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Miras A.D.,Institute of Clinical science | Le Roux C.W.,University College Dublin
Nature Reviews Gastroenterology and Hepatology

The clinical efficacy of bariatric surgery has encouraged the scientific investigation of the gut as a major endocrine organ. Manipulation of gastrointestinal anatomy through surgery has been shown to profoundly affect the physiological and metabolic processes that control body weight and glycaemia. The most popular bariatric surgical procedures are gastric bypass, adjustable gastric banding and vertical sleeve gastrectomy. Even though these procedures were designed with the aim of causing restriction of food intake and nutrient malabsorption, evidence suggests that their contributions to weight loss are minimal. Instead, these interventions reduce body weight by decreasing hunger, increasing satiation during a meal, changing food preferences and energy expenditure. In this Review, we have explored these mechanisms as well as their mediators. The hope is that that their in-depth investigation will enable the optimization and individualization of surgical techniques, the development of equally effective but safer nonsurgical weight-loss interventions, and even the understanding of the pathophysiology of obesity itself. © 2013 Macmillan Publishers Limited. Source

Minas C.,Institute of Clinical science | Curry E.,Imperial College London | Montana G.,Statistics Section

Motivation: Due to rapid technological advances, a wide range of different measurements can be obtained from a given biological sample including single nucleotide polymorphisms, copy number variation, gene expression levels, DNA methylation and proteomic profiles. Each of these distinct measurements provides the means to characterize a certain aspect of biological diversity, and a fundamental problem of broad interest concerns the discovery of shared patterns of variation across different data types. Such data types are heterogeneous in the sense that they represent measurements taken at different scales or represented by different data structures. Results:We propose a distance-based statistical test, the generalized RV (GRV) test, to assess whether there is a common and non-random pattern of variability between paired biological measurements obtained from the same random sample. The measurements enter the test through the use of two distance measures, which can be chosen to capture a particular aspect of the data. An approximate null distribution is proposed to compute P-values in closed-form and without the need to perform costly Monte Carlo permutation procedures. Compared with the classical Mantel test for association between distance matrices, the GRV test has been found to be more powerful in a number of simulation settings. We also demonstrate how the GRV test can be used to detect biological pathways in which genetic variability is associated to variation in gene expression levels in an ovarian cancer sample, and present results obtained from two independent cohorts. Availability: R code to compute the GRV test is freely available from http://www2.imperial.ac.uk/ ~gmontanaContact: g.montana@imperial.ac.uk Supplementary data: Supplementary data are available at Bioinformatics online. © The Author 2013. Published by Oxford University Press. Source

Chapman S.,National Health Research Institute | Eisinga A.,National Health Research Institute | Hopewell S.,National Health Research Institute | Clarke M.,Institute of Clinical science
Journal of Clinical Epidemiology

Objectives: To determine the extent to which abstracts of methodology research, initially presented at annual meetings of The Cochrane Collaboration, have been published as full reports and over what period of time. A secondary aim was to explore whether full publication varied in different methodological subject areas. Study Design and Setting: The Cochrane Methodology Register (CMR) was searched for all abstracts reporting methodology research, presented at the 11 Cochrane Colloquia from 1997 to 2007. EMBASE, PubMed, and CMR were searched for full publications of the same research. Results: We identified 908 eligible conference abstracts and found full publications for 312 (34.4%) of these, almost half of which (47.1%) had appeared by the end of the first year after the relevant Colloquium. The proportion of abstracts that had not been published by 3 years was 69.7%, falling to 66.2% at 5 years. Publication varied considerably between different methodological areas. Conclusion: Approximately two-thirds of methodological research studies presented at Cochrane Colloquia remain unpublished as full papers at least 5 years later. This highlights the importance of searching conference abstracts if one wishes to find as comprehensive and complete a sample of methodological research as possible. © 2012 Elsevier Inc. All rights reserved. Source

Panda S.,Umea University | Nilsson J.A.,Institute of Clinical science | Gekara N.O.,Umea University

Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response. © 2015 Elsevier Inc. Source

Sheffield N.C.,Duke University | Thurman R.E.,University of Washington | Song L.,Duke University | Safi A.,Duke University | And 6 more authors.
Genome Research

Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and gene expression data for 112 human samples representing 72 cell types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHSs and promoters, CpG islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHSs and evaluated the tissue of origin for cancer cell types. A similar classifier identified three sex-specific loci on the X chromosome, including the XIST lincRNA locus. By correlating DNase I signal and gene expression, we predicted regulated genes for more than 500K DHSs. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell types. © 2013, Published by Cold Spring Harbor Laboratory Press. Source

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