In humans, brain-derived neurotrophic factor (BDNF) has been shown to play a pivotal role in neurocognition, and its gene contains a functional polymorphism  that may explain individual differences in brain volume and memory-related activity.n = 45), Val/Met (n = 86) and Val/Val (n = 55). Seed-based analysis was performed focusing on four SCN networks. Neurobehavioral scores served as the major outcome factor.In this study, we enrolled 186 Alzheimer's disease (AD) patients who underwent 3D T1 magnetic resonance imaging, and explored the gray matter (GM) structural covariance networks (SCN). The patients were divided into three groups according to their genotype: Met/Met (Only peak cluster volumes of default mode medial temporal lobe network showed significant genotype interactions, of which the interconnected peak clusters showed dose-dependent genotype effects. There were also significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex.These findings support the hypothesis that BDNF rs6265 polymorphisms modulate entorhinal cortex-interconnected clusters and the valine allele was associated with stronger structural covariance patterns that determined the cognitive outcomes. Neurotrophins are a group of molecules which play a key role in regulating neural survival, development and maintenance. The most abundant neurotrophic factor is brain-derived neurotrophic factor (BDNF) , 2 and hvs. Val/Val), recessive  and additive  carriers. Another meta-analysis reported that the Met66 allele conferred susceptibility to AD in women but not in men [In humans, the BDNF gene has been mapped to chromosome 11p14.1. A common single nucleotide polymorphisms (SNP) consisting of a missense change of the coding exon at position 66  has been shown to produce non-conservative amino acid changes . The Met allele carriers have been shown to have poorer episodic memory, and this may be reflected in lower activities of BDNF with impaired neuronal processing and trafficking . A recenThe influence of BDNF polymorphisms on human cognition has been linked with its impact on changes in brain structure. However, whether the Met allele leads to worse outcomes is controversial. Smaller brain volumes have been reported in Met carriers in the hippocampal and dorsolateral prefrontal areas , hippocaRecent research has suggested that highly related regions show covariance in morphometric characteristics, so called structural covariance. Structural covariance networks (SCNs) can be used to test the influence of the genotype with careful control of other factors. Three SCNs have been reported to be relevant to patients with AD: default mode network (DMN) –22, saliThe potential mechanisms of genetic-based neurobiology are still under investigation, however a number of studies have highlighted how genetic variations –30, epigThe demographic characteristics and neuropsychiatric test results of the three genotype groups are listed in Table Among the three BDNF genotypes and four seed regions Figure , there wIn the entorhinal seed-based DMN networks, the Met/Met homozygotes showed no clusters with a voxel size > 100 , while tFor the frontoinsular seed, the Met/Met homozygotes   Figure .The clinical significance of each peak cluster linking to the entorhinal seed showing a genotype effect was evaluated by correlation analysis Figure . Among tvia modulation of the strength of structural covariance between spatially scattered but functionally coherent regions rather than having a direct impact on the seed or peak cluster volume. Third, while the volumes of the seed and peak clusters of the DMN medial temporal subsystem correlated significantly with cognitive test scores, only the orbitofrontal peak cluster volume predicted cognitive test scores in the three BDNF genotype groups.The results of this study provide data on the network-specific genetic influence of BDNF Val66Met in the early stages of AD. There were three main findings. First, the seed-based SCN pattern validated the hypothesis that the BDNF functional polymorphism targets large-scale brain networks rather than selectively in a focal brain region. Second, a genetic dosage effect of the BDNF Val allele was found only in the DMN medial temporal subsystem with cortical hubs consisting of entorhinal, PCC and prefrontal regions. The presence of the genetic dosage effect suggests that the mechanism related to this functional polymorphism may be via synaptic connections, and BDNF has been reported to attenuate the neurotoxicity [The salient episodic memory impairment in AD has been reported to be strongly associated with hippocampal/entorhinal volume , 36, whitoxicity , 8. The While our results suggest that there was no direct effect of BDNF genotype on hippocampal or entorhinal volume, we found that the BDNF genotype may specifically modulate the DMN medial temporal lobe subsystem structural covariance patterns, of which the increased correlations between entorhinal seed and peak clusters demonstrated the genetic dosage effect of the Val allele. While early amyloid burden or GM atrophy has been reported to involve the DMN medial temporal lobe subsystem in the early stage of AD , lower BThese alterations can be caused by several factors, and the disease- and genetic-related changes in structural covariance can be difficult to interpret. As the cortical hubs of the DMN are highly functionally anchored, the spatially scattered DMN-related clusters that show structural covariance may validate the notion that BDNF Val66Met polymorphisms only affect activity-dependent pathways . AttenuaIn contrast, stronger correlations modulated by increased BDNF activity may suggest greater regional connectivity and synchronized GM loss in regions targeted by the pathological process. Although the pair-wise correlations did not necessarily influence the global organizational properties of structural covariance, as shown by the lack of differences in regional volumes among genotypes, the significant correlations between cognitive outcomes and seed  volumes within the DMN hubs still address the pathological-genetic alterations of local clustering. The findings of the DMN still reflect segregated and less integrated components in AD networks that could predict cognitive outcomes.Among the four seed-based SCNs, the Val  carriers had more extended voxels of structural covariance in the DMN medial temporal lobe subsystem. In contrast, the Met  carriers showed stronger structural associations in the DMN midline core system, salience and executive control networks. As BDNF activity was different among the genotypes, the SCN patterns may reflect different strengths of structural covariance between cortical GM and seed region. The SCN patterns may therefore provide evidence that BDNF genotypes target specific large-scale brain networks in patients with AD that may modulate distinct degenerative patterns. In normal human cortical morphology, Met carriers have been reported to have smaller hippocampal and prefrontal cortical volumes , 43. HowStudies on the genetic risk of developing AD , 11 or tvia BDNF gene expression [Possible explanations why the BDNF genotypes showed inconsistent results on brain structures may be related to epistasis , variabipression , 53. In pression .As such,Despite our observations that BDNF Val66Met polymorphisms may affect structural covariance patterns, there were no significant differences in cognitive measurements in our genotype groups. On the basis of the none-significance in the PCC and dorsolateral prefrontal seed volumes among the three genotype groups, the volumes of both seeds were still significantly correlated with the cognitive scores. The finding supports the hypothesis that brain structure may be considered to be an endophenotype that is more sensitive to a genetic effect than behavioral level. The PCC is an early target of amyloid deposition in both patients with AD  and in cAn important limitation of this study is that we did not include a control group. The effects of BDNF Val66Met genetic variations on regional GM volume and functional state in healthy subjects have been reported , 47, 50.In summary, our structural covariance analysis supports the role of BDNF functional polymorphisms in modulating the GM degenerative scaffold in the early stages of AD. Our results suggest that the Val66Met functional polymorphism carries different weightings on the DMN, salience and executive control networks. Within the DMN medial temporal lobe subsystem, the genetic dosage effect of the Val allele on entorhinal seed-based SCN was validated by correlation strength gradients between seed and peak clusters, thus supporting the importance of BDNF in AD degenerative network.This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital. The study participants were treated at the Cognition and Aging Center, Department of General Neurology, Kaohsiung Chang Gung Memorial Hospital. A total of 186 subjects  were included after the consensus of a panel composed of neurologists, neuropsychologists, neuroradiologists and experts in nuclear medicine . AD was n = 45), Met/Val (n = 86) and Val/Val homozygotes (n = 55). To avoid possible confounding, the three genotype groups were matched for gender, age, educational level, clinical dementia rating [The patients were classified into three groups based on the genotype: Met/Met homozygotes , followed by genotyping for BDNF Val66Met polymorphisms using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. Genotyping was conducted with the operator blinded to the clinical data. The apolipoprotein E4 genotype was also determined using a PCR-restriction fragment length polymorphism assay and restriction enzyme HhaI .It has been reported that factors such as oxidative stress, deregulated neuroinflammation and an elevated blood sugar level are related to changes in BDNF expression –69. We i3.MR images were acquired using a 3.0T MRI scanner . Structural images were acquired for structural covariance analysis using the following protocols: a T1-weighted, inversion-recovery-prepared, three-dimensional, gradient-recalled acquisition in a steady-state sequence with a repetition time/echo time/inversion time of 8,600 ms/minimal/450 ms, a 256 × 256 mm field of view, and a 1-mm slice sagittal thickness with a resolution of 0.5 × 0.5 × 1 mmhttp://www.fil.ion.ucl.ac.uk/spm/). The T1 images were reoriented, realigned, and normalized using the standard Montreal Neurological Institute (MNI) space. The images were then segmented into GM and white matter. Related tissue segments were used to create a custom template using the diffeomorphic anatomical registration using exponentiated lie algebra (DARTEL) approach. The DARTEL approach is one of the highest ranking registration methods in patients with AD [p < 0.05, corrected for a false discovery rate (FDR) with a cluster size > 100 voxels.Image preprocessing and statistical analysis were performed using SPM8 . Statistical significance was set at p < 0.05.Clinical and laboratory data were expressed as mean ± standard deviation. Analysis of variance with Bonferroni correction for multiple comparisons was used to compare levels of cerebrovascular risk biomarkers or continuous variables among the Val/Val homozygotes, and Met/Val and Met/Met homozygotes. All statistical analyses were conducted using SPSS software  were extracted from the 186 preprocessed images. The seed ROI included the right entorhinal cortex , left posterior cingulate cortex , right frontoinsular cortex , and right dorsolateral prefrontal cortex  Figure . Accordip < 0.01, corrected for FDR with a cluster size > 100 voxels.From the modified GM images, the GM volumes of a 4-mm radius sphere around the seed ROI coordinates were calculated, followed by four separate correlation analyses using the extracted GM volumes as the covariates of interest. The three BDNF genotype groups were modeled separately. For each BDNF genotype group, specific contrasts were set to identify voxels that showed positive correlations for each seed ROI. The results reflected the SCNs of each ROI and the threshold was set at in vivo study in which the expression of BDNF was found to be highest in Val/Val, followed by Val/Met and Met/Met [p < 0.001 (uncorrected) with a cluster size > 100 voxels. In addition, for the peak clusters showing significant between-group differences, a 4-mm radius sphere was placed on the peak voxel, and the GM volumes were then calculated for regression analysis. The seed ROI was considered to be the predictive variable for the extracted SCN peak voxel, and the threshold was set at p < 0.05 with multiple corrections. To evaluate the clinical significance of the seed or identified peak voxel, we used a linear regression model with the cognitive test scores serving as the dependent variable. The threshold was set at p < 0.05 with multiple corrections.In addition, to investigate how genetic variance may interfere with structural covariance patterns, voxels showing significant differences in the regression slopes in each seed-peak cluster correlations were compared, pointing to possible interactions between Val/Val > Met/Met or Val/Met > Met/Met. The genetic dosage model was based on an  Met/Met . Specifi


This paper addresses continuous fusion frames and fusion pairs which are extensions of discrete fusion frames and continuous frames. The study of equalities and inequalities for various frames has seen great achievements. In this paper, using operator methods we establish some new inequalities for continuous fusion frames and fusion pairs. Our results extend and improve ones obtained by Balan, Casazza and Găvruţa. The notion of frame in a general Hilbert space was first introduced by Duffin and Schaeffer in 1952 to study nonharmonic Fourier series . We say that H if there exist constants F(x). The numbers A, B are called lower and upper frame bounds for the continuous fusion frame, respectively. If only the right-hand inequality of ifthen(ii)ifthenWe only prove (i), and (ii) can be proved similarly. It is easy to check thatIfare bounded, self-adjoint linear operator satisfyingthen for allwe have be a Parseval continuous fusion frame forH. Then forandwe haveH, then H and Suppose that mentclass2pt{minimObserve that we have  by 13)  12\documNext we prove . ObserveF, v) is a H. As an immediate consequence of Theorem 3.1, we haveObserve that Let  be atight continuous fusion frame forH. Then forandwe haveH and Next we will give a equality for tight continuous fusion frames. To do so, we first define two operators Letbe a continuous Bessel fusion mapping onHwith boundB, thenare bounded linear operators, andWe only treat Letbe atight continuous fusion frame forH. Then forandwe havewhereis the conjugate ofH, that is By Proposition As an immediate consequence of Theorem Letbe atight continuous fusion frame forH, withbeing real. Then forwe haveThis section focuses on fusion pairs. We begin with the following lemma which can be proved similarly to Proposition Letandbe continuous Bessel fusion mappings onH, FandGbe a fusion pair, andDefine the operatoras follows:thenis a bounded linear operator, andLetandbe continuous Bessel fusion mappings onH, FandGbe a fusion pair, andThen forwe haveLet erefore,  holds byTheorem Letandbe continuous Bessel fusion mappings onH, FandGbe a fusion pair, andThen forwe haveBy Theorem Corollary TakeLetandbe continuous Bessel fusion mappings onH, FandGbe a fusion pair. Then forwe haveLetandbe continuous Bessel fusion mappings onH, FandGbe a fusion pair, andThen forwe haveBy Theorem H, F and G be a fusion pair. Define the operators Let Letandbe continuous Bessel fusion mappings forH, FandGbe a fusion pair. Then forwe haveIn this paper, we obtain three inequalities for Parseval continuous fusion frames, an equality for


ASCOT) and overall quality of life. Findings indicated that Shared Lives can deliver good outcomes for older people, particularly for overall quality of life. In comparison to the matched group of older people using other forms of support, there was some evidence that Shared Lives may deliver better outcomes in some aspects of quality of life. Limitations to the research mean, however, that more work is needed to fully understand the role Shared Lives could play in supporting older people.Shared Lives (adult placement) is a model of community‐based support where an adult who needs support and/or accommodation moves into or regularly visits the home of an approved Shared Lives carer, after they have been matched for compatibility. It is an established but small service which has been used mainly by people with learning disabilities but which has the potential to offer an alternative to traditional services for some older people. However, there is little research on the outcomes for older users of Shared Lives. This paper presents findings from a survey of 150 older people using Shared Lives support across 10 Shared Lives schemes in England, which took place between June 2013 and January 2014. The aim was to identify outcomes for older users of Shared Lives and compare these to outcomes for older users of other social care services. In the absence of an ideal study design involving randomised allocation, statistical matching was used to generate a comparison group from the Adult Social Care Survey from 2011/12, with 121 cases matched to 121 Shared Lives cases. The main outcome measures were Social Care‐Related Quality of Life (measured by the  Shared Lives support is mainly used by people with learning disabilities.There is some evidence of high levels of satisfaction among users and Shared Lives is rated highly by the Care Quality Commission in England.Shared Lives has been identified as a potential option for older people.Shared Lives appears to deliver good outcomes for older people.In comparison to a matched group of older people using other forms of social care, Shared Lives users reported better quality of life in some areas.Shared Lives should be included as part of support options offered to older people and their families.et al. et al. et al. At a time of substantial cuts to social care spending and an ageing population, policy makers and practitioners must ascertain how best to provide for the care and support needs of older people. Central to current social care policy in the UK and Western Europe is the personalisation agenda with an emphasis on giving people active choice and control over their care and support DH, , 2012. Aet al. Scoping research funded by the National Institute for Health Research (NIHR) School for Social Care Research (SSCR) highlighted Shared Lives (previously known as adult or family placement) as a personalised service mainly used by people with learning disabilities, which may have the potential to deliver good outcomes for older people  were used to estimate that over 9660 people were supported by SL at the end of 2013, 1600 of whom were older people. This includes older people who are receiving support from SL for other reasons such as a learning disability or physical impairment. Overall, it was projected that around 7% of the total number of people receiving SL support had dementia or were frail older people  was used to generate a comparison group from the Adult Social Care Survey (ASCS) from 2011/2012.et al. http://www.pssru.ac.uk/ascot). The eight domains of social care‐related quality of life (SCRQoL) that the ASCOT measure draws on are personal cleanliness and comfort; food and drink; accommodation cleanliness and comfort; safety; control over daily life; social participation and involvement; occupation; and dignity. Items are coded to represent the ‘ideal’ state, having no needs, some needs or high needs in each domain , including people with learning disabilities, and using any form of SL support (including outreach delivered in the service user's own home). Only individuals with capacity to consent and to understand the questions were included, a judgement made by the SL workers distributing the questionnaire based on their knowledge of the service users in their scheme. Schemes were sent questionnaires corresponding to the number of eligible service users they had (ranging from 3 to over 200), a total of 430. Data collection took place between June 2013 and January 2014.2) tests were used for variables with unordered categories. Kruskal–Wallis or Mann–Whitney tests were computed for variables with small numbers of ordered categories. When the variable was continuous or had more than five meaningfully ordered categories, t‐tests or ANOVA were used. Posthoc comparisons (the Bonferroni comparison) were used where appropriate to compare differences between groups. Multivariate analyses were used to explore factors associated with variations in outcome in the SL sample. Screening of the data indicated that it did not meet a number of assumptions needed to perform ordinary least squares (OLS) multiple regression, and so regression with robust standard errors   and approximately 9% of the total number of older people estimated by Shared Lives Plus to be using SL at the time of the survey.Half of the sample were female. The age of respondents ranged from 65 to 102, with an average age of 77 (SD = 8.68). The vast majority (98%) of the sample was white British, with one Asian/Asian British and two black/black British respondents.Questionnaires were returned from 10 SL schemes, with a range of 1–64 per scheme. Four ‘types’ of SL were represented: long‐term/residential, day support, respite/short breaks and outreach support , while outreach users were more likely to have used a proxy and less likely to have received no assistance. These differences need to be taken into account when describing the outcomes for older people using SL; users of different types of SL should not be treated as a homogenous group.Overall, 74% of the older people using SL rated their quality of life as ‘good’ or ‘very good’, 22% as ‘alright’, and 4% as ‘bad’ or ‘very bad’. The average SCRQoL score was 0.84, with a range of 0.22–1.00. Sixty‐eight per cent reported that they were ‘extremely’ or ‘very satisfied’ with their care and support, while a further 24% were ‘quite satisfied’.Table In order to discover whether the easy‐read element of the sample (many of whom were likely to have had a learning disability) was biasing these results, tests were re‐run without this group. Outcomes for people using long‐term SL were still statistically better for this smaller sample.However, as described above, people using different types of SL support differ in terms of age, health and dependency and it is likely that this has an effect on their quality of life. In addition, people using long‐term/residential SL receive more of the support, which may also have an influence. To allow for this, multiple regression analyses were conducted to facilitate assessment of the unique effect of each variable on SCRQoL and on overall quality of life. The models analysed 123 and 116 cases respectively (the remainder were excluded through casewise deletion due to missing data on one or more variables). Table 2(1) = 22.45, P < 0.001). The SL sample were also younger, with a greater proportion of people aged between 65 and 74 and fewer over 85 (χ2(2) = 63.88, P < 0.001), and less dependent (t(28530) = −3.20, P = 0.0014). They experienced less pain or discomfort (χ2(2) = 8.92, P = 0.012) and rated their health more favourably .A key aim of the survey was to facilitate comparison of outcomes of older SL users to older users of other social care services using data from the ASCS. The ASCS 2012 data set contains 164,569 cases. In order to reflect older people using SL, excluded were anyone: under 65; receiving nursing care; receiving equipment services from the LA but no other services; and those without information on outcomes. This resulted in a sample of over 30,000. Tests for differences between this subset of the ASCS 2012 and the SL data set indicated that the two samples differed on various background variables. There was a smaller proportion of females in the SL data set  that any individual in the two samples (ASCS or SL) might be allocated to SL was estimated using logistic regression. The choice of conditioning variables in the logistic regression model is best informed by prior evidence and theory . The predictive ability of all models tested was poor for SL cases, due in part to the small proportion that SL formed of the overall sample; however, this does not invalidate the match achieved. The final model included gender, age group, experience of pain, ability to get in and out of bed, ability to deal with paperwork, and overall health. PSM was conducted using STATA/PSMATCH2 based on nearest neighbour matching with calliper (1/4 SD) and without replacement . The matched ASCS sample included people using a mix of social care services including home care, day support and residential care, reflecting the varied nature of support available through SL. As they now ‘matched’ the SL users, this sample of the ASCS was on average younger (χ2(2) = 57.35, P < 0.001), less dependent (t(117.362) = −4.26, P < 0.001), in better health  and experienced less pain and discomfort than the overall sample (χ2(2) = 8.74, P = 0.01). There was a greater proportion of men (χ2(1) = 21.21, P < 0.001) and of people who completed the easy‐read questionnaire (χ2(1) = 18.13, P < 0.001) in the matched sample.The matched SL sample was similar to the overall SL sample, differing only in terms of one indicator of dependency: ability to feed themselves  = 12.58, P < 0.001). It would not have been appropriate to use these variables in the logistic regression model, as they were not true background variables, but a feature of the questionnaire.After matching, there was balance between the SL and ASCS samples on all the characteristics entered as variables in the model. However, there were significant differences between the groups in terms of the source of help received to complete the questionnaire. In addition, more people in the SL sample completed the easy‐read questionnaire  to analyse results by scheme; again a limitation to the findings presented here.There are also limitations to the analysis used to compare the ASCS and SL samples. In the absence of a ‘real world’ comparison group, statistical matching techniques offer an alternative. However, the comparison made can only apply to the matched sample, not to those for whom there was no ‘match’ – in this case, the matched sample represents a tiny proportion of older people using social care and support services in 2011/2012. Although the older people drawn from the ASCS data set were using a range of types of care and support, they were younger, relatively able and in better health compared to the overall sample of older people. More information is needed about the characteristics of the older people using SL in order to be confident that this was comparing like with like.The research presented suggests that SL can provide a viable option alongside other forms of care and support for older people and one which reflects a number of current policy initiatives, offering choice and control and personalised support in a community setting DH . However


These resistant infections arehaving a significant impact on treatment outcomes and contribute toapproximately 25,000 deaths in the U.S. annually. If additional therapeuticoptions are not identified, the number of annual deaths is predicted to rise to317,000 in North America and 10,000,000 worldwide by 2050. Identifyingtherapeutic methodologies that utilize our antibiotic arsenal more effectivelyis one potential way to extend the useful lifespan of our current antibiotics.Recent studies have indicated that modulating metabolic activity is one possiblestrategy that can impact the efficacy of antibiotic therapy. In this review, wewill address recent advances in our knowledge about the impacts of bacterialmetabolism on antibiotic effectiveness and the impacts of antibiotics onbacterial metabolism. We will particularly focus on two studies, Lobritz, Mycobacterium tuberculosis can becomeantibiotic-tolerant by entering a metabolically quiescent, slow-growing state. This isaccomplished by shunting carbon flux away from the tricarboxylic acid (TCA) cycle andinto storage as triacylglycerol instead. If this pathway is inhibited, M.tuberculosis remains susceptible to a variety of antibiotics when placedunder stress, providing a potential therapeutic target to increase the efficacy ofavailable drugs. The TCA cycle is also an important determinant of antibiotic tolerancein the opportunistic pathogen Staphylococcus epidermidis. In S.epidermidis, disabling the TCA cycle has a protective effect againstbeta-lactam antibiotics due to suppression of reactive oxygen species (ROS) generationduring antibiotic exposure, as well as increased tolerance of oxidative stress. TCAcycle defects are also common in clinical isolates of S. epidermidis,suggesting that such mutations may be a common antibiotic defense. In addition, inStaphylococcus aureus and Escherichia coli,antibiotic-tolerant persister and biofilm cells can have reduced proton motive force(PMF), leading to inhibited uptake of aminoglycoside antibiotics . Thistolerance can be reversed by the addition of metabolism-stimulating sugars that boostPMF and the uptake of antibiotics.These two papers build on a significant body of evidence that suggests that reducedmetabolic activity leads to an antibiotic-tolerant state and that elevated metabolicactivity contributes to bactericidal antibiotic toxicity in susceptible bacteria . For example, A growing compendium of evidence suggests that in non-tolerant bacteria, elevated centralmetabolism contributes to bactericidal antibiotic toxicity through the production ofreactive oxidants and other damaging molecules. At low therapeutically-relevantconcentrations, drug-target interactions of bacteriostatic antibiotics induce ROS as theprincipal cause of antibiotic toxicity under oxygenated conditions. At higherconcentrations of antibiotics, ROS and other damaging reactive species appear to play alesser role in toxicity. The link between ROS and antibiotic toxicity has been recentlydisputed, but in general a preponderance of evidence suggests that the induction of ROSand metabolic activity are inexorably linked to bacterial death.et al., which utilized in silico genome scalemetabolic models to identify perturbations that increase intracellular production ofendogenous ROS species. In particular, they found that perturbations to the productionor usage of ATP were associated with predicted increases in ROS. Chiefly, targetingglycolysis, the TCA cycle, and aerobic respiration led to endogenous ROS production andsusceptibility to antibiotic-induced oxidative stress. Subsequent work identifiedexperimentally-tractable futile cycling reactions that decrease net intracellular ATPlevels. Furthermore, actively cycling strains were significantly more susceptible tooxidative stress and certain antibiotics (aminoglycosides). This suggests that thisincrease in sensitivity is attributable to increased damage and/or impaired repairmechanisms caused by perturbations in ROS. Along with other recent studies, this hasforcefully demonstrated that artificially inducing oxidative metabolism can impactantibiotic susceptibility. Under natural conditions, metabolically-costly futile cyclesalso contribute to bactericidal efficacy. Cho et al. demonstrated thatthe bactericidal activity of beta-lactam antibiotics is due, in part, to the inductionof a futile cycle between peptidoglycan cell wall synthesis and degradation. This is ametabolically-costly process that likely contributes considerably to ATP consumption, asseen in previous futile cycle studies. The total body of previous work suggests thatmetabolic activity contributing to ROS production is an integral part of bactericidaltoxicity.Initial evidence about this metabolic link came from a 2013 article by Brynildsenet al.: 8173-8180) and Belenky et al. :968-980) expand on this foundation of work by testing the impacts of bactericidalantibiotics on respiratory metabolism and the toxic consequences of this elevatedmetabolic activity respectively. Lobritz et al. utilized a novelhigh-throughput microplate-based method of analyzing bacterial oxygen consumption . They found that bactericidal antibioticsinduced a rapid induction in oxygen consumption indicative of elevated respiration. On the other hand, the same assay found that treatment with bacteriostaticantibiotics rapidly and permanently eliminated essentially all respiratory activity.They also found that inhibiting respiration eliminated bactericidal activity, whereasincreasing respiration led to boosted toxicity. This indicates that induction ofrespiration is essential for bactericidal antibiotic efficacy. Finally, and mostimportantly, this work identified that many bacteriostatic drugs are antagonistic tobactericidal drugs when used in combinatorial therapy, because thebacteriostatic-dependent inhibition of respiration supersedes the bactericidalrespiration-based benefit. The impact of this observation is that many currentlyutilized empirical therapeutic combinations are detrimental because they may lead todirect inhibition of an essential metabolic burst.The two papers at the heart of this microreview, by Lobritz et al. continued the study of antibiotic-induced metabolicactivity by conducting a total metabolomic profile of antibiotic-treated E.coli. This work found that bactericidal antibiotics - aminoglycosides,fluoroquinolones and beta-lactams - induce a common initial set of metabolicperturbations. These changes included an induction of central carbon metabolites,exemplified by dramatically elevated TCA cycle intermediates, as well as raised levelsof glutathione, which are suggestive of an active antioxidant response. These data areconsistent with the bacteriotoxic metabolic burst hypothesis proposed and tested inLobritz et al. In addition to the TCA cycle and glutathione signatures,Belenky et al. also found metabolic signatures suggestive of nucleotidedamage and perturbed lipid homeostasis. This observation led them to test potentialend-target consequences of metabolically-induced oxidative stress. They found thatbactericidal antibiotics lead to higher levels of malondialdehyde adducts, proteincarbonylation, and 8-oxo-guanine, indicative of lipid, protein, and nucleotide oxidationrespectively . Finally using a fluorescence-based protein assay, they showedthat antibiotic treatment induced double-strand DNA breaks likely due to oxidativedamage.Belenky When taken together, the two papers make a very convincing argument about the importanceof a metabolic burst for the damage of bacterial cells and eventual toxicity duringbactericidal treatment. This perspective comes at a very critical time, when antibioticefficacy is being increasingly compromised by rising rates of resistance. Modulatingmetabolic activity may provide important therapeutic methodologies to extend the usefullife span of our current antibiotics. In addition, the metabolic signature of thisrespiratory burst could be used as a potent readout to aid in the development of newdrugs and for screening of antibiotic resistance in laboratory and clinical settings. Ingeneral, the developing perspective that antibiotic-induced death is not a single,one-step response but rather a programmed set of discernable processes is a wonderfulchange. This new perspective opens up a large set of cellular processes that can bemodulated and utilized to improve therapy. Before this appreciation, antibiotic researchwas very much limited to drug-target interactions, while now the entire cell is open forbusiness.


Multiple cause-of-death (MCOD) data allow analyzing the contribution to mortality of conditions reported on the death certificate that are not selected as the underlying cause of death. Using MCOD data, this study aimed to fully describe the cause-specific mortality of people with AIDS (PWA) compared to people without AIDS.We conducted a nationwide investigation based on death certificates of 2,515 Italian PWA and 123,224 people without AIDS who had died between 2006 and 2010. The conditions most frequently associated with PWA mortality, compared to people without AIDS, were identified using an age-standardized proportion ratio (ASPR) calculated as the ratio between the age-standardized proportion of a specific cause among PWA and the same proportion among people without AIDS.The most frequently reported conditions at death among PWA were infectious/parasitic diseases (52%), digestive (36%), respiratory (33%), and circulatory (32%) system diseases, and neoplasms (29%). All AIDS-defining conditions resulted highly associated (ASPR significantly greater than unity) with PWA deaths. Significant associations also emerged for leishmaniasis (ASPR = 188.0), encephalitis/myelitis/encephalomyelitis (ASPR = 14.3), dementia (ASPR = 13.1), chronic viral hepatitis (ASPR = 13.1), liver fibrosis/cirrhosis (ASPR = 4.4), pneumonia (ASPR = 4.4), anal (ASPR = 12.1) and liver (ASPR = 1.9) cancers, and Hodgkin’s disease (ASPR = 3.1).Study findings identified the contribution of several non-AIDS-defining conditions on PWA mortality, emphasizing the need of preventive public health interventions targeting this population. In Italy, about 4,000 new HIV diagnoses and approximately 800 AIDS cases are reported yearly to the National HIV and AIDS surveillance systems, with a steady trend observed in the last decade. However, the distribution of new AIDS cases by transmission mode has changed over time, with a decreasing proportion of injecting drug users (31.2% in 2005 and 11.3% in 2015) and an increasing proportion of cases acquired through sexual contact (61.3% in 2005 and 79.8% in 2015)  emerged . Suicide by hanging – frequently mentioned among non-AIDS/HIV (proportion = 2.4%) – showed a low value of the ASPR .This is the first time that MCOD data have been used to investigate cause-specific mortality of PWA in Italy, providing a detailed picture of the causes listed in their death certificates. The analysis of MCOD, compared to the use of UC data only, stressed the leading role of infectious diseases among the causes of death for AIDS patients, and it also showed the major contribution to death of other causes  that were more frequently mentioned in AIDS than in non-AIDS/HIV death certificates. Moreover, although neoplasms and diseases of the circulatory system were not frequently the UC in PWA , their contribution to death rose when MCOD were considered (respectively mentioned in 29% and 32% of AIDS deaths).Our results showed that although infectious diseases provided a small contribute to the UC among PWA, they represented the most common cause of death when considering the MCOD Fig. ; this reExtremely high values of ASPR were observed for conditions included in the AIDS-defining disease list , 17: toxNeoplasms, in particular AIDS-defining ones, are among the most common underlying causes of death among people with HIV infection or AIDS , 8. The Overall, 13% of death certificates of deceased PWA reported one or more diseases of the blood and/or immunological disorders – a proportion that was 3-fold higher than among deceased people without AIDS/HIV. Notably, anaplastic and hemorrhagic conditions turned out to be associated with highly positive ASPR, a potentially surrogate marker of HIV-immunosuppression. Although a comparison with similar investigations is made difficult, it seems that our findings are in agreement with the existing evidence indicating that anemia is a frequent complication of HIV infection associated with an elevated risk of death .A negative association between unspecified diabetes mellitus and AIDS was found, due to a double proportion of this disease among non-AIDS deaths compared to AIDS deaths. The proportion of diabetes mellitus reported among non-AIDS deaths was consistent with the results from the PASSI Italian Surveillance System , suggestThe proportion of mental and behavioral disorders resulted similar between the two study groups, although a high value of ASPR for dementia was observed. Dementia is commonly associated to AIDS. It could be caused by specific characteristics of HIV that reaches the central nervous system, immediately after primary infection, and plays a central role in determining pathological alterations and neurocognitive deficits . The preMental and behavioral disorders due to psychoactive drugs also resulted highly associated with AIDS: historically, injecting drug users are indeed the first Italian group which acquired the HIV infection .Among diseases of the nervous system, the highest value of the ASPR corresponded to encephalitis, myelitis and encephalomyelitis, indicating that these causes are about 14-fold more frequent in AIDS deaths than in non-AIDS/HIV deaths . These cDiseases of the circulatory system were more frequently reported among non-AIDS/HIV deaths than among AIDS deaths. However, they were mentioned in about 32% of death certificates of PWA. This remarkable proportion is consistent with the role of circulatory system diseases  as causes of death in people with AIDS or HIV infection described in previous studies , 6.The only two diseases with a higher frequency among AIDS deaths, i.e., acute and subacute endocarditis and other pulmonary heart diseases, are very common cardiac complications due to injecting drug use .Values of ASPR for ischemic heart diseases and heart failure, in both cases lower than unity, are in agreement with the results obtained by Whiteside and colleagues (2015) in comparing mortality rates of people with HIV infection to those of the general population in the US, by means of MCOD data.With regard to the frequency of respiratory conditions, it is worth noting that one out of three AIDS deaths had a respiratory disease listed in the death certificate – a frequency magnitude concealed when the UC approach is used. Pneumonia (organism unspecified) wasthe most common listed respiratory condition, in agreement with what was observed by Schwarz (2014) in the same period.Hepatic diseases accounted for the largest proportion of causes of death and showed significantly high proportions among AIDS deaths. Liver diseases are one of the most frequent non-AIDS-defining causes of death in people living with HIV for a number of reasons: the high prevalence of hepatotropic viral co-infections, the hepatotoxicity of antiretroviral drugs, and the emergence of new liver conditions, including non-alcoholic fatty liver disease and non-cirrhotic portal hypertension . ConsideGenitourinary diseases were rarely mentioned as UC, but they appeared to be listed in about 11% of death certificates of PWA when the MCOD approach was used. Our finding is in agreement with previous evidence showing that up to 3% of HIV-infected patients may suffer of chronic kidney diseases in the HAART era . The MCOSymptoms, signs, and ill-defined causes were reported in about 40% of certificates for AIDS deaths: the condition most frequently mentioned was cachexia, typically linked to the wasting syndrome, as reported in other international studies on AIDS deaths .Among external causes of deaths, only “accidental poisoning by and exposure to narcotics psychodysleptics” showed positive association with AIDS due to overdose among injecting drug users, that constituted the majority of Italian AIDS cases reported from the beginning of the epidemic .The main strengths of this study were the national coverage of the population-based registries used to identify people with and without AIDS, the AIDS case definition based on official diagnoses mandatorily reported to the RAIDS, and the use of MCOD data.The exclusion from the analysis of death certificates from the Trento and Bolzano provinces is expected to not affect the results, since the number of cases from these areas is expected to be very small .The choice to focus on deaths aged 35–54 years enabled feasible (robust) MCOD analysis by detailed cause-of-death category. Furthermore, it prevented possible bias due to misdiagnosis of HIV/AIDS in people at older ages, which could result in undiagnosed AIDS cases among the comparison group. However, future developments of the study will include the analysis of deaths of PWA aged 55 years and over, in order to investigate also the mortality pattern of older AIDS patients.A quota of death certificates were not matched to the RAIDS mentioned codes B20-B24 or R75  and were then excluded from the comparison group. These cases are currently under investigation to establish how many of them referred to AIDS deaths or, more plausibly, to deaths of people reported with HIV infection. This in-depth analysis requires to take into account both multiple cause codes and the text reported by the certifier.Only a really small number of death certificates of PWA reported codes B20-B24 or R75 as single cause of death , without any impact on the validity of MCOD analysis.The ASPR compares proportions of deaths and needs only mortality data without the risk exposed population. The indicator highlights the conditions most frequently mentioned in AIDS versus non-AIDS/HIV deaths. Therefore, the ASPR does not measure the overall mortality risk of PWA compared to the general population, as in other analyses . BrieflyIt is well known that mortality data derived from death certificates have some limitations. Among these, the death certificate completion is entrusted to the medical knowledge of the certifying physician, and it can suffer from a lack of specificity and/or underreporting . On the The present study is the first application of MCOD analysis to PWA in Italy. This approach, based on all the conditions that were directly responsible for the death or may have contributed to it, allowed identifying the circumstances leading PWA to death in a more comprehensive picture compared to the traditional UC analysis. From a public health perspective, interventions targeted at preventing all causes of death beside the UC can lead to both improvements in the health status and mortality reductions for a given population. Indeed, many of the contributing causes the MCOD approach allowed to focus on, are consequences or complications of the UC (or its therapy) to which tertiary prevention is typically addressed (for instance cardiovascular diseases as consequence of HAART therapy). Study findings could be of aid in planning public health interventions oriented to the prevention of death among PWA in the late HAART era, by directing the attention to the role of non-AIDS-defining conditions.


The use of fiber reinforced polymer (FRP) bars in reinforced concrete members enhances corrosion resistance when compared to traditional steel reinforcing bars. Although there is ample research available on the behavior of FRP bars and concrete members reinforced with FRP bars under elevated temperatures (due to fire), there is little published information available on their post-fire residual load capacity. This paper reports residual tensile strength, modulus of elasticity, and bond strength (to concrete) of glass fiber reinforced polymer (GFRP) bars after exposure to elevated temperatures of up to 400 °C and subsequent cooling to an ambient temperature. The results showed that the residual strength generally decreases with increasing temperature exposure. However, as much as 83% of the original tensile strength and 27% of the original bond strength was retained after the specimens were heated to 400 °C and then cooled to ambient temperature. The residual bond strength is a critical parameter in post-fire strength assessments of GFRP-reinforced concrete members. Corrosion resistance and a superior strength-to-weight ratio are among the beneficial properties that have generated interest in fiber-reinforced polymer (FRP) reinforcing bars as a viable replacement for steel bars in reinforced concrete structural members . Common The mechanical properties of FRP reinforcement differ from steel reinforcement. FRP materials exhibit linearly elastic behavior and fail in a brittle manner. The compressive and shear strengths of FRP materials are dependent on the resin strength and are generally significantly lower than their corresponding tensile strength . For thiThe mechanical properties of all common structural materials are adversely affected, to varying degrees, by exposure to high temperatures associated with fire. However, strength, stiffness, and bond properties of FRP reinforcements are affected more adversely by elevated temperatures when compared to steel reinforcing bars ,3,8. ManAvailable data indicate that the bond between the FRP bar and concrete is reduced at high temperatures , but litThe properties of a FRP composite material are dependent on the fiber, the polymer matrix, and the relative proportions of the fiber, known as the fiber-volume ratio. The tensile strength and stiffness of the composite in the direction of the fiber are a function of the fiber material and the fiber-volume ratio. On the other hand, resin properties influence the compressive strength, shear strength, and bond characteristics of the composite . Matrix In addition to fiber and matrix properties, the size of a bar also affects its mechanical properties . The rat−6/°C in the longitudinal direction, and between 21.0 and 23.0 × 10−6/°C in the transverse direction [GFRP bars exhibit different longitudinal and transverse thermal expansion properties. The coefficient of thermal expansion of GFRP compares reasonably well with that of the concrete in the longitudinal direction. However, it could be as high as twice that of concrete in the transverse direction . The coeg), the polymer softens, resulting in a lower elastic modulus. The value of Tg is dependent on the type of resin but is typically between 65 °C and 120 °C [g. Wang et al. [Drastic degradation of the post-fire mechanical properties of polymer composites occurs as the intensity or duration of the fire increases. The degradation of the mechanical properties of the FRP materials with non-organic fibers, such as glass fibers, relate to the decomposition of the polymer matrix . When thd 120 °C . Becauseg et al.  investigRobert and Benmokrane  investigThree main mechanisms influence the development of bond stress between FRP reinforcing bars and concrete ,16,17,18The difference in the transverse thermal expansion coefficient of concrete and FRP rebars can cause thermal stresses at contact surfaces of concrete and FRP rebars. As these thermal stresses increase up to the tensile strength of concrete, microcracks occur, resulting in bond loss and reduction in structural capacity. However, experimental results have shown that additional concrete cover may significantly mitigate the reduction in structural capacity due to fire exposure ,21,22,23Okelo and Yuan  performeMasmoudi et al.  studied Katz et al.  conducteThe degradation of the mechanical properties of the FRP rebars with exposure to elevated temperature causes a reduction in the structural capacity of FRP-reinforced concrete members . Bai et Abbasi and Hogg  conducteThe study reported in this paper provides experimental data on the strength and stiffness of GFRP bars with prior exposure to high temperatures. The results can form the basis for estimating the residual post-fire strength of GFRP-reinforced concrete flexural members using analytical models. The effects of prior exposure to elevated temperatures on residual tensile strength, modulus of elasticity, and bond between concrete and GFRP bar are reported.The GFRP bar used in the test specimen was a commercially available product, “Aslan 100”   was placed in a universal testing machine at ambient temperature and loaded incrementally until the specimen ruptured. The universal tension-compression test machine was a screw-driven Tinius Olsen machine. To determine the stress-strain behavior of the bar material, two linear variable differential transformers (LVDT) were attached to the bar such as to measure the extension of the bar within the middle third of its free length, and the center-to-center distance between attaching arms (gage length) was recorded. The specimen was then loaded at a rate of about 8.9 KN/min until the bar ruptured. To prevent damage to the LVDTs, the devices were removed prior to the rupture of the rebar so the strain at rupture of the rebar in the specimens was not measured, and only partial displacement data were obtained for the tension specimens.2 and a maximum temperature of 760 °C. The temperature at the surface of the reinforcing bar was measured at 5-min intervals during the heating. After the attainment of the desired temperature, the heat was turned off and the specimen was unloaded and removed from the tensile testing machine and allowed to cool down to ambient temperature in the laboratory for at least 24 h. Then, the specimens were placed back into the testing machine, the LVDT’s were attached, and the specimens were loaded until the bar ruptured.A heating tape was wrapped around the free length of the other TS specimens after placement of the bar in the test machine. Two thermocouples were attached to the bar surface under the heating tape. The free length of the bar was further wrapped with a ceramic insulation material. The specimen was loaded to 80.0 kN or 42% of the average rupture load obtained from the tests performed at ambient temperature. This load level was meant to represent the applied service load at the time of fire. The target service load was applied and held constant before heating the specimen to the desired temperature (within its free length). The heat was supplied to the specimens using custom-built equipment that consisted of a temperature controller and heating tapes capable of supplying a heat flux of 20.16 kW/mDetails of the bond test specimens were based on the ASTM D7913  and simiThe concrete used in the cylinder was designed to achieve a 28-day compressive strength of 27.6 MPa. The specimens had a high-temperature thermocouple embedded in the concrete such that the thermocouple touched the surface of the reinforcing bar at a depth of 143 mm from the top surface of the concrete (middle of the bonded height of the reinforcing bar). To perform the bond tests, the specimens were placed in the universal testing machine with the concrete cylinder bearing on the top cross-head of the machine and the gripping end of the specimen in the grips in the lower cross-head . LVDTs wFor B-100, B-200, and B-400, the concrete cylinder was heated while the specimens were in an unloaded state and lying horizontally on ceramic insulation on the laboratory floor. The cylinders were not heated under full “service loading”, because the first specimen heated under such loading failed (pulled out) when the temperature reached 85 °C. The failure of the bond specimen under the maximum service load (at 85 °C) indicates that the bar development length used in design calculations should be adjusted for the effect of elevated temperatures because of its significant influence. However, in common reinforced concrete beams, the length from the point of maximum moment  to the end of bar (bond length) may be larger than the required bar development length, with or without elevated temperatures. The failure that was observed in the bond test specimen occurred under the full service-load over a short embedment length (resulting in high bond stresses). The focus of this study was on residual post-fire behavior, assuming survival during the fire. Therefore, if the bond failure did not occur and the structure survived, the bond stresses were necessarily lower than the corresponding bond strength because of low axial loads, long bond length, and/or low temperature exposure. Therefore, to allow for the assessment of the residual bond given survival after a fire, the bond test specimens were heated without a service axial load applied. The same special-built heating equipment that was used in the tensile tests provided the heat for the bond tests. The specimens were heated by wrapping the heating tape around the concrete cylinder. All perimeter concrete surfaces, and the heating tape wrapped around it, were covered with ceramic insulation prior to the commencement of heating. A thermocouple was placed at the surface of the concrete at the location of the heating tape so that the corresponding concrete surface temperature could be monitored while the temperature at the reinforcing bar was also being recorded. Another thermocouple was placed inside the concrete at the surface of the bar. To accommodate the temperature increases due to thermal lag, the temperature controller was set to shut the heat supply off when the reinforcing bar temperature was 15 °C less than the desired temperature. After the desired temperature at the location of the reinforcing bar was attained, the insulation and heating tape were removed from the specimens, and the specimens were left in the laboratory to cool to ambient temperature. After cooling naturally in the laboratory for at least 24 h, the specimens were placed in the tensile testing equipment as shown in Each of the B-A specimens (bond specimens that were not exposed to elevated temperature) failed by pull-out of the rebar from the concrete cylinder and no cracking of the concrete was observed a. Some rAfter the heating, tapes were removed from the B-100 specimens; small random cracks, forming a web-like pattern, were observed on the concrete surface that had direct contact with the heating tape. Failure of all three of the B-100 specimens was by pull-out of the rebar from the concrete. However, unlike the unheated specimens, failure of the B-100 specimens was associated with cracks that radiated from the rebar to the surface of the concrete cylinder c. AdditiIn all cases, failure of the B-200 specimens occurred by pull-out of the rebar from the concrete cylinder. Failure involved cracks  radiating from the rebar location to the surface of the concrete cylinder e. SignifOne of the B-400 specimens was damaged during test setup. Consequently, only two B-400 specimens were available for complete testing. There was significant discrepancy between the failure loads observed for the two specimens. However, both specimens failed by rebar pull-out and there was no evidence of any cracking in concrete g. SignifThe average ultimate tensile strength of 649 MPa, obtained from the T-A tests, compares favorably with the guaranteed ultimate strength of 621 MPa provided in physical properties data published by the manufacturer . Also, tThe 87% residual strength for T-100 specimens appears to be consistent with the findings of Wang et al. . It is tAlso of interest is the fact that the average strength of the T-200 specimens was 11% higher than that of the T-100 specimens and only 2% lower than the average strength of the T-A specimens. The high strength of the T-200 specimens relative to the T-100 specimens may be explained in terms of a phenomenon called post-cure (further molecular cross-linking) that has been observed at temperatures between 100 °C and 150 °C by Mouritz and Gibson . Post-cuAs with the other tensile test specimens, all T-400 specimens ruptured within the free length of the bar, thereby providing validation for the test setup. The fact that one of the specimens ruptured during heating while subjected only to the sustained load raises questions about reliability of the bar when it is exposed to temperatures above 400 °C. The mean bond strength of 11.25 MPa obtained from the tests of the B-A specimens compares favorably with the bond stress of 11.57 MPa provided in the manufacturer’s literature . AdditioIn B-100 specimens, the resin and glass residue observed on the concrete and the damage seen on the bar surface indicate that the failure mechanism also involved shear failure within the outer layer of the bar. The fact that more resin residue was observed on the concrete surface of the B-100 specimens is likely due to the reduced shear strength of the resin. This would also account for the 4% reduction in bond strength of the B-100 specimens relative to the B-A specimens. The concrete splitting (cracking) suggests the effect of the mechanical interlock mechanism . The bond-slip curve for B-200 specimens showed lower strength and stiffness compared to the B-100 curve. The flatter slope on the linear portion of the load-slip curve and the lower bond strength observed for the B-200 specimens suggests lower shear stiffness and shear strength in the outer layer of the bar in the B-200 specimens. Also, more resin residue was observed on the concrete, providing more evidence of reduced resin shear strength. There were radial cracks in the concrete cylinder associated with the failure of the B-200 specimens. However, because of the reduced shear strength of the resin, smaller stresses are transferred to the concrete, thereby producing cracks with smaller widths and lower frictional forces compared to B-A and B-100 specimens.During the tensile testing, improvement of the strength in the bar that was heated to 200 °C relative to the strength in the bar that was heated to 100°C was observed. This suggests an improvement in the resin properties. This contrasts with the reduction in shear strength of the resin implied by the reduced bond strength (relative to the B-100 specimens) observed in the B-200 specimens. That is, the post-cure effect was not observed in the bond specimens. It is possible that this is due to the moisture in the concrete, which is known to degrade the properties of resins, or it may be due to redistribution of bond stresses ,35.The load-slip response for the B-400 specimens  indicateAlthough substantial information exists regarding the performance of FRP bars under high-temperature conditions, data on residual tensile strength and bond (to concrete) properties after cooling are not widely available. In cases in which an FRP-reinforced concrete structure survives a fire, it is important to assess the residual strength properties. Experiments performed as a part of this study provide information on the residual tensile properties of GFRP bars after they have been exposed to elevated temperatures of up to 400 °C.Further details of this research including analytical aspects are provided by Ellis .The residual tensile strength and modulus of vinyl ester GFRP bars generally decreases as the exposure temperature increases. However, the residual strength of the bar that was exposed to 200 °C was larger than the bar exposed 100 °C, which is attributed to the post-cure phenomenon.Vinyl ester GFRP bars retain a significant percentage of their tensile strength and elastic modulus after they have cooled from elevated temperatures of up to 400 °C. For example, after exposure to a temperature of 400 °C, the average residual strength of the bar (upon cooling) was 83% of its ambient temperature strength. This contrasts with the percentage of retained properties during exposure to elevated temperature. According to Wang et al. [Generally, the residual pull-out bond strength of the GFRP bars decreased as the exposure temperature increased. There was no significant change in bond stiffness with exposure temperatures of less than 100 °C. The mechanisms of bond transfer also change for different levels of temperature exposure. There is a drastic reduction in bond strength and bond stiffness as prior exposure temperatures reach 400 °C. This is believed to be a major factor affecting post-fire strength assessments of GFRP-reinforced concrete beams, and must be carefully considered in such assessments.The conclusions of this study can be summarized as follows:


Quantum-dot cellular automata (QCA) is a developing nanotechnology, which seems to be a good candidate to replace the conventional complementary metal-oxide-semiconductor (CMOS) technology. In this article, we present the dataset of average output polarization (AOP) for basic reversible logic gates presented in Ali Newaz et al. (2016)  Specifications TableValue of the data•Reversible gates are the basic building block of reversible logic systems. This dataset helps researcher to enhance the performance and reliability of digital systems.•The presented data analysis can support the researchers to find the maximum operating temperature of a particular QCA design.•The proposed dataset can be used to design robust and lossless arithmetic logic unit (ALU) in quantum computers.1This article describes the average output polarization (AOP) for basic reversible logic gates of Double Feynman, Toffoli, TR, R, NG, SCL and BVF gates at different temperature levels are shown in 22.1The average output polarization is declined gradually with the increment of temperature −23 J, clock high = 9.8e−22 J, clock amplitude factor = 2.000, layer separation = 11.5 nm and maximum iterations per sample = 100. The graphical representation of AOP of different reversible logic gates presented in To analysis the AOP, QCADesigner tool ver. 2.0.3


MET gene amplification. A total of 816 gastric adenocarcinoma patients were included and MET and HER2 immunohistochemical (IHC) staining were performed. IHC and dual-color silver in situ hybridization analysis were performed in the tissue microarrays, constructed from the 240 patients who were randomly selected. MET overexpression (IHC 3+) was observed in 6.0% (49/816) of the cohort. MET overexpression rate was higher in patients with poor prognostic factors, such as clinical stages III/IV (p =0.012) and pathologic stages T3/T4 (p =0.027). The HER2 overexpression (IHC 3+) rate was 8.8% (72/816) and MET overexpression rate was higher in HER2 positive patients . A high concordance rate (94.6%) between MET overexpression and gene amplification was demonstrated. Therefore, MET overexpression could serve as a prognostic biomarker and a potential therapeutic target for gastric cancer.This study was conducted to investigate the expression of MET in Chinese gastric adenocarcinoma cohort, the correlation between MET overexpression and clinical pathological features, HER2 expression and  Gastric adenocarcinoma (GC) continues to be a significant public health threat. It is the fourth most common cancer and the second leading cause of cancer related death worldwide , 2. The MET gene amplification showed transient sensitivity to the targeted MET inhibitor-Crizotinib [Mesenchymal–epithelial transition factor (MET) is the so called hepatocyte growth factor (HGF) receptor. MET overexpression and its gene amplification have recently been indicated as survival prognostic factors for many cancers including GC. Multiple studies have shown that MET is also a potential therapeutic target in advanced or metastatic GC –8. Interizotinib , 13. Theizotinib . Rilotumizotinib  and currizotinib , 17.MET gene amplification rates vary from 2% to 24% [MET gene amplification has rarely been studied. The primary objective of our study is to develop a modified score system for categorizing MET expression level using as standardized criteria, and assessed the incidence of MET overexpression in a large Chinese GC cohort. The relationship between MET overexpression and gene amplification and clinicopathological parameters including HER2 expression were also investigated in this study.Although MET targeted agents for gastric cancer have been intensively investigated, the categorizing the MET expression level into under/over expression is lacking standardized scoring system. Data from previous studies have shown MET overexpression rates vary from 4% to 82.4% , 19, and% to 24% , which mA total of 816 patients were evaluated by IHC. The patients’ clinicopathological characteristics were summarized in Table p =0.012). MET was overexpressed in 7.5%(39/484) of pT3/pT4 stage patients which is significantly higher than that in pT1/T2 stages . No correlation was observed between MET overexpression and age group, sex, tumor location, Lauren classification and tumor differentiation.Table p =0.164).The correlation between MET expression and HER2 expression in GC was summarized in Table MET gene amplification was observed in 62.5% (10/16) of MET IHC 3+ cases, 2.6% (5/189) of MET IHC 2+/1+/0 cases, showing a concordance rate of 94.6% between IHC and DISH with a relatively low k value of 0.3  analysis was performed in 240 GC and GEJ adenocarcinoma cases randomly selected, with high cell density (> 30% tumor cells/area) were selected. Finally, 205 fragments met the inclusion criteria for the study, including 16 cases with IHC 3+, 78 cases with IHC 2+, and 111 cases with IHC 0/1+. Due to the inconsistent scoring criteria used in MET IHC interpretation in previous studies, in which the positivity rate of MET overexpression varying from 4% to 82.4% , 20, 21,Whether cases with MET IHC 2+ should be defined as MET overexpression is controversial. Some studies considered MET IHC 2+ as MET overexpression cases which is different from ours . PreviouMET gene amplification and showed shorter overall survival and disease-free survival compared with patients without MET overexpression [The membranous and/or cytoplasmic expression levels of MET were considered while defining MET overexpression status. Jianji Jiang, et al have indicated that only simultaneous membranous and cytoplasmic overexpression of MET was significantly correlated with pression . In our p = 0.041). We applied the method in our study and summarized the result in Table p < 0.001), MET positive was higher in pN0 stage. We had contradictory conclusion with a large sample, so this method maybe not scientific and maybe IHC intensity was the only factor need to be considered in MET IHC scoring system.Other semi-quantitative methods for evaluating MET IHC staining were also explored. In the study of Tiankang Guo et al., proportional score  and intensity score  were summed to obtain a total score. A score ≥ 3 was considered as positive expression . They reWe also explored the modified H-score system mentioned in the review of Luigi Marano et al. . The anaPrevious studies have indicated MET overexpression activated MET signal pathway to promote tumor cell growth, survival, migration, and invasion as well as tumor angiogenesis , 30, 31.p =0.164), we found that MET overexpression rate was higher in HER2 positive patients . Similarly, other researchers revealed that the HER2-positive rate was significantly higher in MET–positive tumors than that in MET–negative tumors (p =0.036) [The present study retrospectively evaluated the correlation of MET expression and HER2 expression. According to Table  =0.036) . Meanwhi =0.036) .MET gene amplification, other mechanisms such as mutation or alternative splicing were responsible for MET protein overexpression. Five cases with MET/CEP 7 ratios ≥2 showed MET expression with IHC 2+, and they were low ratios with MET/CEP 7 ranging from 2.01 to 2.46. Due to the limitation of the sample size, the relationship between MET overexpression and MET gene amplification and the definition of MET gene amplification should be further investigated in future studies with larger sample sizes.In this study, the concordance rate between MET expression and gene amplification was 94.6%. Six cases with MET IHC 3+ didn't show gene amplification. These results suggest that, instead of MET gene amplification was the main reason for MET overexpression. MET overexpression could serve as a prognostic biomarker and a potential therapeutic target for gastric cancer.In summary, there were 6.0% (49/816) cases showing MET overexpression (IHC 3+) in this Chinese cohort of Chinese GC without history of treatment. MET overexpression (IHC 3+) was more common in cases with deeper infiltrating tumor and advanced clinical stages. A total of 1206 patients with primary GC, who were diagnosed by postoperative pathology, between January 2014 and January 2015, at the Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China, were screened in this retrospective study. In total, 816 patients without history of neoadjuvant chemotherapy, radiotherapy and endoscopic submucous resection were included in this study. All tumor samples were fixed in 10% neutral buffered formalin for 24-48 hours and embedded in paraffin. MET and HER2 IHC staining were routinely performed in all tumor samples, and the MET, HER2 IHC slides and the relevant hematoxylin and eosin (H&E) staining slides were assessed independently by two pathologists. Clinicopathological parameters including age at diagnosis, sex, tumor localization, histological classification, Lauren's classification, pathological TNM stage and clinical stages were also recorded.A total of 240 formalin-fixed paraffin-embedded samples were randomly selected to construct tissue microarrays (TMA). Two tumor cores of 1.0 mm diameter were taken from each sample based on H&E staining for conducting IHC staining and dual-color silver in situ hybridization (DISH) analysis.Expression of MET was evaluated by IHC analysis using rabbit monoclonal primary antibody against MET . Automated IHC was performed on 4-μm-thick sections using the Ventana Benchmark ULTRA automated slide processing system according to the manufacturer's instructions. A 4-step scoring system was used as follows: no cell membrane and/or cytoplasm staining or cell membrane and/or cytoplasm staining in < 10% of tumour cells (score 0), faint/barely perceptible partial cell membrane and/or cytoplasm staining in > 10% of tumour cells (score 1+), weak-to-moderate staining of the entire cell membrane and/or cytoplasm in > 10% of tumour cells (score 2+), and strong staining of the entire cell membrane and/or cytoplasm in > 10% of tumour cells (score 3+). MET overexpression negative is defined for patient with IHC staining scores of 0, 1+ and 2+, and positive if IHC staining scores of 3+ . The kit contains dual-color-labeled DNA probes, MET gene (labeled with Spectrum Black) and CEP 7 . Pretreatment was carried out with the Paraffin Pretreatment Kit. The MET signals and CEP 7 signals of 20-40 nuclei of gastric tumor cells in different areas were counted using a LEICA DM3000 light microscope ×400. The MET/CEP 7 ratios were interpreted as follows: a MET/CEP 7 ratios≥2 was defined as amplification of the MET gene, while a ratio lower than 2 was defined as no amplification of the MET gene  analysis was carried out with the Both the IHC scoring and DISH analysis were performed microscopically by two independent pathologists who were blinded to the clinical characteristics of each individual patients. The case-by-case final consensus result was discussed and determined in a common session.Statistical analysis was carried out using SPSS 21.0 statistical software . Statistical associations between clinicopathological characteristics and MET status were assessed using the χ2 test or Fisher's exact test (if subgroup figure is below expectation). All tests were two-sided, with significance level of 0.05. Kappa analysis was also conducted to assess the concordance of MET overexpression and MET gene amplification.


The c-Met receptor, also known as the HGF receptor, is one of the most studied tyrosine kinase receptors, yet its biological functions and activation mechanisms are still not fully understood. c-Met has been implicated in embryonic development and organogenesis, in tissue remodelling homeostasis and repair and in cancer metastasis. These functions are indicative of the many cellular processes in which the receptor plays a role, including cell motility, scattering, survival and proliferation. In the context of malignancy, sustained activation of c-Met leads to a signalling cascade involving a multitude of kinases that initiate an invasive and metastatic program. Many proteins can affect the activation of c-Met, including a variety of other cell surface and membrane-spanning molecules or receptors. Some cell surface molecules share structural homology with the c-Met extracellular domain and can activate c-Met via clustering through this domain , whereas other receptor tyrosine kinases can enhance c-Met activation and signalling through intracellular signalling cascades . In this review, we provide an overview of c-Met interactions and crosstalk with partner molecules and the functional consequences of these interactions on c-Met activation and downstream signalling, c-Met intracellular localization/recycling and c-Met degradation. The stronveyors  , including the receptor, PTPs density-enhanced phosphatase 1 (DEP1), the non-receptor, PTPs PTP1B, leukocyte common antigen-related (LAR) and T-cell PTP (TCPTP), act as antagonistic c-Met partners in order to prevent prolonged c-Met signalling ,20,21.Activation and crosstalk between several signalling pathways has been described following stimulation of the c-Met receptor with its ligand, HGF, leading to a global change in gene expression ,23.C-terminus [The mitogen-activated protein kinases (MAPKs) and the extracellular signal-regulated kinases (ERK1/2) are among the major c-Met executors downstream of c-Met activation and interaction with docking molecules . Two maiterminus  and one terminus . Both ofterminus ,7,8,9,26terminus ,27. Alteterminus ,29,30. Sterminus ,32.et al. demonstrated that internalization and degradation was dependent on c-Met binding to the endophilins, CIN85 and Cbl, through a process of clathrin-coated vesicle formation [et al. and provided evidence that the signalling adaptor protein, Grb2, is required for c-Met endocytosis [et al., who showed that the translocation of c-Met from the endosomal compartment to the perinuclear compartment is dependent on PKCα, and inhibition of PKCα resulted in a decreased signalling of c-Met to STAT3 [p-ERK1/2 accumulation at focal complexes upon c-Met activation [As with all growth factor-induced receptors, ligand-induced signalling through c-Met is tightly controlled. One of the control mechanisms comprises the rapid internalization and degradation/recycling of the receptor in a process called receptor-mediated endocytosis . The rapormation . Howeverormation . A pivotocytosis . Other focytosis , sortingocytosis  and the ocytosis   on the cell membrane [Other CD44 isoforms have similarly been shown to promote c-Met function. In prostate cancer cell lines, HGF-dependent activation of c-Met stimulated hyaluronan/CD44v9 signalling, which stabilized the androgen receptor and promoted its function . Singletmembrane . The CD4Integrins are heterodimeric membrane receptors responsible for the adhesive interactions between the cell and its surroundings, including the extracellular matrix and neighbouring cells . They exThe crosstalk between c-Met and integrins is complex and involves a reciprocal regulation that can be ligand-dependent or -independent and signalling to similar downstream signalling molecules, leading to enhanced activation of those molecules and a c-Met-dependent transcriptional regulation of integrin expression .The best-studied integrin receptor in relation to c-Met signalling is probably the α6β4 receptor, which binds laminin. Although both receptors can individually promote invasion , severalet al. reported that in epithelial cells, fibronectin promoted the association between α5β1 integrin and c-Met, leading to c-Met phosphorylation and increased Src and FAK activation [c-Met was found to associate with other integrins, including the β1 integrins, and, thereby, promoted an invasive program or induced kidney development ,83,84,85tivation . Interestivation ,130.Together, these data demonstrate that a variety of integrins and, by implication, cell adhesion can positively influence c-Met signalling. The interaction between other RTKs and integrins has been studied in more detail and revealed more details on how integrins and the extracellular matrix can regulate RTK function . For exaet al. first showed in human salivary gland cells that CD151 associates with c-Met and α3 or α6 integrin subunits, enhancing HGF/c-Met signalling to promote cell migration and proliferation [et al. revealed that CD151 associates with the c-Met receptor to drive β4 integrin phosphorylation and facilitated the coupling between c-Met and Gab1–Grb2 to promote MAPK phosphorylation and tumour growth [c-Met was also found to interact with members of the tetraspanin superfamily of membrane-spanning proteins. These molecules are known for their tight association with integrins and can modulate their function, possibly through compartmentalization of integrins . It is tferation . Similarferation . In GTL1r growth .Conversely, many publications have demonstrated an inhibitory role for the tetraspanin CD82 in c-Met signalling ,74,75,76vice versa and that amplification or activation of c-Met contributes to chemoresistance. RTKs comprise a family of 58 proteins [As signalling from RTKs is often amplified in human cancers, many therapeutics aim to target and inhibit RTKs. Using such inhibitors, it has become obvious that c-Met plays an important role in activating or potentiating the response of other RTKs or proteins  and the proteins . Ligand-proteins .et al. analysing this crosstalk revealed that in epithelial cancer cells, but not in “normal” liver cells, c-Met was constitutively phosphorylated upon TGFα and EGF exposure in the absence of HGF [et al. confirmed the findings of Jo et al. and, in addition, revealed that overexpression of TGF-α could confer resistance to EGFR inhibitors through enhancing the EGFR/c-Met interaction and c-Met phosphorylation [et al. using xenograft models. Where H1993-derived tumours reacted to combination therapy by promoting apoptosis and suppressing proliferation, H1373-derived tumours only responded with decreased proliferation [A large number of publications describe EGFR and c-Met crosstalk in which either RTK can promote the function of the other RTK and/or converge at similar hubs in their signalling pathways. One of the first reports by Jo e of HGF . The aute of HGF . A coopee of HGF ,138. As rylation . EGFR inrylation ,89, and rylation ,98,139. feration . Severalferation ,100,101.feration , pointinferation ,143. EGFferation ,96, a prferation .et al. revealed differential functional consequences in a cell line that overexpresses c-Met upon heterodimerization between c-Met and RET, EGFR, Her2 or Her3 [Similar reciprocal relationships were found between c-Met and the EGFR family members, Her2 and Her3 ,104,105, or Her3 . Loss of or Her3 . These rc-Met mRNA expression levels [Other membrane spanning molecules that affect c-Met function or that are affected by c-Met interaction are mucins and death receptors. Mucins are transmembrane glycoproteins, and tumour-associated Muc1 has been shown to be important in activating signal transduction pathways to promote invasion, metastasis, proliferation and chemoresistance . As oppon levels , suggestActivation of RAF/MEK/ERK and the PI3K/PDK/Akt promotes proliferation and survival, while preventing apoptosis . Via actIt is clear that c-Met function is dynamically regulated and modulated by its localization, through protein modifications and interaction with a large variety of signalling molecules, co-receptors and other membrane molecules. These interactions can greatly affect the way c-Met reacts to its ligand, HGF, but can also change the way in which c-Met will react to drug strategies that are designed to inhibit c-Met function. Inhibiting c-Met alone might not be enough to fully inhibit the c-Met signalling cascade, as other RTKs might take over this function or RTKs or other cell membrane receptors simply transactivate c-Met in a ligand-independent manner. Inhibiting multiple cell surface molecules , including c-Met, might therefore have some therapeutic potential. Trials in which c-Met and the EGFR are targeted simultaneously reveal that some NSCLC  patients responded with an increased progression-free survival and overall survival, although in some patients, dependent on the molecular alterations in their genome, worse outcomes were noted ,149. OthIn conclusion, a better understanding of the c-Met interactors and the consequences of these interactions on c-Met signaling will help in the design of novel therapeutic strategies and in understanding the shortcomings of current strategies, including drug resistance.