935 research outputs found

    FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle

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    Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohn’s disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC

    Geodetic reanalysis of annual glaciological mass balances (2001-2011) of Hintereisferner, Austria

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    This study presents a reanalysis of the glaciologically obtained annual glacier mass balances at Hintereisferner, Ötztal Alps, Austria, for the period 2001-2011. The reanalysis is accomplished through a comparison with geodetically derived mass changes, using annual high-resolution airborne laser scanning (ALS). The grid-based adjustments for the method-inherent differences are discussed along with associated uncertainties and discrepancies of the two methods of mass balance measurements. A statistical comparison of the two datasets shows no significant difference for seven annual, as well as the cumulative, mass changes over the 10-year record. Yet, the statistical view hides significant differences in the mass balance years 2002/03 (glaciological minus geodetic records=+0.92mw.e.), 2005/06 (+0.60mw.e.), and 2006/07 (-0.45mw.e.). We conclude that exceptional meteorological conditions can render the usual glaciological observational network inadequate. Furthermore, we consider that ALS data reliably reproduce the annual mass balance and can be seen as validation or calibration tools for the glaciological method.(VLID)3146447Version of recor

    Single Nucleotide Polymorphism Typing of Mycobacterium ulcerans Reveals Focal Transmission of Buruli Ulcer in a Highly Endemic Region of Ghana

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    Buruli ulcer (BU) is an emerging necrotizing disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. While proximity to stagnant or slow flowing water bodies is a risk factor for acquiring BU, the epidemiology and mode of M. ulcerans transmission is poorly understood. Here we have used high-throughput DNA sequencing and comparisons of the genomes of seven M. ulcerans isolates that appeared monomorphic by existing typing methods. We identified a limited number of single nucleotide polymorphisms (SNPs) and developed a real-time PCR SNP typing method based on these differences. We then investigated clinical isolates of M. ulcerans on which we had detailed information concerning patient location and time of diagnosis. Within the Densu river basin of Ghana we observed dominance of one clonal complex and local clustering of some of the variants belonging to this complex. These results reveal focal transmission and demonstrate, that micro-epidemiological analyses by SNP typing has great potential to help us understand how M. ulcerans is transmitted

    Paneth cells as a site of origin for intestinal inflammation.

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    The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells

    Communicating climate knowledge proxies, processes, politics

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    This forum article is the product of interdisciplinary discussion at a conference on climate histories held inCambridge, United Kingdom, in early 2011, with the specific aim of building a network around the issue of communicating cultural knowledge of environmental change. The lead articles, by Kirsten Hastrup as an anthropologist and Simon Schaffer as a historian of science, highlight the role of agents and proxies. These are followed by five interdisciplinary commentaries, which engage with the lead articles through new ethnographic material, and a set of shorter commentaries by leading scholars of different disciplines. Finally, the lead authors respond to the discussion. In this debate, climate change does not emerge as a single preformed "problem." Rather, different climate knowledges appear as products of particular networks and agencies. Just as the identification of proxies creates agents (ice, mountains, informants) by inserting them into new networks, we hope that these cross-disciplinary exchanges will produce further conversations and new approaches to action. © 2012 by The Wenner-Gren Foundation for Anthropological Research

    Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

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    The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability
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