmath5 exponentially damped complex sinusoids @xmath6 + e_n \ ; , \label{eq : model}\ ] ] where @xmath2 and @xmath7 , respectively , represent the measured and modelled intensities at the _ n - th _ scattering angle @xmath8 , with @xmath9 the sampling angular interval and @xmath10 the initial scattering angular position , @xmath11 is the amplitude , @xmath12 the phase , @xmath13 the damping factor and @xmath14 the frequency of the _ k - th _ sinusoid , @xmath15 , with @xmath5 the number of damped sinusoids , and @xmath16 is complex white noise with a circular gaussian distribution . it is worth noting that the value of @xmath5 increases or decreases by 2 in order to guarantee that the modelled intensity is real . the @xmath17 data points defined in ( [ eq : model ] ) are arranged into a hankel matrix @xmath0 of dimensions @xmath18 , with @xmath19 and @xmath20 @xmath21_{l \times m}. \label{eq : matrix}\ ] ] the svd of the hankel matrix is computed as @xmath22 where @xmath23 , @xmath24 , @xmath25 , @xmath26 and @xmath27 are orthogonal matrices and the superscript h denotes the hermitian conjugate . the svd is computed by using the lanczos bidiagonalization algorithm with partial reorthogonalization @xcite . this algorithm computes two matrix - vector products at each step . exploiting the structure of the matrix ( [ eq : matrix ] ) by using the fft , the latter computation requires @xmath28 rather than @xmath29 . in order to obtain the `` signal '' subspace , the matrix @xmath0 is truncated to a matrix @xmath30 of rank @xmath5 @xmath31 where @xmath32 , @xmath33 , and @xmath34 are defined by taking the first @xmath5 columns of @xmath26 and @xmath27 , and the @xmath35 upper - left matrix of @xmath36 , respectively . as subsequent step , the least squares solution of the following over - determined set of equations is computed @xmath37 where @xmath38 and @xmath39 are derived from @xmath33 by deleting its first and last row , respectively . the @xmath5 eigenvalues @xmath40 of the matrix @xmath41 are used to estimate the frequencies @xmath42 and the damping factors @xmath43 of the model damped sinusoids from the relationship @xmath44 , \label{eq : eigen}\ ] ] with @xmath15 . the values so obtained are inserted into the model eq . ( [ eq : model ] ) which yields the set of equations @xmath45 + e_n \ ; , \label{eq : model_eigen}\ ] ] with @xmath46 . the least - squares solution of ( [ eq : model_eigen ] ) provides the amplitude @xmath47 and phase @xmath48 estimates of the model sinusoids . the hlsvd pro filter was applied to synthetic as well as real xrd data . in this section , the generation of xrd intensity profiles and the experimental setup for the acquisition of real data are described . both synthetic and real xrd data refer to au nanocrystalline samples . nanocrystals are made of clusters of three different structure types : cuboctahedral @xmath49 , icosahedral @xmath50 , and decahedral @xmath51 . for each fixed structure type @xmath52 ( @xmath53 ) the size @xmath54 of clusters follows a log - normal distribution @xmath55 } \ ; , \label{eq : nano_size_distr}\ ] ] with mode @xmath56 and logarithmic width @xmath57 . structural distances for the different structure types @xmath52 are generally studied independently of the actual nanomaterial . the nearest distance between atoms in the crystals is chosen as a reference length and arbitrarily set to @xmath58 , a constant in various structures @xmath52 and for all sizes @xmath54 of the clusters . actual distances in nanoclusters are then recovered by applying a correction factor @xmath59 for strain , supposed to be uniform and isotropic . a convenient description of the strain factor as a function of the structure type and cluster size is @xmath60 given in terms of the four parameters @xmath61 $ ] . intensities scattered by nanoclusters with size @xmath54 and structure type @xmath52 are computed by using the diffractional model based on the debye function method @xcite : @xmath62 } { 2 \pi q u^{{\mathcal x},n}_{i , j } a_{\mathcal x } ( n ) } \right \ } \ ; , \label{eq : debye}\ ] ] where @xmath63 is the incident x - ray intensity , @xmath64 the debye - waller factor , @xmath65 the atomic form factor ; @xmath66 ^ 2 $ ] , @xmath67 and @xmath68 are , respectively , the dimensionless and the usual scattering vector length with @xmath69 being the f.c.c . bulk lattice constant ; @xmath70 is the number of atoms in the cluster , @xmath71 the distance between the _ i - th _ and _ j - th _ atom , @xmath72 the strain factor . the total scattered intensity is computed as @xmath73 where @xmath74 denotes the size of the largest cluster of type @xmath52 , @xmath75 is the number fraction of each structure type ( @xmath76 ) , and @xmath77 is the value of log - normal size distribution ( [ eq : nano_size_distr ] ) . it is worth noting that both intensities in ( [ eq : debye ] ) and ( [ eq : tot_i ] ) are actually functions of the scattering angle @xmath78 being @xmath79 . experimental xrd intensity profiles are collected by counting , at each scattering angle @xmath3 , the number of scattered photons giving the diffracted intensity signal @xmath2 . for such events data are affected by poisson noise . since the number of photons scattered at each angle @xmath3 is large , the poisson - distributed noise can be approximated by a gaussian - distributed noise as required in section [ sec : hsvd ] . noisy synthetic xrd intensity profiles were built by generating poisson distributed random profiles with intensity @xmath80 ( [ eq : tot_i ] ) taken as the mean value of the poisson process . as a measure of the noise level , the noise - to - signal ratio ( nsr ) was defined as follows : @xmath81 where @xmath82 denotes a poisson process with mean value @xmath80 . figure [ fig_1 ] displays xrd intensity profiles with increasing nsrs . they were obtained by setting @xmath83 nm and @xmath84 nm in eq . ( [ eq : debye ] ) . the set of parameters used to compute the synthetic profiles are summarized in table [ table_0 ] . different nsr values were obtained by scaling the scattered intensity ( [ eq : tot_i ] ) by a factor @xmath85 . figure [ fig_2 ] shows the nsr of the synthetic profiles as a function of the scaling factor f ranging from 0 to 2 . this range contains the nsr values usually measured in experimental profiles we also considered real data in order to validate our method . three different samples were prepared with a resultant mean diameter of 2.0 , 3.2 and 4.1 nm , respectively ( as measured by tem ) . the size distributions were approximately characterized by the same width ( fwhm @xmath86 1 nm ) for all three systems . powder xrd studies were realized on the xrd beam line at the brazilian synchrotron light facility ( lnls campinas , brazil ) using 8.040 kev photons at room temperature . for further details see ref . @xcite . noisy synthetic xrd patterns were generated corresponding to nanocrystalline samples of increasing size from 2 to 4 nm , and poisson - distributed noise with increasing nsr from 2% to 10% . the hlsvd pro filter was then applied to the noisy synthetic xrd signals in order to study its properties under controlled conditions . a key step in the filtering procedure is the selection of the number @xmath5 of damped sinusoids characterizing the model function of the hlsvd pro filter . here , a possible approach is presented , which is based on the following frequency selection criterion : the singular values @xmath87 , @xmath88 , are plotted vs. the corresponding frequencies @xmath14 of the sinusoids in eq . ( [ eq : model ] ) . this choice facilitates a direct comparison of the results of the proposed filter with those obtained by other filters based on a frequency approach . it was observed that , generally , crystallographic xrd intensity signals show a clear transition from a low - frequency region , characterized by high singular values @xmath89 to a high - frequency region with small singular values . the index @xmath5 of the frequency @xmath90 corresponding to the transition , provides the number of damped sinusoids to be used in the hlsvd pro filter . figure [ fig_3 ] displays an example of application of the hlsvd pro filter . a noisy synthetic xrd intensity profile is shown at the top of the figure . it corresponds to x - ray scattering from a au sample having a 3 nm size with a poisson - like noise with nsr=10% . the filtered signal shown in the middle of the figure was obtained by setting @xmath91 in the hlsvd pro filter . this value was estimated by visually inspecting the plot of the singular values @xmath87 vs the frequencies @xmath14 ( see top of fig . ( [ fig_4 ] ) ) . specifically , a transition from high to small @xmath87 was observed at frequency @xmath92 rad@xmath93 which represents the @xmath94 frequency in the set of the sorted frequencies starting from the smallest one . for a comparison , the discrete fourier transform ( dft ) of the noisy synthetic xrd signal is reported at the bottom of fig . ( [ fig_4 ] ) . again , a phenomenon of transition from high to small singular values occurs in the same region of the spectrum , as observed at the top of figure . however , the transition frequency is much more difficult to localize than in the hlsvd pro filter case . this makes troublesome the application of dft and wf filters to clean noisy xrd data . it is worth noting that this difference between the hlsvd pro and fourier frequency based filters is relevant when the filter is intended to be used during interactive xrd data analysis . in this case the successful application of a blackbox filter easy - to - use becomes crucial . coming back to fig . ( [ fig_3 ] ) , the difference between the values of noisy and filtered profiles is shown at the bottom . to quantify the performance of the filter , the filtered signal was compared with the noiseless synthetic xrd signal ( see fig . ( [ fig_5 ] ) ) . this can be done only with synthetic signals as experimental xrd data without noise are not available . the filter performance was evaluated using the measure @xmath95 to give a statistical significance to these measures a monte carlo experiment was carried out . more precisely , the hlsvd pro was applied to 1000 noisy synthetic profiles generated by starting from the same sample size , with different nsrs . for each filtered profile , the measure @xmath96 of filter performance was estimated by calculating the mean value and the standard deviation . table [ table_1 ] summarizes the outcome of the aforementioned monte carlo experiments . for each sample size and nsr , the mean and standard deviation are obtained using @xmath97 synthetic xrd intensity profiles with different noise realizations having the same nsr . the sensitivity to the number @xmath5 of sinusoids of the hlsvd pro filter was also studied . this number was slightly varied around the optimal @xmath5 value selected by using the frequency criterion . the performance results were compared in order to validate the choice of the optimal @xmath5 value . in particular , @xmath5 was increased and decreased by 2 , as discussed in section i. the results of such a comparison are summarized in table [ table_2 ] and show that the proposed frequency criterion provides the value of @xmath5 corresponding to the best performance of the hlsvd pro filter . the filter was also applied to real xrd intensity profiles of au samples of size 2 , 3.2 and 4.1 nm . figure [ fig_6 ] shows at top the profile of a 3.2 nm au sample with @xmath98 computed as @xmath99 , where @xmath100 and @xmath80 are vectors with the measured error and the intensity values , respectively . since in the case of xrd signals the noise follows the poisson distribution , @xmath100 is given by @xmath101 . the result obtained by hlsvd pro is displayed in the middle of the figure . at bottom the plot of singular values is depicted vs. the frequency . components with a frequency higher than @xmath102 rad@xmath103 , due to noise , were removed . denoising a real xrd profile of 500 intensity data samples , as typical ones used in the present study , requires about 11 seconds , using matlab 7 on a machine with a intel xeon 1.80 ghz processor and a 512 kb cache size . a filter based on the hlsvd pro method has been presented . it has been applied to filter xrd patterns of nanocluster powders . the filter performance has been studied on synthetic and real xrd patterns with different nsrs . results show that the proposed filter is robust and computationally efficient . a further advantage is its user - friendliness that makes it a useful blackbox tool for the processing of xrd data . we thank a. cervellino , c. giannini and a. guagliardi for kindly providing us with experimental xrd data . b. mierzwa , j. pielaszek , _ smoothing of low - intensity noisy x - ray diffraction data by fourier filtering : application to supported metal catalyst studies _ , 1em plus 0.5em minus 0.4emjournal of applied crystallography , * 30 * , 544 - 546 , 1997 . a. hieke , h.d . d " orfler , _ methodical developments for x - ray diffraction measurements and data analysis on lytropic liquid crystals applied to k - soap / glyceral systems _ , 1em plus 0.5em minus 0.4emcolloid polym . sci . , * 277 * , 762 - 776 , 1999 . m. schmidt , s. rajagopal , z. ren , k. moffat , _ application of singular value decomposition to the analysis of time - resolved macromolecular x - ray data _ , 1em plus 0.5em minus 0.4embiophysical journal , * 84 * , 2112 - 2129 , 2002 . s. rajagopal , m.schmidt , s. anderson , h. ihee , k. moffat , _ analysis of time - resolved crystallographic data by singular value decomposition _ , 1em plus 0.5em minus 0.4emacta crystallographica , * d60 * , 860 - 871 , 2004 . h. barkhuijsen , r. de beer , d. van ormondt , _ improved algorithm for noniterative time - domain model fitting to exponentially damped magnetic resonance signals _ , 1em plus 0.5em minus 0.4emjournal of magnetic resonance , * 73 * , 553 - 557 , 1987 . t. laudadio , n. mastronardi , l. vanhamme , p. van hecke and s. van huffel , _ improved lanczos algorithms for blackbox mrs data quantitation _ , 1em plus 0.5em minus 0.4emjournal of magnetic resonance , * 157 * , 292 - 297 , 2002 . siegel , e. hu , d.m . cox , h. goronkin , l. jelinski , c.c . koch , j. mendel , m.c . roco , d.t . shaw , _ nanostructure science and technolgy . a worldwide study _ , 1em plus 0.5em minus 0.4emthe interagency working group on nanoscience , engineering and technolgy , http://itri.loyola.edu/nano . a. cervellino , c. giannini and a. guagliardi , _ determination of nanoparticle structure type , size and strain distribution from x - ray data for monoatomic f.c.c .- derived non - crystallographic nanoclusters _ , 1em plus 0.5em minus 0.4emjournal of applied crystallography , * 36 * , 1148 - 1158 , 2003 . .values of parameters used in eq . ( [ eq : debye ] ) to compute synthetic xrd intensity profiles . the wavelength and the @xmath104 bulk lattice constant were set to @xmath105 nm and @xmath84 nm , respectively . [ cols="^,^,^,^",options="header " , ] summarizes the parameters used in eq . ( [ eq : debye ] ) to compute the diffraction intensities . they are characteristics of au samples . the wavelength and bulk lattice constant have been set to @xmath83 nm and @xmath84 nm , respectively . from the upper to the lower profile , the nsr increases from @xmath106 to @xmath107 ( see fig . [ fig_2 ] and text for details).,title="fig:",scaledwidth=95.0% ] + ) synthetic xrd intensity profile as a function of the scattering angle @xmath78 ; ( middle ) filtered xrd intensity profile . the hlsvd pro filter removes signal components with frequency above @xmath108 rad@xmath103 ( see fig . ( [ fig_4 ] ) ) ; ( bottom ) difference between measured and filtered profiles.,title="fig:",scaledwidth=95.0% ] + : ( top ) amplitude of eigenvalues @xmath87 vs. frequency @xmath14 , @xmath88 . the frequency @xmath108 rad@xmath103 was used to separate ( filter ) high frequency components due to noise ; ( bottom ) portion of the dft amplitude spectrum of the noisy synthetic xrd intensity profile . both plots refer to the xrd intensity profile shown at the top of fig . ( [ fig_3 ] ) . , title="fig:",scaledwidth=95.0% ] + : ( top ) noiseless synthetic xrd intensity profile as a function of the scattering angle @xmath78 ; ( bottom ) difference between noiseless and filtered ( see middle plot of fig . ( [ fig_3 ] ) ) profiles.,title="fig:",scaledwidth=95.0% ] + ; ( middle ) filtered xrd intensity profile . the hlsvd pro filter removes signal components with frequency above @xmath102 rad@xmath103 ; ( bottom ) amplitudes of eigenvalues @xmath87 vs frequency @xmath14 , @xmath109 . , title="fig:",scaledwidth=95.0% ] +

a filter based on the hankel lanczos singular value decomposition ( hlsvd ) technique is presented and applied for the first time to x - ray diffraction ( xrd ) data . synthetic and real powder xrd intensity profiles of nanocrystals are used to study the filter performances with different noise levels . results show the robustness of the hlsvd filter and its capability to extract easily and efficiently the useful crystallographic information . these characteristics make the filter an interesting and user - friendly tool for processing xrd data . singular value decomposition , lanczos methods , x - ray diffraction

SECTION 1. SHORT TITLE. This Act may be cited as the ``National Commission on the Future of the Army Act of 2014''. SEC. 2. PROHIBITION ON USE OF FISCAL YEAR 2015 FUNDS TO REDUCE END STRENGTHS OF ARMY PERSONNEL. None of the funds authorized to be appropriated or otherwise made available for fiscal year 2015 for the Army may be used to reduce or prepare to reduce personnel of the Army, including any cancellation of training, below the authorized fiscal year end strengths for personnel of the Army as follows: (1) 450,000 for active duty personnel of the Army. (2) 345,000 for the Army National Guard. (3) 195,000 for the Army Reserve. SEC. 3. LIMITATION ON USE OF FISCAL YEAR 2015 FUNDS FOR TRANSFER OR DIVESTMENT OF CERTAIN AIRCRAFT ASSIGNED TO THE ARMY NATIONAL GUARD. (a) Limitation.-- (1) Aircraft.--None of the funds authorized to be appropriated or otherwise made available for fiscal year 2015 for the Army may be used to divest, retire, or transfer, or prepare to divest, retire, or transfer, any AH-64 Apache aircraft of the Army assigned to units of the Army National Guard as of January 15, 2014. (2) Personnel.--None of the funds authorized to be appropriated or otherwise made available for fiscal year 2015 for the Army may be used to reduce personnel related to any AH- 64 Apache aircraft of the Army National Guard below the levels of such personnel as of September 30, 2014. (3) Readiness of aircraft and crews.--The Secretary of the Army shall ensure the continuing readiness of the AH-64 Apache aircraft referred to in paragraph (1) and the crews of such aircraft during fiscal year 2015, including through the allocation of funds for operation and maintenance and support of such aircraft and for personnel connected with such aircraft as described in paragraph (2). (b) Scope of Limitation.--Nothing in subsection (a) shall be construed to limit the use of funds described in that subsection for the training of members of the Army National Guard or Army Reserve who are pilots of Apache aircraft on any other aircraft. (c) Exception.--Notwithstanding subsection (a), funds described in that subsection may be used after the date of the report required by section 5(b)(3) to prepare for the transfer of not more than 72 AH-64 Apache aircraft from the Army National Guard to the regular Army if the Secretary of Defense certifies in writing to the congressional defense committees that such a transfer would not-- (1) degrade the strategic depth or regeneration capacities of the Army; (2) degrade the Army National Guard in its role as the combat reserve of the Army; and (3) occur before October 1, 2014. SEC. 4. NATIONAL COMMISSION ON THE FUTURE OF THE ARMY. (a) Establishment.--There is established the National Commission on the Future of the Army (in this Act referred to as the ``Commission''). (b) Membership.-- (1) Composition.--The Commission shall be composed of eight members, of whom-- (A) 4 shall be appointed by the President; (B) 1 shall be appointed by the Chairman of the Committee on Armed Services of the Senate; (C) 1 shall be appointed by the Ranking Member of the Committee on Armed Services of the Senate; (D) 1 shall be appointed by the Chairman of the Committee on Armed Services of the House of Representatives; and (E) 1 shall be appointed by the Ranking Member of the Committee on Armed Services of the House of Representatives. (2) Appointment date.--The appointments of the members of the Commission shall be made not later than 90 days after the date of the enactment of this Act. (3) Effect of lack of appointment by appointment date.--If 1 or more appointments under subparagraph (A) of paragraph (1) is not made by the appointment date specified in paragraph (2), the authority to make such appointment or appointments shall expire, and the number of members of the Commission shall be reduced by the number equal to the number of appointments so not made. If an appointment under subparagraph (B), (C), (D), or (E) of paragraph (1) is not made by the appointment date specified in paragraph (2), the authority to make an appointment under such subparagraph shall expire, and the number of members of the Commission shall be reduced by the number equal to the number otherwise appointable under such subparagraph. (4) Expertise.--In making appointments under this subsection, consideration should be given to individuals with expertise in reserve forces policy. (c) Period of Appointment; Vacancies.--Members shall be appointed for the life of the Commission. Any vacancy in the Commission shall not affect its powers, but shall be filled in the same manner as the original appointment. (d) Chair and Vice Chair.--The Commission shall select a Chair and Vice Chair from among its members. (e) Initial Meeting.--Not later than 30 days after the date on which all members of the Commission have been appointed, the Commission shall hold its initial meeting. (f) Meetings.--The Commission shall meet at the call of the Chair. (g) Quorum.--A majority of the members of the Commission shall constitute a quorum, but a lesser number of members may hold hearings. (h) Administrative and Procedural Authorities.--The following provisions of law do not apply to the Commission: (1) Section 3161 of title 5, United States Code. (2) The Federal Advisory Committee Act (5 U.S.C. App.). SEC. 5. DUTIES OF THE COMMISSION. (a) Study on Structure of the Army.-- (1) In general.--The Commission shall undertake a comprehensive study of the structure of the Army, and policy assumptions related to the size and force mixture of the Army, in order-- (A) to determine the proper size and force mixture of the regular component of the Army and the reserve components of the Army, and (B) to make recommendations on how the structure should be modified to best fulfill current and anticipated mission requirements for the Army in a manner consistent with available resources and anticipated future resources. (2) Considerations.--In undertaking the study required by subsection (a), the Commission shall give particular consideration to the following: (A) An evaluation and identification of a structure for the Army that-- (i) has the depth and scalability to meet current and anticipated requirements of the combatant commands; (ii) achieves a cost-efficiency balance between the regular and reserve components of the Army, taking advantage of the unique strengths and capabilities of each, with a particular focus on fully burdened and lifecycle cost of Army personnel; (iii) ensures that the regular and reserve components of the Army have the capacity needed to support current and anticipated homeland defense and disaster assistance missions in the United States; (iv) provides for sufficient numbers of regular members of the Army to provide a base of trained personnel from which the personnel of the reserve components of the Army could be recruited; and (v) maximizes and appropriately balances affordability, efficiency, effectiveness, capability, and readiness. (B) An evaluation and identification of force generation policies for the Army with respect to size and force mixture in order to best fulfill current and anticipated mission requirements for the Army in a manner consistent with available resources and anticipated future resources, including policies in connection with-- (i) readiness; (ii) training; (iii) equipment; (iv) personnel; and (v) maintenance of the reserve components in an operational state in order to maintain the level of expertise and experience developed since September 11, 2001. (b) Study on Partial Transfer of Certain Aircraft.-- (1) In general.--The Commission shall also conduct a study of the feasibility and advisability of a partial transfer of Army National Guard AH-64 Apache aircraft from the Army National Guard to the regular Army. (2) Considerations.--In conducting the study required by paragraph (1), the Commission shall consider the full cost and cost savings of the Army Aviation Restructuring Initiative as proposed for fiscal year 2015, including costs associated with retraining, rebasing, and remissioning. (3) Interim report.--Not later than 90 days after the appointment date for members of the Commission specified in section 4(b)(2), the Commission shall submit to the President and the congressional defense committees a report setting forth the results of the study conducted under paragraph (1). (c) Final Report.--Not later than February 1, 2016, the Commission shall submit to the President and the congressional defense committees a report setting forth a detailed statement of the findings and conclusions of the Commission as a result of the study required by subsection (a), together with its recommendations for such legislation and administrative actions as the Commission considers appropriate in light of the results of the study. SEC. 6. POWERS OF THE COMMISSION. (a) Hearings.--The Commission shall hold such hearings, sit and act at such times and places, take such testimony, and receive such evidence as the Commission considers advisable to carry out its duties under this Act. (b) Information From Federal Agencies.--The Commission may secure directly from any Federal department or agency such information as the Commission considers necessary to carry out its duties under this Act. Upon request of the Chair of the Commission, the head of such department or agency shall furnish such information to the Commission. (c) Postal Services.--The Commission may use the United States mails in the same manner and under the same conditions as other departments and agencies of the Federal Government. (d) Gifts.--The Commission may accept, use, and dispose of gifts or donations of services or property. SEC. 7. COMMISSION PERSONNEL MATTERS. (a) Compensation of Members.--Each member of the Commission who is not an officer or employee of the Federal Government shall be compensated at a rate equal to the daily equivalent of the annual rate of basic pay prescribed for level IV of the Executive Schedule under section 5315 of title 5, United States Code, for each day (including travel time) during which such member is engaged in the performance of the duties of the Commission. All members of the Commission who are officers or employees of the United States shall serve without compensation in addition to that received for their services as officers or employees of the United States. (b) Travel Expenses.--The members of the Commission shall be allowed travel expenses, including per diem in lieu of subsistence, at rates authorized for employees of agencies under subchapter I of chapter 57 of title 5, United States Code, while away from their homes or regular places of business in the performance of services for the Commission. (c) Staff.-- (1) In general.--The Chair of the Commission may, without regard to the civil service laws and regulations, appoint and terminate an executive director and such other additional personnel as may be necessary to enable the Commission to perform its duties. The employment of an executive director shall be subject to confirmation by the Commission. (2) Compensation.--The Chair of the Commission may fix the compensation of the executive director and other personnel without regard to chapter 51 and subchapter III of chapter 53 of title 5, United States Code, relating to classification of positions and General Schedule pay rates, except that the rate of pay for the executive director and other personnel may not exceed the rate payable for level V of the Executive Schedule under section 5316 of such title. (d) Detail of Government Employees.--Any Federal Government employee may be detailed to the Commission without reimbursement, and such detail shall be without interruption or loss of civil service status or privilege. (e) Procurement of Temporary and Intermittent Services.--The Chair of the Commission may procure temporary and intermittent services under section 3109(b) of title 5, United States Code, at rates for individuals which do not exceed the daily equivalent of the annual rate of basic pay prescribed for level V of the Executive Schedule under section 5316 of such title. SEC. 8. TERMINATION OF THE COMMISSION. The Commission shall terminate 90 days after the date on which the Commission submits its final report under section 5(c). SEC. 9. CONGRESSIONAL DEFENSE COMMITTEES DEFINED. In this Act, the term ``congressional defense committees'' has the meaning given that term in section 101(a)(16) of title 10, United States Code. SEC. 10. FUNDING. Amounts authorized to be appropriated for fiscal year 2015 and available for operation and maintenance for the Army may be available for the activities of the Commission under this Act.

National Commission on the Future of the Army Act of 2014 - Prohibits the use of funds made available for FY2015 for the Army to: (1) reduce Army personnel below the authorized fiscal year end strengths of 450,000 for active duty personnel of the Army, 345,000 for the Army National Guard, and 195,000 for the Army Reserve; or (2) divest, retire, or transfer any AH-64 Apache aircraft assigned to units of the Army National Guard as of January 15, 2014, or to reduce related personnel below the levels of such personnel as of September 30, 2014. Directs the Secretary of the Army to ensure the continuing readiness of the AH-64 Apache aircraft and crews during FY2015. Permits the use of such funds, after the Commission established by this Act submits its interim report, to prepare for the transfer of not more than 72 AH-64 Apache aircraft from the Army National Guard to the regular Army if the Secretary of Defense (DOD) certifies that such a transfer would not: (1) degrade the strategic depth or regeneration capacities of the Army, (2) degrade the Army National Guard in its role as the combat reserve of the Army, and (3) occur before October 1, 2014. Establishes the National Commission on the Future of the Army, which shall: (1) undertake a comprehensive study of the structure of the Army and policy assumptions related to its size and force mixture in order to make recommendations on how the structure should be modified to best fulfill mission requirements in a manner consistent with available resources, and (2) submit a final report to the President and the congressional defense committees by February 1, 2016. Directs the Commission to study and submit an interim report on the feasibility and advisability of a partial transfer of Army National Guard AH-64 Apache aircraft from the Army National Guard to the regular Army.

For millions of iPhone owners, or would-be iPhone owners, who dislike AT&T's wireless service or prefer Verizon Wireless service, liberation is at hand. Starting Feb. 10, Apple's iconic smart phone finally will be available in the U.S. on a second carrier, Verizon, instead of just on AT&T, which has been the exclusive iPhone network since the device launched in 2007. Current Verizon customers can pre-order the iPhone Thursday. Walt Mossberg compares the new Verizon iPhone 4 to an AT&T; iPhone 4, and finds that they aren't interchangeable. The Verizon has much better voice calls, he says, but there's a trade off in data speed. Complaints about dropped voice calls, or calls that can't be initiated, on AT&T's service, especially on iPhones, have been legion. Meanwhile, Verizon has enjoyed a general reputation for reliable voice service. So, many frustrated AT&T iPhone users and those scared off by reports of dropped calls, or simply loyal to Verizon, have been eagerly anticipating this move. To these people, I'm here to say: Yes, there are some major benefits to having your iPhone on Verizon, but, as with all good things, there are also trade-offs. I've been testing a Verizon iPhone 4 and comparing it to an AT&T iPhone 4, which has been out since last summer. The phones themselves are essentially identical, except for the fact that they have different radios inside to accommodate the two carriers' differing network technologies. They aren't interchangeable. Mossberg's Mailbox A Computer for Preparing Taxes On the big question, I can say that, at least in the areas where I was using it, the Verizon model did much, much better with voice calls. In numerous tries over nine days, I had only three dropped calls on the Verizon unit, and those were all to one person who was using an AT&T iPhone in an especially bad area for AT&T: San Francisco. With the nearly identical AT&T model, I often get that many dropped calls in one day. Calls on the Verizon unit were mostly crisp and clear, including speakerphone calls and those made over my car's Bluetooth connection. On my first full day of testing, I did have several Verizon calls that dropped out for a few seconds, before recovering. Apple attributed this to a very minor glitch I'd encountered in my initial setup of the phone and urged me to reboot it. I did and suffered no more momentary dropouts. The Verizon model also introduces a feature that some iPhone power users have been craving but that AT&T hasn't allowed in the past: the ability to use the phone, for an extra monthly fee, as a Wi-Fi hot spot for Internet connectivity to multiple laptops or other devices. In my tests, this worked fine with Windows and Macintosh laptops, and an iPad. Wednesday afternoon, AT&T countered by announcing a similar Wi-Fi hot spot plan for the iPhone at an unspecified future date. Bloomberg News For an extra fee, Verizon iPhone users can use the phone as a Wi-Fi hot spot. AT&T has rushed to counter this feature with one of its own. Also, Verizon is, for an unspecified but limited time, offering an unlimited $30 a month data plan for the iPhone. That is something AT&T once offered new customers, but has since replaced with capped plans offering fixed amounts of data at $15 or $25 a month. (Existing AT&T customers have been allowed to keep their $30 unlimited plans.) What about the trade-offs? Chief among them is data speed. I performed scores of speed tests on the two phones, which I used primarily in Washington, and its Maryland and Virginia suburbs, and for part of one day at Chicago's O'Hare Airport. In these many tests, despite a few Verizon victories here and there, AT&T's network averaged 46% faster at download speeds and 24% faster at upload speeds. This speed difference was noticeable while doing tasks like downloading large numbers of emails, or waiting for complicated Web pages to load. AT&T's speeds varied more while Verizon's were more consistent, but overall, AT&T was more satisfying at cellular data. Also, because Verizon's iPhone—like most other Verizon phones—doesn't work on the world-wide GSM mobile-phone standard, you can't use it in most countries outside the U.S. AT&T's iPhone does work on this standard, and can be used widely abroad, albeit at very high roaming rates. In the midst of my testing, I had to travel to Hong Kong, one of the few countries where the Verizon iPhone functions. But even there, it only worked for voice, not data, at least in the areas where I was working. The AT&T model handled both voice and data everywhere I tried it there. Finally, the Verizon model can't fetch Internet data at the same time it is making a voice call, something the AT&T model can do. In fact, if you try to, say, call up a Web page while on a voice call with the Verizon model, you get an error message warning the two things can't be done simultaneously. While this distinction is a weapon in the war of words between the carriers, I doubt it's a big deal for most average users. My guess is that the most common things you'd want to check while talking would be your calendar, contacts and notes. And, in my tests, it was possible to check all those things on the Verizon model during calls, even though I have them set up to sync via the Internet. I did have some issues with the Verizon model. In the D.C. area, long a coverage stronghold for Verizon, it kept switching briefly from 3G mode to slower 2G mode. This didn't affect voice quality, and didn't last long, but it slowed data downloads drastically for short periods. Also, on my first day of testing—after the setup glitch but before I rebooted—the Verizon phone showed poor battery life, and had trouble connecting to my car's Bluetooth setup. After that, these problems disappeared. Bluetooth worked fine and I was able to make it through a day with the battery on both phones. Apple lists the specs on the two models as identical. They both start at $199, both have the same battery-life rating, both run the same operating software. In my tests, I was easily able to transfer all my apps, music, photos, settings, music and videos from the AT&T iPhone to the Verizon model, using iTunes, and I didn't run into any apps or media that failed to work as expected. Prices for voice and data plans are a bit different. The least you can pay monthly for an iPhone on Verizon is $75, which includes 450 voice minutes, 250 text messages and unlimited data. On AT&T, you can pay just $65, but your data is limited to a paltry 200 megabytes, though you get 1,000 text messages in this scenario. The Verizon wireless hot-spot plan costs $20 a month for 2 gigabytes of data, but gets expensive if you run over: $20 for each extra gigabyte. One big question about the Verizon iPhone that neither company is answering is whether it will be updated to a new iPhone 5 model when the AT&T model is updated. Such updates typically have occurred in June or July, which could make people who buy a Verizon iPhone now resentful that their new phone was bested so soon. Of course, Verizon customers who wait might be resentful if their version of the iPhone isn't upgraded at the same time as AT&T's. Officials at both Apple and Verizon will only say they don't intend to make Verizon customers unhappy, but that could mean anything. Bottom line: In my tests, the new Verizon version of the iPhone did much better at voice calling than the AT&T version, and offers some attractive benefits, like unlimited data and a wireless hot-spot capability. But if you really care about data speed, or travel overseas, and AT&T service is tolerable in your area, you may want to stick with AT&T. —See a video of Walt Mossberg discussing the Verizon iPhone at WSJ.com/PersonalTech. Find all his columns and videos at the All Things Digital website, walt.allthingsd.com. Email him at [email protected]. ||||| Yesterday, I made a 45-minute phone call from my office. This seemingly unremarkable statement is remarkable for two reasons. First, I was able to place a call from my office — something which was impossible for me to do a week prior. Second, I made it through the entire 45-minutes without the call being dropped once. Again, this was impossible a week prior. So what changed? Well, my iPhone changed. I’ve been an iPhone user since day one: June 29, 2007. Over the course of the past three and a half years, the coverage I’ve gotten from my service provider for the device, AT&T, has gone from bad to worse. AT&T would talk about how much money they were putting into upgrades for their system, and would continually promise that things would get better soon. But for whatever reason, in major cities like San Francisco and New York City, the situation has continued to deteriorate. It’s so bad, in fact, that in the TechCrunch office in the SoMa district of San Francisco it’s impossible to make or receive calls. Perhaps our office is a Faraday cage — one that only seems to affect AT&T — I’m not sure. But what I am sure of is that our office is hardly the only place in the city where the same is true. And even outside of the Bay Area, there’s a reason why there’s so much excitement for the Verizon iPhone. And now it’s here. And yes, it works. Beautifully. Build I’ve had a chance to carry around a Verizon iPhone for the past week or so. It’s a bit odd to write a review about it now because, well, I’ve already reviewed this product before. This initial Verizon iPhone, of course, is just an iPhone 4. It’s the same phone that was released on AT&T’s network last summer. But it has been slightly reworked to make room for a CDMA chip that Verizon’s network requires, replacing the GSM chip that AT&T’s network requires. But holding it in your hand, most regular users would have no idea that there’s any difference. In fact, the only physical difference is that the single rivet at the top of the device near the headphone jack has been replaced by two matching rivets on either side of the top of the Verizon version of the device. While Apple won’t talk specifics, presumably, this is a change made to the antenna of the device, which is the metal band that wraps around the iPhone 4. As you’re probably aware, Apple had an antenna issue shortly after the iPhone 4’s launch this past summer. As I’ve said time and time again, the issue was real, but it wasn’t a really big issue. And the millions of iPhone 4s that Apple has sold so far are testament to that. This Verizon version of the iPhone 4 seems to have none of the same antenna issues. Try as I might, using the “death grip” and every other grip I can actually do, I can no longer reproduce the same attenuation problem that the previous iPhone 4 model had. I death grip the thing, and no bars drop. More importantly, calls don’t drop and data doesn’t stop. Again, Apple won’t comment, but problem, apparently, solved. Moving on. (Quickly, as an aside, I have noticed that the back of the Verizon version of the iPhone 4 is missing some of the FCC, etc symbols usually found at the bottom of the device — no clue why those are gone, but it’s another small change in the design. It makes the back look even cleaner!) Service The single most important thing that would-be AT&T switchers and some new iPhone customers will want to know is: how does it compare to the AT&T version in terms of signal, dropped calls, data, etc. The answer, at least in my neck of the woods (again, San Francisco), is very, very good. It’s funny, if you spend time in various parts of this city, you’ll know where you can and cannot use an iPhone. Huge swaths of SoMa, for example, are awful. Some parts of the Mission are even worse. Then there are random streets throughout the entire city where AT&T service seemingly disappears into a black hole. I’ve more or less trained myself to know not to even try to use the iPhone in these parts of the city. So it was very, very odd to test out the Verizon iPhone in many of those areas. But guess what? Nearly across the board, the Verizon version of the iPhone worked — as both a phone and a mini data-sucking machine. I can’t tell you how wonderful it has been to walk through the city while being able to maintain a phone call, or Internet connection. Naturally, there are still a few places I was unable get service, but they’re typically places where it’s understandable — like underground. Many skeptics will be quick to point out that things may change when Verizon’s network gets swamped with iPhones in the same way that AT&T’s was. The difference is that Verizon’s network is already swamped with data-sucking Android devices. Millions of them. Maybe I’m being naive, but I really don’t expect there to be a problem with Verizon’s network in the same way that there was with AT&T’s. And neither does Verizon. We’ll see, I guess. But the early results are very promising. Speed AT&T, in their PR scramble to attempt to hold on to some of their disgruntled users, has been playing up two key things that are advantages of their network over Verizon’s. The first is the ability to make a call and surf the web at the same time. It’s true, you definitely cannot make a call and surf the web at the same time on the Verizon iPhone. To some people, this will matter. But I have really never seen this as a huge issue. If I’m talking on the phone with someone, I’m concentrating on talking with them, not surfing the web. But I realize that everyone is different. But apparently some 90+ million current Verizon subscribers don’t have too much of a problem with this either — as none of them have that capability. The second issue AT&T has been playing up is the speed of their network. It’s “the fastest 3G network” according to their ad campaigns. In my tests, when both phones have had signal, that is also true. There’s no question that AT&T’s network is faster than Verizon’s for data transfers — both up and down. I’ve tried this all over the city a number of times. AT&T is faster. But — and this is a very big but — in order for AT&T to be faster, it needs to have a signal. And again, that’s simply not the case in large parts of the city. So speed or not, Verizon still wins this battle hands down in my book. I’ll take Verizon’s coverage over AT&T’s speed any day. As sort of an aside, the one other issue brought up when taking about CDMA versus GSM is that the CDMA version of the iPhone won’t be able to roam internationally. For many countries, particularly those in Europe, that is true. One can only hope that Verizon or Apple come up with some sort of way around this — perhaps partner with another carrier for a deal on a per-use MiFi card to carry around in another country. Or better, just make a CDMA/GSM version of the phone. For now, if you’re going to be doing a lot of traveling, you’re likely to be out of luck. Hotspot The big new feature that was touted at the press conference unveiling the Verizon iPhone was the “Personal Hotspot” option. This allows you to turn your iPhone 4 into a WiFi hub that can accept up to five connections. I’ve previously done a walk-through of how this will work. And in the field, it’s just as easy as it initially seemed. I’ve used this feature a number of times over the past week. It’s brilliant. It could not be any easier to set up and manage. Once you enable it and connect, a blue bar will appear at the top of the phone’s screen letting you know that the hotspot feature is enabled. And it will tell you how many devices are currently connected. Unlike with phone calls, other data can also come in at the same time you’re using the phone as a hotspot. For example, Push Notifications still stream in when you’re connected. If you receive a call, the phone will ask you if you want to connect. If you do, it will sever your data connection, ending the hotspot capabilities. But when you hang up, you can push one button to resume. Yes, I realize other phones have had this hotspot capability for some time now. In fact, when I reviewed the EVO 4G, it was pretty much the only thing I liked about the device. But the iPhone 4’s Personal Hotspot blows it away for one reason: battery life. The EVO’s battery lasted something ridiculously low, like 90 minutes, with the hotspot feature turned on. In my tests, the iPhone 4 can give you a solid 4 hours of hotspot/tethering time. That’s from a fully charged battery, all the way down to zero. I’ve run it down fully twice. Both times, just about four hours. Verizon plans to charge an extra $20 for the hotspot feature. That’s on top of the $30 you’ll pay for data for the iPhone 4 (which is currently unlimited, unlike AT&T’s capped plans). But if you’ve ever owned a wireless dongle, you’ll know that $20 is well worth it — the dongles usually cost you upwards of $60 a month for the same 2 GB of data usage. The Verizon iPhone Versus The iPhone On Verizon’s Network A few months ago, before the Verizon iPhone was announced, I wrote a post entitled: The “Verizon iPhone” Versus “The iPhone On Verizon’s Network”. The main idea behind the post was to wonder what the Verizon version of the device would be like when Verizon and Apple finally came to terms they could agree upon? As I said at the time, Verizon would undoubtedly love to load the device up with crapware in the same fashion that they’ve done with their Android devices, and all of the other devices they’ve sold over time. Apple, on the other hand, obviously would not want that. But would they have to make any concessions to get a deal done? The best part of the Verizon iPhone is that no, Apple did not have to make any concessions. The Verizon iPhone is not a “Verizon iPhone” — it’s an “iPhone on Verizon’s network”. There’s no Verizon branding anywhere on the device aside from the upper left of the screen which shows you the carrier next to the signal strength. There are no pre-loaded Verizon apps. There are no apps that work on the AT&T iPhones that won’t work on this model. Every app you’ve bought in the App Store will install and work on this Verizon version of the device. FaceTime is interoperable over the two devices. So is Game Center. Will Verizon have their own apps in the App Store that they’ll want you to buy? Undoubtedly. But this is very clearly Apple’s device. Not Verizon’s. So Is It Worth It? If you’re an AT&T iPhone customer at the end of your contract who lives in an area with poor AT&T service, you need to get to an Apple or Verizon store next week to get this updated device. Seriously, mark down February 9 on your calendar so that you pre-order it. Then show up at a store on February 10 to pick it up. If you’re an AT&T iPhone customer still on contract who lives in an area with poor AT&T service, I would definitely consider getting this updated device. It may be a few hundred dollars out of pocket, but think of that compared to what you’ve paid to AT&T over the years. If you’re anything like me, it makes you want to scream. If you’re an AT&T iPhone customer still on contract who lives in an area with good AT&T service, then no, this probably isn’t the device for you. If you’re a non-iPhone user who is interested in checking it out but has been waiting for it to come to Verizon, this is absolutely for you. The caveat to all of this is that it’s well known that Apple releases a new version of the iPhone every summer. Expect this summer to be no different. So if you buy this iPhone 4 on Verizon right now, know that there’s a good chance that an iPhone 5 will be out in six months or less. One can only hope that Apple and Verizon would do the right thing and allow the early Verizon iPhone adopters to upgrade to the iPhone 5 for a heavily discounted (if not fully subsidized price). But it’s still very much up in the air. Hell, we don’t even know for sure that Verizon will get the iPhone 5 this summer. Perhaps it will be AT&T-only based on some sort of contractual agreement. But the latest rumors suggest that a CDMA/GSM hybrid iPhone 5 that works on both AT&T and Verizon may be the most likely bet. So again, it comes down to how badly you want an iPhone on Verizon right now — and the hope that Verizon and Apple will do the right thing for customers in a few months. For me, as someone who has spent three and a half years fed up with AT&T, the Verizon iPhone is absolutely, 100 percent worth it. I’ve already cancelled my AT&T contract (by way of Google Voice, actually) and I cannot forsee a future where I ever go back. There’s long been a slogan that goes along with many Apple products — “it just works”. It’s also the best way to sum up this review. The iPhone 4 on Verizon: it just works. ||||| Most impressively, the Verizon iPhone effortlessly made calls in the Cellphone Signal Torture Chamber of Doom: my house. Advertisement Continue reading the main story The Verizon iPhone did drop one call — in baggage claim at the Los Angeles airport. And, of course, there are regions where AT&T coverage is better than Verizon’s. But in general, my testing matches the conclusions of Consumer Reports and RootMetrics.com: the Verizon iPhone has more bars in more places. (Hey, that might make a good slogan! Oh, wait...) In general, the Verizon and AT&T iPhones are identical. Same sleek, thin, satisfying, plastic-free body — all glass and metal. Same gorgeous, high-resolution screen — 960 by 640 pixels. Same battery life — you’ll need a recharge every night. Same camera on the back, which can take 5-megapixel stills or excellent hi-def video — the flash doubles as a video light. Same low-resolution camera on the front, suitable for Wi-Fi videochats, using Apple’s FaceTime software for iPhone or Mac. Even the prices are about the same. The 16-gigabyte phone costs $200 with two-year contract. The monthly service costs, for example, $70 for unlimited voice calls, plus $20 for 5,000 text messages, plus $30 a month for unlimited Internet use. (Verizon says that it will soon eliminate that unlimited plan, just as AT&T recently did. Instead, you’ll pay something like $25 a month for 2 gigabytes of Internet data. Good luck figuring out how much that is.) The single new feature in Verizon’s iPhone is Personal Hotspot, where the iPhone becomes a Wi-Fi base station. Up to five laptops, iPod Touches or other gadgets can get online, using the phone as a glorified Internet antenna. That’s incredibly convenient. Many other app phones have it — AT&T says its iPhone will get it soon — but Apple’s execution is especially nice. For example, the hot spot shuts itself off 90 seconds after the last laptop disconnects. That’s hugely important, because these personal hot spot features are merciless battery drains. The hot spot feature costs $20 a month extra, and buys only 2 gigabytes of data for all of those laptops. Think e-mail, not YouTube. (AT&T will charge $45 a month for 4 gigabytes of data.) Now, there are two kinds of cellphone networks in this country. They’re known as C.D.M.A. (Verizon and Sprint use this technology) and G.S.M. (the system for AT&T and T-Mobile). Making an iPhone that works on a C.D.M.A. network entailed four adjustments, some of which you won’t like. Photo First, Apple moved the volume and Ringer Off switches a fraction of an inch to accommodate the C.D.M.A. antenna inside. It’s not a big deal, but those buttons no longer fit existing AT&T iPhone cases. (Contrary to blogger belief, the redesign doesn’t help with the famous Death Grip issue, in which holding the phone in a certain way makes your signal bars drop. Then again, the problem emerges only when you’re in a very weak signal area, so you’ll see it less often on Verizon. I couldn’t reproduce it at all.) Advertisement Continue reading the main story A second C.D.M.A. difference: When you exchange long text messages with non-Verizon phones, they get split up into 160-character chunks. G.S.M. phones are smart enough to reconstitute those chunks into one more readable, consolidated message. Third: You can’t talk on an C.D.M.A. phone while you’re online. That is, if you’re on a call, you can’t simultaneously check a Web site or send e-mail over the cellular network — and, annoyingly, the Personal Hotspot feature cuts off. (It reconnects when you hang up.) If the top of your screen says “3G,” an indication that you’re in a high-speed Internet area of Verizon’s network, incoming calls take priority and interrupt your online connection. If you’re online in an older, 2G area, you stay online and the call goes directly to voice mail. It’s not such a big deal. Continuing processes like downloads, Personal Hotspot and GPS navigation resume automatically when you end your call. You can still send text and get messages when you’re on a call. And none of this applies when you’re in a Wi-Fi hot spot; in that case, you can call and surf simultaneously, no problem. For business travelers, the fourth C.D.M.A. difference is the most disappointing: not many other countries use C.D.M.A. The Verizon iPhone works in about 40 countries, including Mexico, Canada and China; AT&T phones, on the other hand, work in 220 countries. (In both cases, you pay through the nose if you use them overseas.) Still interested? Here are a few final points to ponder before you plunge. Even if Verizon’s network is the best in America, its policies and prices are still among the worst. This is the company, after all, that admitted to billing $2 every time you accidentally hit the up-arrow button. (Verizon refunded $52 million and paid the Federal Communications Commission a record $25 million fine.) This is the company that just eliminated its “new phone every two years” discount policy, that just cut its new-phone return policy to 14 days from 30, that doubled its early-termination fee (to $350 if you cancel your two-year contract before it’s up). Consider, too, that if surveys are any indication, Verizon can expect an enormous stampede of new iPhone customers. Last time this happened — to AT&T — the weight of all those bandwidth-sucking iPhones swamped the network, causing interruptions that persist to this day. The same thing might happen to Verizon. Verizon swears that it’s prepared for the onslaught. Then again, that’s what AT&T said, too. Remember, too, that so far, Apple has released a new iPhone model every July. Apple won’t say if there will be an iPhone 5 for Verizon this summer. (“Let’s put it this way: We’re not stupid,” is all an Apple rep would say.) But if it does, and you buy an iPhone 4 now, you’ll be stuck with an outdated phone in only five months. Advertisement Continue reading the main story Finally, a lot has changed in the years it’s taken the iPhone to come to Verizon. Phones that run Google’s Android software have eaten a lot of the iPhone’s lunch. A huge part of that, of course, was the AT&T factor; people bought Android phones so they could be on Verizon’s network. Even now, though, Android phones are superior in some ways. For example, they offer amazingly good spoken GPS navigation, you can dictate text into any text box, and you can get one with a bigger screen. Of course, the iPhone still wins on battery life, simplicity and both the quality and quantity of the app store. (Google doesn’t screen or supervise what’s on the Android store, as Apple does. Some call that a blessing, others a curse.) Yes, that’s a lot of footnotes and “yes, buts.” Even so, most people don’t care about overseas compatibility or simultaneous calling and surfing or Verizon’s tactics. They want an iPhone — an iconic, beautiful, fast, elegant iPhone — that doesn’t drop calls. Now, after years of pining, they have it at last.

– The iPhone 4 has finally arrived on Verizon, and what that means is … now you can actually make successful phone calls on your iPhone. Reviewers give it a thumbs-up: “The Verizon iPhone is nearly the same as AT&T’s iPhone 4—but it doesn’t drop calls. For several million Americans, that makes it the holy grail,” writes David Pogue in the New York Times. In five cities, including San Francisco and New York (“the two Bermuda Triangles of AT&T reception”), the Verizon version successfully held a call to a landline while the AT&T version dropped it, sometimes more than once. OK, the “holy grail” did drop one call, and AT&T has better coverage in some areas, but the bottom line is: “The Verizon iPhone has more bars in more places.” Walter S. Mossberg concurs that the Verizon version is “much, much better with voice calls,” and it also has “the ability to use the phone, for an extra monthly fee, as a Wi-Fi hot spot for Internet connectivity to multiple laptops or other devices,” a feature he found to work fine. But, he writes in the Wall Street Journal, “if you really care about data speed, or travel overseas, and AT&T service is tolerable in your area, you may want to stick with AT&T.” “It’s here. And yes, it works. Beautifully,” writes MG Siegler on TechCrunch. “I can’t tell you how wonderful it has been to walk through the city while being able to maintain a phone call, or Internet connection. Naturally, there are still a few places I was unable get service, but they’re typically places where it’s understandable—like underground.” The stellar reviews did come with some caveats (Verizon's "policies and prices are still among the worst" in America, Pogue writes). Click through for more reasons you might want to hold off on buying a Verizon iPhone.

the health information technology for economic and clinical health act enables providers to receive incentive payments for transitioning to electronic medical records . allowing patient access to medical records for example , electronic portals enable patients to securely communicate with their physician , request medication refills , and view lab results . electronic resources such as patient portals may even assist patients in disease self - management by tracking refill history and changes in health status . although growing in popularity , only 7% of americans utilize patient portals . however , internet use among older adults is increasing . in 2005 , approximately 30% of adults aged 65 and older reported ever using internet or e - mail , and only 46% of those who used the internet reported daily internet use . more recent estimates suggest that 53% of american adults aged 65 and older report internet or e - mail use and that 70% of those regularly use the internet . as internet use increases , older adults will be better suited to take advantage of electronic resources for healthcare purposes . however , previous estimates of internet use in older adults have not focused on individuals with chronic diseases such as heart failure . as patient portals increase in popularity , patients with chronic conditions requiring considerable symptom monitoring , such as heart failure , may be more likely to access electronic resources for disease self - care . these electronic resources may provide the tools needed to reduce the burden of extensive self - management . the prevalence of internet and email use among patients with heart failure is not currently known , and heart failure patients may have barriers limiting their ability to successfully navigate electronic resources and apply information . barriers known to be prevalent in heart failure patients include low health literacy , poor heart failure self - management knowledge , and cognitive impairment . these barriers are associated with decreased compliance , increased rehospitalization , and increased mortality [ 10 , 11 ] . low health literacy is associated with poorer condition - related knowledge [ 1214 ] including worse heart failure knowledge . adults with limited health literacy struggle to search for pertinent health information on the internet . although cognitive impairment is prevalent in heart failure [ 1719 ] , no studies have explored whether cognitive impairment impacts electronic resource use and electronic communication in heart failure patients . finally , whether patients who use the internet and e - mail have used these resources to gain disease - specific knowledge has not been investigated . despite increasing internet use among older adults , it is unclear whether internet and e - mail use among heart failure patients are influenced by health literacy or cognitive impairment and whether internet use relates to increased heart failure knowledge . the current study sought to investigate patterns of electronic resource use among older adults with heart failure and whether heart failure patients who report internet and e - mail use have higher health literacy and less cognitive impairment than heart failure patients who do not use internet or e - mail . additionally , the present study explored whether heart failure patients who use the internet demonstrate more heart failure - related knowledge than individuals who do not use the internet . the sample consisted of 119 english - speaking older adults with systolic heart failure who were participating in an nih - funded study examining cognitive function and self - management in older adults with heart failure . participants were 50 to 85 years of age diagnosed as new york heart association ( nyha ) heart failure class ii or iii with documented left ventricular ejection fraction less than 40% confirmed by a medical chart review . participants were excluded if they had untreated sleep apnea , renal failure requiring dialysis , developmental disability impacting functions of daily living , history of substance abuse , neurological disorder ( e.g. , dementia , stroke ) , psychotic disorder ( e.g. , schizophrenia ) , terminal illness , cabg surgery within the previous 3 months , or head injury with greater than 10 minutes loss of consciousness according to their self - report . a brief neuropsychological battery was administered to assess multiple domains of cognitive functioning , including tests of global cognitive function , executive function , attention , and memory . the heart failure connectivity questionnaire was created for this study to measure computer and internet use and patterns . this questionnaire was developed by adapting questions from a survey in the kaiser family foundation 2005 report e - health and the elderly : how seniors use the internet for health information . fifteen questions were taken from the survey and altered to apply to heart failure patients . the questions assessed the following : internet access and use , e - mail use , internet - related communication with healthcare professionals , reasons for not using a computer or internet , and heart - failure - related internet use . meter . the meter demonstrates high internal consistency ( i.e. , cronbach 's alpha = 0.93 ) . the dutch heart failure knowledge scale was used to assess general heart failure knowledge as well as knowledge related to symptoms , symptom recognition , and treatment ( e.g. , diet and fluid restriction ) . scores range from 0 to 15 , with higher scores indicating more heart failure knowledge . the modified minimental state examination is a short screening measure of global cognitive function , tapping aspects of memory , spatial abilities , and attention . the 3ms includes a variety of short tasks such as letter sequencing , animal naming , mental reversal , and temporal orientation . this test takes approximately 7 minutes to complete and is sensitive to a range of cognitive impairments including alzheimer 's disease and other forms of dementia . participant e - mail and internet use were described using descriptive statistics ( % ) . logistic regression was conducted to examine the relationship between health literacy and cognitive function and the dichotomous variables of internet use ( 0 = no internet use ; 1 = internet use ) and e - mail use ( 0 = no e - mail use ; 1 = e - mail use ) . analysis of covariance ( ancova ) was used to determine whether heart failure knowledge differed between internet users and nonusers . most participants reported internet access at home or work ( 82.4% ) , using the internet ( 78.2% ) and using e - mail ( 71.4% ) . forty - five percent of the sample reported looking up heart failure on the internet ( see table 2 ) . most participants demonstrated functional health literacy ( see table 3 ) . with regard to the dutch heart failure knowledge scale , 79.8% of the patients had scores in the 1115 range , and 20.2% of the patients had lower to marginal scores in the 710 range . two separate logistic regression analyses were conducted to investigate whether meter scores predicted internet use and e - mail use after controlling for age and education . the results of the logistic regression for internet and e - mail use are presented in tables 4 and 5 , respectively . results of the analysis of e - mail use indicated that individuals with higher health literacy were more likely to report e - mail use ( b = .08 , p < .05 ) . controlling for age and education , logistic regression indicated that individuals with higher 3ms scores were more likely to report e - mail use ( b = .09 , p < .05 ) . ancova between internet use and heart failure knowledge , controlling for age and education , revealed no effect of internet use on the dutch heart failure knowledge survey , f(1,116 ) = .089 , p = .77 . scores were similar in participants who reported internet use ( m = 12.24 , sd = 1.89 ) and those who reported no internet use ( m = 11.92 , sd = 2.40 ) . here we report that the majority of heart failure patients surveyed have internet access and use both the internet and e - mail . however , higher health literacy and better cognitive function predicted e - mail use but not internet use . eventually , internet use may become ubiquitous among heart failure patients , which would limit the ability of patient characteristics to predict use of course , our patients were not randomly selected and may not be representative of all patients with heart failure . however , they were recruited from two large medical centers in the midwest and were typically over 65 years of age . what was striking was the contrast between access and use of the internet and e - mail for heart failure - related purposes ; few patients reported having discussed the use of these resources with their physicians , and less than half reported using the internet to find information on heart failure . although there is little literature on use of the internet and e - mail by patients with heart failure , use of these resources will only increase and may hold promise for educating patients regarding heart failure and facilitating communication with healthcare providers . for example , a randomized trial of providing an online medical record to patients with heart failure reported that patients were able to use the system and that self - reported adherence to medications improved . furthermore , the american college of cardiology has created a website ( https://www.cardiosmart.org/ ) for patient education that includes many conditions including heart failure . thus , thought leaders are anticipating a need for internet - based resources for patient use . supporting effective use of available resources is important given that patients are expected to appropriately manage their health and respond to changes in symptoms . in this sample , heart failure knowledge did not differ between internet users and individuals who do not use the internet . many medical websites exist to provide heart failure - related information , but less than half ( 45.4% ) of the sample reported having looked up heart failure on the internet . whether information obtained on the internet can help to address poor self - care requires further study . toward that end , a review of information regarding heart failure on the internet suggested that many websites provide primarily biomedical information as opposed to information designed to be useful to patients and recommended that healthcare providers carefully consider the content of websites prior to recommending them to patients . we are unaware of any trials of internet - delivered patient education for heart failure . however , there are many cases where the patients themselves are not solely in charge of their medical needs . it may be a family member , friend , or even a nurse who is in charge of making sure they take their medication or even bathing them . the internet could be a reliable tool for these caregivers if they have questions about the patient 's medications or notice some unusual symptoms . in fact , fox and brenner of the pew research center stated that eight in ten caregivers ( 79% ) have access to the internet . they also found that some of searches that these caregivers made on the internet were for reviews of drugs , treatments , doctor , and even hospital facility ratings . this pew report reflects that the internet can be a reliable tool for health information , even if it is not the patients themselves directly going online . convenience sampling may limit the generalizability of these findings , and we did not intend for this to be an epidemiological investigation of rates of internet and e - mail use . rates of use of electronic resources change rapidly , and we suspect that increasing numbers of patients with heart failure will be using the internet and e - mail . although the heart failure connectivity questionnaire was a simple survey , the reliability is admittedly not known and the questions do not lend themselves to evaluation of internal consistency as they do not total up to create a score . in sum , the current findings suggest that many heart failure patients can access and use the internet and that higher health literacy and cognitive functioning predict e - mail use , although this sample generally had functional health literacy and dementia was an exclusion criteria . finally , less than half of the participants used the internet to obtain heart failure knowledge and use of the internet was not related to more heart failure knowledge when compared with individuals who did not report internet use . electronic health educational resources , including patient portals and medical websites , may represent an untapped resource for bridging the gap between the healthcare team and patient self - management . interventions using the internet should capture usage statistics to demonstrate an adequate dose , as mere access and availability does not ensure use and patient learning . future studies are needed to investigate the use of health care portal use among heart failure patients and methods to enhance their use .

background . the internet offers a potential for improving patient knowledge , and e - mail may be used in patient communication with providers . however , barriers to internet and e - mail use , such as low health literacy and cognitive impairment , may prevent patients from using technological resources . purpose . we investigated whether health literacy , heart failure knowledge , and cognitive function were related to internet and e - mail use in older adults with heart failure ( hf ) . methods . older adults ( n = 119 ) with heart failure ( 69.84 9.09 years ) completed measures of health literacy , heart failure knowledge , cognitive functioning , and internet use in a cross - sectional study . results . internet and e - mail use were reported in 78.2% and 71.4% of this sample of patients with hf , respectively . controlling for age and education , logistic regression analyses indicated that higher health literacy predicted e - mail ( p < .05 ) but not internet use . global cognitive function predicted e - mail ( p < .05 ) but not internet use . only 45% used the internet to obtain information on hf and internet use was not associated with greater hf knowledge . conclusions . the majority of hf patients use the internet and e - mail , but poor health literacy and cognitive impairment may prevent some patients from accessing these resources . future studies that examine specific internet and email interventions to increase hf knowledge are needed .

einstein s general relativity is not only the most successful classical theory of gravity in four dimensions , it is also the simplest theory possessing some nice properties . the two of the most important characteristics being general covariance and second order field equations . in fact , it was shown by lovelock that , in four dimensions , general relativity is the unique generally covariant theory of gravity ( upto an addition of a cosmological constant ) which gives second order equations of motion @xcite . however , in higher dimensions , there exists higher curvature theories , namely the lovelock theories , which also gives second order field equations . these theories are generically characterized by higher curvature invariants in the action . at each order @xmath0 , the combination of higher curvature invariants is unique , the integral of which on a compact manifold of dimension @xmath1 gives the euler characteristic of the manifold . there are also other interesting characteristics of the lovelock class of theories . primarily , exact analytic black hole solutions are known to exist @xcite ( see also @xcite and references therein ) . black holes are widely believed to exist in nature as a final state of a gravitational collapse . they are also the simplest objects to study in any gravitational theory . therefore , exact black hole solutions are of significant importance . more recently , in the context of ads / cft correspondence , exact asymptotically ads black hole solutions in a gravity theory have been proven to be useful in studying the holographic properties of a finite temperature conformal field theory on the boundary @xcite . secondly , the lovelock theories also admit birkhoff s theorem , which states that any solution which has spherical , planar or hyperbolic symmetry must be locally isometric to the corresponding static black hole solution @xcite . generically , the admittance of birkhoff s theorem suggests the lack of spin-@xmath2 mode excitations in the linearized field equations . there are also other theories of gravity which admit exact analytic black hole solutions and further admit birkhoff s theorem . these theories , being outside the lovelock class , are generically higher derivative theories and consequently possess ghost degrees of freedom . one well known higher derivative theory is the conformal theory of gravity in four dimensions , which is obtained from an action quadratic in the conformal weyl tensor . the action is thus invariant under weyl rescalings and the field equations are traceless . birkhoff s theorem in conformal gravity states that modulo a conformal factor the most general spherically symmetric solution is static @xcite . considering the same action in dimensions other than four , one loses the property of invariance under weyl rescalings . even then , the theory admits exact analytic black hole solutions with spherical , planar or hyperbolic symmetry , and further admits birkhoff s theorem @xcite . note that , in arbitrary dimensions , though the field equations are of fourth order , the trace of the field equations are of order two . this can easily be seen as follows . varying the action gives @xmath3 now , consider infinitesimal weyl - rescalings of the metric @xmath4 . under such variations , the lagrangian will vary as @xmath5 , which implies @xmath6 . this shows that the trace of the field equations , being proportional to the lagrangian density , must be of second order . recently , a theory of massive gravity was constructed in three dimensions @xcite , where the lagrangian is a particular combination of quadratic curvature invariants given by @xmath7 again , the theory admits exact analytic black hole solutions @xcite . the lagrangian of this theory has a unique property in three dimensions , that the field equations have a second order trace . so , it is natural to wonder if there could be other theories of gravity which , although non - realistic , have some special properties which allows one to obtain exact analytic black hole solutions and can serve as toy models of gravitational theories . specifically , it might be useful to classify higher - derivative theories of gravity whose traced field equations have a reduced order . in this paper we construct the most general lagrangian which is a linear combination of scalars of the form @xmath8 which are characterized by the number of derivatives of the metric ( hereafter , the degree of differentiation ) @xmath9 , such that the trace of the field equations is of order three or less . we will show that when the trace is resticted to be of order two , then , in dimensions six or higher , there are only three linearly independent possible invariants which have a second order trace . they are the six - dimensional euler density , and the two linearly independent scalars constructed by contracting all the indices of three conformal weyl tensors . however , in five dimensions , we obtain a peculiar independent invariant which can be thought of as a cubic generalization of ( [ knmg ] ) and has been studied separately in @xcite and @xcite . we also obtain the general static spherically symmetric solution for some of these theories . based on our analysis for six - derivative theories , we present a conjecture classifying all the scalars of arbitrary order , which give second order traced field equations in various dimensions . when the trace is restricted to be of order three , in arbitrary dimensions , we obtain two additional scalars . these two scalars are not independent in dimensions three and six . in six dimensions they reduce to one of the conformal anomalies . one future direction of study is to see which of these theories admit a birkhoff s theorem . in section [ quadratic ] , for completeness we review the @xmath10 case . the case @xmath9 is analyzed in section [ cubic ] . in section [ exact solutions ] we focus our attention on obtaining the general static , spherically symmetric solution for some of the theories defined in section [ cubic ] in arbitrary dimensions . in this section , we review how to obtain the most general quadratic lagrangian , having second order traced field equations @xcite . the most general quadratic combination of curvature invariants in arbitrary dimension is given by is @xmath11 , which is boundary term . ] @xmath12 where @xmath13 and @xmath14 are arbitrary constants . the trace of the field equations coming from this lagrangian are@xmath15 imposing the trace @xmath16 to be of second order , implies that the coefficients @xmath13 and @xmath14 must be chosen such that the first two terms in ( [ trqua ] ) vanish , i.e.,@xmath17 = 0 . \label{seedqua}\ ] ] the above equation is satisfied only if the term inside the bracket is proportional to the einstein tensor , which is the most general divergenceless , symmetric , rank two tensor linear in the curvature can not be constructed locally out of the curvature , the equation @xmath18 , with @xmath19 $ ] , does not have any non - trivial solution . ] . consequently , the coefficients in ( [ seedqua ] ) must fulfill@xmath20 since there are four variables ( @xmath21 ) and two equations , there is a bi - parametric family of solutions given by@xmath22 one can further factor out the four dimensional euler density to write ( [ lq2 ] ) in the form@xmath23 where @xmath24 and @xmath25 are arbitrary constants , @xmath26 is defined by@xmath27 and @xmath28 is the gauss - bonnet combination which corresponds to the four dimensional euler density . thus , we have shown that for combinations quadratic in the curvature , the most general lagrangian which has second order traced field equation , can be expressed as a linear combination of the four dimensional euler density @xmath29 and @xmath26 defined in eq . ( [ f4 ] ) . in dimensions higher than three , one can further use the following relation@xmath30 where @xmath31 is the weyl tensor and @xmath32 is the four - dimensional conformal weyl invariant . this means that for dimensions higher than three , @xmath33 in ( [ lq2 ] ) can be equivalently expressed as a linear combination of the four - dimensional weyl invariant and the euler density . in this section , we generalize the previous discussion for lagrangians of degree of differentiation six in arbitrary dimensions @xmath34 . we start by considering a generic combination of the twelve linearly independent @xcite , curvature invariants of degree six @xmath35 where @xmath36 s are arbitrary coefficients and @xmath37 s are given by@xmath38 note however that when we neglect a total derviative the twelve terms are not linearly independent , as one can write two of the invariants in terms of the other ten in the following way@xmath39\nonumber\\ l_{12 } & = l_{5}-l_{6}+{\frac{1}{4}}l_{9}+\nabla_{a}\nabla_{c}[r_{\ b}^{a}r^{bc}-rr^{ac}+{\frac{1}{4}}g^{ac}r^{2}]\end{aligned}\ ] ] using the above relations , one can rewrite the lagrangian as a linear combination of only ten curvature invariants with coefficients @xmath40 ( @xmath41 ) . extremizing the action constructed with the lagrangian ( [ lcubic ] ) with respect to the metric gives the field equations@xmath42 where @xmath43 are defined respectively in equations ( [ gab1]-[gab8 ] ) in the appendix [ eom ] . now , requiring the trace @xmath44 to be of order three , is the same as imposing trace to be proportional to @xmath45 ( see appendix [ tofe ] ) . this gives us a set of eight equations ( [ systemd ] ) for the twelve variables ( @xmath36 ) and a parameter @xmath46 ( analoguous to @xmath47 in the quadratic case ( [ constraintsquadratic ] ) ) . solving these equations for arbitrary dimensions , we obtain a five - parameter family of solutions . the details of the equations and its solution are given in the appendix [ eom ] . this implies that in @xmath48 , there are five linearly independent curvature invariants ( of degree of differentiation six ) which gives rise to third ( or lower ) order traced field equations . they are as follows . firstly , the six - dimensional euler density given by @xmath49 obviously gives second - order traced field equations . secondly , there are two independent algebraic invariants constructed out of three weyl tensors , namely @xmath50 and @xmath51 , which also gives second order traced filed equations . these two weyl invariants are given in terms of the @xmath37 s as@xmath52 and @xmath53 in addition , there are two other curvature invariants @xmath54 and @xmath55 listed in equations ( [ sigma ] ) and ( [ theta ] ) respectively which give third order traced field equations . however , in dimensions @xmath56 , the above curvature invariants are not all linearly independent . for example , in @xmath57 and @xmath58 , the invariants @xmath54 and @xmath55 are proportional to each other modulo a total derivative . it is interesting to note that , in six dimensions , requiring the traced field equations to be of third order ( or less ) , we recover all the four ( @xmath59 type - a and @xmath60 type - b ) non - trivial conformal anomalies @xcite-@xcite . in table i below , we list all the curvature invariants in dimensions greater than or equal to @xmath60 , which lead to third ( or less ) order traced field equations . [ c]|c|c|c|c|c|c|@xmath61 & @xmath57 & @xmath62 & @xmath63 & @xmath64 & @xmath48 + @xmath65 & @xmath66 & @xmath67 & @xmath67 , @xmath68 & @xmath69 & @xmath70 @xmath71 + @xmath72 & @xmath73 & @xmath74 & @xmath74 & @xmath75 & @xmath74 + returning to the set of invariants that gives second order traced field equations we find that in dimensions @xmath76 , they are spanned by the basis set @xmath77 up to a total derivative . however , in @xmath63 this is not the case . in particular , there exists a special " linearly independent invariant which generalizes @xmath26 to the cubic case . this is realized by noting that the following relation is analogous to equation ( [ keyrelation ] ) @xmath78 where @xmath79 is the cubic counterpart of @xmath26 . let us rewrite equation ( [ relforn6 ] ) in the form @xmath80 the term inside the parenthesis on the right hand side vanishes identically in dimensions lower than five , since for @xmath81 @xmath82 however , in @xmath63 ( and greater than @xmath83 ) this gives a non - vanishing invariant as can be seen by expressing @xmath84 , @xmath85 and @xmath71 in terms of @xmath86 , thereby obtaining the expression ( [ definen6 ] ) . this imples that in @xmath63 , the basis is @xmath87 up to a total derivative . similar results have been found for quartic invariants ( see appendix b of reference @xcite ) i.e. , in dimensions @xmath88 , any invariant giving second order traced field equations can be expressed as a linear combination of the eight - dimensional euler density , and all the linearly independent weyl invariants , however , in @xmath89 there is an additional special invariant which completes the basis . based on these results , we present the following conjecture * conjecture : * _ ( i ) in dimensions @xmath90 , any curvature invariant of order @xmath0 , , we mean a scalar constructed out of @xmath0 curvature tensors without any derivatives acting on them . ] which gives second ( or less ) order traced field equations can be expressed as a linear combination of the @xmath1-dimensional euler density , the weyl invariants and a total derivative . _ _ ( ii ) in dimensions @xmath91 , any curvature invariant of order @xmath0 , which gives second order traced field equations can be expressed as a linear combination of the weyl invariants , in dimensions @xmath91 is one less than that in dimensions @xmath92 , due to the identity @xmath93}^{\ \ \ $ ] . ] a total derivative and a special invariant which can be obtained by evaluating _ @xmath94 _ in @xmath91 . _ we now show that @xmath95 evaluated in @xmath91 indeed gives second order traced field equations . first , consider the following invariant of order @xmath0 @xmath96 obviously , the above invariant vanishes in dimensions lower than @xmath1 . however , if one expands the weyl tensor in terms of the riemann tensor , then it can be factorized by @xmath97 . this can be seen as follows . consider the basis set of @xmath0-th order riemann invariants in arbitrary dimensions . in @xmath91 , not all elements of this set are linearly independent . in fact , the basis set contains one less invariant than in @xmath92 . this is because of the vanishing of the @xmath0-th order lovelock density . now , after the expanding in terms of the riemann tensors , the term ( [ termone ] ) will not contain any @xmath98 . so , this invariant can not vanish identically in @xmath91 unless it is factorized by @xmath97 . since one obtains another identity involving the riemann invariants which is obtained be contracting the ricci tensor with the @xmath99-th order lovelock equation . ] further expanding all the weyl tensors , one can convince one self that the dimensional dependence of the coefficient of the term with @xmath100 riemann tensors and one ricci tensor must be @xmath101 . we can now divide this factor out to get a non - vanishing invariant in @xmath91 . thus , we write the @xmath0th order generalization of @xmath26 by evaluating @xmath102 in @xmath91 . note that , by construction , the trace of the field equation arising from the above invariant is of second order in all dimensions . in this section , we present exact , static solutions for the theories defined previously . for simplicity we will first focus on the theories having fourth order field equations , defined by an arbitrary linear combination of the invariants @xmath84 and @xmath103 , defined respectively in equations ( [ w1 ] ) and ( [ w2 ] ) . the theory defined by the combination @xmath68 in the table i , has further interesting properties in five dimensions , which we discuss in detail in reference @xcite . finally we comment on the new three dimensional theory shown in table i , which possesses third order traced field equations . the class of metrics considered is:@xmath104 where @xmath105 is the line element of a @xmath106-dimensional compact , orientable euclidean manifold of constant curvature @xmath47 . for @xmath107 the manifold @xmath108is locally equivalent to the sphere @xmath109 , while for @xmath110 it reduces to a locally flat manifold . finally for @xmath111 the geometry of @xmath112 is given by the quotient @xmath113 , where @xmath114 is a freely acting , discrete subgroup of @xmath115 . after a coordinate transformation and a redefinition of the arbitrary functions , the line element ( [ anz2 ] ) takes the form@xmath116 \ . \label{anzreal}\ ] ] as shown below , this gauge choice is much more convenient for our purposes . here we will consider lagrangians of the form@xmath118 it has been proved in @xcite that , for the metric ( [ anzreal ] ) , the two invariants @xmath84 and @xmath85 defined in ( [ w1 ] ) and ( [ w2 ] ) respectively , are proportional . consequently , for a particular choice of @xmath119 , both the lagrangian @xmath45 and the field equations vanish identically . in such a situation any metric within the family ( [ anzreal ] ) is a solution of the system . hereafter we assume that @xmath120 and @xmath121 are generic . since , in six dimensions the gravity theories defined by combinations of @xmath84 and @xmath85 are invariant under weyl rescalings , let us concentrate on this case first . @xmath122 * * @xmath123 using weyl rescalings , one can gauge away the function @xmath124 in ( [ anzreal ] ) . then , one finds that the solution reduces to@xmath125 where @xmath126 and @xmath127 are constants , which are related by@xmath128{cc}k=\gamma\text { and } & c\left ( b-2ke\right ) = 0\\ \text{or } & \\ k=-\frac{1}{2}\gamma\text { and } & c=0\text { } \end{array } \right . \ .\ ] ] the ricci scalar of this geometry diverges at @xmath129 , while at @xmath130 the differential scalar @xmath131 diverges . for negative @xmath127 , the region @xmath132 must be removed from the spacetime , since otherwise the metric is imaginary , unless @xmath14 vanishes . for vanishing @xmath14 and @xmath133 , we obtain a conformally flat solution which may possess one or two horizons surrounding the singularity at the origin . for @xmath134 , the spacetime is not conformally flat and may also describe a black hole . let us note that , since in six dimensions the theory is conformally invariant , any metric conformally related to ( [ sol6 ] ) , will be a solution of the system . @xmath122 * * @xmath135 for dimensions other than six , the situation is different . since the theory defined by ( [ lagw1andw2 ] ) is not invariant under local weyl rescaling , one naively expects the factor @xmath136 in ( [ anzreal ] ) to be fixed by the field equations . however , this is not the case , and for arbitrary dimensions , the most general solution within the family ( [ anzreal ] ) , for the theory ( [ lagw1andw2 ] ) is@xmath137 \ , \label{conftempobh}\ ] ] @xmath138 being an arbitrary function . this can be easily seen as follows : since in dimensions other than six , the trace of the field equations for the theory ( [ lagw1andw2 ] ) is proportional to the lagrangian , the invariants @xmath67 evaluated on a solution should vanish . for the spacetime under consideration ( [ anzreal ] ) , it has been shown in @xcite , that all the components of the weyl tensor are proportional to a single function @xmath139 , such that the vanishing of @xmath139 implies that the metric should be conformally flat . since the restriction @xmath140 , transforms covariantly under weyl rescalings , it does not involve the function @xmath124 , and the mentioned restriction reduces to @xmath141 , which implies @xmath142 . then one is left with a conformally flat space , and since the field equations explicitly contain a weyl tensor , they are fulfilled for any arbitrary function @xmath143 provided @xmath144 . in four dimensions , for @xmath145 , this solution was found in @xcite , where it was mentioned that the corresponding model is the simplest one that does not admit schwazschild horizons . ] . for a smooth conformal factor @xmath124 , the spacetime ( [ conftempobh ] ) is conformally flat and it has been studied within the context of conformal gravity in four dimensions in @xcite for @xmath107 and in reference @xcite for arbitrary @xmath47 . the three dimensional cousin of this metric , in which @xmath146 is replaced by a single compact direction @xmath147 and @xmath47 is an integration constant , can be obtained through conformal gluing " of btz black holes , and is a solution of three dimensional conformal gravity @xcite . in @xcite this metric was obtained within the context of bht new massive gravity @xcite at the special point where the two possible maximally symmetric solutions of the theory coincide . in that case , @xmath47 is an arbitrary constant , the parameter @xmath148 plays the role of a gravitational hair , while @xmath149 is fixed in terms of the coupling constant . the metric ( [ conftempobh ] ) may possess an event and a cauchy horizon , depending on the zeros of @xmath150 . it generically possesses a curvature singularity located at @xmath151 , and depending on the sign of the integration constant @xmath149 , it represents an asymptotically locally ( a)ds or flat spacetime for ( @xmath152 ) @xmath153 or @xmath154 respectively . the details of the different causal structures are given in @xcite . as stated in table i , in five dimensions , there are two linearly independent invariants whose traced field equations are of second order . now , consider the following linear combination as the lagrangian @xmath155 evaluated on @xmath63 . this is the unique cubic invariant for which all the components of field equation , for static spherically symmetric spacetimes , are of second order . as shown in reference @xcite , the most general , non - degenerate spherically symmetric solution , is given by @xmath156 where @xmath14 is an integration constant and @xmath157 is the curvature of @xmath158 . let us note that this spacetime is not conformally flat ( it possesses a nonvanishing weyl tensor ) unless @xmath159 . for positive @xmath14 and @xmath111 , the metric ( [ sols ] ) represents a black hole possessing an event horizon located at located at @xmath160 . in this case the geometry of the horizon is given by @xmath161 , where @xmath114 is a freely acting discrete subgroup@xmath162of @xmath163 . the horizon hides the curvature singularity located at @xmath151 , and the asymptotic region ( @xmath164 ) is locally flat . further interesting features of this solution are discussed in @xcite . it is also interesting to note that among the class of theories considered here , this is the only one which does not admit an ( a)ds solution , in the same way as the pure @xmath165 combination of bht new massive gravity @xcite . as shown in table i , within the family considered , the only nontrivial theory having third order traced field equations in three dimensions can be written as @xmath73 , where @xmath166 is the cotton tensor . in this theory , the most general static , spherically symmetric solution is given by@xmath167 \ , \ ] ] where @xmath13 and @xmath168 are integration constants and @xmath124 is an arbitrary function . for smooth @xmath124 , as mentioned above , this metric has an event and a cauchy horizon , depending on the value of the parameters . it will be interesting to study the thermodynamical properties of the black hole within the context of ads / cft . in this work , we have classified all the six - derivative lagrangians of gravity for which the trace of the field equations have a reduced order . we have seen that , in dimensions greater or equal to six , when the trace of the field equations from a generic lagrangian is restricted to order two , we obtain an arbitrary linear combination of three linearly independent curvature invariants , namely , the six - dimensional euler density and the two independent weyl invariants . these invariants are no longer independent in lower dimensions due to the schouten identities . however , in five dimensions , there is a special invariant @xmath169 , which also gives field equations with second order trace . these invariants can be used to construct interesting cubic theories of gravity that can serve as toy models for higher derivative theories . we have also provided a conjecture regarding all the possible invariants of arbitrary order which gives second order traced field equations in any dimensions . in addition , we have obtained the general spherically symmetric solutions for a sub - class of such theories in arbitrary dimensions . our analysis shows that this is possible due to the reduced order of the trace of the field equations . when the order of the trace is restricted to three , we obtain two further invariants @xmath54 and @xmath55 in arbitrary dimensions . these two invariants are not globally independent in three and six dimensions . in six dimensions , they reduce to the third type - b anomaly , and @xmath55 in dimensions three and six . ] whereas in three dimensions they are equivalent to the square of the cotton tensor @xmath170 . we have further obtained a general spherically symmetric solution of this theory in three dimensions . _ _ we thank nicolas boulanger , hideki maeda , david tempo and steven willison , for useful comments . this research is partially funded by fondecyt grants number 3095018 , 11090281 , and by the conicyt grant southern theoretical physics laboratory act-91 . the centro de estudios cientficos ( cecs ) is funded by the chilean government through the millennium science initiative and the centers of excellence base financing program of conicyt . cecs is also supported by a group of private companies which at present includes antofagasta minerals , arauco , empresas cmpc , indura , naviera ultragas and telefnica del sur . cin is funded by conicyt and the gobierno regional de los ros . here , we prove a general property of the trace of the field equations for any lagrangian of the form @xmath171 with a fixed degree of differentiation @xmath172 . it has been shown in @xcite that the lagrangian can always be reexpressed as @xmath173\ ] ] the field equations obtained by variation of the action with respect to the metric takes the form @xmath174 where @xmath175 is the energy - momentum tensor of the matter fields . taking the trace of the field equations we obtain , @xmath176 now , if the lagrangian is of fixed @xmath172 , then it can be expressed as a linear combination of terms of the form @xmath177^{q_{1}}[r_{ .... }]^{q_{3}}\cdots\lbrack\underset{p\ times}{\underbrace{\nabla_{.}\cdots\nabla_{.}}}r_{ .... }]^{q_{p+2}},\ ] ] such that @xmath178 then , under the scaling @xmath179 , @xmath180 , the lagrangian scales as @xmath181 . however , @xmath182 can be expressed in terms of other @xmath183 s as @xmath184\nonumber\\ & = \frac{1}{2}[2(q_{2}+q_{3}+\cdots+q_{p+2})+(2q_{2}+3q_{3}+\cdots + ( p+2)q_{p+2})]\nonumber\\ & = ( q_{2}+q_{3}+\cdots+q_{p+2})+\frac{n}{2}.\end{aligned}\ ] ] this implies that the lagrangian scales as @xmath185 . now , one can apply euler s theorem of homogenous functions to write the following relation @xmath186 therefore , the trace of the field equations can be written in the form @xmath187 now , suppose that the trace of the field equations , from a lagrangian of @xmath9 , is of third order . then it must be some linear combination of the invariants @xmath188 . according to ( [ trace ] ) , in dimensions @xmath189 , the lagrangian must be proportional to this combination up to a total derivative . in dimensions @xmath190 , since the trace of the field equations is a total derivative , the only way the trace can be of at most third order is when it identically vanishes , which is the case for conformally invariant theories . in this appendix , we provide the details of the analysis for the classification presented in table i. the equations of motion for each term in the general lagrangian are listed below @xcite : @xmath191-\dfrac{1}{2}g_{ab}l_{10}\\ g_{11ab}^{(3 ) } & = 2g_{1ab}^{(3)}-4g_{2ab}^{(3)}+2g_{3ab}^{(3)}-4g_{5ab}^{(3)}+4g_{6ab}^{(3)}-g_{9ab}^{(3)}+4g_{10ab}^{(3)}\\ g_{12ab}^{(3 ) } & = g_{5ab}^{(3)}-g_{6ab}^{(3)}+\frac{1}{4}g_{9ab}^{(3)}\ .\label{gab8}\ ] ] therefore the trace of the full field equations can be expressed as @xmath192\end{aligned}\ ] ] now we impose the trace to be proportional to the lagrangian . this in turn requires the second term on the right hand side to vanish . to realize this , one has to choose the coefficients in such a way that , the symmetric tensor quadratic in curvature inside the operator @xmath193 is proportional to the gauss - bonnet field equations . this gives us a set of @xmath194 equations in @xmath195 variables and one arbitrary parameter @xmath46 . they are @xmath196 the matrix of linear equations has rank @xmath194 , which implies that the general solution can be written in terms of @xmath83 arbitrary parameters @xmath197 and @xmath198 . in @xmath199 , the solution is given as @xmath200 , \nonumber\\ & a^{2}=-\frac{1}{6}\left [ 8(2d-3)x+2(d-2)^{2}y-8(2d+3)z+(d^{2}-4)v+4(d-1)u\right ] \nonumber\\ & a^{3}=2(d-1)x-2z - u\nonumber\\ & a^{4}=x\nonumber\\ & a^{5}=-4x-(d-2)y+\frac{8(d-1)}{d-2}z-\frac{d}{2}v-2u\nonumber\\ & a^{6}=\frac{1}{3}\left [ 8x-2y-\frac{24}{d-2}z+v\right ] \nonumber\\ & a^{7}=y\nonumber\\ & a^{8}=-\frac{1 } { 24(d-1)^{2}}\left [ 8(d-1)y+16dz-(d^{2}-d+2)v-4(d-1)u\right ] \nonumber\\ & a^{9}=\frac{1}{4(d-1)(d-2)}\left [ 8z+(d-2)v\right ] \nonumber\\ & a^{10}=-\frac{4}{d-2}z - v\nonumber\\ & a^{11}=z\nonumber\\ & a^{12}=v.\end{aligned}\ ] ] in dimensions @xmath199 , one can apply the following transformation @xmath201 , \nonumber\label{reparam}\\ & y\rightarrow-{\frac{3}{(d-2)^{3}(d-1)}}\left [ 4(d-2)^{3}(d-1)a+8(2d-3)b+(d^{2}+d-4)c\right ] , \nonumber\\ & z\rightarrow d,\nonumber\\ & u\rightarrow6(d-5)a,\nonumber\\ & v\rightarrow24e.\end{aligned}\ ] ] such that @xmath202 where @xmath203 note that the determinant of the transformation ( [ reparam ] ) is @xmath204 . now in @xmath81 , one needs to solve the system of equations ( [ systemd ] ) for each value of @xmath34 separately . the lagrangians obtained are tabulated in table @xmath59 .

we classify all the six derivative lagrangians of gravity , whose traced field equations are of second or third order , in arbitrary dimensions . in the former case , the lagrangian in dimensions greater than six , reduces to an arbitrary linear combination of the six dimensional euler density and the two linearly independent cubic weyl invariants . in five dimensions , besides the independent cubic weyl invariant , we obtain an interesting cubic combination , whose field equations for static spherically symmetric spacetimes are of second order . in the later case , in arbitrary dimensions we obtain two combinations , which in dimension three , are equivalent to the complete contraction of two cotton tensors . moreover , we also recover all the conformal anomalies in six dimensions . finally , we present the general static , spherically symmetric solution for some of these lagrangians .

Sam Kim and Donald Walker tape up the windows Wednesday, Sept. 12, 2018 at Sam's Hair and Beauty Supply in Kinston, N.C., ahead of Hurricane Florence. (Janet S. Carter/Daily Free Press via AP) (Associated Press) Sam Kim and Donald Walker tape up the windows Wednesday, Sept. 12, 2018 at Sam's Hair and Beauty Supply in Kinston, N.C., ahead of Hurricane Florence. (Janet S. Carter/Daily Free Press via AP) (Associated Press) WILMINGTON, N.C. (AP) — The Latest on Hurricane Florence (all times local): 6 a.m. National Hurricane Center: Florence about to make landfall in N. Carolina causing life-threatening storm surge. The National Hurricane Center says Florence is about to make landfall in North Carolina bringing with it life-threatening storm surges and hurricane force winds. As of 6 a.m., Florence was 10 miles (20 kilometers) east of Wilmington, North Carolina. Its forward movement was 6 mph (9 kph). Hurricane-force winds extended 90 miles (150 kilometers) from its center, and tropical-storm-force winds up to 195 miles (315 kilometers). The Miami-based center says Florence is bringing "catastrophic" fresh water flooding over a wide area of the Carolinas. ___ 5:50 a.m. A North Carolina city says about 70 people have been rescued from a hotel whose structural integrity is being threatened by Hurricane Florence. The city of Jacksonville's statement says people have been moved to the city's public safety center as officials work to find a more permanent shelter. Officials found a basketball-sized hole in the hotel wall and other life-threatening damage, with some cinder blocks crumbling and parts of the roof collapsing. None of the people rescued were injured. ___ 5:00 a.m. The National Hurricane Center says Florence is about to make landfall in North Carolina bringing with it life-threatening storm surges and hurricane force winds. As of 5 a.m., Florence was 25 miles (55 kilometers) east of Wilmington, North Carolina. Its forward movement was 6 mph (9 kph). Hurricane-force winds extended 90 miles (150 kilometers) from its center, and tropical-storm-force winds up to 195 miles (315 kilometers). The Miami-based center had said earlier Friday Florence's arrival would come with "catastrophic" fresh water flooding over portions of the Carolinas. ___ 4:25 a.m. A North Carolina city situated between two rivers says it has around 150 people waiting to be rescued from rising flood waters from Hurricane Florence. WXII-TV reports the city of New Bern said Friday that two out-of-state FEMA teams were working on swift-water rescues and more teams were on the way. City spokeswoman Colleen Roberts tells WRAL-TV that 200 people have already been rescued. The National Hurricane Center says the Neuse River near the city is recording more than 10 feet (3.05 meters) of inundation. Roberts says the storm surge continues to increase as Florence passes over the area. The city warns that people "may need to move up to the second story" but tells them to stay put as "we are coming to get you." ___ 4 a.m. The National Hurricane Center says the eyewall of Hurricane Florence is beginning to reach the North Carolina coast. As of 4 a.m., Florence was 30 miles (45 kilometers) east of Wilmington, North Carolina. Its forward movement was 6 mph (9 kph). Hurricane-force winds extended 90 miles (150 kilometers) from its center, and tropical-storm-force winds up to 195 miles (315 kilometers). Forecasters said conditions will deteriorate as the storm pushes ashore early Friday near the North Carolina-South Carolina line and makes its way slowly inland. ___ 3:30 a.m. Life-threatening storm surge is being reported along the coast of the Carolinas. The National Hurricane Center said early Friday that a gauge in Emerald Isle, North Carolina, recently reported 6.3 feet (1.92 meters) of inundation. Emerald Isle is about 84 miles (135 kilometers) north of Wilmington. As of 3 a.m., Florence hadn't moved and was still centered about 35 miles (55 kilometers) east of Wilmington, North Carolina. Its forward movement increased slightly to 6 mph (9 kph). Hurricane-force winds extended 90 miles (150 kilometers) from its center, and tropical-storm-force winds up to 195 miles (315 kilometers). Forecasters say the combination of a life-threatening storm surge and the tide will cause normally dry areas near the coast to be flooded by rising waters moving inland from the shoreline. ___ 2 a.m. The National Hurricane Center says that "catastrophic" freshwater flooding is expected over portions of the Carolinas as Hurricane Florence inches closer to the U.S. East Coast. The now Category 1 storm's intensity diminished as it neared land, with winds dropping to 90 mph (135 kph) by nightfall. But that, combined with the storm's slowing forward movement and heavy rains, had Gov. Roy Cooper warning of an impending disaster. As of 2 a.m., Florence was centered about 35 miles (55 kilometers) east of Wilmington, North Carolina. Its forward movement increased slightly to 6 mph (9 kph). Hurricane-force winds extended 90 miles (150 kilometers) from its center, and tropical-storm-force winds up to 195 miles (315 kilometers). Forecasters say the combination of a life-threatening storm surge and the tide will cause normally dry areas near the coast to be flooded by rising waters moving inland from the shoreline. ___ 11 p.m. Hurricane Florence already has inundated coastal streets with ocean water and left tens of thousands without power, and more is to come. Screaming winds bent trees and raindrops flew sideways as Florence's leading edge battered the Carolina coast Thursday. The storm's intensity diminished as it neared land, with winds dropping to 90 mph (135 kph) by nightfall. But that, combined with the storm's slowing forward movement and heavy rains, had Gov. Roy Cooper warning of an impending disaster. Forecasters said Florence's surge could cover all but a sliver of the Carolina coast under as much as 11 feet (3.4 meters) of ocean water, and days of downpours could unload more than 3 feet (0.9 meters) of rain, touching off severe flooding. ||||| These crawls are part of an effort to archive pages as they are created and archive the pages that they refer to. That way, as the pages that are referenced are changed or taken from the web, a link to the version that was live when the page was written will be preserved.Then the Internet Archive hopes that references to these archived pages will be put in place of a link that would be otherwise be broken, or a companion link to allow people to see what was originally intended by a page's authors.The goal is to fix all broken links on the web . Crawls of supported "No More 404" sites. ||||| Media playback is unsupported on your device Media caption Gusts & floods: the impact of the storm Five people have been killed as Florence mauls the US East Coast, knocking out power for hundreds of thousands of homes and downing trees. The weather event has been downgraded from a hurricane to a tropical storm but forecasters still warn of life-threatening storm surges. Winds of up to 70mph (110km/h) are also expected for several days as the weather system slowly grinds over. Evacuation warnings have been in place for 1.7 million people in the area. All five deaths were reported in North Carolina: A mother and her infant were killed in Wilmington when a tree fell on their home on Friday. Officials say the child's father was also transported to hospital for injuries. Image copyright Reuters Image caption Trees were downed across North Carolina amid high winds on Thursday and Friday Two men in their 70s were killed in Lenoir County. One was killed when connecting an electrical generator, and family members say another man was killed in a wind-related death when checking on dogs outside his property A woman died from cardiac arrest in the town of Hampstead after emergency responders had their route to her blocked by downed trees, a county official said What is the latest on the storm? The storm originally made landfall at Wrightsville Beach, North Carolina, on Friday morning as a category one hurricane. Image copyright Getty Images Image caption Volunteers are helping to rescue residents from flooded homes US officials say it remains extremely dangerous because of the risks posed by catastrophic flooding. Forecasters say the storm surge, together with up to 3.5ft (1m) of rain over the next few days, could spawn a slow-motion disaster. Some parts of North Carolina have already seen surges as high as 10ft in places. Media playback is unsupported on your device Media caption The Weather Channel uses virtual reality to show deadly storm surge Governor Cooper said the hurricane was likely to "continue its violent grind across the state for days". Forecasters say it is now moving into eastern South Carolina, crawling along at just 3mph. It is expected to dump 18 trillion gallons of rainwater on US soil, meteorologist Ryan Maue tweeted. Almost 800,000 people are reported to be without power already in North Carolina, and officials have warned restoring electricity could take days or even weeks. How are residents coping? More than 20,000 residents have packed into North Carolina emergency shelters, and officials have told those still in the storm's path to stay in place. In Jacksonville, North Carolina, officials had rescued more than 60 people overnight from a hotel that was collapsing in the storm. Parts of New Bern, North Carolina, which is home to 30,000 people, were 10ft underwater on Friday. At least 200 householders in the riverfront city had to be plucked to safety by authorities. Ask a question Local resident Peggy Perry told CNN she was "stuck in the attic" along with three relatives. "In a matter of seconds, my house was flooded up to the waist, and now it is to the chest," she added. Officials have warned people against entering attics, so as to avoid drowning, unless they have a means to cut through to the roof. The White House said on Friday that President Donald Trump would travel to the region next week unless his trip would disrupt clean-up and rescue efforts. ||||| Hundreds of people were rescued from rising floodwaters in Eastern North Carolina through Friday. In Craven County, emergency crews reported rescuing multiple residents from Hurricane Florence floodwaters through Friday afternoon, despite a mandatory evacuation. The county has responded to nearly 200 calls for water rescues since the severe flooding started with those calls representing 488 people who need help, Assistant County Manager Gene Hodges said Friday afternoon. The water rescues are continuing, he said. “It’s still dumping water right now,” Hodges said. Be the first to know. No one covers what is happening in our community better than we do. And with a digital subscription, you'll never miss a local story. SIGN ME UP! There’s no telling now how long the emergency will last, he said, and the county is hoping that the state and federal government will bring helicopters to help with the rescues. There have been no fatalities, he said. About 40 miles north, water rescues in Beaufort County and its capital, Washington, started late Thursday night and hit a peak after midnight, said County Manager Brian Alligood. About 300 people had been rescued from flood waters by Friday afternoon, he said. Storm surge was the main contributor to the flooding, Alligood said. The Pamlico River cuts through the county. “We have pretty high winds pushing water in,” Alligood said. Local volunteer departments, state agencies, the National Guard and FEMA all contributed to the water rescues, he said. Alligood hoped the worst was over. “It has slowed,” he said. “We have started to see the water recede. The winds are starting to fall.” Craven County has five swift-water rescue teams and is using boats and vehicles that can motor through high water. The Cajun Navy, Louisiana volunteers, are helping, Hodges said. SHARE COPY LINK A look at New Bern, NC as the storm surge from Hurricane Florence pushes the Neuse and Trent Rivers into the streets of the town on Friday, Sept. 14, 2018. New Bern, which sits at the intersection of the Neuse and Trent rivers, has been placed under a 24-hour curfew until further notice, city spokeswoman Colleen Roberts said in an interview just before 7 a.m. The city is not turning away anyone who offers help, she said. Individuals and groups who want to help should meet at the New Bern Fire Department, located at 1401 Neuse Blvd., Roberts said. The city said on its website Friday afternoon that preliminary estimates show at least 4,325 homes and 300 businesses are damaged and railroad tracks have been washed away. The rescues began around 4 p.m. Thursday, Craven County spokeswoman Amber Parker said. Parker said emergency crews were doing their best to reach areas that were “just too dangerous” because of extreme flooding, storm surges, and winds of 40 mph to 50 mph. Currently ~150 awaiting rescue in New Bern. We have 2 out-of-state FEMA teams here for swift water rescue. More are on the way to help us. WE ARE COMING TO GET YOU. You may need to move up to the second story, or to your attic, but WE ARE COMING TO GET YOU. #FlorenceNC — City of New Bern (@CityofNewBern) September 14, 2018 Most of the swift-water rescues were being made in areas along the Neuse River, including portions of New Bern, Fairfield Harbour, Adams Creek and Township 7, Parker said. Local officials were seeing at least 8 inches of water across Adams Creek Road by 11 a.m. Thursday, Parker said. Water levels by early Friday morning already had exceeded what the area got from Hurricane Irene in 2011, she said. The National Hurricane Center was reporting over 10 feet of inundation in New Bern. Parker said the water in places had topped mailboxes and filled the first and second floors of homes in low-lying places. “This storm has been hovering over us for a while, and we expect it to continue to hover over us,” she said. “Lots of water, lots of wind, lots of storm surge.” SHARE COPY LINK ABC11 video shows rising water in New Bern, NC as Hurricane florence moves inland overnight. SHARE COPY LINK Rivers in New Bern overflow ahead of Hurricane Florence. Residents reached out for help through the night by phone and on social media. Tom Ballance, who lives about 250 feet uphill from the Neuse River, told The Weather Channel in a 5:30 a.m. phone interview that he was able to get to the second floor of his house “so I’m not gonna die.” The water came up quick, Ballance said. He’s lived in New Bern since 2003 and has stayed put in every hurricane, he said. His neighbors also stayed, he said. “Nobody was expecting this, nobody,” Ballance told The Weather Channel. “We were fools.” Even as a little boy, when Hurricane Hazel hit in 1954, it was not that bad, he said. “I have a business on Middle Street and in all the years, nothing’s ever flooded Middle Street,” Ballance said. “That’s the one street. And even though I haven’t made it downtown I’ve been listening to the police radio and it sounds like Middle Street’s underwater. So it’s a double whammy here.” This is Breeanna Best Friend! I’m actively tweeting on her account bc I have direct contact with her. Her cell phone has died. They’re alive and currently still stuck in the attic. 611 Watson Ave, New Bern NC — bree (@Breeanna_xoxo) September 14, 2018 Help have rescued them! Thanks for all your help truly couldn’t have done it without you #NewBernStrong — bree (@Breeanna_xoxo) September 14, 2018 Parker noted that 839 people had sought to stay at one of five inland shelters in Craven County. Just more than a hundred people had been evacuated to a shelter in Sanford, and others were directed to a mega-shelter at the Lawrence Joel Veterans Memorial Coliseum in Winston-Salem, she said. “The most important thing we need right now is for people to shelter in place and stay off the roads, to watch out for dangerous conditions, including downed power lines, and flooding water,” she said. “If water gets into people’s homes, we need them to call our emergency management line at 252-636-6608.” A map sent out by the city of New Bern showed just how widespread the flooding had become. The North Carolina Department of Transportation’s Ferry Division reported a 10-foot high storm surge above the normal water level at the Cherry Branch Ferry Terminal in Havelock, which is located in Craven County. “Interactive map showing the high water areas in New Bern so far. Unfortunately this will get worse,” the city’s account tweeted around 9 p.m. The map showed the Trent River had overflowed as well. The Neuse flows into the Pamlico Sound, which is separated from the Atlantic by the Outer Banks. The city said more than 17,000 customers were without power Thursday night. WCTI, New Bern’s ABC affiliate, was forced to evacuate its building Thursday night, a development it noted while giving updates on the weather. Outlaw said the winds had reached 50 mph to 60 mph as rescue crews attempted to retrieve people stranded in their houses, on rooftops and in cars. They will begin to assess the damage once the storm subsides, he said. “We’re not going to be satisfied until the last resident is rescued and in a shelter, and then we can assess damages and go from there,” Outlaw said. “We’re a resilient community, we work well together, we’ll get through this.” ||||| Tropical Storm Florence, 'An Uninvited Brute,' Brings Floods, And At Least 5 Deaths Hide caption Overflow from the surge of the Cape Fear River along with rain floods downtown Wilmington, N.C. on Friday. Florence's winds have dropped, reducing the hurricane to a tropical storm. Previous Next Phyllis B. Dooney for NPR Hide caption Indiana Task Force One tends to a house on Weaver Street in Wilmington. The slow-moving giant still poses danger to people in North and South Carolina, as its storm surge and intense rains bring high floodwaters to towns both on the coast and inland. Previous Next Phyllis B. Dooney for NPR Hide caption The hurricane has moved at only 3 to 6 mph on Friday, increasing the effect of its torrential rains. Previous Next Phyllis B. Dooney for NPR Hide caption A fallen tree shows the force of Florence's wind gusts. Florence has dumped more than a foot of rainwater on parts of southeastern North Carolina since making landfall near Wrightsville Beach at 7:15 a.m. ET on Friday. Previous Next Phyllis B. Dooney for NPR Hide caption Abbie Hohl watches Hurricane Florence outside a window at Hotel Ballast in Wilmington, N.C., on Friday. The Hohl family lives a half-mile from the hotel but was concerned about flooding from the Cape Fear River. Previous Next Phyllis B. Dooney for NPR Hide caption Reduced winds and rains gave Hopper Baumgardner (left) a chance to walk his dog, Dottie. He was joined by sister Maysie and father Matt at the Hotel Ballast in Wilmington, N.C., on Friday. Previous Next Phyllis B. Dooney for NPR Hide caption Allison and Mark Potter take their dogs out for a walk. The Potters live in Wilmington and were concerned about old trees falling in the storm. Previous Next Phyllis B. Dooney for NPR Hide caption Ray Ryan gets some fresh air outside the hotel, where he and his wife, Ruth, went after being forced to evacuate their beach home. Previous Next Phyllis B. Dooney for NPR Hide caption Marc Hohl (left) plays checkers with his father Greg as his sisters Abbie (center) and Ava watch with their grandmother Lola Grio in their hotel room. Previous Next Phyllis B. Dooney for NPR Hide caption George and Zelda Allen find a quiet corner in the Hotel Ballast. The Allens live in Hampstead, northeast of Wilmington, and checked in on Wednesday to seek refuge from the storm. They stayed home during Hurricane Hugo and felt it was too "nerve-wracking" to do it again. Previous Next Phyllis B. Dooney for NPR 1 of 10 i View slideshow Updated at 5:20 a.m. ET Saturday Tropical Storm Florence is still a slow-moving giant that poses danger to people in North and South Carolina, as its storm surge and intense rains bring high floodwaters to towns both on the coast and inland. The storm has been linked to at least five deaths, a toll that is expected to climb. At 5 a.m. Saturday, the storm was moving toward the west-southwest at about 5 mph and sustained winds had decreased to around 50 mph. Water levels could reach between 2 and 5 feet above ground in parts of North and South Carolina, the National Weather Service said. "This rainfall will continue to produce catastrophic flash flooding and prolonged significant river flooding," the agency said Saturday morning. The storm's center was located about 35 miles west of Myrtle Beach, S.C., and 45 miles south-southeast of Florence, S.C. Florence is expected to turn toward the north and go through the Ohio Valley by Monday, according to the weather service. On Friday, a woman and infant were killed in Wilmington, N.C., when a tree fell on their home, according to the local police department. Another victim of the storm — a 78-year-old man — died in North Carolina while plugging in a generator, the state's governor says. A second man, 77, in Lenoir County, appears to have been killed by a gust of wind that knocked him to the ground when he was checking on his hunting dogs. In Hampstead, N.C., a woman had a heart attack and debris in the roads prevented emergency responders from reaching her to provide care, a dispatcher confirms to member station WUNC. Florence has dumped at least 16 inches of rain over southeastern North Carolina since making landfall near Wrightsville Beach at 7:15 a.m. ET. The storm moved at only 3 to 6 mph on Friday, increasing the effect of its torrential rains. "Florence is an uninvited brute who doesn't want to leave," North Carolina Gov. Roy Cooper told NPR's Morning Edition Friday. "We know we're in for a long haul here," Cooper said of predictions that the storm will linger all weekend. "But I think we're ready." White House press secretary Sarah Sanders said Friday that President Trump "is expected to travel to areas affected by the storm early to middle of next week, once it is determined his travel will not disrupt any rescue or recovery efforts." In New Bern, N.C., rescuers have pulled more than 100 people from their homes to safer ground. Dana Outlaw, the town's mayor, told NPR's All Things Considered in the late afternoon that there had been 1,200 requests to 911 over the previous 12 hours. Enlarge this image toggle caption Chris Seward/AP Chris Seward/AP New Bern sits between the Neuse and Trent rivers, which quickly overflowed even before Florence made landfall. On Friday morning, nearly every street in the downtown area was flooded, sending some of the signature bear statues that are normally bolted to the ground floating down city streets. Outlaw detailed the city's efforts to help residents evacuate before the storm struck New Bern. "We went door to door. Our policemen, our firemen drove firetrucks with PA systems" warning people about the imminent danger of the storm, he said. The city also sent out recreation department buses "and urged residents to get in the bus and go to a shelter." But despite mandatory evacuation orders, many residents stayed home. "New Bern has gotten a free pass quite a few times that what we thought was going to be a terrible storm did not happen. This time it did. Unfortunately, this is kind of a wake-up call that these things do happen," Outlaw told NPR. Along the coast, floodwaters have been hitting inland towns near rivers that normally discharge into the ocean. But with a storm surge putting pressure on water to head back inland and heavy rains swelling those rivers, widespread flooding is the result. As Cooper said, "There's nowhere for the water to go." Record water levels occurred at Wrightsville Beach, said National Oceanic and Atmospheric Administration's Ocean Service, which reported the ocean "reached 4.11 ft above high tide, breaking a record set by Hurricane Joaquin in 2015 by more than a foot." Multiple areas in North Carolina are expected to reach record high-water levels, forecasters say, and floodwaters could linger at above-average levels for several weeks. Tropical Storm Florence, 'An Uninvited Brute,' Brings Floods, And At Least 5 Deaths Listen · 5:09 5:09 In the evening, North Carolina Emergency Management instructed people to stay off the roads. "It's starting to get dark, and # HurricaneFlorence is still causing power outages, heavy rainfall and hazardous wind conditions. If possible, avoid venturing out of your home. Flooded roads are deadly. Never drive past barricades or through standing water," the agency tweeted. The agency also warned private well users to beware of the possibility of contaminated water, and warned people to wait until the flooding is over to restart their pumps. Some evacuation shelters have been forced to close after losing power, the University of North Carolina-Chapel Hill reported. Campus administration is collaborating with the Red Cross and Gov. Cooper's office to establish new shelters to house people displaced by the hurricane. The No. 1 mission right now, Cooper said, is to save lives. "We've rescued over 100 people in New Bern, N.C.; people from Jacksonville, N.C., had to rescued from a hotel," Cooper said, describing efforts to save people in towns north of Wilmington where high floods have already hit. "We've got almost 20,000 people in 157 shelters," Cooper said. Enlarge this image toggle caption Chip Somodevilla/Getty Images Chip Somodevilla/Getty Images The storm has caused more than 770,000 power outages in North Carolina, with more than 150,000 reported in South Carolina, according to website poweroutage.us. As the power outages spread, federal authorities are warning of the risks of carbon monoxide poisoning, emphasizing that generators and grills should never be used indoors. Florence's eyewall reached shore near Wilmington, N.C., just before 6 a.m. ET Friday; more than an hour later, the National Hurricane Center announced, it had "finally" made landfall near Wrightsville Beach. YouTube The news came more than 10 hours after the storm began punishing the coastal area with sustained hurricane-force winds, the hurricane center said. In New Bern, Sarah Risty-Davis is one of the residents who opted not to follow a mandatory evacuation order that was issued three days ago. "We had pretty high floodwaters up until the early morning hours," Risty-Davis tells NPR's Morning Edition. "I'm not sure if it's a shift in the wind or low tide — but the water has miraculously disappeared." There's still a threat from rising tides, Risty-Davis says. And she has seen reports of people fleeing to rooftops to escape high floodwaters. Still, she said, "I think we're going to stay put," noting her neighborhood's past success in avoiding power outages and flooding. The storm surge that has hit New Bern is "approximately 2 feet higher" now than it was during Hurricane Irene seven years ago, the National Weather Service office in Morehead City says. The agency adds that people trapped by flooding should "never enter attics or crawl spaces." At the Wilmington airport, the wind was measured at 105 mph — the highest since 1958, Cooper said. Enlarge this image toggle caption NOAA/NWS, Esri, HERE, Garmin, Earthstar Geographics NOAA/NWS, Esri, HERE, Garmin, Earthstar Geographics Florence arrived at the Carolina coast as a Category 1 storm, its 90-mph winds far slower than the fearsome 150 mph of just a few days ago. "Rapid weakening [is] forecast over the weekend," the hurricane center said. But forecasters say Florence's biggest threat, as with all hurricanes, lies in its water: a storm surge of up to 11 feet and rainfall that will trigger catastrophic flooding. "A USGS gauge in Emerald Isle, N.C., recently recorded 6.1 feet above normal water levels," the National Hurricane Center said of the storm surge early Friday. As it moves inland, the storm is expected to bring its high winds and intense rain bands across the southeastern corner of North Carolina and a large chunk of South Carolina. Rainfall of up to 20 to 40 inches could fall over the next several days in some areas, forecasters say. Enlarge this image toggle caption NOAA/STAR NOAA/STAR To prepare for this storm, businesses boarded up, and supplies were readied for what is expected to be a large-scale relief operation. States of emergency were declared in both North and South Carolina. Thousands of soldiers from their National Guard forces have been mobilized. This landfall has been a long time coming: The hurricane arrived more than two weeks after the National Hurricane Center issued its first advisory for the storm. That advisory came out on Aug. 30, when Florence was developing near the Cabo Verde Islands across the Atlantic. Its designation then was "potential tropical cyclone six."

– Newly downgraded to a Category 1 storm, Hurricane Florence was already wreaking havoc on North Carolina as the gigantic storm crept slowly ashore early Friday, with hundreds of people already rescued. The storm is packing winds of 90mph—much lower than once feared—and is moving at 6mph, reports NPR. Authorities stress that even with the lower wind speed, the storm is extremely dangerous and could still kill "a lot of people," with inland flooding posing the biggest risk, the BBC reports. The National Hurricane Center said Florence made landfall at Wrightsville Beach, NC, about 7:45am. Authorities say Florence is bringing "catastrophic" flooding to a large area of the Carolinas, and at least six tornadoes have been spotted in eastern North Carolina. the AP reports. The Guardian reports that North Carolina's Department of Public Safety says more than 320,000 homes in the state are without power. The coastal city of New Bern, which sits at the intersection of two rivers, tweeted that 150 people were awaiting rescue from out-of-state FEMA teams, the News & Observer reports. Mayor Dana Outlaw said around 200 people had been rescued earlier. He could not confirm whether there were fatalities. Authorities in Jacksonville, around 30 miles south of New Bern, say 70 people had to be rescued from a hotel that was in danger of collapsing.