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  • 1
    Publication Date: 2016-03-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thingstad, T Frede -- Bratbak, Gunnar -- England -- Nature. 2016 Mar 24;531(7595):454-5. doi: 10.1038/nature17303. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Bergen, 5020 Bergen, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982732" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthozoa/*virology ; *Ecosystem ; *Host-Pathogen Interactions ; Viruses/*pathogenicity
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-01-21
    Description: RNA polymerase (Pol) II produces messenger RNA during transcription of protein-coding genes in all eukaryotic cells. The Pol II structure is known at high resolution from X-ray crystallography for two yeast species. Structural studies of mammalian Pol II, however, remain limited to low-resolution electron microscopy analysis of human Pol II and its complexes with various proteins. Here we report the 3.4 A resolution cryo-electron microscopy structure of mammalian Pol II in the form of a transcribing complex comprising DNA template and RNA transcript. We use bovine Pol II, which is identical to the human enzyme except for seven amino-acid residues. The obtained atomic model closely resembles its yeast counterpart, but also reveals unknown features. Binding of nucleic acids to the polymerase involves 'induced fit' of the mobile Pol II clamp and active centre region. DNA downstream of the transcription bubble contacts a conserved 'TPSA motif' in the jaw domain of the Pol II subunit RPB5, an interaction that is apparently already established during transcription initiation. Upstream DNA emanates from the active centre cleft at an angle of approximately 105 degrees with respect to downstream DNA. This position of upstream DNA allows for binding of the general transcription elongation factor DSIF (SPT4-SPT5) that we localize over the active centre cleft in a conserved position on the clamp domain of Pol II. Our results define the structure of mammalian Pol II in its functional state, indicate that previous crystallographic analysis of yeast Pol II is relevant for understanding gene transcription in all eukaryotes, and provide a starting point for a mechanistic analysis of human transcription.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bernecky, Carrie -- Herzog, Franz -- Baumeister, Wolfgang -- Plitzko, Jurgen M -- Cramer, Patrick -- England -- Nature. 2016 Jan 28;529(7587):551-4. doi: 10.1038/nature16482. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Gottingen, Germany. ; Gene Center Munich, Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. ; Max Planck Institute for Biochemistry, Department of Molecular Structural Biology, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789250" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Motifs ; Animals ; Catalytic Domain ; Cattle ; *Cryoelectron Microscopy ; DNA/genetics/metabolism/ultrastructure ; Humans ; Models, Molecular ; Nucleic Acids/chemistry/metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA Polymerase II/chemistry/*metabolism/*ultrastructure ; RNA, Messenger/biosynthesis/genetics/ultrastructure ; Saccharomyces cerevisiae/enzymology ; Templates, Genetic ; *Transcription Elongation, Genetic
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  • 3
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGilvray, Annabel -- England -- Nature. 2016 May 11;533(7602):S65-7. doi: 10.1038/533S65a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27167395" target="_blank"〉PubMed〈/a〉
    Keywords: Access to Information ; Animals ; Anti-Bacterial Agents/*analysis/*chemistry/pharmacology ; *Crowdsourcing/economics ; Diffusion of Innovation ; Drug Evaluation, Preclinical/economics/*methods ; Drug Industry/economics/methods ; *High-Throughput Screening Assays/economics ; *Information Dissemination ; Intellectual Property ; Microbial Sensitivity Tests
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  • 4
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McKinlay, Roger -- England -- Nature. 2016 Mar 31;531(7596):573-5. doi: 10.1038/531573a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Royal Institute of Navigation, and a former head of engineering at Thales UK. He sits on the EPSRC Quantum Technology Strategic Advisory Board.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029262" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cues ; Facility Design and Construction ; Geographic Information Systems/instrumentation/*utilization ; Hippocampus/anatomy & histology/physiology ; Humans ; Maps as Topic ; Orientation/physiology ; Satellite Communications/utilization ; Smartphone/utilization ; Spatial Learning/*physiology ; Spatial Memory/physiology ; Spatial Navigation/*physiology
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    Electronic ISSN: 1476-4687
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  • 5
    Publication Date: 2016-03-05
    Description: Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846772/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846772/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beyaz, Semir -- Mana, Miyeko D -- Roper, Jatin -- Kedrin, Dmitriy -- Saadatpour, Assieh -- Hong, Sue-Jean -- Bauer-Rowe, Khristian E -- Xifaras, Michael E -- Akkad, Adam -- Arias, Erika -- Pinello, Luca -- Katz, Yarden -- Shinagare, Shweta -- Abu-Remaileh, Monther -- Mihaylova, Maria M -- Lamming, Dudley W -- Dogum, Rizkullah -- Guo, Guoji -- Bell, George W -- Selig, Martin -- Nielsen, G Petur -- Gupta, Nitin -- Ferrone, Cristina R -- Deshpande, Vikram -- Yuan, Guo-Cheng -- Orkin, Stuart H -- Sabatini, David M -- Yilmaz, Omer H -- AI47389/AI/NIAID NIH HHS/ -- DK043351/DK/NIDDK NIH HHS/ -- K08 CA198002/CA/NCI NIH HHS/ -- K99 AG041765/AG/NIA NIH HHS/ -- K99 AG045144/AG/NIA NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 AG041765/AG/NIA NIH HHS/ -- R00 AG045144/AG/NIA NIH HHS/ -- R01 AI047389/AI/NIAID NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32DK007191/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 3;531(7592):53-8. doi: 10.1038/nature17173.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA. ; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA. ; Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA. ; Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, Missisippi 39216, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935695" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; Cell Self Renewal/drug effects ; Cell Transformation, Neoplastic/*drug effects ; Colonic Neoplasms/*pathology ; Diet, High-Fat/*adverse effects ; Female ; Genes, APC ; Humans ; Intestines/*pathology ; Male ; Mice ; Obesity/chemically induced/pathology ; Organoids/drug effects/metabolism/pathology ; PPAR delta/metabolism ; Signal Transduction/drug effects ; Stem Cell Niche/drug effects ; Stem Cells/*drug effects/metabolism/*pathology ; beta Catenin/metabolism
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  • 6
    Publication Date: 2016-04-21
    Description: Planktonic organisms play crucial roles in oceanic food webs and global biogeochemical cycles. Most of our knowledge about the ecological impact of large zooplankton stems from research on abundant and robust crustaceans, and in particular copepods. A number of the other organisms that comprise planktonic communities are fragile, and therefore hard to sample and quantify, meaning that their abundances and effects on oceanic ecosystems are poorly understood. Here, using data from a worldwide in situ imaging survey of plankton larger than 600 mum, we show that a substantial part of the biomass of this size fraction consists of giant protists belonging to the Rhizaria, a super-group of mostly fragile unicellular marine organisms that includes the taxa Phaeodaria and Radiolaria (for example, orders Collodaria and Acantharia). Globally, we estimate that rhizarians in the top 200 m of world oceans represent a standing stock of 0.089 Pg carbon, equivalent to 5.2% of the total oceanic biota carbon reservoir. In the vast oligotrophic intertropical open oceans, rhizarian biomass is estimated to be equivalent to that of all other mesozooplankton (plankton in the size range 0.2-20 mm). The photosymbiotic association of many rhizarians with microalgae may be an important factor in explaining their distribution. The previously overlooked importance of these giant protists across the widest ecosystem on the planet changes our understanding of marine planktonic ecosystems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biard, Tristan -- Stemmann, Lars -- Picheral, Marc -- Mayot, Nicolas -- Vandromme, Pieter -- Hauss, Helena -- Gorsky, Gabriel -- Guidi, Lionel -- Kiko, Rainer -- Not, Fabrice -- England -- Nature. 2016 Apr 28;532(7600):504-7. doi: 10.1038/nature17652. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sorbonne Universites, UPMC Universite Paris 06, CNRS, Laboratoire Adaptation et Diversite en Milieu Marin UMR7144, Station Biologique de Roscoff, 29688 Roscoff, France. ; Sorbonne Universites, UPMC Universite Paris 06, CNRS, Laboratoire d'Oceanographie de Villefranche (LOV) UMR7093, Observatoire Oceanologique, 06230 Villefranche-sur-Mer, France. ; GEOMAR Helmholtz Centre for Ocean Research Kiel, Wischhofstrasse 1-3, 24148 Kiel, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096373" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biomass ; *Biota ; Carbon/metabolism ; Carbon Sequestration ; Earth (Planet) ; Microalgae/metabolism ; *Oceans and Seas ; Photosynthesis ; Rhizaria/classification/*isolation & purification/metabolism ; Seawater/chemistry ; Symbiosis ; Zooplankton/classification/*isolation & purification/metabolism
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  • 7
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meharg, Andrew A -- England -- Nature. 2016 Mar 17;531(7594):S60. doi: 10.1038/531S60a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Queen's University Belfast, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26981731" target="_blank"〉PubMed〈/a〉
    Keywords: *Agriculture ; Animals ; Carbon Footprint ; *Cities ; *Environmental Monitoring ; Environmental Pollution ; Insect Vectors ; Water Supply
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  • 8
    Publication Date: 2016-03-08
    Description: The conserved Piwi family of proteins and piwi-interacting RNAs (piRNAs) have a central role in genomic stability, which is inextricably linked to germ-cell formation, by forming Piwi ribonucleoproteins (piRNPs) that silence transposable elements. In Drosophila melanogaster and other animals, primordial germ-cell specification in the developing embryo is driven by maternal messenger RNAs and proteins that assemble into specialized messenger ribonucleoproteins (mRNPs) localized in the germ (pole) plasm at the posterior of the oocyte. Maternal piRNPs, especially those loaded on the Piwi protein Aubergine (Aub), are transmitted to the germ plasm to initiate transposon silencing in the offspring germ line. The transport of mRNAs to the oocyte by midoogenesis is an active, microtubule-dependent process; mRNAs necessary for primordial germ-cell formation are enriched in the germ plasm at late oogenesis via a diffusion and entrapment mechanism, the molecular identity of which remains unknown. Aub is a central component of germ granule RNPs, which house mRNAs in the germ plasm, and interactions between Aub and Tudor are essential for the formation of germ granules. Here we show that Aub-loaded piRNAs use partial base-pairing characteristics of Argonaute RNPs to bind mRNAs randomly in Drosophila, acting as an adhesive trap that captures mRNAs in the germ plasm, in a Tudor-dependent manner. Notably, germ plasm mRNAs in drosophilids are generally longer and more abundant than other mRNAs, suggesting that they provide more target sites for piRNAs to promote their preferential tethering in germ granules. Thus, complexes containing Tudor, Aub piRNPs and mRNAs couple piRNA inheritance with germline specification. Our findings reveal an unexpected function for piRNP complexes in mRNA trapping that may be generally relevant to the function of animal germ granules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795963/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795963/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vourekas, Anastassios -- Alexiou, Panagiotis -- Vrettos, Nicholas -- Maragkakis, Manolis -- Mourelatos, Zissimos -- GM072777/GM/NIGMS NIH HHS/ -- R01 GM072777/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):390-4. doi: 10.1038/nature17150. Epub 2016 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, Division of Neuropathology, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine; PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26950602" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/metabolism ; Base Pairing ; Binding Sites ; Cytoplasm/*genetics/*metabolism ; DNA Transposable Elements/genetics ; Diffusion ; Drosophila Proteins/metabolism ; Drosophila melanogaster/cytology/*genetics/metabolism ; Female ; Male ; Membrane Transport Proteins/metabolism ; Oocytes/*cytology/metabolism ; Oogenesis ; Peptide Initiation Factors/metabolism ; RNA Interference ; *RNA Transport ; RNA, Messenger/chemistry/*genetics/metabolism ; RNA, Small Interfering/chemistry/*genetics/metabolism ; Ribonucleoproteins/metabolism ; Transcriptome/genetics
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  • 9
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morishita, Joji -- England -- Nature. 2016 Mar 3;531(7592):35. doi: 10.1038/531035a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Research Institute of Far Seas Fisheries, Shizuoka, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935687" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Minke Whale ; Research/*legislation & jurisprudence/*standards
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  • 10
    Publication Date: 2016-03-10
    Description: The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina, for example, develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and collagen-rich stroma of the cornea have a neural crest origin. Recent work with pluripotent stem cells in culture has revealed a previously under-appreciated level of intrinsic cellular self-organization, with a focus on the retina and retinal cells. Moreover, we and others have demonstrated the in vitro induction of a corneal epithelial cell phenotype from pluripotent stem cells. These studies, however, have a single, tissue-specific focus and fail to reflect the complexity of whole eye development. Here we demonstrate the generation from human induced pluripotent stem cells of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. In some respects the concentric SEAM mimics whole-eye development because cell location within different zones is indicative of lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. It thus represents a promising resource for new and ongoing studies of ocular morphogenesis. The approach also has translational potential and to illustrate this we show that cells isolated from the ocular surface ectodermal zone of the SEAM can be sorted and expanded ex vivo to form a corneal epithelium that recovers function in an experimentally induced animal model of corneal blindness.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayashi, Ryuhei -- Ishikawa, Yuki -- Sasamoto, Yuzuru -- Katori, Ryosuke -- Nomura, Naoki -- Ichikawa, Tatsuya -- Araki, Saori -- Soma, Takeshi -- Kawasaki, Satoshi -- Sekiguchi, Kiyotoshi -- Quantock, Andrew J -- Tsujikawa, Motokazu -- Nishida, Kohji -- England -- Nature. 2016 Mar 17;531(7594):376-80. doi: 10.1038/nature17000. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. ; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. ; Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan. ; Structural Biophysics Group, School of Optometry and Vision Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF24 4HQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958835" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Cornea/*cytology/*growth & development/physiology ; Corneal Transplantation ; Ectoderm/cytology ; Epithelial Cells/cytology ; Epithelium, Corneal/cytology ; Female ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Lens, Crystalline/cytology ; Mice ; Morphogenesis ; Phenotype ; Rabbits ; *Recovery of Function ; Retinal Pigment Epithelium/cytology
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  • 11
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wald, Chelsea -- England -- Nature. 2016 May 5;533(7601):S47. doi: 10.1038/533S47a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27144610" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Austria ; Entrepreneurship/economics/organization & administration ; Humans ; Inventions/economics ; Inventors/economics/education/psychology ; Research/*economics/*organization & administration ; Research Personnel/economics/education/psychology ; *Technology Transfer ; Uncertainty
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  • 12
    Publication Date: 2016-04-12
    Description: Asymmetric cell division, the partitioning of cellular components in response to polarizing cues during mitosis, has roles in differentiation and development. It is important for the self-renewal of fertilized zygotes in Caenorhabditis elegans and neuroblasts in Drosophila, and in the development of mammalian nervous and digestive systems. T lymphocytes, upon activation by antigen-presenting cells (APCs), can undergo asymmetric cell division, wherein the daughter cell proximal to the APC is more likely to differentiate into an effector-like T cell and the distal daughter is more likely to differentiate into a memory-like T cell. Upon activation and before cell division, expression of the transcription factor c-Myc drives metabolic reprogramming, necessary for the subsequent proliferative burst. Here we find that during the first division of an activated T cell in mice, c-Myc can sort asymmetrically. Asymmetric distribution of amino acid transporters, amino acid content, and activity of mammalian target of rapamycin complex 1 (mTORC1) is correlated with c-Myc expression, and both amino acids and mTORC1 activity sustain the differences in c-Myc expression in one daughter cell compared to the other. Asymmetric c-Myc levels in daughter T cells affect proliferation, metabolism, and differentiation, and these effects are altered by experimental manipulation of mTORC1 activity or c-Myc expression. Therefore, metabolic signalling pathways cooperate with transcription programs to maintain differential cell fates following asymmetric T-cell division.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851250/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851250/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Verbist, Katherine C -- Guy, Cliff S -- Milasta, Sandra -- Liedmann, Swantje -- Kaminski, Marcin M -- Wang, Ruoning -- Green, Douglas R -- R01 GM096208/GM/NIGMS NIH HHS/ -- R37 GM052735/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):389-93. doi: 10.1038/nature17442. Epub 2016 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27064903" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Transport Systems/metabolism ; Amino Acids/metabolism ; Animals ; CD8-Positive T-Lymphocytes/*cytology/*metabolism ; Cell Differentiation/genetics ; *Cell Division ; *Cell Polarity/genetics ; Female ; *Lymphocyte Activation ; Male ; Mice ; Multiprotein Complexes/metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Signal Transduction/genetics ; TOR Serine-Threonine Kinases/metabolism ; Transcription, Genetic
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  • 13
    Publication Date: 2016-01-14
    Description: The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This has been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Surprisingly, we now show that NMDA does not raise the intracellular Ca(2+) concentration ([Ca(2+)]i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular [K(+)] and decrease of membrane K(+) conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca(2+)]i, [Mg(2+)]i and [H(+)]i, and buffering intracellular pH reduces the [Ca(2+)]i and [Mg(2+)]i increases, showing that these are evoked by the rise of [H(+)]i. The H(+)-gated [Ca(2+)]i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733665/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733665/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamilton, Nicola B -- Kolodziejczyk, Karolina -- Kougioumtzidou, Eleni -- Attwell, David -- Wellcome Trust/United Kingdom -- England -- Nature. 2016 Jan 28;529(7587):523-7. doi: 10.1038/nature16519. Epub 2016 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Physiology &Pharmacology, University College London, Gower St., London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26760212" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain Ischemia/*metabolism/*pathology ; Calcium/*metabolism ; Calcium Signaling/drug effects ; Electric Conductivity ; Female ; Hydrogen-Ion Concentration ; Magnesium/metabolism ; Male ; Mice ; Mice, Transgenic ; Multiple Sclerosis/metabolism/pathology ; Myelin Sheath/drug effects/*metabolism/*pathology ; N-Methylaspartate/metabolism/pharmacology ; Oligodendroglia/drug effects/metabolism/pathology ; Potassium/metabolism ; *Protons ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Stroke/metabolism/pathology ; Transient Receptor Potential Channels/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; White Matter/metabolism/pathology
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  • 14
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wald, Chelsea -- England -- Nature. 2016 Mar 3;531(7592):S14-5. doi: 10.1038/531S14a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934520" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Animals ; Brain/*physiology ; Cognition/*physiology ; Cognition Disorders/prevention & control/psychology ; Communication ; Female ; Friends/psychology ; Humans ; Inflammation/pathology/prevention & control/therapy ; *Interpersonal Relations ; Longevity/physiology ; Male ; Memory/physiology ; Primates/anatomy & histology/physiology ; *Social Networking ; Thinking/physiology ; White Matter/pathology
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  • 15
    Publication Date: 2016-01-28
    Description: Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1beta and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7(-/-) or Nlrp3(-/-) haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Yuan -- Zeng, Melody Y -- Yang, Dahai -- Motro, Benny -- Nunez, Gabriel -- R01AI063331/AI/NIAID NIH HHS/ -- R01DK091191/DK/NIDDK NIH HHS/ -- T32 HL007517/HL/NHLBI NIH HHS/ -- T32DK094775/DK/NIDDK NIH HHS/ -- T32HL007517/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):354-7. doi: 10.1038/nature16959. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814970" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/deficiency/genetics/metabolism ; Biocatalysis ; Carrier Proteins/chemistry/genetics/*metabolism ; Caspase 1/metabolism ; Catalytic Domain ; Cells, Cultured ; Cryopyrin-Associated Periodic Syndromes/genetics ; Enzyme Activation ; HEK293 Cells ; Humans ; Inflammasomes/*chemistry/*metabolism ; Interleukin-1beta/secretion ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Potassium/*metabolism ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/chemistry/deficiency/genetics/*metabolism
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  • 16
    Publication Date: 2016-03-17
    Description: Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed 'waves' of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer anti-metastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Headley, Mark B -- Bins, Adriaan -- Nip, Alyssa -- Roberts, Edward W -- Looney, Mark R -- Gerard, Audrey -- Krummel, Matthew F -- P01 HL024136/HL/NHLBI NIH HHS/ -- R21 CA167601/CA/NCI NIH HHS/ -- R21CA167601/CA/NCI NIH HHS/ -- U54 CA163123/CA/NCI NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):513-7. doi: 10.1038/nature16985. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA. ; Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef, 91105AZ Amsterdam, The Netherlands. ; Departments of Medicine and Laboratory Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW512, California 94143-0511, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982733" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capillaries/pathology ; Cell Line, Tumor ; Cell Lineage ; *Cell Movement ; Dendritic Cells/cytology/immunology ; Female ; Genes, Reporter/genetics ; Humans ; Lung/blood supply/cytology/*immunology/*pathology ; Lung Neoplasms/*immunology/pathology/*secondary ; Male ; Melanoma, Experimental/immunology/pathology ; Mice ; Microscopy, Confocal ; Myeloid Cells/cytology ; Neoplasm Metastasis/*immunology/*pathology ; Neoplastic Cells, Circulating/pathology
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  • 17
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nardone, Roland M -- MacLeod, Roderick A F -- Capes-Davis, Amanda -- England -- Nature. 2016 Apr 21;532(7599):313.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27127813" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; DNA Contamination ; Databases, Factual ; *Disease Models, Animal ; Guidelines as Topic ; Heterografts/*standards ; Humans ; National Cancer Institute (U.S.) ; Neoplasms/*pathology ; Quality Control ; Reproducibility of Results ; United States ; Xenograft Model Antitumor Assays/*standards
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  • 18
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nagata, Shigekazu -- England -- Nature. 2016 May 18;533(7604):474-6. doi: 10.1038/nature18439.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biochemistry and Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27225115" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caspases/*metabolism ; *Cell Differentiation ; Cytochrome c Group/*metabolism ; Drosophila melanogaster/*cytology ; Male ; Spermatozoa/*cytology/*metabolism
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  • 19
    Publication Date: 2016-02-09
    Description: The tremendous pandemic potential of coronaviruses was demonstrated twice in the past few decades by two global outbreaks of deadly pneumonia. Entry of coronaviruses into cells is mediated by the transmembrane spike glycoprotein S, which forms a trimer carrying receptor-binding and membrane fusion functions. S also contains the principal antigenic determinants and is the target of neutralizing antibodies. Here we present the structure of a mouse coronavirus S trimer ectodomain determined at 4.0 A resolution by single particle cryo-electron microscopy. It reveals the metastable pre-fusion architecture of S and highlights key interactions stabilizing it. The structure shares a common core with paramyxovirus F proteins, implicating mechanistic similarities and an evolutionary connection between these viral fusion proteins. The accessibility of the highly conserved fusion peptide at the periphery of the trimer indicates potential vaccinology strategies to elicit broadly neutralizing antibodies against coronaviruses. Finally, comparison with crystal structures of human coronavirus S domains allows rationalization of the molecular basis for species specificity based on the use of spatially contiguous but distinct domains.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walls, Alexandra C -- Tortorici, M Alejandra -- Bosch, Berend-Jan -- Frenz, Brandon -- Rottier, Peter J M -- DiMaio, Frank -- Rey, Felix A -- Veesler, David -- GM103310/GM/NIGMS NIH HHS/ -- T32GM008268/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 3;531(7592):114-7. doi: 10.1038/nature16988. Epub 2016 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Institut Pasteur, Unite de Virologie Structurale, 75015 Paris, France. ; CNRS UMR 3569 Virologie, 75015 Paris, France. ; Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26855426" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Neutralizing/immunology ; Cell Line ; Coronavirus Infections/immunology/virology ; *Cryoelectron Microscopy ; Drosophila melanogaster ; Mice ; Models, Molecular ; Molecular Sequence Data ; Murine hepatitis virus/*chemistry/immunology/*ultrastructure ; Protein Multimerization ; Protein Structure, Tertiary ; Spike Glycoprotein, Coronavirus/*chemistry/immunology/*ultrastructure ; Viral Vaccines/chemistry/immunology ; Virus Internalization
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  • 20
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    Nature Publishing Group (NPG)
    Publication Date: 2016-02-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heuckeroth, Robert O -- England -- Nature. 2016 Mar 3;531(7592):44-5. doi: 10.1038/nature16877. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863191" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage ; *Cell- and Tissue-Based Therapy ; Drug Discovery/*methods ; Enteric Nervous System/*pathology ; Female ; Hirschsprung Disease/*drug therapy/*pathology ; Humans ; Male ; Neurons/*pathology
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  • 21
    Publication Date: 2016-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wan, Zheng -- Zhu, Mo -- Chen, Shun -- Sperling, Daniel -- England -- Nature. 2016 Feb 18;530(7590):275-7. doi: 10.1038/530275a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Transportation Studies, at the University of California, Davis, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887477" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conservation of Natural Resources/*legislation & jurisprudence/methods/trends ; Environmental Pollution/*legislation & jurisprudence/*prevention & ; control/statistics & numerical data ; *International Cooperation ; Ships/instrumentation/*legislation & jurisprudence/methods ; Vehicle Emissions/analysis/*legislation & jurisprudence/*prevention & control
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  • 22
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hollon, Nick G -- Phillips, Paul E M -- England -- Nature. 2016 Mar 31;531(7596):588-9. doi: 10.1038/nature17314. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Psychiatry &Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007851" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Decision Making ; Humans ; Male ; Neurons/*metabolism ; Nucleus Accumbens/*cytology/*metabolism ; Receptors, Dopamine D2/*metabolism ; *Risk Management
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  • 23
    Publication Date: 2016-04-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nowogrodzki, Anna -- England -- Nature. 2016 Mar 31;531(7596):561. doi: 10.1038/nature.2016.19599.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029258" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Specimen Banks/*economics/trends ; Climate Change ; Financing, Government/*economics/trends ; Financing, Organized/economics ; Museums ; Research Support as Topic/*economics/trends ; Time Factors ; United States ; United States Government Agencies/economics/trends
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  • 24
    Publication Date: 2016-05-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2016 May 5;533(7601):20-1. doi: 10.1038/533020a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27147014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Zoo/physiology ; Conservation of Natural Resources/economics/*methods ; *Extinction, Biological ; Female ; Fertilization in Vitro/economics/*veterinary ; Induced Pluripotent Stem Cells/*cytology ; Kenya ; Male ; Ovum/*cytology ; *Perissodactyla/physiology ; Reproduction/physiology ; Spermatozoa/*cytology
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  • 25
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ward, Alyssa -- Baldwin, Thomas O -- Antin, Parker B -- England -- Nature. 2016 Apr 14;532(7598):177. doi: 10.1038/532177d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ; University of California, Riverside, USA. ; University of Arizona, Tucson, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075087" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Confounding Factors (Epidemiology) ; *Learning ; Mice ; Mice, Transgenic/genetics ; National Institutes of Health (U.S.)/economics ; Reproducibility of Results ; Research/*standards ; United States
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  • 26
    Publication Date: 2016-03-24
    Description: (beta-)Arrestins are important regulators of G-protein-coupled receptors (GPCRs). They bind to active, phosphorylated GPCRs and thereby shut off 'classical' signalling to G proteins, trigger internalization of GPCRs via interaction with the clathrin machinery and mediate signalling via 'non-classical' pathways. In addition to two visual arrestins that bind to rod and cone photoreceptors (termed arrestin1 and arrestin4), there are only two (non-visual) beta-arrestin proteins (beta-arrestin1 and beta-arrestin2, also termed arrestin2 and arrestin3), which regulate hundreds of different (non-visual) GPCRs. Binding of these proteins to GPCRs usually requires the active form of the receptors plus their phosphorylation by G-protein-coupled receptor kinases (GRKs). The binding of receptors or their carboxy terminus as well as certain truncations induce active conformations of (beta-)arrestins that have recently been solved by X-ray crystallography. Here we investigate both the interaction of beta-arrestin with GPCRs, and the beta-arrestin conformational changes in real time and in living human cells, using a series of fluorescence resonance energy transfer (FRET)-based beta-arrestin2 biosensors. We observe receptor-specific patterns of conformational changes in beta-arrestin2 that occur rapidly after the receptor-beta-arrestin2 interaction. After agonist removal, these changes persist for longer than the direct receptor interaction. Our data indicate a rapid, receptor-type-specific, two-step binding and activation process between GPCRs and beta-arrestins. They further indicate that beta-arrestins remain active after dissociation from receptors, allowing them to remain at the cell surface and presumably signal independently. Thus, GPCRs trigger a rapid, receptor-specific activation/deactivation cycle of beta-arrestins, which permits their active signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nuber, Susanne -- Zabel, Ulrike -- Lorenz, Kristina -- Nuber, Andreas -- Milligan, Graeme -- Tobin, Andrew B -- Lohse, Martin J -- Hoffmann, Carsten -- 1 R01 DA038882/DA/NIDA NIH HHS/ -- BB/K019864/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2016 Mar 31;531(7596):661-4. doi: 10.1038/nature17198. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Pharmacology and Toxicology, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg, Germany. ; Rudolf Virchow Center, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg, Germany. ; Comprehensive Heart Failure Center, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg, Germany. ; Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. ; MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrestins/chemistry/*metabolism ; Biosensing Techniques ; Cattle ; Cell Line ; Cell Membrane/metabolism ; Cell Survival ; Crystallography, X-Ray ; Fluorescence Resonance Energy Transfer ; Humans ; Kinetics ; Models, Molecular ; Protein Binding ; Protein Conformation ; Receptors, G-Protein-Coupled/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity ; Time Factors
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  • 27
    Publication Date: 2016-05-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watson, Traci -- England -- Nature. 2016 May 5;533(7602):155. doi: 10.1038/nature.2016.19864.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27172024" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Egypt ; Female ; *Flowers ; History, Ancient ; Humans ; Infrared Rays ; *Mummies/history ; Religion/history ; *Symbolism ; Tattooing/*history
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  • 28
    Publication Date: 2016-03-05
    Description: The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Travis K -- Jordan, Robert -- Lo, Michael K -- Ray, Adrian S -- Mackman, Richard L -- Soloveva, Veronica -- Siegel, Dustin -- Perron, Michel -- Bannister, Roy -- Hui, Hon C -- Larson, Nate -- Strickley, Robert -- Wells, Jay -- Stuthman, Kelly S -- Van Tongeren, Sean A -- Garza, Nicole L -- Donnelly, Ginger -- Shurtleff, Amy C -- Retterer, Cary J -- Gharaibeh, Dima -- Zamani, Rouzbeh -- Kenny, Tara -- Eaton, Brett P -- Grimes, Elizabeth -- Welch, Lisa S -- Gomba, Laura -- Wilhelmsen, Catherine L -- Nichols, Donald K -- Nuss, Jonathan E -- Nagle, Elyse R -- Kugelman, Jeffrey R -- Palacios, Gustavo -- Doerffler, Edward -- Neville, Sean -- Carra, Ernest -- Clarke, Michael O -- Zhang, Lijun -- Lew, Willard -- Ross, Bruce -- Wang, Queenie -- Chun, Kwon -- Wolfe, Lydia -- Babusis, Darius -- Park, Yeojin -- Stray, Kirsten M -- Trancheva, Iva -- Feng, Joy Y -- Barauskas, Ona -- Xu, Yili -- Wong, Pamela -- Braun, Molly R -- Flint, Mike -- McMullan, Laura K -- Chen, Shan-Shan -- Fearns, Rachel -- Swaminathan, Swami -- Mayers, Douglas L -- Spiropoulou, Christina F -- Lee, William A -- Nichol, Stuart T -- Cihlar, Tomas -- Bavari, Sina -- R01 AI113321/AI/NIAID NIH HHS/ -- R01AI113321/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA. ; United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. ; Boston University School of Medicine, Boston, Massachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934220" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use ; Amino Acid Sequence ; Animals ; Antiviral Agents/pharmacokinetics/pharmacology/*therapeutic use ; Cell Line, Tumor ; Ebolavirus/drug effects ; Female ; HeLa Cells ; Hemorrhagic Fever, Ebola/*drug therapy/prevention & control ; Humans ; Macaca mulatta/*virology ; Male ; Molecular Sequence Data ; Organ Specificity ; Prodrugs/pharmacokinetics/pharmacology/therapeutic use ; Ribonucleotides/pharmacokinetics/pharmacology/*therapeutic use
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  • 29
    Publication Date: 2016-04-07
    Description: In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have 'colour-opponent' visual responses-excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a 'blue shift' in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joesch, Maximilian -- Meister, Markus -- England -- Nature. 2016 Apr 14;532(7598):236-9. doi: 10.1038/nature17158. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049951" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Color ; Color Perception/*physiology/radiation effects ; Color Vision/*physiology/radiation effects ; Darkness ; Female ; Humans ; Male ; Mice ; Models, Neurological ; Neural Pathways/*physiology/radiation effects ; Retinal Cone Photoreceptor Cells/*metabolism/radiation effects ; Retinal Ganglion Cells/metabolism/radiation effects ; Retinal Rod Photoreceptor Cells/*metabolism/radiation effects ; Synapses/metabolism/radiation effects ; Territoriality ; Ultraviolet Rays
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  • 30
    Publication Date: 2016-01-19
    Description: Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body's abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seung-Kyun -- Murphy, Rory K J -- Hwang, Suk-Won -- Lee, Seung Min -- Harburg, Daniel V -- Krueger, Neil A -- Shin, Jiho -- Gamble, Paul -- Cheng, Huanyu -- Yu, Sooyoun -- Liu, Zhuangjian -- McCall, Jordan G -- Stephen, Manu -- Ying, Hanze -- Kim, Jeonghyun -- Park, Gayoung -- Webb, R Chad -- Lee, Chi Hwan -- Chung, Sangjin -- Wie, Dae Seung -- Gujar, Amit D -- Vemulapalli, Bharat -- Kim, Albert H -- Lee, Kyung-Mi -- Cheng, Jianjun -- Huang, Younggang -- Lee, Sang Hoon -- Braun, Paul V -- Ray, Wilson Z -- Rogers, John A -- F31MH101956/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Feb 4;530(7588):71-6. doi: 10.1038/nature16492. Epub 2016 Jan 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Republic of Korea. ; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Engineering Science and Mechanics, Materials Research Institute, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Institute of High Performance Computing, Singapore 138632, Singapore. ; Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Biomicrosystem Technology, Korea University, Seoul 136-701, South Korea. ; Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-713, South Korea. ; Weldon School of Biomedical Engineering, School of Mechanical Engineering, The Center for Implantable Devices, Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana 47907, USA. ; School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, USA. ; Department of Mechanical Engineering, Civil and Environmental Engineering, Materials Science and Engineering, and Skin Disease Research Center, Northwestern University, Evanston, Illinois 60208, USA. ; Department of Biomedical Engineering, College of Health Science, Korea University, Seoul 136-703, South Korea. ; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26779949" target="_blank"〉PubMed〈/a〉
    Keywords: *Absorbable Implants/adverse effects ; Administration, Cutaneous ; Animals ; Body Temperature ; Brain/*metabolism/surgery ; Electronics/*instrumentation ; Equipment Design ; Hydrolysis ; Male ; Monitoring, Physiologic/adverse effects/*instrumentation ; Organ Specificity ; Pressure ; *Prostheses and Implants/adverse effects ; Rats ; Rats, Inbred Lew ; *Silicon ; Telemetry/instrumentation ; Wireless Technology/instrumentation
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  • 31
    Publication Date: 2016-03-31
    Description: It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N(6)-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N(6)-methyladenine. An increase of N(6)-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N(6)-methyladenine deposition is inversely correlated with the evolutionary age of LINE-1 transposons; its deposition is strongly enriched at young (〈1.5 million years old) but not old (〉6 million years old) L1 elements. The deposition of N(6)-methyladenine correlates with epigenetic silencing of such LINE-1 transposons, together with their neighbouring enhancers and genes, thereby resisting the gene activation signals during embryonic stem cell differentiation. As young full-length LINE-1 transposons are strongly enriched on the X chromosome, genes located on the X chromosome are also silenced. Thus, N(6)-methyladenine developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. Our results demonstrate that N(6)-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Tao P -- Wang, Tao -- Seetin, Matthew G -- Lai, Yongquan -- Zhu, Shijia -- Lin, Kaixuan -- Liu, Yifei -- Byrum, Stephanie D -- Mackintosh, Samuel G -- Zhong, Mei -- Tackett, Alan -- Wang, Guilin -- Hon, Lawrence S -- Fang, Gang -- Swenberg, James A -- Xiao, Andrew Z -- P20GM103429/GM/NIGMS NIH HHS/ -- P30 ES010126/ES/NIEHS NIH HHS/ -- P42 ES005948/ES/NIEHS NIH HHS/ -- R01 GM114472-01/GM/NIGMS NIH HHS/ -- R01GM106024/GM/NIGMS NIH HHS/ -- R01GM114205-01/GM/NIGMS NIH HHS/ -- S10OD018445/OD/NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):329-33. doi: 10.1038/nature17640. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Pacific Biosciences, 1380 Willow Road, Menlo Park, California 94025, USA. ; Environmental Sciences &Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA. ; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. ; Yale Stem Cell Center and Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Molecular Biophysics &Biochemistry, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027282" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/*analogs & derivatives/metabolism ; Animals ; Cell Differentiation/genetics ; *DNA Methylation ; DNA Transposable Elements/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/deficiency/genetics/metabolism ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/*genetics ; Evolution, Molecular ; Gene Silencing ; Long Interspersed Nucleotide Elements/genetics ; Mammals/genetics ; Mice ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Up-Regulation/genetics ; X Chromosome/genetics/metabolism
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  • 32
    Publication Date: 2016-04-15
    Description: Numerous natural systems contain surfaces or threads that enable directional water transport. This behaviour is usually ascribed to hierarchical structural features at the microscale and nanoscale, with gradients in surface energy and gradients in Laplace pressure thought to be the main driving forces. Here we study the prey-trapping pitcher organs of the carnivorous plant Nepenthes alata. We find that continuous, directional water transport occurs on the surface of the 'peristome'--the rim of the pitcher--because of its multiscale structure, which optimizes and enhances capillary rise in the transport direction, and prevents backflow by pinning in place any water front that is moving in the reverse direction. This results not only in unidirectional flow despite the absence of any surface-energy gradient, but also in a transport speed that is much higher than previously thought. We anticipate that the basic 'design' principles underlying this behaviour could be used to develop artificial fluid-transport systems with practical applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Huawei -- Zhang, Pengfei -- Zhang, Liwen -- Liu, Hongliang -- Jiang, Ying -- Zhang, Deyuan -- Han, Zhiwu -- Jiang, Lei -- England -- Nature. 2016 Apr 7;532(7597):85-9. doi: 10.1038/nature17189.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Mechanical Engineering and Automation, Beihang University, Beijing 100191, China. ; Laboratory of Bio-inspired Smart Interface Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China. ; School of Chemistry and Environment, Beihang University, Beijing 100191, China. ; Key Laboratory for Bionic Engineering, Ministry of Education, Jilin University, Changchun 130022, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27078568" target="_blank"〉PubMed〈/a〉
    Keywords: Angiosperms/*anatomy & histology/*metabolism ; Animals ; Biological Transport ; Biomimetics ; Insects ; Plant Epidermis/anatomy & histology/metabolism ; Surface Properties ; Water/*metabolism ; Water Movements
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  • 33
    Publication Date: 2016-03-05
    Description: How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kay, Kenneth -- Sosa, Marielena -- Chung, Jason E -- Karlsson, Mattias P -- Larkin, Margaret C -- Frank, Loren M -- R01 MH090188/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 10;531(7593):185-90. doi: 10.1038/nature17144. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UCSF Center for Integrative Neuroscience and Department of Physiology, University of California San Francisco, California 94158, USA. ; Howard Hughes Medical Institute, University of California San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934224" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Hippocampus/anatomy & histology/*cytology/*physiology ; Male ; Models, Neurological ; Movement ; Neurons/*physiology ; Orientation/*physiology ; Rats ; Rats, Long-Evans ; Sleep/*physiology ; Space Perception/*physiology ; Spatial Memory/physiology
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  • 34
    Publication Date: 2016-03-17
    Description: CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Wei -- Bai, Yibing -- Xiong, Ying -- Zhang, Jin -- Chen, Shuokai -- Zheng, Xiaojun -- Meng, Xiangbo -- Li, Lunyi -- Wang, Jing -- Xu, Chenguang -- Yan, Chengsong -- Wang, Lijuan -- Chang, Catharine C Y -- Chang, Ta-Yuan -- Zhang, Ti -- Zhou, Penghui -- Song, Bao-Liang -- Liu, Wanli -- Sun, Shao-cong -- Liu, Xiaolong -- Li, Bo-liang -- Xu, Chenqi -- HL 60306./HL/NHLBI NIH HHS/ -- R01 HL060306/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Mar 31;531(7596):651-5. doi: 10.1038/nature17412. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Haven 03755, USA. ; Rheumatology and Immunology Department of ChangZheng Hospital, Second Military Medical University, Shanghai 200433, China. ; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. ; College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China. ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982734" target="_blank"〉PubMed〈/a〉
    Keywords: Acetates/*pharmacology/therapeutic use ; Acetyl-CoA C-Acetyltransferase/antagonists & ; inhibitors/deficiency/genetics/metabolism ; Animals ; Atherosclerosis/drug therapy ; CD8-Positive T-Lymphocytes/*drug effects/*immunology/metabolism ; Cell Membrane/drug effects/metabolism ; Cholesterol/*metabolism ; Esterification/drug effects ; Female ; Immunological Synapses/drug effects/immunology/metabolism ; Immunotherapy/*methods ; Male ; Melanoma/*drug therapy/*immunology/metabolism/pathology ; Mice ; Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology ; Receptors, Antigen, T-Cell/immunology/metabolism ; Signal Transduction/drug effects ; Sulfonic Acids/*pharmacology/therapeutic use
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  • 35
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pollock, Kevin -- England -- Nature. 2016 Mar 17;531(7594):S64-6. doi: 10.1038/531S64a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26981733" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cities ; *City Planning ; Feedback ; Humans ; *Physics ; Plague/epidemiology ; Rats ; *Urbanization ; Vietnam/epidemiology
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  • 36
    Publication Date: 2016-02-26
    Description: The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) 〉 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780242/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kerr, Emma M -- Gaude, Edoardo -- Turrell, Frances K -- Frezza, Christian -- Martins, Carla P -- MC_UU_12022/4/Medical Research Council/United Kingdom -- MC_UU_12022/6/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):110-3. doi: 10.1038/nature16967. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909577" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic/drug effects/genetics/metabolism/pathology ; Citric Acid Cycle ; DNA Copy Number Variations/*genetics ; Disease Progression ; Female ; Fibroblasts/metabolism ; Genes, ras/*genetics ; Genotype ; Glucose/*metabolism ; Glutathione/biosynthesis/metabolism ; *Glycolysis ; Lung Neoplasms/*drug therapy/genetics/*metabolism/pathology ; Male ; Mice ; Mutation/*genetics ; Oxidation-Reduction ; Phenotype ; Prognosis
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 37
    Publication Date: 2016-03-31
    Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027295" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/drug effects
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 38
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    Nature Publishing Group (NPG)
    Publication Date: 2016-01-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Jan 28;529(7587):437-8. doi: 10.1038/529437b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26819007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; China ; Cities ; Congo ; Conservation of Natural Resources/*legislation & jurisprudence ; Ecosystem ; Great Britain ; *Parks, Recreational/legislation & jurisprudence ; Pleasure ; Uganda ; United States ; *Wilderness
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  • 39
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉King, Anthony -- England -- Nature. 2016 Mar 3;531(7592):S18-9. doi: 10.1038/531S18a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934522" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/metabolism ; Animals ; Brain/*physiology ; Bullying ; DNA Methylation ; Depression/complications/prevention & control/therapy ; Emotional Adjustment ; Epigenesis, Genetic/genetics ; Female ; Hippocampus/metabolism ; Humans ; Hydrocortisone/metabolism ; Maternal Behavior ; Memory/physiology ; Mice ; Models, Animal ; Oxytocin/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/genetics ; Psychological Trauma/complications/genetics/metabolism ; Rats ; *Resilience, Psychological ; Social Isolation/psychology ; Stress, Psychological/complications/genetics/metabolism/therapy
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  • 40
    Publication Date: 2016-03-31
    Description: Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/beta-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864035/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Zinan -- Tang, Alan T -- Wong, Weng-Yew -- Bamezai, Sharika -- Goddard, Lauren M -- Shenkar, Robert -- Zhou, Su -- Yang, Jisheng -- Wright, Alexander C -- Foley, Matthew -- Arthur, J Simon C -- Whitehead, Kevin J -- Awad, Issam A -- Li, Dean Y -- Zheng, Xiangjian -- Kahn, Mark L -- P01 HL075215/HL/NHLBI NIH HHS/ -- P01 HL120846/HL/NHLBI NIH HHS/ -- P01 NS092521/NS/NINDS NIH HHS/ -- P01NS092521/NS/NINDS NIH HHS/ -- R01 HL094326/HL/NHLBI NIH HHS/ -- R01HL-084516/HL/NHLBI NIH HHS/ -- R01HL094326/HL/NHLBI NIH HHS/ -- R01NS075168/NS/NINDS NIH HHS/ -- T32HL07439/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA. ; Laboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia. ; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois 60637, USA. ; Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA. ; Sydney Microscopy &Microanalysis, University of Sydney, Sydney, New South Wales 2050, Australia. ; Division of Cell Signaling and Immunology, University of Dundee, Dundee DD1 5EH, UK. ; Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA. ; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences &Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China. ; Faculty of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027284" target="_blank"〉PubMed〈/a〉
    Keywords: ADAM Proteins/metabolism ; Animals ; Animals, Newborn ; Carrier Proteins/genetics/metabolism ; Disease Models, Animal ; Endothelial Cells/enzymology/*metabolism ; Female ; Hemangioma, Cavernous, Central Nervous System/etiology/*metabolism/pathology ; Humans ; Kruppel-Like Transcription Factors/deficiency/*metabolism ; MAP Kinase Kinase Kinase 3/deficiency/*metabolism ; *MAP Kinase Signaling System ; Male ; Mice ; Protein Binding ; rho GTP-Binding Proteins/metabolism
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  • 41
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cressey, Daniel -- England -- Nature. 2016 Apr 7;532(7597):18-9. doi: 10.1038/532018a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27078545" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aquatic Organisms/genetics/isolation & purification ; *Biodiversity ; Conservation of Natural Resources/*legislation & jurisprudence ; International Cooperation/*legislation & jurisprudence ; *Negotiating ; Oceans and Seas ; United Nations/legislation & jurisprudence
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  • 42
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    Nature Publishing Group (NPG)
    Publication Date: 2016-01-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Jan 7;529(7584):5. doi: 10.1038/529005a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738571" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bibliometrics ; *Cooperative Behavior ; Developed Countries ; Developing Countries ; *Group Processes ; Humans ; *International Cooperation ; Research/manpower/*organization & administration
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