359 research outputs found
Low rank positive partial transpose states and their relation to product vectors
It is known that entangled mixed states that are positive under partial
transposition (PPT states) must have rank at least four. In a previous paper we
presented a classification of rank four entangled PPT states which we believe
to be complete. In the present paper we continue our investigations of the low
rank entangled PPT states. We use perturbation theory in order to construct
rank five entangled PPT states close to the known rank four states, and in
order to compute dimensions and study the geometry of surfaces of low rank PPT
states. We exploit the close connection between low rank PPT states and product
vectors. In particular, we show how to reconstruct a PPT state from a
sufficient number of product vectors in its kernel. It may seem surprising that
the number of product vectors needed may be smaller than the dimension of the
kernel.Comment: 29 pages, 4 figure
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Resilience in Healthcare (RiH): a longitudinal research programme protocol
INTRODUCTION: Over the past three decades, extensive research has been undertaken to understand the elements of what constitutes high quality in healthcare. Yet, much of this research has been conducted on individual elements and their specific challenges. Hence, goals other than understanding the complex of factors and elements that comprises quality in healthcare have been privileged. This lack of progress has led to the conclusion that existing approaches to research are not able to address the inherent complexity of healthcare systems as characterised by a significant degree of performance variability within and across system levels, and what makes them resilient. A shift is, therefore, necessary in such approaches. Resilience in Healthcare (RiH) adopts an approach comprising a comprehensive research programme that models the capacity of healthcare systems and stakeholders to adapt to changes, variations and/or disruptions: that is, resilience. As such, RiH offers a fresh approach capable of capturing and illuminating the complexity of healthcare and how high-quality care can be understood and advanced.
METHODS AND ANALYSIS: Methodologically, to illuminate what constitutes quality in healthcare, it is necessary to go beyond single-site, case-based studies. Instead, there is a need to engage in multi-site, cross-national studies and engage in long-term multidisciplinary collaboration between national and international researchers interacting with multiple healthcare stakeholders. By adopting such processes, multiple partners and a multidisciplinary orientation, the 5-year RiH research programme aims to confront these challenges and accelerate current understandings about and approaches to researching healthcare quality.The RiH research programme adopts a longitudinal collaborative interactive design to capture and illuminate resilience as part of healthcare quality in different healthcare settings in Norway and in five other countries. It combines a meta-analysis of detailed empirical research in Norway with cross-country comparison from Australia, Japan, Netherlands, Switzerland and the UK. Through establishing an RiH framework, the programme will identify processes with outcomes that aim to capture how high-quality healthcare provisions are achieved. A collaborative learning framework centred on engagement aims to systematically translate research findings into practice through co-construction processes with partners and stakeholders. ETHICS AND
DISSEMINATION: The RiH research programme is approved by the Norwegian Centre for Research Data (No. 864334). The empirical projects selected for inclusion in this longitudinal research programme have been approved by the Norwegian Centre for Research Data or the Regional Committees for Medical and Health Research Ethics. The RiH research programme has an embedded publication and dissemination strategy focusing on the progressive sharing of scientific knowledge, information and results, and on engaging with the public, including relevant patient and stakeholder representatives. The findings will be disseminated through scientific articles, PhD dissertations, presentations at national and international conferences, and through social media, newsletters and the popular media
Activation and Inhibition of Transglutaminase 2 in Mice
Transglutaminase 2 (TG2) is an allosterically regulated enzyme with transamidating, deamidating and cell signaling activities. It is thought to catalyze sequence-specific deamidation of dietary gluten peptides in the small intestines of celiac disease patients. Because this modification has profound consequences for disease pathogenesis, there is considerable interest in the design of small molecule TG2 inhibitors. Although many classes of TG2 inhibitors have been reported, thus far an animal model for screening them to identify promising celiac drug candidates has remained elusive. Using intraperitoneal administration of the toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly(I∶C)), we induced rapid TG2 activation in the mouse small intestine. Dose dependence was observed in the activation of TG2 as well as the associated villous atrophy, gross clinical response, and rise in serum concentration of the IL-15/IL-15R complex. TG2 activity was most pronounced in the upper small intestine. No evidence of TG2 activation was observed in the lung mucosa, nor were TLR7/8 ligands able to elicit an analogous response. Introduction of ERW1041E, a small molecule TG2 inhibitor, in this mouse model resulted in TG2 inhibition in the small intestine. TG2 inhibition had no effect on villous atrophy, suggesting that activation of this enzyme is a consequence, rather than a cause, of poly(I∶C) induced enteropathy. Consistent with this finding, administration of poly(I∶C) to TG2 knockout mice also induced villous atrophy. Our findings pave the way for pharmacological evaluation of small molecule TG2 inhibitors as drug candidates for celiac disease
Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules
Celiac disease is caused by an abnormal intestinal T-cell response to gluten proteins of wheat, barley and rye. Over the last few years, a number of gluten T-cell epitopes restricted by celiac disease associated HLA-DQ molecules have been characterized. In this work, we give an overview of these epitopes and suggest a comprehensive, new nomenclature
To respond or not to respond - a personal perspective of intestinal tolerance
For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research
MultiRTA: A simple yet reliable method for predicting peptide binding affinities for multiple class II MHC allotypes
abstract: Background
The binding of peptide fragments of antigens to class II MHC is a crucial step in initiating a helper T cell immune response. The identification of such peptide epitopes has potential applications in vaccine design and in better understanding autoimmune diseases and allergies. However, comprehensive experimental determination of peptide-MHC binding affinities is infeasible due to MHC diversity and the large number of possible peptide sequences. Computational methods trained on the limited experimental binding data can address this challenge. We present the MultiRTA method, an extension of our previous single-type RTA prediction method, which allows the prediction of peptide binding affinities for multiple MHC allotypes not used to train the model. Thus predictions can be made for many MHC allotypes for which experimental binding data is unavailable.
Results
We fit MultiRTA models for both HLA-DR and HLA-DP using large experimental binding data sets. The performance in predicting binding affinities for novel MHC allotypes, not in the training set, was tested in two different ways. First, we performed leave-one-allele-out cross-validation, in which predictions are made for one allotype using a model fit to binding data for the remaining MHC allotypes. Comparison of the HLA-DR results with those of two other prediction methods applied to the same data sets showed that MultiRTA achieved performance comparable to NetMHCIIpan and better than the earlier TEPITOPE method. We also directly tested model transferability by making leave-one-allele-out predictions for additional experimentally characterized sets of overlapping peptide epitopes binding to multiple MHC allotypes. In addition, we determined the applicability of prediction methods like MultiRTA to other MHC allotypes by examining the degree of MHC variation accounted for in the training set. An examination of predictions for the promiscuous binding CLIP peptide revealed variations in binding affinity among alleles as well as potentially distinct binding registers for HLA-DR and HLA-DP. Finally, we analyzed the optimal MultiRTA parameters to discover the most important peptide residues for promiscuous and allele-specific binding to HLA-DR and HLA-DP allotypes.
Conclusions
The MultiRTA method yields competitive performance but with a significantly simpler and physically interpretable model compared with previous prediction methods. A MultiRTA prediction webserver is available at http://bordnerlab.org/MultiRTA.The electronic version of this article is the complete one and can be found online at: http://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-11-48
Arctic coastal dynamics of Eurasia – results of two ACD-related INTAS projects : extended abstract
Under the framework of the Arctic Coastal Dynamics (ACD) program two projects of the International Association for the Promotion of Co-operation with Scientists from the New Independent States of the Former Soviet Union (INTAS) focused on ACD related topics.
The objectives of the first project "Arctic coastal dynamics of Eurasia: classification, modern state and prediction of its development based on GIS technology" (2002-2004) had been to develop a coastal classification and to generate GIS based map products for the coastal Zone of the Eurasian Arctic. The Russian Part of the circum-Arctic ACD classification and segmentation has been completed within this project.
The overall objective of the second project "Arctic coasts of Eurasia: dynamics, sediment budget and carbon flux in connection with permafrost degradation" (2002-2005) is to quantify the material flux through coastal erosion in order to improve our understanding of the Arctic sediment and organic carbon budget.
This presentation summarizes the main results of the two projects and provides an overview
of more specific results which are shown in a series of Posters
Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci
Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12 014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case–control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10−16). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10−75). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10−18). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42
Gut microbiota trajectory in early life may predict development of celiac disease.
BACKGROUND: To investigate whether alterations in the developing intestinal microbiota and immune markers precede celiac disease (CD) onset in infants at familial risk of developing the disease. METHODS: A nested case-control study was carried out as part of a larger prospective cohort study, which included healthy full-term newborns (> 200) with at least one first relative with biopsy-verified CD. The present study includes cases of CD (n = 10) and the best-matched controls (n = 10) who did not develop the disease after 5-year follow-up. Fecal microbiota, assessed by high-throughput 16S rRNA gene amplicon sequencing, and immune parameters were profiled at 4 and 6 months of age and related to CD onset. RESULTS: The microbiota of infants who remained healthy showed an increase in bacterial diversity over time, characterized by increases in Firmicutes families, but not those who developed CD. Infants who subsequently developed CD showed a significant reduction in sIgA levels over time, while those who remained healthy showed increases in TNF-α correlated to Bifidobacterium spp. An increased relative abundance of Bifidobacterium longum was associated with control children while increased proportions of Bifidobacterium breve and Enterococcus spp. were associated with CD development. CONCLUSION: The findings suggest that alterations in the early trajectory of gut microbiota in infants at CD risk could influence the immune maturation process and predispose to CD, although larger population studies are warranted to confirm this hypothesis
Increased frequency of the immunoglobulin enhancer HS1,2 allele 2 in coeliac disease
Background: Coeliac disease ( CD) is characterized by increased immunological responsiveness to ingested gliadin in genetically predisposed individuals. This genetic predisposition is not completely defined. A dysregulation of immunoglobulins (Ig) is present in CD: since antiendomysium antibodies (anti-EMA) are of the IgA class. One polymorphic enhancer within the locus control region (LCR) of the immunoglobulin heavy chain cluster at the 3' of the C alpha-1 gene was investigated. The correlation of the penetrance of the four different alleles of the HS1,2-A enhancer of the LCR-1 3' to C alpha-1 in CD patients compared to a control population was analysed. Methods: A total of 115 consecutive CD outpatients, on a gluten-free diet, and 248 healthy donors, age- and sex-matched, from the same geographical area were enrolled in the study. HS1,2-A allele frequencies were investigated by nested polymerase chain reaction (PCR). Results: The frequency of allele 2 of the enhancer HS1,2-A gene was increased by 30.8% as compared to the control frequency. The frequency of homozygosity for allele 2 was significantly increased in CD patients. Crude odds ratio ( OR) showed that those with 2/2 and 2/4 ( OR 2.63, P < 0.001 and OR 2.01, P = 0.03) have a significantly higher risk of developing the disease. In contrast, allele 1/2 may represent a protective genetic factor against CD ( OR 0.52, P = 0.01). Conclusions: These data provide further evidence of a genetic predisposition in CD. Because of the Ig dysregulation in CD, the enhancer HS1,2-A may be involved in the pathogenesis
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