ALBERT

Description: It is presently assumed that lethal hit delivery by cytotoxic T lymphocytes (CTLs) is mechanistically linked to centrosome polarization toward target cells, leading to dedicated release of lytic granules within a confined secretory domain. Here we provide three lines of evidence showing that this mechanism might not apply as a...

Description: As humans migrated around the world, they came to inhabit environments that differ widely in the soil levels of certain micronutrients, including selenium (Se). Coupled with cultural variation in dietary practices, these migrations have led to a wide range of Se intake levels in populations around the world. Both excess and deficiency of Se in the diet can have adverse health consequences in humans, with severe Se deficiency resulting in diseases of the bone and heart. Se is required by humans mainly due to its function in selenoproteins, which contain the amino acid selenocysteine as one of their constituent residues. To understand the evolution of the use of this micronutrient in humans, we surveyed the patterns of polymorphism in all selenoprotein genes and genes involved in their regulation in 50 human populations. We find that single nucleotide polymorphisms from populations in Asia, particularly in populations living in the extreme Se-deficient regions of China, have experienced concerted shifts in their allele frequencies. Such differentiation in allele frequencies across genes is not observed in other regions of the world and is not expected under neutral evolution, being better explained by the action of recent positive selection. Thus, recent changes in the use and regulation of Se may harbor the genetic adaptations that helped humans inhabit environments that do not provide adequate levels of Se in the diet.

Description: Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450 Cell Death and Disease 6, e1782 (June 2015). doi:10.1038/cddis.2015.134 Authors: C Cerella, F Muller, A Gaigneaux, F Radogna, E Viry, S Chateauvieux, M Dicato & M Diederich

Description: Toll-like receptor (TLR) 3 is an endosomal TLR that mediates immune responses against viral infections upon activation by its ligand double-stranded RNA, a replication intermediate of most viruses. TLR3 is expressed widely in the body and activates both the innate and adaptive immune systems. However, little is known about how TLR3 intracellular trafficking and maturation are regulated. Here we show that newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved. TLR3 protein expression is up-regulated by its own ligand, leading to the accumulation of its cleaved form. In agreement with its proposed role as a transporter, UNC93B1 expression is required for TLR3 cleavage and signaling. Furthermore, TLR3 signaling and cleavage are sensitive to cathepsin inhibition. Cleavage occurs between aa 252 and 346, and results in a functional receptor that signals upon activation. A truncated form of TLR3 lacking the N-terminal 345 aa also signals from acidic compartments in response to ligand activation. Screening of the human cathepsin family by RNA interference identified cathepsins B and H as key mediators of TLR3 processing. Taken together, our data indicate that TLR3 proteolytic processing is essential for its function, and suggest a mechanism of tight control of TLR3 signaling and thus immunity.

Description: Observations in all electromagnetic bands show that many supernova remnants (SNRs) have a very aspherical shape. This can be the result of asymmetries in the supernova explosion or a clumpy circumstellar medium. We study the generation of inhomogeneities and the mixing of elements arising from these two sources in multidimensional hydrodynamic simulations of the propagation of a supernova blast wave into a cloudy environment. We model a specific SNR, Vela Jr (RX J0852.0–4622). By comparing our results with recent observations, we can constrain the properties of the explosion. We find that a very energetic explosion of several 10 51 erg occurring roughly about 800 years ago is consistent with the shape and emission of the SNR, as well as a supernova with an energy closer to the canonical value of 10 51 erg a few thousand years ago.

Description: Niemann–Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3β,5α,6β-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18–90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3β,5α,6β-triol levels were observed for all NP-C cases ( n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.

Description: The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a two-layered mucus system where the inner mucus is attached to the epithelium,...

Description: Motivation: Improvement of sequencing technologies and data processing pipelines is rapidly providing sequencing data, with associated high-level features, of many individual genomes in multiple biological and clinical conditions. They allow for data-driven genomic, transcriptomic and epigenomic characterizations, but require state-of-the-art ‘big data’ computing strategies, with abstraction levels beyond available tool capabilities. Results: We propose a high-level, declarative GenoMetric Query Language (GMQL) and a toolkit for its use. GMQL operates downstream of raw data preprocessing pipelines and supports queries over thousands of heterogeneous datasets and samples; as such it is key to genomic ‘big data’ analysis. GMQL leverages a simple data model that provides both abstractions of genomic region data and associated experimental, biological and clinical metadata and interoperability between many data formats. Based on Hadoop framework and Apache Pig platform, GMQL ensures high scalability, expressivity, flexibility and simplicity of use, as demonstrated by several biological query examples on ENCODE and TCGA datasets. Availability and implementation : The GMQL toolkit is freely available for non-commercial use at http://www.bioinformatics.deib.polimi.it/GMQL/ . Contact: marco.masseroli@polimi.it Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Andersson, Robin -- Gebhard, Claudia -- Miguel-Escalada, Irene -- Hoof, Ilka -- Bornholdt, Jette -- Boyd, Mette -- Chen, Yun -- Zhao, Xiaobei -- Schmidl, Christian -- Suzuki, Takahiro -- Ntini, Evgenia -- Arner, Erik -- Valen, Eivind -- Li, Kang -- Schwarzfischer, Lucia -- Glatz, Dagmar -- Raithel, Johanna -- Lilje, Berit -- Rapin, Nicolas -- Bagger, Frederik Otzen -- Jorgensen, Mette -- Andersen, Peter Refsing -- Bertin, Nicolas -- Rackham, Owen -- Burroughs, A Maxwell -- Baillie, J Kenneth -- Ishizu, Yuri -- Shimizu, Yuri -- Furuhata, Erina -- Maeda, Shiori -- Negishi, Yutaka -- Mungall, Christopher J -- Meehan, Terrence F -- Lassmann, Timo -- Itoh, Masayoshi -- Kawaji, Hideya -- Kondo, Naoto -- Kawai, Jun -- Lennartsson, Andreas -- Daub, Carsten O -- Heutink, Peter -- Hume, David A -- Jensen, Torben Heick -- Suzuki, Harukazu -- Hayashizaki, Yoshihide -- Muller, Ferenc -- FANTOM Consortium -- Forrest, Alistair R R -- Carninci, Piero -- Rehli, Michael -- Sandelin, Albin -- MC_PC_U127597124/Medical Research Council/United Kingdom -- MC_UP_1102/1/Medical Research Council/United Kingdom -- R01 DE022969/DE/NIDCR NIH HHS/ -- England -- Nature. 2014 Mar 27;507(7493):455-61. doi: 10.1038/nature12787.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark [2]. ; 1] Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany [2] Regensburg Centre for Interventional Immunology (RCI), D-93042 Regensburg, Germany [3]. ; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. ; The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. ; 1] The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark [2] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ; Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany. ; 1] RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan [2] RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. ; Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, C.F. Mollers Alle 3, Building 1130, DK-8000 Aarhus, Denmark. ; 1] The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark [2] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark [2] The Finsen Laboratory, Rigshospitalet and Danish Stem Cell Centre (DanStem), University of Copenhagen, Ole Maaloes Vej 5, DK-2200, Denmark. ; Roslin Institute, Edinburgh University, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK. ; Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road MS 64-121, Berkeley, California 94720, USA. ; EMBL Outstation - Hinxton, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; 1] RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan [2] RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan [3] RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. ; 1] RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan [2] RIKEN Preventive Medicine and Diagnosis Innovation Program, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. ; Department of Biosciences and Nutrition, Karolinska Institutet, Halsovagen 7, SE-4183 Huddinge, Stockholm, Sweden. ; 1] RIKEN OMICS Science Centre, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan [2] RIKEN Center for Life Science Technologies (Division of Genomic Technologies), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan [3] Department of Biosciences and Nutrition, Karolinska Institutet, Halsovagen 7, SE-4183 Huddinge, Stockholm, Sweden. ; Department of Clinical Genetics, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands. ; 1] Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany [2] Regensburg Centre for Interventional Immunology (RCI), D-93042 Regensburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670763" target="_blank"〉PubMed〈/a〉