Characterisation of epitopes, including relationship between linear and conformational epitopes, is an essential task for understanding the basic molecular mechanisms of food allergy.The aim of this study was to investigate the importance of linear versus conformational antibody epitopes of the three cow's milk allergens; β-lactoglobulin (BLG), α-lactalbumin (ALA) and β-casein.Specific antibodies were raised in a Brown Norway (BN) rat model of food allergy. BN rats were dosed either (1) intraperitoneally (i.p.) with the purified native cow's milk allergens with or without the use of Al(HO)3 as adjuvant or (2) orally with skimmed milk powder without the use of adjuvant. The specific IgG1 and IgE antibody responses were analysed against native and denatured allergens by means of different ELISAs.A decrease in antibody reactivity towards the denatured allergen compared to the native allergen was seen for all three cow's milk proteins, independent of the administration route. This shows an importance of conformational epitopes for all three allergens. The specific antibody response towards denatured BLG was statistically significantly lower than towards native BLG. The BLG results showed that about 15 times more antibodies were raised against conformational epitopes compared to linear epitopes and that this was independent of the administration route. In contrast, the specific antibody response towards denatured β-casein was shown not to be statistically different from that of the native protein, again independent of the administration route. Here only around half of the antibodies seemed to be raised against conformational epitopes. Whereas both BLG and β-casein showed no differences between administration routes, ALA showed a statistically significant difference between the denatured and native allergen state, only with the use of i.p. administration. Here more than 50 times more antibodies had been raised against conformational epitopes compared to linear epitopes. In contrast, this number was only 4 times when dosing via the oral route. Moreover, the study showed that use of adjuvant strongly influenced the importance of conformational epitopes, as Al(OH)3 increased the reactivity towards linear epitopes.Collectively the study shows that the role of conformational epitopes greatly depends on the individual allergen, the use of adjuvant, and may for some be affected by their structural stability.


Thrombosis Journal would like to thank all of our reviewers who have contributed to the journal in Volume 13 (2015) and whose valuable support is fundamental to its success.The Editors of  Robert AriensUKJuan BadimonUSAErik BeckersNetherlandsLars BorrisDenmarkAnnemieke BoumanNetherlandsSuzanne CannegieterNetherlandsMario M D'EliosItalyMatteo Nicola Dario Di MinnoItalyMarcello Di NisioItalyJonathan DouxfilsBelgiumWilliam FisherCanadaSatoshi FujiiJapanAlexander GallusAustraliaEsteban GandaraCanadaHadi Goubran MessihaCanadaJosé Govers-RiemslagNetherlandsNil GulerTurkeyKarly HamulyakNetherlandsYvonne HenskensNetherlandsMasahiro IekoJapanDavid JiménezSpainFrederikus KlokNetherlandsTakao KobayashiJapanAmartya KunduUSASeiji MadoiwaJapanHarry MagnaniNetherlandsKarina MeijerNetherlandsMarco MoiaItalyMashio NakamuraJapanMarisa NinivaggiNetherlandsMichael NurmohamedNetherlandsToshiyuki OjimaJapanMarina Panova-NoevaGermanyRon PistersNetherlandsDomenico PriscoItalyJürgen ProchaskaGermanyTomohiro SakamotoJapanMasato SakonJapanCarlos Santos-gallegoUSANobuyuki SatoJapanCraig SeamanUSAToshiro ShinkeJapanTomonori SugiuraJapanHiroyuki SumiJapanHideyuki TakedaniJapanHiroki TanakaJapanArina Ten Cate-HoekNetherlandsKazuo UmemuraJapanNaoki UnnoJapanTom van der HulleNetherlandsNick Van EsNetherlandsMinka VriesNetherlandsJeanine WalengaUSAMark WalshUSATheodore WarkentinCanadaSiegfried WieshammerGermanyKristien WinckersNetherlandsYi WuUSAAizhen YangChinaUrooj ZafarUSA


Staphylococcus aureus and coagulase-negative Staphylococcus are the most common pathogenic bacteria for SSI after vascular surgery. Although SSI in vascular surgery often lacks of typical clinical characters, some clinical symptoms, laboratory data and certain imaging procedures may help to diagnose. In most cases of SSI after vascular procedures, the artificial grafts must be removed and sensitive antibiotics should be administered. However, for different cases, personalized management plan should be made depending on the severity and location of SSI.Surgical site infection (SSI) is an important component of infections acquired from hospital. The most significant feature of vascular surgery different from other surgeries is frequent application of artificial grafts. Once SSI occurs after vascular operations with grafts, it might results in a serious disaster.  Besides has the general characteristics of other surgical disciplines, vascular surgery is characterized in that a variety of artificial graft  are widely used in clinical. Most vascular surgical operation is clean operation, but the chance of infection is usually increased, due to the application of artificial graft, and that vascular surgery patients are often elderly, and may be combined with a variety of internal medicine diseases such as diabetes, hypertension and heart disease, immune disease, weak body resistance. Once surgical site infection (SSI) is induced, the consequences would be disastrous. It’s not enough, sometimes, with antibiotic therapy alone for graft infection, and if necessary, removal of the infected vascular graft and revascularization pathway have to be operated -3, other2.Staphylococcus aureus and coagulase-negative staphylococci are the most common pathogens of vascular surgery SSI. According to statistics, both early (within 4 months after operation) and late (more than 4 months after graft infection), one forth to a half risk is caused by Staphylococcus aureus, gram-negative bacteria, and fungal infections are rare, generally only occurs in immunosuppressed patients (Table 1) [Table 1) .2.1The epidermis is the main source of bacteria. The graft surface can be contaminated by microbe through the following 3 ways: (1) Through transplantation of direct planting. An important way for the occurrence of the operation process of bacteria; and sweat glands, lymph node contact; graft and artery wall lesions connected; intestinal grafts or exudate pollution, exposure to injury or open gastrointestinal or genitourinary tract. (2) Through the operation incision. (3) By blood or lymphatic spread.2.27 colony forming units (CFUs) of Staphylococcus aureus, experimental animal almost 100% in postoperative graft infection [The spread of bacteria by hematogenous pathway and planted in the graft or endovascular stent graft infection occurred is a common cause, but it is a very important mechanism. The animal experiments, perfused 10nfection  occurredinfection . After s2.3Because of the skin, gastrointestinal or genitourinary tract pollution, vascular graft infection can be caused around.3.3.1Vascular graft infection is lack of typical clinical manifestations, such as aortic graft infection, may be manifested as unexplained bacteremia, or simply manifested as abdominal distension and muscle tension; lower extremity, groin or neck vascular transplantation, if graft infection can appear to invade surrounding tissue, vascular grafts exposed around the tumor, wound drainage sinus formation or pulsatile anastomotic aneurysm. In short, as long as there are no signs suggesting vascular graft infection, should be further examined.3.21, Table 2) [Once the vascular graft infection, the patient may have inflammation phenomenon of fever, white blood cell counts increased, erythrocyte sedimentation rate higher nonspecific  . Routine3.3Using vascular ultrasound, CT and MRI, can be detected in vascular plants infected graft shift caused by the abscess or anastomotic aneurysm, selective joint use of such special vascular examination, diagnosis of vascular graft infection sensitivity can reach more than 80%, the specificity was 50% ~ 90%, and to help determine the surgical approach and the scope of 3; angiography in the planning of treatment has a guiding role; on suspicion of aortic graft infection patients must be two-way angiography, in order to understand the host and graft patency by the extent of infection and the proximal and distal vessels, in order to make further treatment.4.3) [Without the use of artificial vascular surgical operation shift plant, the postoperative SSI treatment is same with other disciplines, including the principle of surgical debridement, washing, dressing and antibiotics when necessary. The use of artificial graft vascular surgical operation of plants, if SSI, has the special treatment, the standard surgical treatment plant blood vessel graft infection is: removal of the infected vascular graft, for extra anatomic bypass graft. But because of graft infection at different degree and scope, clinicians should according to the specific circumstances of vascular graft infection, to develop individualized treatment (Table 3) .4.1Local treatment of plant blood vessel graft infection includes transplantation of vascular bed to infection fully debridement and drainage, need debridement, remove of purulent necrotic tissue, and the persistent aortic stump debridement treatment. Positive vascular graft is an effective local treatment of retained vascular grafts, reduce the basis of amputation. Through effective treatment, 70% cases can be successfully preserved vascular graft -8.Vascular graft infection is widespread or involving the anastomosis, artificial blood vessels should be removed, both ends of the artery by single strand suture. Persistent aortic wall and surrounding tissues, especially in the presence of suppurative change or pseudoaneurysm arterial wall, should debridement to normal form artery, artery stump covered with sterile tissue with activity. Artery debridement must be used to confirm the histological examination, such as arterial wall bacterial cultures were positive, need long-term antibiotic therapy.The removal of residual bed infection of vascular graft, thoroughly debridement, removal of necrotic tissue purulent, until the normal tissue exposure, the wound, the closed negative pressure drainage tube, do sufficient drainage.4.25 units (CFUs), cloning is possible in situ transplantation of blood vessel [2) [The occurrence of vascular graft infection, limb collateral circulation only when fully established, only consider the simple removal of infected vascular grafts, without vascular reconstruction. But such cases are rare, usually removed vascular grafts were performed after revascularization. The general remove of the infected vascular graft, the need for extra anatomic bypass grafting, in order to save the organs and limbs. After removal of the infected graft, in situ with autogenous vein, artery allograft or antibiotic containing artificial blood vessel revascularization, extra anatomic bypass graft compared with more standard, simplify the operation process, shorten the operation time, improve the superiority and graft patency rate. But for in situ vascular transplantation, prone to infection and infection of retransplantation vascular anastomosis, so only without systemic infection, and perivascular per gram of tissue culture of less than 10d vessel -11. RevaThe general remove of the infected vascular graft, the need for extra anatomic bypass, in order to save the organs and limbs. The following is the classification of treatment according to different parts of the vascular graft infection.4.2.1The aorta and iliac artery vascular graft infection, the most reasonable treatment principle is: first the right axillary artery to bilateral femoral artery bypass surgery; complete dissection, with sterile dressings covering all the wounds, and then open the complete removal of vascular graft infection. In extra anatomic revascularization, should be heparin therapy; artificial blood vessel and remove the infection, with heparin antagonists.The extra anatomic bypass surgery and postoperative complications, statistical data shows that: the operation mortality was 11% ~ 27%, the amputation rate occurred as 9%~27% ,13, so a4.2.2Aorta bilateral femoral artery graft infection treatment is difficult, because the inguinal region of vascular graft infection, affect the lower limb blood supply, for extra anatomic bypass reconstruction, the distal anastomosis should be built in the deep femoral artery or superficial femoral artery to artery, even, in order to avoid the occurrence of lower extremity ischemic necrosis. The graft should choose diameter greater than 5mm or PTFE artificial blood vessels of saphenous vein.Occurred in the late postoperative and localized in the inguinal region of vascular graft infection, can be considered part of the partial resection of the infected vessels, after thorough debridement, in situ revascularization; postoperative intravenous antibiotics for 2~4 weeks, and continued to take 3 months.4.2.3Inguinales artificial vascular bypass vascular graft infection, are generally required to remove the artificial blood vessel. The treatment should follow the principle of treatment of vascular aortic graft infection, although the mortality rate is low, but the possibility of amputation is higher than 50% -17.Such as the removal of the infected vessels, ankle arterial pressure or forearm pressure greater than 40mmHg (1mmHg = 0.133kPa), suggesting that body can delay the establishment of collateral circulation, graft revascularization, and anti-inflammatory treatment, control of infection after revascularization, again to increase vascular grafting patency rate, reduce complications.4.2.4Intrathoracic vascular graft infection, the treatment principle is: to remove the entire graft, vascular reconstruction with autologous vascular graft materials as much as possible, and intravenous injection of antibiotics. The remove of grafts, in order to control the proximal vessels, often require incision and median clavicle, cardiopulmonary bypass.Because the upper limb ischemia underwent transthoracic or extrathoracic bypass surgery, and the occurrence of vascular graft infection, resection of the infected vascular graft, generally do not need immediate revascularization; because the upper limb necrosis due to ischemia and rarely occur. Re revascularization in complete control after infection, and can increase the success rate of transplantation operation.Carotid artery bypass vascular graft infection, artery ligation in general can’t tolerate simple, only when the carotid stump pressure is greater than 70mmHg, it can only simple ligation of common carotid artery and internal carotid artery . But in Carotid endarterectomy artificial patch infection, should be artificial patch resection of the carotid artery, using autologous vascular patch, in the process of operation, the carotid artery bypass is safe and effective measures of cerebral blood flow.4.2.5Staphylococcus aureus, artery plants and infection involving the shift treatment including removal of the cavity, parallel extra anatomic bypass, according to different parts of the vascular graft infection. Select the vascular reconstruction schemes of different [The endovascular exclusion in the surgical trauma, the intestinal tract and other organs significantly reduce interference, shorten the operation time, intraoperative and postoperative blood transfusion without the above factors, significantly reduce the chance of graft infection. Therefore, intraluminal vascular graft infections are more rare. But the endoscopic operation of complex technology and instruments are more numerous, the need for surgery in the DSA, so as to increase the chance of graft infection. Once the endovascular graft infection, often associated with sepsis and infection of the aneurysm and thrombus shedding bacteria, the most common pathogenic bacteria were ifferent .Antibiotic-loaded PMMA beads may serve as an adjunct in the management of VSSIs and may also expand treatment options for graft preservation or in situ reconstruction, with expected recurrent infection rate approaching 20%. Further experience with this adjunct may help elucidate its role in the management of this complicated problem, including the need for bead exchanges, until perigraft cultures are free of microbes.


On January 1st, 2009, we started our editorial adminstration of the Brazilian Annals ofDermatology (ABD). Next December 31st, 2015, it will be terminated. It has been 7 years ofhard work and dedication, with the competent associate editors Andrelou Vallarelli, RenanBonamigo and Vitor Reis.In March 2009, after 38 years of deindexation and several efforts of the editorial teamthat preceeded us, headed by our colleague Prof. Bernardo Gontijo, ABD finally returned tothe main and longed base PubMed/MEDLINE. This was an achievement of great importance.Currently, a mean of more than 400 new articles per year are submitted from Brazil and fromcountries all around the world. In the last 7 years, over 1400 articles were published,besides 5 supplements.The impact factor has risen steadily and, hopefully, soon the journal will no longer be B3in Qualis/Capes, gradually reaching better positions. Moreover, we should point out that inSCIELO ranking, ABD has always been placed among the top 10 most accessed journals.Other important achievements happened and should be mentioned, such as in 2009, when weimplemented the online submission system, crucial to an indexed journal in bases of thismagnitude. Also in 2009, a new section was created, the Dermatopathology section. Theformatting of the magazine's cover and pages has been completely restyled since then, thusgreatly improving the visual aspect of our journal. In 2010, we created the new sectionsDermatology Images and Tropical Dermatology Images. It was also the year of the specialcommemorative stamp of 85 years of ABD. In 2011, we began to receive articles with videosso the authors could illustrate their work in a diverse and complete way. In SBD'scentennial, in 2012, we edited a valuable supplement on the historical evolution of ABD.The same was thoroughly made by our team of editors and a section called "Ephemeris",present in all the issues in 2012, also collaborated with the festivities of the SBD'scentennial. In 2013, ABD started to provide open access to their articles not only inSciELO, but also on PubMed Central, reaching international coverage, an important milestonefor foreign readers and a great way to increase its international visibility. In 2014, theEpidemiology and Biostatistics section was created, of great importance to the scientificand academic enrichment of authors and readers. In 2015, the comemorative stamp of the 90years of ABD was made. It was also a year of consolidation of the work developed since2009. Today, ABD have over 120 reviewers, valuable in their opinions, and a competenteditorial production, well-trained and highly dedicated to the journal.I would like to express my deepest gratitude to all the authors who have contributed andcontinue to choose ABD for publication. Special thanks also to the reviewers, the editorialproduction (it's impossible not to mention the dedicated and sweet Vanessa Zampier) and thevarious boards of SBD with whom we lived and we could count on the support. Veryaffectionately, I thank the dear and great friends, the associate editors AndrelouVallarelli, Renan Bonamigo and Vitor Reis. The journal would never have reached such a highlevel and in a relatively short time without them. I will never forget this joint andharmonious work and our beloved and nearly century-old journal, ABD - Brazilian Annals ofDermatology.I foresee a future of glories to the official publication of the Brazilian Dermatology. Itremains my hope that it is the first choice of national authors!My sincere and best wishes to the new 2016 editors. Brasilia, spring 2015. Prof. Dr. Izelda Maria Carvalho Costa


Life (ISSN 2075-1729) since June 2009. Life science as a topic covers a very broad area. We decided to focus the scope of this new journal on the origin of life and the evolution of biosystems such as molecular evolution. Of course any fundamental theoretical topics and experimental discoveries in biology, biochemistry and biophysics will be welcomed also.Our publishing company MDPI  planned to launch this journal International Journal of Molecular Sciences, 23 papers guest edited by the chemistry professor Marie-Paule Bassez were published in the special issue “Origin of Life” [International Journal of Molecular Sciences, and has been guest edited by Prof. Dr. Jack Green and Prof. Dr. Robert Root-Bernstein [Life science is a typical multidisciplinary research field that chemists like me can also participate in. Specifically, the open question of the origin of life can be attacked by scientists, including many curious chemists, physicists and biologists. In another MDPI journal the of Life” . A seconLife (ISSN 2075-1729), I will be pleased to run this journal as a good venue to publish high quality research results and to promote the progress of life science. All kinds of different opinions, theories and experimental findings are welcomed for consideration and publication.Many authors believe the well-known processes of molecular recognition (such as enzymatic processes), protein folding, and molecular self-assembly are driven by energy minimization while I think entropy increase is the main or the exclusive driving force ,4,5. Of Life (ISSN 2075-1729) will be an ideal scholarly avenue to bring such important research achievements to a wide audience.The fundamental problems in science interest a large readership. As an open access journal, Enjoy publishing with us.


From 2004 to 2012 the IEDB curation of journal articles published since 1960 has caught up to the present day, with >95% of relevant published literature manually curated amounting to more than 15 000 journal articles and more than 704 000 experiments to date. The revised curation target since 2012 has been to make recent research findings quickly available in the IEDB and thereby ensure that it continues to be an up-to-date resource. Having gathered a comprehensive dataset in the IEDB, a complete redesign of the query and reporting interface has been performed in the IEDB 3.0 release to improve how end users can access this information in an intuitive and biologically accurate manner. We here present this most recent release of the IEDB and describe the user testing procedures as well as the use of external ontologies that have enabled it.The IEDB,  As an exception, all publications describing the 3D structure of an epitope in complex with its adaptive immune receptor or major histocompatibility complex (MHC) molecule are included regardless of origin of the epitope in order to provide a complete dataset of this particularly valuable type of information. Details describing the curation process put in place and followed by the curation team, including quality controls for accuracy and consistency, have been discussed previously  protein Phl p 1. All experimental assays that characterize the epitope or its recognition by immune receptors are entered into the IEDB, including all negative data. For example, the FEIKCTKPEACS epitope has 15 assays curated from three different references. Details on the gender and age of the host who made the immune response and on the process that led to it  are also captured. Important aspects of antibodies are presented such as isotype, antibody name, clonality, etc. The processes and/or purification steps used to generate epitope-specific T cells, including in vitro restimulation steps are stored. Additionally, the type of assay used and every antigen studied are curated. As often as possible, external authoritative resources are utilized to provide standardized nomenclature and additional richness to the data. Examples include: use of NCBI Taxonomy (http://purl.bioontology.org/ontology/GAZ) for geographic location and the Human Disease Ontology , antibody or MHC molecule to an experimentally tested antigen or epitope. The structure entered as the epitope is limited to the exact entity that was actually tested in the assay or was clearly deduced to be the epitope by the authors. In many cases this is not the minimal epitope and may not be limited to the contact residues of the epitope, but is rather a region containing the epitope. The fields of the IEDB describe the details of these experiments in great detail. First, the epitope structure is designated as either peptidic or non-peptidic. Peptidic epitopes are described by their linear amino acid sequence or as discontinuous amino acids by position within their source protein. Peptidic epitopes having 3D structural data are described by the residues found to contact the antibody, TCR or MHC molecule. Non-peptidic epitopes are manually curated by staff from the ChEBI team ” a “Serpent (snake)”?’) users could choose ‘true,’ ‘false’ or ‘I would have to guess.’ The users had a range of taxonomic knowledge, but all made more correct classifications and showed more certainty when classifying pairs from the IEDB organism tree as compared to the NCBI Taxonomy.The organism tree is based on the NCBI Taxonomy , which cThe Molecule Finder has two top-level branches for peptidic and non-peptidic epitopes. Non-peptidic epitopes are assigned to sources in ChEBI  and dispTo simplify the representation of proteins within the IEDB we now use UniProt  referencThe improvements made to the Molecule Finder benefit the Immunome Browser, which can utilize the reference proteomes as mapping targets. Previously available as an on-demand visualization tool in the IEDB , the ImmIn addition to the most common application of mapping epitopes from different protein variants to a common reference antigen, the Immunome Browser can also map any set of epitopes retrieved by a query to any user-specified protein or protein set. This enables analyses such as which viral epitopes have homologs in the human proteome. Controls to change the mapping criteria and the target protein/proteome to which the epitopes are to be mapped are also provided.It is worth noting that the entire process of redesigning the IEDB was performed under the expert guidance of several consultants, including two usability experts and a graphic artist. The usability experts compared the user interface design to established design guidelines and successful extant interaction metaphors . This idAfter catching up on the curation of in-scope journal articles from the past, the focus of IEDB development for the 3.0 release has shifted toward improving query and reporting interfaces. The goal of this release was to provide intuitive ways to extract biologically accurate information from the large amounts of data now stored in the IEDB. We have here described the main new elements of the 3.0 release, all of which were motivated by user feedback gathered over the years. We believe that such development focusing on the usability of the web site is equally important to the introduction of new capabilities which—while often more exciting to implement from a web site developer's perspective—have little value if they are not actually utilized by the user community.


Hepatic venous outflow obstruction following liver transplantation is rare but disastrous. Here we described a 14-year-old boy who underwent a split right lobe liver transplantation with modified (side-to-side) piggyback technique which resulted in hepatic venous outflow obstruction. When the liver graft was lifted up, the outflow drainage returned to normal but when it was placed back into the abdomen, the outflow obstruction recurred. Because reanastomosis would have resulted in hepatic reischemia, alternatively, a second infrahepatic cavocavostomy was planned without requiring hepatic reischemia. During this procedure, the first assistant hung the liver up to provide sufficient outflow and the portal inflow of the graft continued as well. We only clamped the recipient's infrahepatic vena cava and the caudal cuff of the graft cava. After the second end-to-side cavocaval anastomosis, the graft was placed in its orthotopic position and there was no outflow problem anymore. The patient tolerated the procedure well and there were no problems after three months of follow-up. A second cavocavostomy can provide an extra bypass for some hepatic venous outflow problems after piggyback anastomosis by avoiding hepatic reischemia. There are several vascular complications of liver transplantation diagnosed intraoperatively. Venous outflow obstruction during liver transplantation is a serious problem which may lead to loss of the graft. It can be corrected with a reanastomosis; however, this is potentially harmful due to the necessity of reclamping of hepatic inflow that prolongs the warm ischemia time. Here, a case of hepatic outflow obstruction during a split right lobe liver transplantation with a modified piggyback cavocaval anastomosis technique was described. The problem was solved by an infrahepatic second cavocaval anastomosis without occlusion of the hepatic inflow or outflow.A 14-year-old boy, weighing 24 kg, with hepatic failure secondary to Wilson's disease was admitted for liver transplantation. Physical examination revealed decreased skin tonus, jaundice, malnutrition, oliguria, and depression of mental status. Among laboratory test results, aspartate aminotransferase was 251 IU/L, alanine aminotransferase was 121 IU/L, alkaline phosphatase was 267 IU/L, gamma glutamyl transpeptidase was 56 IU/L, creatinine was 0.7 mg/dL, albumin was 4.1 g/dL, total bilirubin was 31.8 mg/dL, and INR was 1.6. Child-Pugh score was 8 and Model for End-Stage Liver Disease (MELD) score was 25.During the transplant waiting period, a deceased liver was accepted from the National Organ Sharing System for a small baby who had acute liver failure. The full-size liver was divided into two parts as the left lobe was for this small baby and the remaining right lobe with the caudate lobe and retrohepatic inferior vena cava was used for the 14-year-old patient. The graft belonged to a 31-year-old male, weighing 60 kg. The right lobe graft weighed 695 g and the graft to recipient weight ratio (GRWR) was 2.89%.At the back table, the graft was prepared for the modified piggyback cavocaval anastomosis. Supra- and infrahepatic orifices of the graft vena cava were closed with 5/0 polypropylene sutures. It was anastomosed to the recipient's vena cava by side-to-side, under total caval clamping. A 4 cm length anastomosis was performed to the most cranial parts of the recipient's and the donor's vena cava. Anastomosis was accomplished to the anterior wall of the recipient vena cava without removing any slit from the cava. Before the portal anastomosis, preservation solution in the liver was washed out through a small orifice at the corner of the donor's infrahepatic vena cava and this orifice was closed by sutures after wash-out. Portal vein anastomosis was completed and reperfusion was accomplished.The systolic arterial blood pressure was between 70 and 90 mmHg before the implantation and it dropped to 40 mm/Hg following reperfusion and did not recover. The liver became hard and dark, and venous bleeding came out from the cut surface. When we lifted the graft up, blood pressure increased to normal level, the tonus/color of the liver returned to normal, and cut surface bleeding ceased. When we left the graft to the right subphrenic space back, the same bad scenario repeated. At first, to eliminate the possibility of positional occlusion, we filled the right subphrenic space with a compress; however, the liver was not released. Secondly, to exclude the external pressure on the inferior vena cava, we resected the caudate lobe of the graft, but it did not provide any benefit . During Caudal stump of the donor's vena cava clamped and the sutured end was released. The infrahepatic vena cava of the recipient was totally cross-clamped. The graft was lifted up for good drainage during the anastomosis. We performed an infrahepatic anastomosis between the end of the graft's vena cava and the anterolateral wall of the recipient's vena cava. During the procedure, the venous inflow and outflow of the graft were not interrupted. After the new cavocavostomy, the caval clamps were released and the graft was left in the right subphrenic space . SystoliSeveral mechanisms can cause hepatic venous obstruction after liver transplantation. Positional problems can be a reason and placement of tissue expanders behind the graft is an option for correction  and compA similar secondary caval anastomosis during liver transplantation was described in the literature by partial side clamping of the recipient's cava , 7. In tRegardless of the reason, hepatic venous outflow occlusion and its treatment by an additional anastomosis after piggyback liver transplantation have been described in a limited number of studies , 6–8. ThAs a conclusion, an infrahepatic second cavocavostomy is a good option for the intraoperative management of some hepatic venous outflow obstruction without resulting in any additional graft ischemia.


In a previous work , it was The spike-time difference map (STDM) formalism of  uses the


Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA) infections have attracted much research attention. Recent efforts have been made to select manganese transport protein C, or manganese binding surface lipoprotein C (MntC), which is a metal ion associated with pathogen nutrition uptake, as potential candidates for an S. aureus vaccine. Although protective humoral immune responses to MntC are well-characterised, much less is known about detailed MntC-specific B cell epitope mapping and particularly epitope vaccines, which are less-time consuming and more convenient. In this study, we generated a recombinant protein rMntC which induced strong antibody response when used for immunisation with CFA/IFA adjuvant. On the basis of the results, linear B cell epitopes within MntC were finely mapped using a series of overlapping synthetic peptides. Further studies indicate that MntC113-136, MntC209-232, and MntC263-286 might be the original linear B-cell immune dominant epitope of MntC, furthermore, three-dimensional (3-d) crystal structure results indicate that the three immunodominant epitopes were displayed on the surface of the MntC antigen. On the basis of immunodominant MntC113-136, MntC209-232, and MntC263-286 peptides, the epitope vaccine for S. aureus induces a high antibody level which is biased to TH2 and provides effective immune protection and strong opsonophagocytic killing activity in vitro against MRSA infection. In summary, the study provides strong proof of the optimisation of MRSA B cell epitope vaccine designs and their use, which was based on the MntC antigen in the development of an MRSA vaccine.Vaccination strategies for  Staphylococcus aureus (S. aureus) is an opportunistic bacterial pathogen responsible for a diverse range of human infection diseases [S. aureus) that are resistant to vancomycin or multi-antibiotic strategies are now endemic in many health care institutions and communities [diseases  2], inc, incStapdiseases  4] 5]. [5].Stap. [5].Stadiseases . In partmunities  8]This This Stapmunities .S. aureus is achieved by the manganese transport protein complex . Mn. MnS. aufections  14] . He. HeS. auS. aureus.Using recombinant MntC protein plus CFA/IFA adjuvant, we analysed antigen-specific antibody responses from the pooled sera of immunised mice. As shown in S. aureus, the mechanism of antibody immunity was explored. Previous reports indicate that B-cell epitopes, as the least immune unit, are strong enough to elicit a potent humoral immune response without harmful side effects to the human body  of  of 33] oS. aureus have been identified as vaccine candidate antigens such as SEB [S. aureus [Some important protective antigens against h as SEB  and MntCh as SEB . Althoug. aureus  infectio. aureus  41], th, thS. au. aureus .S. aureus, and identified the key effective B-cell immunodominant epitopes of its humoral response. Peptides of MntC113-136, MntC209-232, and MntC263-286, as the immunodominant epitopes, were analysed by sequence alignments and were located on the surface of the 3-d crystal structure of MntC. Furthermore, we provided preclinical evidence for a polypeptide vaccine based on the three immunodominat epitopes of MntC against S. aureus as a component of a potential multi-antigen prophylactic anti-staphylococcal vaccine. Immunisation with the polypeptide vaccine, which contained three immunodominant epitopes, was able to confer protective effect against S. aureus disease in S. aureus bacteraemia infection, as assessed by an evaluation of survival rates, antibody response, and opsonophagocytic activity. In conclusion, these results indicated that three novel immunodominant epitopes–MntC113-136, MntC209-232, and MntC263-286 –played a vital role in the protection of MntC and could be a rational, cost-effective, and simple component in the development of a design for an epitope vaccine against S. aureus infections.In this study, we verified the immune protective efficacy of the rMntC antigen of S1 FigSchematic diagram showing the primary structure of rMntC (A); Purified recombinant protein (rMntC) analysed by SDS-PAGE (B) and gel filtration(C).(TIF)Click here for additional data file.


This study aimed to evaluate the feasibility of total endovascular repair of the aortic arch in pigs using improved integrated double-branched stent grafts.Improved self-expandable stent grafts with a main body and two integrated branches were prepared for the repair of the aortic arch in six pigs. The feasibility of using these stent grafts was evaluated with arteriography, computed tomography (CT), computed tomography angiography (CTA) and autopsy three months following the procedure.The double-branched stent grafts were placed successfully in the aortic arch in all six pigs. All pigs survived for at least three months and their biological behaviour was normal. Arteriography, CTA and animal necropsy revealed good fixation in all cases. Aortic valve function and coronary ostia remained intact, and CT of the head did not detect any lesion of cerebral infarction.Endovascular repair of the aortic arch with an integrated double-branched stent graft is safe and feasible in animal studies. Aortic arch diseases including aortic dissection and aneurysm contribute substantially to morbidity and mortality. Currently, surgery remains the main treatment for aortic arch diseases. Despite recent advances in traditional surgical techniques and anaesthetic management, the surgical repair of the thoracic aorta is still associated with significant mortality and morbidity, probably due to related surgical trauma.Endovascular management of arch vessels consists of two approaches: hybrid operations and total endovascular repair without open revascularisation of the arch vessels prior to stent graft insertion. The latter approach comprises three techniques: in vivo fenestrated stent grafts, the chimney stent graft technique and homemade fenestrated plus branched stent grafts. Application of these techniques allows a greater number of individuals to undergo endovascular repair of the aortic arch.We have developed a new method of managing supraarch vessels in which an improved integrated stent graft with side branches for these vessels is employed. This study aimed to evaluate the feasibility of total endovascular repair of the aortic arch using the custom made integrated double-branched stent graft in a porcine model.Six domestic hybrid pigs weighing 31–40kg  were provided by the laboratory animal research centre of the Second Military Medical University (SMMU). The study was approved by the ethics committee of the SMMU and all animals received humane care throughout the study.® . The thickness of the graft was about 0.1mm. The size of the stent graft was customised based on the size of the target vessels measured via preoperative arteriography. The external diameter of the stent graft was 20% larger than that of the proximal and distal landing zones of the target vessels as such an oversized design was able to achieve better fixation.A self-expandable integrated stent graft was designed that consisted of two branches for the two supra-arch branch vessels and a main body for the aortic arch of pigs . The rawThe delivery system consisted of an inner (soft) and an outer (stiff) sheath. The stent graft was compressed evenly and tied with a control wire passing through crossed bundling coils. It was then crimped to fit into the inner sheath. Each branch of the stent graft was folded in a protective cap adhered to the traction wire . The outOn delivery, the outer sheath was pulled back. The system thereby became flexible and was located in the correct position of the aortic arch. The stent graft remained in the folded state when the inner and outer sheaths were both withdrawn, which allowed the adjustment of the in vivo location of the stent graft. Only when the control wire was pulled out, did the bundling coils spontaneously untie themselves, and the stent graft was fully released and inserted . The extThere were three parallel independent lumens in the triple lumen catheter. One was for the carrying wire and the other two for the traction wires of the two branches. The triple lumen catheter prevented the wires from becoming twisted during the procedure .® 300; Schering, Berlin, Germany) was injected at a rate of 15ml per second via a 5Fr marked pigtail catheter.The pigs were sedated with an intramuscular injection of ketamine hydrochloride (8mg/kg) followed by induction with intravenous pentobarbital (12mg/kg). After sedation and tracheal intubation, an intravenous injection of heparin (100iu/ kg) was administered to each pig and the sheath catheters were inserted in the right femoral artery of the pigs using the Seldinger method. A total of 25ml of contrast agent  and tracheal intubation. The pigs were placed in the dorsal decubitus position, and the infrarenal aorta, RSA and LSA were exposed surgically.the triple lumen catheter  for five consecutive days to prevent bacterial infection. They also received an anticoagulation regimen . In some cases, they received a preventive anticoagulation regimen instead, which included three days of low molecular heparin  and warfarin , starting from the third day after the stent graft deployment. In addition, the pigs received proper intravenous fluid replacement until regular food intake was commenced.After implantation of the stent graft, the animals were reared for an additional three months before they were evaluated for biological behaviour such as life habit and limb movements. CT of the head without contrast enhancement was performed to identify potential cerebrovascular infarctions. Arteriography and CTA were used to evaluate the in vivo status of the deployed stent grafts in the third month after the procedure. At the end of three months, the pigs were sacrificed and the thoracic aortas were dissected to examine the fixation status of the stent grafts. The arterial segments in which the stent grafts were placed were sectioned, stained with haematoxylin and eosin, and analysed under light microscopy.The details and outcomes of the stent graft deployment are shown in The pigs were followed up for three months and their average weight increased from 35.7kg (SD: 3.2kg) to 45.3kg (SD: 4.0kg). Their postoperative digestive function and biological behaviour remained normal without any sign of motor function deficits, dysarthria, dysphagia or claudication. CT of the head without contrast enhancement indicated no evidence of cerebral infarction.Three months after the operation, arteriography and CTA confirmed the immobilisation of the double-branched stent graft in every pig . None ofAfter the deployment, all blood supply to the brain and upper extremities passed through the branches of the stent graft, which were the narrowest part of the stent graft with an internal diameter of no more than 7mm. To assess whether blood supply to these areas was sufficient, the pre and postoperative arterial blood pressure was measured in the BCT and LSA in the third month after stent graft deployment. The results are shown in p=0.23). Furthermore, there was no significant difference between the postoperative arterial pressure (116.2mmHg [SD: 12.7mmHg]) and the preoperative arterial pressure (120.7mmHg [SD: 13.6mmHg]) in the LSA .There was no significant difference between the average postoperative arterial pressure (115.3mmHg [SD: 11.3mmHg]) and the preoperative arterial pressure (121.0mmHg [SD: 13.8mmHg]) in the BCT  and The Youth Innovation Fund of Fujian Province (grant number 2011J05088).


String-of-beads polypeptides allow convenient delivery of epitope-based vaccines. The success of a polypeptide relies on efficient processing: constituent epitopes need to be recovered while avoiding neo-epitopes from epitope junctions. Spacers between epitopes are employed to ensure this, but spacer selection is non-trivial.We present a framework to determine optimally the length and sequence of a spacer through multi-objective optimization for human leukocyte antigen class I restricted polypeptides. The method yields string-of-bead vaccines with flexible spacer lengths that increase the predicted epitope recovery rate fivefold while reducing the immunogenicity from neo-epitopes by 44 % compared to designs without spacers.The online version of this article (doi:10.1186/s13073-016-0263-6) contains supplementary material, which is available to authorized users. One of the most promising approaches of rational vaccine design uses so-called epitope-based vaccines (EVs). Vaccines based on T-cell epitopes, short immunogenic peptide sequences derived from antigens, offer several advantages over traditional whole attenuated or subunit vaccines . Unlike Rational development of EVs relies on bioinformatics for prediction of viable epitopes. Machine-learning methods, such as probabilistic models, neural networks, and support vectors machines, are routinely used with high accuracy for epitope prediction –5. DiffeNevertheless, the stability and delivery of EVs remain major obstacles. Several strategies have been explored in clinical studies and range from administration of peptide cocktails to assembly of selected peptides into polypeptides . One pop. suggested a genetic algorithm that simultaneously performs epitope selection and assembly  indicates the xth character of sequence S, nc represents the number of amino acids used to predict a cleavage site, and ic, jc denote the start of the segments used to predict the cleavage likelihoods at site ci and cj, respectively. The PSSM ϕC is a 20 × nc matrix, where each row represents an amino acid and each column the position within a sequence of length nc. The entry ϕC of an amino acid a at position i represents the influence of an amino acid at a particular position on the cleavage likelihood. Thus, the log-likelihood of being cleaved is obtained by summing over the entries of ϕC for a given sequence of length nc.Here ., which assumes that each epitope independently influences the immune response with respect to a target population or individual represented by a set of HLA alleles H  fraction of the maximal cleavage score achieved by solving P1. α represents the trade-off between cleavage likelihood and the likelihood of decreasing the immunogenicity score.Here, we restrict P2 to obtain at least ei, ej ∈ E of epitopes with varying spacer length k ∈ {0, …, K}. The design with the highest minimum of both cleavage site likelihoods is selected and the scores obtained are used to initialize a fully connected and directed graph, where the negative cleavage scores represent the weights of the edges between epitopes pairs. Following Toussaint et al., a TSP instance is formulated based on this graph by adding a node that represents the N- and C-termini of the SBV and connecting it with all other nodes with zero edge weights  and the Lin–Kernighan–Helsgaun heuristic [www.epitoolkit.de under Spacer Design [https://github.com/FRED-2/OptiVac. The implementations currently support SYFPEITHI [www.r-project.org). Statistical significance was considered at a significance level of 0.05. Data used in the statistical analysis can be found in Additional files To solve the problem efficiently, the spacer design was parallelized and the TSP solution was approximated using the Lin–Kernighan–Helsgaun heuristic . The modeuristic . The comr Design . The souYFPEITHI , SMM [27YFPEITHI  for epitYFPEITHI  and ProtYFPEITHI  for protα = 0.99. The fold change in cleavage likelihood as well as neo-immunogenicity were compared for concatenated epitopes without spacers, a commonly used fixed spacer (AAY) [To validate the model performance, 1000 random epitope pairs, predicted for proteins of the cytomegalic virus strain AD169 (UniProt Proteom ID UP000008991), were generated and spacers of length 1–6 designed and optimized for the HLA distribution of the European population using er (AAY) , 31, andFor each spacer length, a significant increase in cleavage likelihood could be observed for epitope pairs with optimized spacers compared to epitope pairs without spacers . In addition, the optimized spacers outperformed the constructs with a fixed spacer after a length of two . The maximum increase in cleavage likelihood was achieved with a spacer length of four, which is not surprising since the applied cleavage model uses four C- and two N-terminal amino acids to predict a cleavage site. The use of optimal spacer sequences resulted in a 7.7-fold increase in cleavage likelihood compared to epitope pairs without spacer sequences and a twofold increase compared to epitope pairs with a fixed AAY spacer.In addition, significant improvements could be observed in terms of reduced neo-immunogenicity when using optimized spacers compared to both designs with fixed spacers and without spacers . With increasing spacer length, the immunogenicity decreased when using optimal spacer sequences. An average neo-immunogenicity reduction of 1.9-fold and 2.7-fold could be achieved at a spacer length of four compared to epitope pairs without spacers and fixed spacers, respectively. Detailed results can be found in Additional file l ∈ {3, 5, 10, 15, 20, 25, 30} were selected. The optimal ordering was determined for the string-of-beads construct without (SBV) and with spacer sequences (SBVspacer) for a maximum spacer length of k = 6 amino acids. Additionally, ten randomly ordered strings-of-beads with fixed AAY spacers (SBVAAY) for the given epitope set were generated. This procedure was repeated 50 times for each set size. The junction cleavage likelihood averaged over the number of arising junction sites, the fraction of recovered epitopes , as well as the neo-immunogenicity of the complete construct normalized by the number of included epitopes were compared between the strings-of-beads with a spacer, without spacer sequences, and the average performance of the random constructs with fixed spacers  and recovery rate (1.25-fold increase).The average junction cleavage scores of SBVα. SBVspacer consistently achieved a lower neo-immunogenicity score (average 1.88 ± 0.59) than SBV (average 3.37 ± 0.93) and SBVAAY (average 4.31 ± 0.99), resulting in a decrease of 44.2 % and 56.8 %, respectively.The differences in neo-immunogenicity were not as strong, which is expected due to the chosen value of The optimal spacer length averaged at 3.23 ± 0.50 amino acids. The run time for instances with 30 epitopes was 5 min on average (maximum 5.6 min) on current commodity hardware (12-core Intel Xeon E5-2620 running at 2 GHz). Detailed results can be found in Additional file Several spacer sequences have been proposed in various settings ranging from a prophylactic vaccine to therapeutic cancer vaccine studies , 32–34. . proposed a therapeutic multiepitope polypeptide consisting of HLA-A*02:01 restricted modified epitopes derived from different melanoma-associated antigens (gp100:209–217(210 M): IMDQVPFSV, gp100:280–288(288 V): YLEPGEVTV; Mart1:27–35(27 L): LAGIGILTV; tyrosinase: 368–376(370D): YMDGTMSQV) and showed the proteasomal-dependent efficacy in vitro using the peripheral blood mononuclear cells of healthy donors and patients undergoing treatment [Levy et alreatment . To combT1/2 ≥ 100) and SMM (predicted IC50 ≤ 500 nM) were used for neo-epitope detection. All therapeutic epitopes could be recovered using the in silico designed spacers with a smaller or equal number of neo-epitopes compared to the best experimentally used spacer sequence. While there are differences in detail between the methods, their overall behavior remained the same. Differences can be attributed to variations in the prediction accuracy of the methods , only one out of four epitopes could be recovered, and ALL induced five neo-epitopes spanning the spacer. The Mart1-derived epitope and the combination of SLL and AAY generated neo-epitopes and resulted in the recovery of one out of four epitopes only. Even the design with optimally ordered epitopes and selected experimental spacer sequences could not recover all epitopes and introduced neo-epitopes. To establish the effect of different (linear) epitope prediction methods, the comparison was repeated with different methods (BIMAS  and SMM . [Similar results could be observed for the SBV construct proposed by Ding et al.  (AdditioIn this work, we propose a mathematical model for designing spacer sequences of flexible length for SBVs by exploiting existing proteasomal cleavage and epitope prediction methods. We combined the model with a TSP approach for optimal epitope ordering. We also addressed the problem of neo-epitopes and non-junction cleavage sites arising from spacer sequences and the order of the epitopes within the string-of-beads by extending the formulation with two additional objective functions. To solve the multi-objective optimization problem efficiently, we employ lexicographical optimization techniques.The efficacy of the model was shown by comparing the recovery rates and neo-immunogenicity of optimal designs with commonly used fixed spacer sequences and spacer-less designs. In each case, the optimal design led to increased predicted epitope recovery and reduced generation of neo-antigens.We also compared experimentally tested string-of-beads designs that used spacer sequences with our optimized designs. The experimentally used spacer sequences were often sub-optimally chosen for the connecting epitopes. As a consequence, there were neo-epitopes spanning the spacer sequences or proteasomal cleavage could not be guided to cleave the therapeutic epitopes correctly. In contrast, the in silico designed string-of-beads with optimally determined spacers showed improved cleavage patterns and reduced neo-immunogenicity. Often all therapeutic epitopes could be correctly cleaved without introducing neo-epitopes.An obvious limitation of the current method is its reliance on computational models for proteasomal cleavage and epitope prediction. While models for HLA class I binding prediction exhibit a high accuracy, proteasomal cleavage models still leave room for improvements . CurrentIn conclusion, our method is a first framework that optimally designs both epitope order and spacers for SBV design. The mathematical method employs state-of-the-art prediction methods, but does not depend on specific methods. Our model predicts an increased recovery of desired epitopes and a reduced production of neo-epitopes compared to both fixed spacer and spacer-less designs.


Journal of Negative Results in BioMedicine warmly thank the 51 reviewers whose comments helped to shape the journal, for their invaluable assistance with review of manuscripts in Volume 14 (2015).A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Although final decisions are always editorial, they are greatly facilitated by the deeper technical knowledge, scientific insights, understanding of social consequences, and passion that reviewers bring to our deliberations. For these reasons, the Editor-in-Chief, Managing Editor and staff of  R Abu BakarMalaysiaThawatchai AkaraviputhThailandAlessandro AlessandriniUSAJessica S AnckerUSAMani ArsalanGermanyAline BozecGermanySimon BrillUKEugene ChangUSAHui ChenAustraliaAf CiceroItalyAbdullah Kursat CinguTurkeyAbdullah CingüTurkeyChristopher EarleyUSABjorn EbdrupDenmarkJorg EllingerGermanyGabor ErdoesSwitzerlandSylvia FittingUSAV M FreitasBrazilChristian GentiliSwitzerlandBettina GroetschGermanyThomas HarrerGermanyCheryl Hubley-KozeyCanadaDirk HubmacherUSASabir HussainPakistanKlaus JungGermanyMaria KosmidouGreeceGerhard KroenkeGermanyChristopher KushmerickBrazilKlea LamnissouGreeceStefanie LangGermanyAlejandro Martinez-FernandezSpainDaniel MedeirosBrazilDirk MielenzGermanyS MiyataJapanPretal MuldoonUSABjorn OlsenUSACaroline OwenUSAD PapazoglouGreeceManuela PlateUKIryna ProtsGermanyJuan Carlos Rodriguez-ManzanequeSpainB SchlehoferGermanyFrederico SorianiBrazilAthina TatsioniGreeceTarnia TavernerCanadaMaria ThomsonUSAUlysses TorresBrazilAngelo TroinaItalyDominique VautieraFranceYe WangChinaJanie WilsonCanada


Israel Journal of Health Policy Research (IJHPR) is about to complete its third year of publication. Over the past year, the journal received its first impact factor, three of its articles crossed the 10,000 accesses threshold, submissions increased by 50%, and the journal published its fifth article collection. These accomplishments are due to the combined efforts of the National Institute of Health Policy and its leadership team, IJHPR's editorial board, our publisher BioMed Central, and the journal's authors, commentators and reviewers from Israel and around the world.The IJHPR is also in the process of moving into a new phase; a more mature phase, with greater stability and a firmer place in the professional literature. We hope that this stability can be used as a springboard for further innovation, experimentation and growth.In Jewish tradition, the transition from a new endeavor's third year to its fourth year is full of significance, reflecting a phase transition in terms of maturity and stability. After 3 years of publication,  Israel Journal of Health Policy Research (IJHPR) about to complete its third year of publication, we are pleased to have this opportunity to share some reflections about the year gone by and some of our hopes for the year – and years - ahead.With the IJHPR's most significant achievements during the course of 2014 was that, in July, the journal received its first impact factor from Thomson Reuters. Perhaps more significant than the actual number (1.25) was the speed with which the journal received its first impact factor; it is extremely rare for this to happen during a journal's first three years of publication. Our understanding is that this achievement is due, first and foremost, to the journal's consistency in publishing a steady stream of high quality articles, on a broad range of significant health policy issues. Other important factors were the journal's unique niche, as a journal combining a national focus with international perspectives, and the high production standards maintained by our publisher, BioMed Central.One of a Over 60% of the article accesses are from countries other than Israel. Naturally enough, most of these are from the English-speaking countries – USA, UK, Canada, and Australia. But we are also honored to have large numbers of readers from such countries as India, Brazil and even Indonesia.Another important achievement is that the journal's articles are reaching a wide and diverse audience. Three of our articles –3 have nIJHPR articles.We are also very pleased by another aspect of the journal's diversity – the range of institutions represented among the authors of the journal's articles. Virtually all of Israel's major institutions are well represented, and several prestigious institutions from outside of Israel are also associated with multiple IJHPR's review process has also played a role.In 2014, the journal also experienced a major up-tick in the number of submissions; as of the end of November, we are running 50% above the year-to-date number for 2013 and 100% above the year-to-date number for 2012. The receipt of an impact factor in July, apparently played a major role in encouraging more submissions. It may be that word-of-mouth encouragement from authors who have been pleased with the quality and courtesy of IJHPR has published 140 articles and, as most articles have more than one author, the number of authors who have published with us is substantially greater – approximately 350. We are greatly appreciative of all of those colleagues who have entrusted us with their hard-earned manuscripts, and hope that we have lived up to their expectations. We are particularly appreciative of those colleagues who submitted manuscripts to IJHPR even before it got "on the map" this past July. We look forward to additional submissions from colleagues who have already published in IJHPR and to expanding the circle of contributors to those who have not yet published with us.To date, IJHPR articles) increasingly serve as unique resources for both policy analysts and for scholars engaged in research or teaching about Israeli health care. Links to all these collections can be found at: http://www.ijhpr.org/series.It is also noteworthy that in 2014 the journal published its fifth article collection. It now has collections on the following topics – quality, equity, prioritization, health promotion & disease prevention, and the healthcare workforce. These collections continue to grow; we are pleased to have heard that they  has published its long-awaited report, we hope that IJHPR will receive a variety of submissions related to the committee's analyses and recommendations.As we look forward to the year, and years, ahead, we hope to build on these achievements and to introduce various new features and modes of operation so that we can handle the growing volume of submissions without sacrificing either speed or quality. For example, we are considering publishing special issues on topics of particular interest to Israel and ● The National Institute of Health Policy, the journal's sponsor, which has provided ongoing financial support for the journal● The Institute's leadership team, which has consistently provided us with sage advice and moral support● The journal's editorial board, which has provided vital input at strategic junctures and has also played a significant role in helping us identify appropriate reviewers and commentators● Biomed Central, our publisher, which provides much of the infrastructure that is vital to the journal's smooth operationIJHPR has published to date● The Israeli health policy/health services research community, whose members have authored most of the original research articles (50) and integrative articles (21) that IJHPR commentaries published to date and, in doing so, highlighted the international significance of numerous studies of Israeli health care● Colleagues from abroad, who have authored most of the 66 ● The over 230 reviewers, from Israel and around the world, who have consistently combined rigor and courtesy to provide our authors with first-rate inputWe want to take this opportunity to thank all those whose efforts have contributed to the journal's success, including: In Jewish tradition, the transition from a new endeavor's third year to its fourth year is full of significance. After planting a new tree, it is only in the fourth year that one begins to eat the fruits  . AccordiIJHPR is also in the process of moving into a new phase; a more mature phase, with greater stability and a firmer place in the professional literature. We hope that together with you, our authors and readers, we can use this stability as a springboard for further innovation, experimentation and growth.As editors, we feel that, after 3 years of publication, We hope and believe that the best is yet ahead.Sincerely,Bruce and AviaThe "alltime" access statistics are naturally influenced by how long ago a particular article was published. The IJHPR website also provides a capacity to identify, at any point in time, how often various articles have been accessed over the past year or over the past 30 days. Please see http://www.ijhpr.org/mostviewed for the latest statistics.IJHPR.Avi Israeli is the Dr. Julien Rozan Professor of Family Medicine and Health Care at the Hadassah – Hebrew University Medical Center; Director of the Department of Health Policy, Health Care Management and Health Economics, Hebrew University – Hadassah Braun School of Public Health & Community Medicine; Chief Scientist of the Ministry of Health; and co-editor of IJHPR.Bruce Rosen is Director of the Smokler Center for Health Policy Research at the Myers-JDC-Brookdale Institute, as well as co-editor of


Landoltia punctata is a widely distributed duckweed species with great potential to accumulate enormous amounts of starch for bioethanol production. We found that L. punctata can accumulate starch rapidly accompanied by alterations in endogenous hormone levels after uniconazole application, but the relationship between endogenous hormones and starch accumulation is still unclear.L. punctata can accumulate starch quickly, with a dry weight starch content of up to 48% after 240 h of growth compared to 15.7% in the control group. Electron microscopy showed that the starch granule content was elevated after uniconazole application. The activities of key enzymes involved in starch synthesis were also significantly increased. Moreover, the expression of regulatory elements of the cytokinin (CK), abscisic acid (ABA) and gibberellin (GA) signaling pathways that are involved in chlorophyll and starch metabolism also changed correspondingly. Importantly, the expression levels of key enzymes involved in starch biosynthesis were up-regulated, while transcript-encoding enzymes involved in starch degradation and other carbohydrate metabolic branches were down-regulated.After spraying fronds with 800 mg/L uniconazole, The increase of endogenous ABA and CK levels positively promoted the activity of ADP-glucose pyrophosphorylase (AGPase) and chlorophyll content, while the decrease in endogenous GA levels inactivated α-amylase. Thus, the alterations of endogenous hormone levels resulted in starch accumulation due to regulation of the expression of genes involved in the starch metabolism pathway.The online version of this article (doi:10.1186/s13068-015-0245-8) contains supplementary material, which is available to authorized users. Environmental pollution, global warming, and energy shortages are urgent problems for sustainable development. To gradually decrease our excessive dependence on oil and reduce greenhouse gas emissions, many countries are looking for alternative energy sources. Renewable and clean bioethanol is a promising alternative to oil. However, most feedstocks for bioethanol production are terrestrial crops, such as corn, cassava, and sweet potato, which may compete with food or feed crops for agricultural land and may lead to other environmental problems -3. There2/day dry weight in warm regions [Duckweed, the smallest and fastest-growing aquatic plant on earth , has bec regions , and its regions . The dry regions . Moreove regions ,12. Impo regions , and it  regions ,15. Ther regions , and pla regions -19. Plan regions ,21. To o regions . It can  regions ,24, and  regions . However regions ,27.Landoltia punctata.Next-generation sequencing (NGS) technology is a new development of sequencing technology, and it can provide a novel method to uncover transcriptomics data. It is difficult to research metabolic pathways using conventional biological techniques in non-model plants. However, NGS technologies are not limited to detecting transcripts that correspond to existing genomic sequences, it is particularly attractive for non-model plants with genomic sequences that are yet to be determined ,29. ThisL. punctata 0202, originally collected from Sichuan, China, is a widely distributed duckweed species with great potential for starch accumulation. In this study, frond samples were collected at 13 time points after treatment with uniconazole for measurement of starch percentages and the activity of enzymes related to starch metabolism.As shown in Figure To gain insight into the rapid accumulation of high starch following uniconazole application, the activity of enzymes involved in starch metabolism was analyzed. The activities of two of the most important key enzymes involved in starch synthesis (starch biosynthesis related enzymes AGPase and soluble starch synthase (SSS)) were measured Figure . The actL. punctata were also investigated . To analyze temporal expression patterns of each transcript following uniconazole treatment, all RNA-Seq reads from each L. punctata sample were used for mapping analysis. The expression value of each transcript was calculated and normalized according to the RESM-based algorithm. We identified 70,090, 71,268, 71,170, 75,092, and 95,367 transcripts expressed at 0, 2, 5, 72, and 240 h, respectively , 2,929 transcripts were shared between these four DET sets. Compared with each other in these four DET sets, 5,503 transcripts were shared between 2 vs 0 h and 5 vs 0 h, 6,281 were shared between 5 vs 0 h and 72 vs 0 h, 5,339 transcripts were shared between 2 vs 0 h and 72 vs 0 h, 5,738 transcripts were shared between 2 vs 0 h and 240 vs 0 h, 6,641 transcripts were shared between 5 vs 0 h and 24 vs 0 h, and 10,621 were shared between 72 vs 0 h and 240 vs 0 h.To investigate the genome-wide expression patterns of uniconazole treated Arabidopsis thaliana response regulator (type-B ARR) interacts with the promoter of STAY-GREEN2 (SGR2) and interrupts transcription of the chlorophyll degradation pathway. SGR expression was up-regulated significantly from an initial value of 8.46 to 130.77 FPKM.The transcripts of regulatory proteins and transcription factors involved in the CK, ABA, and GA signaling pathways changed significantly in response to uniconazole treatment Figure . CytokinThe core ABA signaling components have been well described in recent years. The family of START proteins (PYLs) act as ABA receptors, and 13 of 14 members of the Arabidopsis PYL family have been identified. PYL1 and PYL8 were identified in duckweed, and the expression levels of PYL1 increased from 36.88 FPKM at 0 h to 45.27 FPKM at 240 h. The expression of the PP2C negative regulator (comp31119_c0_seq1) decreased from 308.55 FPKM at 0 h to 122.48 FPKM at 240 h. There were no significant changes observed for the expression of transcript-encoding abscisic acid insensitive 4 (ABI4) (comp31717_c0_seq1). The expression was 0.14, 0.22, 0.05, 0.09 and 0.14 FPKM, respectively. The expression of two identical large subunits of AGPase (AGP-LS comp37255_c0_seq1) was up-regulated from the initial value of 122.13 to 192.48 FPKM at 240 h  were down-regulated from 44.03 to 23.93, 28.28, and 33.5 FPKM at different time points. The expressions of transcript-encoding DELLA proteins (comp33138_c1_seq1) were down-regulated from 6.3 to 4.55, 3.05, 3.61, and 2.12 FPKM, respectively. Moreover, the expression levels of transcript-encoding α-amylase were down-regulated from the initial value of 8.03 to 6 FPKM.Starch is the major storage carbohydrate in plants. To investigate the mechanisms by which uniconazole treatment resulted in starch accumulation, the expression patterns of transcript-encoding key enzymes were analyzed Figure . Gene exTranscript-encoding enzymes involved in starch degradation and other carbohydrate metabolic branches were also analyzed. The expression level of transcript-encoding trehalose-6-phosphate synthase , which catalyze the biosynthesis of trehalose using UDPGlucose as substrate, was down-regulated from 78.1 to 18.7 FPKM (comp36386_c1_seq6) at 240 h after uniconazole treatment. Carbohydrate metabolic branches that compete with the synthesis of starch were also measured, including hexokinase (EC: 2.7.1.1), beta-glucosidase (EC: 3.2.1.21), phosphoglucomutase (EC: 5.4.2.2), sucrose-phosphate synthase (EC: 2.4.1.14), and sucrose synthase (SuSy EC: 2.4.1.13). Specifically, hexokinase (comp24929_c1_seq2) was significantly down-regulated from 59 to 18 FPKM at 240 h. No significant increase was observed for the expression of transcript-encoding α-amylase. However, transcript-encoding β-amylase exhibited an expression level of 15 FPKM at 0 h and increased to 309 FPKM at 240 h (comp16912_c0_seq1).L. punctata.Numerous studies have investigated different types of plant growth regulators that regulate growth and development in plants. Some articles focus their investigations on certain stress responses mediated by one or two types of plant hormones -34. ThesL. punctata. The endogenous hormone content changed dramatically following uniconazole application. ABA content increased from 61.47 to 166.53 ng/g (FW), ZR increased from 7.73 to 11.87 ng/g (FW), and the level of GA1+3 decreased from 9.25 to 5.57 ng/g (FW) following treatment (accompanying report). CKs elevated the chlorophyll content by controlling regulatory proteins involved in the chlorophyll biosynthesis signaling pathway. CKs are a class of plant growth substances that promote cell division, chloroplast synthesis, and amyloplast formation [2/m2/s to 22.05 and 25.6 μmol CO2/m2/s in the control and treatment groups, respectively (accompanying report). Thus, the improvement of chlorophyll content and net photosynthetic rate may lead to starch and biomass accumulation in L. punctata.The alteration of the endogenous CK, ABA, and GAs co-regulates starch metabolism in ormation ,45. Furtormation . In the ormation , CKs areormation . The incApL3) gene expression [ApL3) also increased. Importantly, the up-regulated expression of the AGPase large subunit gene strongly supported the improved activity of AGPase, and the increased activity of AGPase promoted starch accumulation in duckweed.ABA up-regulated the expression of AGPase large subunit gene transcription by controlling the expression of regulatory elements of the ABA signal pathway. Studies have shown that ABA can up-regulate AGPase gene transcription in rice suspension cells  and supppression -55. More3 could substantially reduce the activity of AGPase in the growing tubers of potatoes [GAs suppressed the expression of the amylase gene by controlling expression of regulatory factors. A study of GA regulating the growth and carbohydrate metabolism of potatoes showed that GApotatoes ; therefopotatoes ,58. Morepotatoes . In thisThe improvement of starch accumulation following uniconazole treatment was closely associated with the elevated level of endogenous ABA and CK and reduced GA content in duckweed. In this study, high levels of CKs accelerated the biosynthesis of chlorophyll and the net photosynthetic rate, the increased ABA content promoted the activity of AGPase, and the low levels of GAs inactivated amylase. Overall, the alterations in endogenous hormone levels following uniconazole treatment improved starch accumulation in duckweed by influencing the related enzymes involved in carbohydrate metabolism and processes.L. punctata after uniconazole treatment displayed some similarities to grain filling which is a major process of starch biosynthesis and accumulation in seeds. For instance, both processes are rapid and show similar alteration of endogenous hormone levels such as a decrease in GAs and an increase in ABA. In addition, some key enzymes (AGPase and SSS) involved in starch biosynthesis are regulated in a similar way in both processes.The rapid starch accumulation in fronds of L. punctata accumulated rapidly. After culturing for 240 h, the starch content reached 48% in the treated samples and 15.7% in the control samples from an initial yield of 3.2%  and phosphoglucan water dikinase (PWD) are responsible for starch phosphorylation. Β-amylases catalyze the hydrolysis of a-1, 4-glycosidic linkages and release maltose from the exposed nonreducing ends of glucan chains. Α-amylases hydrolyze α-1, 4 linkages within polymers exposed on the surface or in channels within granules, releasing soluble glucans that are the substrate for further degradation ,61. In tL. punctata.In this study, up-regulation of key enzymes in starch biosynthesis, in combination with down-regulation of transcripts of key enzymes related to starch degradation and other carbohydrate metabolic branches that compete with the synthesis of starch, eventually led to the accumulation of starch in Uniconazole has a similar chemical structure to paclobutrazol. It reduces plant growth more than paclobutrazol when applied as a soil drench in equal amounts. On average, the amount of paclobutrazol required is four to ten times that of uniconazole, to obtain a similar effect on plant size . Early rL. punctata 0202 was achieved after uniconazole application in a nutrient-rich environment. The process of starch accumulation was investigated at physiological, biochemical, and transcriptome levels. The increase in endogenous ABA and CK levels further enhanced the activity of AGPase and chlorophyll biosynthesis, while decreased endogenous GA levels significantly correlated with the inactivation of α-amylase. Moreover, uniconazole increased the levels of substrates of starch synthesis and regulated transcriptional expression of enzymes by changing the biosynthesis of endogenous hormones, resulting in starch accumulation in duckweed. Because of the complex interaction among different hormones, the alteration of endogenous hormone levels can provide further insight into the relationship of endogenous hormones to starch accumulation. In this study, an operable process for high starch accumulation in duckweed was developed, paving the way for large-scale treatment of wastewater and the application of duckweed to bioenergy.In this study, high starch accumulation in L. punctata 0202 was originally collected from Sichuan province, China. It was cultivated in standard 1/6Hoagland E+ solution  [2/s and a temperature of 25°C/15°C at day/night. Then, 6 g of fronds were transferred into 1,000 mL 1/6 Hoagland E+ culture plastic containers (23 × 14 × 4.5 cm) for further cultivation over a period of 10 days. Uniconazole powder was produced in Japan and purchased from Aoke Biotech Corp . The concentration of uniconazole used in this study was 800 mg · L−1. To investigate the effect of uniconazole treatment on L. punctata, a 5-mL solution of 800 mg · L−1 uniconazole was sprayed evenly on the surface of fronds. Controls were sprayed with 5 mL water containing 10% methanol. The experiments were carried out with three replicates. Thirteen different time points, including 0, 1, 2, 3, 5, 7, 12, 24, 48, 72, 120, 168, and 240 h after fronds were cultured in solution and were chosen for composition and enzymatic activity assays. For each time point, fronds were collected from three culture plastic containers. Samples collected at 0, 2, 5, 72, and 240 h were frozen in liquid nitrogen immediately for the RNA-Seq study..8 mg/L)  culture The starch content was described as glucose content in total sugar by HPLC -ELSD  using the following method. The starch content was determined using the total sugar content (starch content = glucose content × 0.909). Dry duckweed powder was hydrolyzed with 1.2 M HCl in a boiling water bath. After adjusting the pH to 7 with 10 M NaOH, PbAc was added to precipitate protein. After the solution was measured, filtered, and treated with a C18 extraction column, the hydrolyzate was analyzed by HPLC  with an Evaporative Lightscattering Detector  .2 F20S-Twin, FEI, Hillsboro, USA) at 200 kV after staining with uranyl acetate and lead citrate.Fronds in the uniconazole treatment group and control group were fixed, embedded, and dehydrated as described ,67. Samp2, 2 mmol/L EDTA, 2% (w/v) polyvinylpyrrolidone-40, and 12.5% (w/v) glycerol. The homogenate was centrifuged at 10,000 × g for 5 min. The supernatant extract was used as a crude enzyme solution stored at −20°C. All procedures were carried out at 0 to 4°C. The activities of α-amylase  and β-amylase  were estimated following the method of Tarrago and Nicolas [et al. [To investigate enzyme activity, 1 g fresh weight duckweed was homogenized with a ceramic pestle in an ice-cold mortar in 5 mL of 50 mmol/L HEPES-NaOH (pH = 7.6), 5 mmol/L DL-Dithiothreitol, 8 mmol/L MgCl Nicolas ,69. The L. punctata samples were collected at the 0, 2, 5, 72, and 240 h time points after treatment with uniconazole. For each sample, total RNA was extracted from 200 mg fronds using the OMEGATM Plant DNA/RNA kit  and genomic DNA was digested by DNase I  according to the manufacturer’s instructions. RNA concentration, OD260/280, OD260/230, 28S/18S and RNA integrity number (RIN) were measured with the Agilent 2100 Bioanalyzer or NanoDrop . Qualified total RNA extracted from each sample was submitted to the Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China, (http://www.genomics.cn) for RNA sequencing by Illumina HiSeq 2000 . cDNA fragment libraries were constructed according to the manufacturer’s instructions using the TruSeq RNA Sample Prep kit. Library quality control analysis was performed using the Agilent 2100 Bio-analyzer.Five http://www.bioinformatics.bbsrc.ac.uk/projects/fastqc/) and then de novo assembled using Trinity (v2012-06-08) [The validated 200 bp fragment cDNA libraries were submitted to the Illumina HiSeq 2000 platform for paired-end (PE) RNA sequencing. PE read sequencing quality was assessed by fastqc (2-06-08)  under de2-06-08) . Accordi2-06-08) .http://www.ncbi.nlm.nih.gov/) by Blast2GO with a threshold of E value <103. Enzyme codes were extracted, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were retrieved from the KEGG web server (http://www.genome.jp/kegg/).All contigs assembled by Trinity (v2012-06-08)  were subP values and log2 fold change (log2FC) were calculated, and significantly DETs between each sample set were identified with P value ≤0.05 and log2FC ≥1. Hypergeometric tests based on the KEGG annotation were performed for each DET group identified between each sample set using R scripts  [To analyze the express levels of each transcript at different time points following uniconazole treatment, all PE reads for each sample were used for mapping analysis with Perl scripts in the Trinity package (v2012-06-08)  under deex.html) .Each data point represents the results of three sample experiments; the results are provided as means ± standard error in the figures.


Philosophical Transactions, the world's first scientific journal that is still going strong .The year 2015 has been a year for celebration when Royal Society publishing has marked the 350th anniversary of the first publication of its Open Biology, by contrast, is now an infant of a little over 4 years old but also thriving. Our aim with Open Biology was to establish an open access journal exploring biological systems at a cellular and molecular level of resolution, an area of biology that was underrepresented in the Society's existing journals. Above all, we wanted to have a journal run for cell and molecular biologists by practicing scientists that would bring first class articles to rapid publication without unnecessary rounds of review. We are making excellent progress towards this goal and Open Biology is publishing papers that are catching the attention of the community as evident from its rising impact factor .Now the roots are secure and we need to grow and branch out to reach more authors and readers. To do so, we rely heavily upon the ambassadorial activities of our editorial board and editors. I would like to thank all our editorial board, a particularly important body whose members actively participate in the first screening of papers and in selecting referees. Our hard-working board hail from wide geographical origins and represent all aspects of biology. As 2015 draws to a close, we are sad to say goodbye to Mark Petronczki and Dario Alessi and would like to thank them so very much for their great help in starting the journal. We are delighted to welcome Ilan Davis, Uttam Surana, Oscar Marín, Richard Wood, Ulrike Gruneberg, Ian Lipkin, Nick Tonks and Corrine Houart to join us on the board.The final decision on publication rests with the smaller number of editors and with an increase in papers in Developmental Biology, we have begun to feel the loss of Jim Smith. Jim's wisdom and pragmatism was extremely important in guiding the journal through these early years. For some time, therefore, we have been looking for his ideal replacement and I am now delighted to announce our success in persuading Marek Mlodzik to take on this role.Drosophila as a model for in vivo studies, cell culture experiments and biochemistry. He is very familiar with vertebrate developmental models through his collaborations with colleagues using zebrafish or mouse models. Marek will be a superb representative for the journal among the developmental biology community and his location of the East Coast is very important to us in gaining a greater presence in the USA.Marek is Professor and Chair of the Department of Developmental and Regenerative Biology at the Icahn School of Medicine at Mount Sinai, New York. Marek's lab is well known for its studies of Wnt/Frizzled-planar cell polarity signalling and associated regulatory mechanisms using I hope you will all join me in welcoming Marek to this position. We are greatly looking forward to working with him in preparing for the challenges of 2016 and beyond. Above all, we look forward to reporting lots of successful science from a growing readership.


Since the founding of PLoS Computational Biology, our publisher, the Public Library of Science, has evolved its own gloss from the piquantly camelesque “PLoS” to the modern “PLOS,” matching its equally emphatic journal ONE. As we review the journal, it seemed appropriate to hearken to its uncertain beginnings, embodied even in its quirky typography.‡ PLoS Computational Biology to advance the science of computational biology and its practitioners. Our goals were appreciation and innovation. At the remove of no longer being active in day-to-day activities of the journal, it is wonderful to look back over the first ten years of the journal. Here we reflect on the journal’s evolution and offer a few thoughts for the next ten years.Ten years ago, we founded The journal began at a propitious time, as computational biology engaged markedly more researchers and as scientific publication was beginning a tectonic shift. Many researchers noted a serious gap in the publishing firmament: there was no respected venue that focused on biological discovery made by computational methodology. This lack of appreciation had implications at many levels. At pre-eminent journals, computational biology research was often was not reviewed by those with expertise to evaluate its technical content and significance, leading to delays and rejections. The alternative of publishing at the existing specialist journals often led to publications in venues that were not appreciated by the most appropriate audience. This meant that the work was not seen by many suitable readers, and that computational biologists had greater challenges in their career development.PLoS Computational Biology is now widely appreciated as a treasury of first-class scientific work, offering a respected venue for publication of work fundamental to our field. For researchers at all tiers, but especially trainees, publication venue is too often taken as a proxy for the significance of their research studies. Such individuals have no time for their papers to accrue citations or become well recognized before their achievements are assessed for career advancement. We hope that those who have published in PLoS Computational Biology have met with success comparable to the burnishing their outstanding work has provided for the journal’s reputation.We are pleased that PLoS Computational Biology has succeeded in providing computational biology researchers consistently informed and thoughtful reviews.Even more important, we have been gratified to see researchers in our field have their work treated with respect and insight by reviewers and editors who understand the significance of their research and its approaches. Certainly, in a journal that rejects two-thirds of the submissions, not all prospective authors are happy, and undoubtedly there have been some significant oversights. However, on the whole, we believe that PLoS Computational Biology initially had a scope statement that emphasized the need for biological outcomes. However, as both our journal and bioinformatics journals became more established, the editorial board increasingly felt we should expand the remit to engage pure methods of the greatest significance. The expansion of authors and readers has been clearly enhanced by embracing methods papers.In order to meet the needs of our field’s researchers, our intent was to establish a computational journal that was read by experimentalists and computational researchers alike, and would drive biologists’ interest in the application of computational techniques. Another early motivator was also not to encroach on existing bioinformatics journals, hence, the niche of computation requiring new biological insights. To this end, A pleasant and unexpected surprise was the scientific scope of papers submitted to the journal. For example, we never envisaged that computational neuroscience would become such a vibrant part of the journal. In retrospect, this would seem to be the result of a combination of lack of suitable venues publishing such papers and the hard work of the early neuroscience editors. The scope has continued to expand even as the number of journals competing has multiplied. An imminent challenge will likely be understanding the relationship with biomedical informatics as the line between basic and clinical research blurs in a translational world. A broader challenge will arise as biology becomes ever more a data science: what should the unique role of the journal be as nearly all biologists become computational biologists?The journal began at a time when open access was still considered by most scientists at best a novelty and at worst a business model doomed to failure. Against this backdrop, many computational biologists rallied behind the cause since they were already accustomed to open and free data and software. A particularly important leap was made by the International Society for Computational Biology (ISCB), which was a key founding partner. Not only did ISCB offer a community supporting the journal, but in doing so, they abandoned the very substantial revenues they had previously garnered from partnership from a journal that was then closed-access. Valuing access over profit is to be highly commended.PLoS Computational Biology has the most elevated tier of open access, using a CC-By license. Amongst other benefits, for our community, this offers machine access to the corpus for knowledge discovery, an undertaking that remains at a nascent stage. Let us hope that such value is commonplace and plain for all to see before the next ten-year anniversary.In the ten interceding years, open access has evolved and is now a mainstream publishing option, which has undoubtedly increased access to scientific discourse. Importantly, The front matter has been a wonderful sandbox in which to experiment with scholarly communication. Not all such experiments have been successful, but some clearly have and can be attributed to both filling a need (not necessarily obvious at the outset) and folks who believed in the experiment and who put in many hours of hard work on behalf of the community. The Education section and the Ten Simple Rules professional development series have blossomed beautifully. The jury is still out on the success of other experiments, but they all speak to doing things differently, which has been a hallmark of the journal since day one.The science of computational biology and the dissemination of that science have changed over the past ten years, and the journal has been there to document and enable those changes, and more disruption will follow. The next ten years will see a further broadening of the scope of what is covered by the field of computational biology, particularly as it relates to the generation and use of a broader range of data types by all investigators, with increased emphasis on the use of clinical data. We hope that more of the research life cycle will be shared and captured as part of a publication. If dreams come true, a journal paper will offer a persistent mechanism for further data exploration and be capable of offering a platform for follow-on sets of experiments. We are sure your community journal will be ready for whatever innovations you can bring.It was a privilege for us to work with so many talented authors, reviewers, editors, and staff—and an honor to see our initial efforts taken to such wonderful levels. All have contributed both appreciation and innovation and, in doing so, helped create a community larger than the journal itself. All of their efforts have truly elevated the field and supported us.


Many surgeons currently use long cephomedullary nails for the treatment of intertrochanteric fractures. The optimal indications for deploying distal interlocks are still debatable. This study examined the torsional biomechanical properties of 3-part intertrochanteric femur fractures in a cadaveric bone model using two different distal fixation strategies, an unlocked long cephalomedullary nail versus a dynamically locked nail. Our hypothesis is that a long cephalomedullary nail does not require distal locking fixation when used for treatment of a 3-part intertrochanteric fracture.Five matched pairs of cadaveric femora were randomly assigned to one of two distal fixation treatment groups; a single distal interlock screw placed in the dynamic orientation or no distal fixation. A 3-part intertrochanteric fracture was produced. Specimens were potted and mounted in a double gimbal fixture facilitating unconstrained motion in the sagittal and coronal planes. Specimens were cyclically loaded dynamically in both internal and external rotation. Range of motion, internal and external rotation stiffness, torsion stiffness, torsion yield and ultimate torsion magnitude were calculated.The samples instrumented with a distal locking screw reported statistically greater external rotational stiffness than the unlocked samples in nondestructive testing. The results of the destructive data demonstrated no statistical difference between the locked and unlocked group with regard to yield torque (p = 0.282), peak torque (p = 0.340), stiffness (p = 0.220), displacement at yield torque (p = 0.0605), and displacement at peak torque (p = 0.280).Distal locking of a long cephalomedullary nail increases the stiffness of the nail-femur construct in a 3-part biomechanical fracture model. However, our testing illustrates that an unlocked construct will tolerate at least equal stress before catastrophic failure in a torsional loading model. Hip fractures are the most common fractures among the elderly in the US and are expected to further increase in frequency over the next several decades as the population ages . The nondestructive mean external (ER) and internal (IR) rotation stiffness for intact femurs  were statistically stiffer  compared to fractured locked specimens  and fractured unlocked specimens . In comparing the locked specimens  to the unlocked specimens , the locked specimens had significantly greater nondestructive stiffness in external rotation (p = 0.04); there was no significant difference in internal rotation stiffness , peak torque (p = 0.340), stiffness (p = 0.220), displacement at yield torque (p = 0.0605), and displacement at peak torque (p = 0.280). See Table 82, peak p value of the yield torque, more testing is needed to investigate this hypothesis.In this model of a three-part intertrochanteric fracture, the distally locked group had increased stiffness to external rotation versus the unlocked group in nondestructive testing. However, there was no significant difference demonstrated in the destructive testing. The yield torque was greater for the unlocked specimens (9.38 Nm/°) compared to the locked specimens (6.32 Nm/°); however, this difference was not statistically significant (p = 0.282). This may indicate that by locking the nail the construct becomes too stiff for the native bone; however, given the non-significant Similarly, the displacement to yield also approached clinical significance, and was increased in the unlocked group . This may imply that an unlocked construct can tolerate a greater degree of rotation before plastic deformity; again, however, more testing would be needed to reach statistical significance.These findings are similar to those in our previous study testing torsional stability in locked versus unlocked treatment groups in a two-part intertrochanteric model  were used for this study. Specimens were pre-screened to exclude anatomical defects. Dual energy x-ray absorptiometry was performed on the proximal femur to acquire density data. The specimens were maintained in a freezer at −20°C until approximately 12 h prior to mechanical testing, then thawed to room temperature and skeletonized by careful dissection. All research was carried out in accordance with our institution’s ethical guidelines. As a biomechanical study, it was exempt from direct oversight by an ethics committee.Specimens within each matched pair were randomly divided into the locked and unlocked groups. Each femur was tested without instrumentation and after the instrumented femur had an osteotomy creating a 3-part intertrochanteric fracture . A surgeon trained in the implantation of these treatment techniques performed all surgical procedures in general accordance with the Instructions for Use Guidelines. Proximally, lag screws were placed in the center–center position, as previously described by Baumgartner, for all treatments . A paired t-test was performed to determine whether significant differences exist between the two treatment groups with regard to bone density and T-Score. In all cases, statistical significance was set to p < 0.05 a priori.