Cohomogeneity one manifolds and selfmaps of nontrivial degree

We construct natural selfmaps of compact cohomgeneity one manifolds with finite Weyl group and compute their degrees and Lefschetz numbers. On manifolds with simple cohomology rings this yields in certain cases relations between the order of the Weyl group and the Euler characteristic of a principal orbit. We apply our construction to the compact Lie group SU(3) where we extend identity and transposition to an infinite family of selfmaps of every odd degree. The compositions of these selfmaps with the power maps realize all possible degrees of selfmaps of SU(3).Comment: v2, v3: minor improvement

FreeContact: fast and free software for protein contact prediction from residue co-evolution

Background: 20 years of improved technology and growing sequences now renders residue-residue contact constraints in large protein families through correlated mutations accurate enough to drive de novo predictions of protein three-dimensional structure. The method EVfold broke new ground using mean-field Direct Coupling Analysis (EVfold-mfDCA); the method PSICOV applied a related concept by estimating a sparse inverse covariance matrix. Both methods (EVfold-mfDCA and PSICOV) are publicly available, but both require too much CPU time for interactive applications. On top, EVfold-mfDCA depends on proprietary software. Results: Here, we present FreeContact, a fast, open source implementation of EVfold-mfDCA and PSICOV. On a test set of 140 proteins, FreeContact was almost eight times faster than PSICOV without decreasing prediction performance. The EVfold-mfDCA implementation of FreeContact was over 220 times faster than PSICOV with negligible performance decrease. EVfold-mfDCA was unavailable for testing due to its dependency on proprietary software. FreeContact is implemented as the free C++ library “libfreecontact”, complete with command line tool “freecontact”, as well as Perl and Python modules. All components are available as Debian packages. FreeContact supports the BioXSD format for interoperability. Conclusions: FreeContact provides the opportunity to compute reliable contact predictions in any environment (desktop or cloud)

Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control

Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and the lateral frontal cortices are involved in such control processes, putatively in close interplay with the BG. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra [SN] and the ventral tegmental area) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial RT prolongations that are thought to reflect cognitive control in a stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and in the absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the BG and the associated subthalamic nucleus

Structured States of Disordered Proteins from Genomic Sequences

Protein flexibility ranges from simple hinge movements to functional disorder. Around half of all human proteins contain apparently disordered regions with little 3D or functional information, and many of these proteins are associated with disease. Building on the evolutionary couplings approach previously successful in predicting 3D states of ordered proteins and RNA, we developed a method to predict the potential for ordered states for all apparently disordered proteins with sufficiently rich evolutionary information. The approach is highly accurate (79%) for residue interactions as tested in more than 60 known disordered regions captured in a bound or specific condition. Assessing the potential for structure of more than 1,000 apparently disordered regions of human proteins reveals a continuum of structural order with at least 50% with clear propensity for three-or two-dimensional states. Co-evolutionary constraints reveal hitherto unseen structures of functional importance in apparently disordered proteins. Keywords: Evolutionary couplings disorder; conformational flexibility; statistical physics; maximum entropy; EVfold; bioinformatics; computational biology; structure predictionNational Institutes of Health (U.S.) (Grant R01GM081871

Allograft rejection is associated with development of functional IgE specific for donor MHC antigens.

BACKGROUND: Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss. OBJECTIVE: This study aimed to investigate whether MHC-specific antibodies of the IgE isotype are induced during allograft rejection. METHODS: Anti-MHC/HLA IgE levels were measured in sera of mice grafted with skin or heart transplants from various donor strains and in sera of kidney transplant patients with high levels of HLA IgG. Mediator release was triggered in vitro by stimulating basophils that were coated with murine or human IgE-positive serum, respectively, with specific recombinant MHC/HLA antigens. Kidney tissue samples obtained from organ donors were analyzed by using flow cytometry for cells expressing the high-affinity receptor for IgE (FcεRI). RESULTS: Donor MHC class I- and MHC class II-specific IgE was found on acute rejection of skin and heart grafts in several murine strain combinations, as well as during chronic antibody-mediated heart graft rejection. Anti-HLA IgE, including donor HLA class I and II specificities, was identified in a group of sensitized transplant recipients. Murine and human anti-MHC/HLA IgE triggered mediator release in coated basophils on stimulation with specific MHC/HLA antigens. HLA-specific IgE was not linked to atopy, and allergen-specific IgE present in allergic patients did not cross-react with HLA antigens. FcεRI+ cells were found in the human renal cortex and medulla and provide targets for HLA-specific IgE. CONCLUSION: These results demonstrate that MHC/HLA-specific IgE develops during an alloresponse and is functional in mediating effector mechanisms

Sequence co-evolution gives 3D contacts and structures of protein complexes

Protein–protein interactions are fundamental to many biological processes. Experimental screens have identified tens of thousands of interactions, and structural biology has provided detailed functional insight for select 3D protein complexes. An alternative rich source of information about protein interactions is the evolutionary sequence record. Building on earlier work, we show that analysis of correlated evolutionary sequence changes across proteins identifies residues that are close in space with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We evaluate prediction performance in blinded tests on 76 complexes of known 3D structure, predict protein–protein contacts in 32 complexes of unknown structure, and demonstrate how evolutionary couplings can be used to distinguish between interacting and non-interacting protein pairs in a large complex. With the current growth of sequences, we expect that the method can be generalized to genome-wide elucidation of protein–protein interaction networks and used for interaction predictions at residue resolution. DOI: http://dx.doi.org/10.7554/eLife.03430.00

ПАТОЛОГИЯ, ВЫЗВАННАЯ ИМПЛАНТАТОМ: АЛГОРИТМ ОПРЕДЕЛЕНИЯ ЧАСТИЦ ПРИ ГИСТОПАТОЛОГИЧЕСКОМ ИССЛЕДОВАНИИ СИНОВИАЛЬНО-ПОДОБНОЙ ОКОЛОПРОТЕЗНОЙ мембраны (SLIM)

In histopathologic SLIM diagnostic (synovial-like interface membrane, SLIM) apart from diagnosing periprosthetic infection particle identification has an important role to play. The differences in particle pathogenesis and variability of materials in endoprosthetics explain the particle heterogeneity that hampers the diagnostic identification of particles. For this reason, a histopathological particle algorithm has been developed. With minimal methodical complexity this histopathological particle algorithm offers a guide to prosthesis material-particle identification. Light microscopic-morphological as well as enzyme-histochemical characteristics and polarization-optical proporties have set and particles are defined by size (microparticles, macroparticles and supra- macroparticles) and definitely characterized in accordance with a dichotomous principle. Based on these criteria, identification and validation of the particles was carried out in 120 joint endoprosthesis pathological cases. A histopathological particle score (HPS) is proposed that summarizes the most important information for the orthopedist, material scientist and histopathologist concerning particle identification in the SLIM.Важную роль при гистопатологическом исследовании синовиально-подобной околопротезной мембраны (SLIM), наряду с диагностикой околопротезной инфекции, играет идентификация частиц. Различия в патогенезе частиц и разнообразии материалов для эндопротезирования объясняют ту гетерогенность, которая затрудняет диагностическую идентификацию частиц. По этой причине был разработан гистопатологический алгоритм диагностики частиц, который при минимальных методологических сложностях обеспечивает идентификацию частиц материала протеза. Простые микроскопически-морфологические и энзим-гистохимические характеристики, а также поляризационно-оптические свойства позволяют определить размер частиц (микрочастицы, макрочастицы и супер-макрочастицы) и характеризовать их по дихотомическому принципу. На основании этих критериев были выполнены идентификация и аттестация частиц в 120 случаях патологической реакции на эндопротез сустава. Предложена гистопатологическая шкала частиц (HPS), которая суммирует важнейшую информацию для ортопедов, материаловедов и гистопатологов, касающуюся идентификации частиц методом SLIM