104 research outputs found

    A novel family of diversified immunoregulatory receptors in teleosts is homologous to both mammalian Fc receptors and molecules encoded within the leukocyte receptor complex

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    Three novel and closely related leukocyte immune-type receptors (IpLITR) have been identified in channel catfish (Ictalurus punctatus). These receptors belong to a large polymorphic and polygenic subset of the Ig superfamily with members located on at least three independently segregating loci. Like mammalian and avian innate immune regulatory receptors, IpLITRs have both putative inhibitory and stimulatory forms, with multiple types coexpressed in various lymphoid tissues and clonal leukocyte cell lines. IpLITRs have an unusual and novel relationship to mammalian and avian innate immune receptors: the membrane distal Ig domains of an individual IpLITR are related to fragment crystallizable receptors (FcRs) and FcR-like proteins, whereas the membrane proximal Ig domains are related to several leukocyte receptor complex encoded receptors. This unique composition of Ig domains within individual receptors supports the hypothesis that functionally and genomically distinct immune receptor families found in tetrapods may have evolved from such ancestral genes by duplication and recombination events. Furthermore, the discovery of a large heterogeneous family of immunoregulatory receptors in teleosts, reminiscent of amphibian, avian, and mammalian Ig-like receptors, suggests that complex innate immune receptor networks have been conserved during vertebrate evolution. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at http://dx.doi.org/10.1007/s00251-006-0134-1 and is accessible for authorized users

    Modular Mass Spectrometric Tool for Analysis of Composition and Phosphorylation of Protein Complexes

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    The combination of high accuracy, sensitivity and speed of single and multiple-stage mass spectrometric analyses enables the collection of comprehensive sets of data containing detailed information about complex biological samples. To achieve these properties, we combined two high-performance matrix-assisted laser desorption ionization mass analyzers in one modular mass spectrometric tool, and applied this tool for dissecting the composition and post-translational modifications of protein complexes. As an example of this approach, we here present studies of the Saccharomyces cerevisiae anaphase-promoting complexes (APC) and elucidation of phosphorylation sites on its components. In general, the modular concept we describe could be useful for assembling mass spectrometers operating with both matrix-assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) ion sources into powerful mass spectrometric tools for the comprehensive analysis of complex biological samples

    Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling

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    Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118–310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.National Science Foundation (U.S.) (DB1-0821391)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-GM089903)National Institutes of Health (U.S.) (P30-ES002109

    Postoperative acute kidney injury in adult non-cardiac surgery:joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative

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    Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research

    Search for Higgs Boson Pair Production in the Four b Quark Final State in Proton-Proton Collisions at root s=13 TeV

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    Search for invisible decays of the Higgs boson produced via vector boson fusion in proton-proton collisions at root s=13 TeV

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    Associations of statin use with motor performance and myalgia may be modified by 25-hydroxyvitamin D: findings from a British birth cohort

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    The objective was to examine whether: (1) statin use was associated with muscle related outcomes at age 60–64, (2) these associations were modifed by 25-hydroxyvitamin D (25(OH)D) status and explained by infammation, body-size or lifestyle in a British birth cohort. Markers of myalgia (intrusive body pain) and myopathy (self-reported and performance-based measures) were examined in 734 men and 822 women (MRC National Survey of Health and Development). Statin use was associated with intrusive body pain, difculty climbing stairs and slower chair rise speed. Some associations were modifed by 25(OH)D e.g. the association with intrusive body pain was evident in the insufcient (13–20ng/l) and defcient(20ng/l (OR=0.8,95% CI 0.5–1.4) (p=0.003 for interaction). Associations were maintained in fully adjusted models of intrusive body pain and difculty climbing stairs, but for chair rise speed they were fully accounted for by infammation, body-size and lifestyle. In a nationally representative British population in early old age, statin use was associated with lower limb muscle-related outcomes, and some were only apparent in those with 25(OH)D status below 20ng/l. Given 25(OH)D is modifable in clinical practice, future studies should consider the links between 25(OH)D status and muscle related outcomes

    The association of neighbourhood and individual social capital with consistent self-rated health: a longitudinal study in Brazilian pregnant and postpartum women.

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    BACKGROUND: Social conditions, social relationships and neighbourhood environment, the components of social capital, are important determinants of health. The objective of this study was to investigate the association of neighbourhood and individual social capital with consistent self-rated health in women between the first trimester of pregnancy and six months postpartum. METHODS: A multilevel cohort study in 34 neighbourhoods was performed on 685 Brazilian women recruited at antenatal units in two cities in the State of Rio de Janeiro, Brazil. Self-rated health (SRH) was assessed in the 1st trimester of pregnancy (baseline) and six months after childbirth (follow-up). The participants were divided into two groups: 1. Good SRH--good SRH at baseline and follow-up, and, 2. Poor SRH--poor SRH at baseline and follow-up. Exploratory variables collected at baseline included neighbourhood social capital (neighbourhood-level variable), individual social capital (social support and social networks), demographic and socioeconomic characteristics, health-related behaviours and self-reported diseases. A hierarchical binomial multilevel analysis was performed to test the association between neighbourhood and individual social capital and SRH, adjusted for covariates. RESULTS: The Good SRH group reported higher scores of social support and social networks than the Poor SRH group. Although low neighbourhood social capital was associated with poor SRH in crude analysis, the association was not significant when individual socio-demographic variables were included in the model. In the final model, women reporting poor SRH both at baseline and follow-up had lower levels of social support (positive social interaction) [OR 0.82 (95% CI: 0.73-0.90)] and a lower likelihood of friendship social networks [OR 0.61 (95% CI: 0.37-0.99)] than the Good SRH group. The characteristics that remained associated with poor SRH were low level of schooling, Black and Brown ethnicity, more children, urinary infection and water plumbing outside the house. CONCLUSIONS: Low individual social capital during pregnancy, considered here as social support and social network, was independently associated with poor SRH in women whereas neighbourhood social capital did not affect women's SRH during pregnancy and the months thereafter. From pregnancy and up to six months postpartum, the effect of individual social capital explained better the consistency of SRH over time than neighbourhood social capital
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