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  • Nature Publishing Group (NPG)  (11)
  • 1
    Publication Date: 2012-09-21
    Description: The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Guofan -- Fang, Xiaodong -- Guo, Ximing -- Li, Li -- Luo, Ruibang -- Xu, Fei -- Yang, Pengcheng -- Zhang, Linlin -- Wang, Xiaotong -- Qi, Haigang -- Xiong, Zhiqiang -- Que, Huayong -- Xie, Yinlong -- Holland, Peter W H -- Paps, Jordi -- Zhu, Yabing -- Wu, Fucun -- Chen, Yuanxin -- Wang, Jiafeng -- Peng, Chunfang -- Meng, Jie -- Yang, Lan -- Liu, Jun -- Wen, Bo -- Zhang, Na -- Huang, Zhiyong -- Zhu, Qihui -- Feng, Yue -- Mount, Andrew -- Hedgecock, Dennis -- Xu, Zhe -- Liu, Yunjie -- Domazet-Loso, Tomislav -- Du, Yishuai -- Sun, Xiaoqing -- Zhang, Shoudu -- Liu, Binghang -- Cheng, Peizhou -- Jiang, Xuanting -- Li, Juan -- Fan, Dingding -- Wang, Wei -- Fu, Wenjing -- Wang, Tong -- Wang, Bo -- Zhang, Jibiao -- Peng, Zhiyu -- Li, Yingxiang -- Li, Na -- Wang, Jinpeng -- Chen, Maoshan -- He, Yan -- Tan, Fengji -- Song, Xiaorui -- Zheng, Qiumei -- Huang, Ronglian -- Yang, Hailong -- Du, Xuedi -- Chen, Li -- Yang, Mei -- Gaffney, Patrick M -- Wang, Shan -- Luo, Longhai -- She, Zhicai -- Ming, Yao -- Huang, Wen -- Zhang, Shu -- Huang, Baoyu -- Zhang, Yong -- Qu, Tao -- Ni, Peixiang -- Miao, Guoying -- Wang, Junyi -- Wang, Qiang -- Steinberg, Christian E W -- Wang, Haiyan -- Li, Ning -- Qian, Lumin -- Zhang, Guojie -- Li, Yingrui -- Yang, Huanming -- Liu, Xiao -- Wang, Jian -- Yin, Ye -- Wang, Jun -- 268513/European Research Council/International -- England -- Nature. 2012 Oct 4;490(7418):49-54. doi: 10.1038/nature11413. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992520" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*genetics ; Animal Shells/chemistry/*growth & development ; Animals ; Apoptosis Regulatory Proteins/genetics ; Crassostrea/*genetics ; DNA Transposable Elements/genetics ; Evolution, Molecular ; Female ; Gene Expression Regulation, Developmental/genetics ; Genes, Homeobox/genetics ; Genome/*genetics ; Genomics ; HSP70 Heat-Shock Proteins/genetics ; Humans ; Larva/genetics/growth & development ; Mass Spectrometry ; Molecular Sequence Annotation ; Molecular Sequence Data ; Polymorphism, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, DNA ; Stress, Physiological/genetics/*physiology ; Transcriptome/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-07-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zeng, Guangming -- Chen, Ming -- Zeng, Zhuotong -- England -- Nature. 2013 Jul 11;499(7457):154. doi: 10.1038/499154c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23846647" target="_blank"〉PubMed〈/a〉
    Keywords: Groundwater/*chemistry ; Methane/*analysis ; Natural Gas/*supply & distribution ; Water Pollutants/*analysis
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-02-07
    Description: Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260937/" 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/PMC4260937/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Correia, Bruno E -- Bates, John T -- Loomis, Rebecca J -- Baneyx, Gretchen -- Carrico, Chris -- Jardine, Joseph G -- Rupert, Peter -- Correnti, Colin -- Kalyuzhniy, Oleksandr -- Vittal, Vinayak -- Connell, Mary J -- Stevens, Eric -- Schroeter, Alexandria -- Chen, Man -- Macpherson, Skye -- Serra, Andreia M -- Adachi, Yumiko -- Holmes, Margaret A -- Li, Yuxing -- Klevit, Rachel E -- Graham, Barney S -- Wyatt, Richard T -- Baker, David -- Strong, Roland K -- Crowe, James E Jr -- Johnson, Philip R -- Schief, William R -- 1R01AI102766-01A1/AI/NIAID NIH HHS/ -- 1UM1AI100663/AI/NIAID NIH HHS/ -- 2T32GM007270/GM/NIGMS NIH HHS/ -- 5R21AI088554/AI/NIAID NIH HHS/ -- P01 AI094419/AI/NIAID NIH HHS/ -- P01AI094419/AI/NIAID NIH HHS/ -- P30 AI036214/AI/NIAID NIH HHS/ -- P30 AI045008/AI/NIAID NIH HHS/ -- P30AI36214/AI/NIAID NIH HHS/ -- R01 AI102766/AI/NIAID NIH HHS/ -- R21 AI088554/AI/NIAID NIH HHS/ -- T32 CA080416/CA/NCI NIH HHS/ -- T32 GM007270/GM/NIGMS NIH HHS/ -- T32CA080416/CA/NCI NIH HHS/ -- U54 AI 005714/AI/NIAID NIH HHS/ -- U54 AI057141/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):201-6. doi: 10.1038/nature12966. Epub 2014 Feb 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] PhD Program in Computational Biology, Instituto Gulbenkian Ciencia and Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Oeiras 2780-157, Portugal [3] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. ; The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. ; The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA [2]. ; 1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pathology, Microbiology and Immunology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA [3] Department of Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499818" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Antibodies, Monoclonal/analysis/immunology ; Antibodies, Neutralizing/analysis/immunology ; Antibodies, Viral/analysis/immunology ; Antigens, Viral/chemistry/immunology ; Crystallography, X-Ray ; *Drug Design ; Enzyme-Linked Immunosorbent Assay ; Epitopes/*chemistry/*immunology ; Macaca mulatta/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Neutralization Tests ; Protein Conformation ; *Protein Stability ; Respiratory Syncytial Virus Vaccines/*chemistry/*immunology ; Respiratory Syncytial Viruses/chemistry/immunology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-09-22
    Description: Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 A. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ge, Jingpeng -- Li, Wanqiu -- Zhao, Qiancheng -- Li, Ningning -- Chen, Maofei -- Zhi, Peng -- Li, Ruochong -- Gao, Ning -- Xiao, Bailong -- Yang, Maojun -- England -- Nature. 2015 Nov 5;527(7576):64-9. doi: 10.1038/nature15247. Epub 2015 Sep 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences or Medicine, Tsinghua University, Beijing 100084, China. ; Ministry of Education, Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26390154" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/metabolism ; *Cryoelectron Microscopy ; Electric Conductivity ; Ion Channel Gating ; Ion Channels/*chemistry/metabolism/*ultrastructure ; Mice ; Models, Molecular ; Pliability ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism
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  • 5
    Publication Date: 2016-05-27
    Description: Quiescent galaxies with little or no ongoing star formation dominate the population of galaxies with masses above 2 x 10(10) times that of the Sun; the number of quiescent galaxies has increased by a factor of about 25 over the past ten billion years (refs 1-4). Once star formation has been shut down, perhaps during the quasar phase of rapid accretion onto a supermassive black hole, an unknown mechanism must remove or heat the gas that is subsequently accreted from either stellar mass loss or mergers and that would otherwise cool to form stars. Energy output from a black hole accreting at a low rate has been proposed, but observational evidence for this in the form of expanding hot gas shells is indirect and limited to radio galaxies at the centres of clusters, which are too rare to explain the vast majority of the quiescent population. Here we report bisymmetric emission features co-aligned with strong ionized-gas velocity gradients from which we infer the presence of centrally driven winds in typical quiescent galaxies that host low-luminosity active nuclei. These galaxies are surprisingly common, accounting for as much as ten per cent of the quiescent population with masses around 2 x 10(10) times that of the Sun. In a prototypical example, we calculate that the energy input from the galaxy's low-level active supermassive black hole is capable of driving the observed wind, which contains sufficient mechanical energy to heat ambient, cooler gas (also detected) and thereby suppress star formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheung, Edmond -- Bundy, Kevin -- Cappellari, Michele -- Peirani, Sebastien -- Rujopakarn, Wiphu -- Westfall, Kyle -- Yan, Renbin -- Bershady, Matthew -- Greene, Jenny E -- Heckman, Timothy M -- Drory, Niv -- Law, David R -- Masters, Karen L -- Thomas, Daniel -- Wake, David A -- Weijmans, Anne-Marie -- Rubin, Kate -- Belfiore, Francesco -- Vulcani, Benedetta -- Chen, Yan-mei -- Zhang, Kai -- Gelfand, Joseph D -- Bizyaev, Dmitry -- Roman-Lopes, A -- Schneider, Donald P -- England -- Nature. 2016 May 25;533(7604):504-8. doi: 10.1038/nature18006.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Kavli Institute for the Physics and Mathematics of the Universe (World Premier International Research Center Initiative), The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Kashiwa, Chiba 277-8583, Japan. ; Sub-department of Astrophysics, Department of Physics, University of Oxford, Denys Wilkinson Building, Keble Road, Oxford OX1 3RH, UK. ; Institut d'Astrophysique de Paris (UMR 7095, CNRS and UPMC), 98 bis Boulevard Arago, F-75014 Paris, France. ; Department of Physics, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330, Thailand. ; Institute for Cosmology and Gravitation, University of Portsmouth, Dennis Sciama Building, Burnaby Road, Portsmouth PO1 3FX, UK. ; Department of Physics and Astronomy, University of Kentucky, 505 Rose Street, Lexington, Kentucky 40506-0055, USA. ; Department of Astronomy, University of Wisconsin-Madison, 475 North Charter Street, Madison, Wisconsin 53706, USA. ; Department of Astrophysical Sciences, Princeton University, Princeton, New Jersey 08544, USA. ; Center for Astrophysical Sciences, Department of Physics and Astronomy, The Johns Hopkins University, Baltimore, Maryland 21218, USA. ; McDonald Observatory, Department of Astronomy, University of Texas at Austin, 1 University Station, Austin, Texas 78712-0259, USA. ; Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, Maryland 21218, USA. ; Department of Physical Sciences, The Open University, Milton Keynes MK7 6AA, UK. ; School of Physics and Astronomy, University of St Andrews, North Haugh, St Andrews, Fife KY16 9SS, UK. ; Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, Massachusetts 02138, USA. ; Cavendish Laboratory, University of Cambridge, 19 J. J. Thomson Avenue, Cambridge CB3 0HE, UK. ; Kavli Institute for Cosmology, University of Cambridge, Cambridge CB3 0HE, UK. ; Department of Astronomy, Nanjing University, Nanjing 210093, China. ; New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates. ; Center for Cosmology and Particle Physics, New York University, Meyer Hall of Physics, 4 Washington Place, New York, New York 10003, USA. ; Apache Point Observatory and New Mexico State University, PO Box 59, Sunspot, New Mexico 88349-0059, USA. ; Sternberg Astronomical Institute, Moscow State University, Moscow, Russia. ; Departamento de Fisica y Astronomia, Facultad de Ciencias, Universidad de La Serena, Cisternas 1200, La Serena, Chile. ; Department of Astronomy and Astrophysics, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Institute for Gravitation and the Cosmos, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27225122" target="_blank"〉PubMed〈/a〉
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  • 6
    Publication Date: 2013-11-15
    Description: Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic beta-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lloyd, David J -- St Jean, David J Jr -- Kurzeja, Robert J M -- Wahl, Robert C -- Michelsen, Klaus -- Cupples, Rod -- Chen, Michelle -- Wu, John -- Sivits, Glenn -- Helmering, Joan -- Komorowski, Renee -- Ashton, Kate S -- Pennington, Lewis D -- Fotsch, Christopher -- Vazir, Mukta -- Chen, Kui -- Chmait, Samer -- Zhang, Jiandong -- Liu, Longbin -- Norman, Mark H -- Andrews, Kristin L -- Bartberger, Michael D -- Van, Gwyneth -- Galbreath, Elizabeth J -- Vonderfecht, Steven L -- Wang, Minghan -- Jordan, Steven R -- Veniant, Murielle M -- Hale, Clarence -- England -- Nature. 2013 Dec 19;504(7480):437-40. doi: 10.1038/nature12724. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Comparative Biology & Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226772" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Cell Nucleus/enzymology ; Crystallography, X-Ray ; Diabetes Mellitus, Type 2/blood/*drug therapy/enzymology ; Disease Models, Animal ; Hepatocytes ; Humans ; Hyperglycemia/blood/drug therapy/enzymology ; Hypoglycemic Agents/chemistry/*pharmacology/*therapeutic use ; Liver/cytology/enzymology/metabolism ; Male ; Models, Molecular ; Organ Specificity ; Phosphorylation/drug effects ; Piperazines/chemistry/metabolism/pharmacology/therapeutic use ; Protein Binding/drug effects ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use
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  • 7
    Publication Date: 2018-07-17
    Description: Deep learning sequence-based ab initio prediction of variant effects on expression and disease risk Deep learning sequence-based ab initio prediction of variant effects on expression and disease risk, Published online: 16 July 2018; doi:10.1038/s41588-018-0160-6 ExPecto is a deep learning–based framework that can predict the tissue-specific transcriptional effects of mutations on the basis of DNA sequence alone. ExPecto can prioritize causal variants from GWAS loci and be used to predict the disease risk of a variant.
    Print ISSN: 1061-4036
    Electronic ISSN: 1546-1718
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2018-10-31
    Description: Subclinical hypothyroidism and depression: a meta-analysis Subclinical hypothyroidism and depression: a meta-analysis, Published online: 30 October 2018; doi:10.1038/s41398-018-0283-7 Subclinical hypothyroidism and depression: a meta-analysis
    Electronic ISSN: 2158-3188
    Topics: Medicine
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  • 9
    Publication Date: 2015-11-26
    Description: Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sztainberg, Yehezkel -- Chen, Hong-mei -- Swann, John W -- Hao, Shuang -- Tang, Bin -- Wu, Zhenyu -- Tang, Jianrong -- Wan, Ying-Wooi -- Liu, Zhandong -- Rigo, Frank -- Zoghbi, Huda Y -- 1U54HD083092/HD/NICHD NIH HHS/ -- 5P30HD024064/HD/NICHD NIH HHS/ -- 5R01NS057819/NS/NINDS NIH HHS/ -- P30 HD024064/HD/NICHD NIH HHS/ -- R01 NS057819/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 3;528(7580):123-6. doi: 10.1038/nature16159. Epub 2015 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA. ; The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA. ; Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA. ; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605526" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Attachment Sites, Microbiological/genetics ; Cells, Cultured ; Disease Models, Animal ; Electroencephalography ; Gene Dosage/*genetics ; Gene Duplication/genetics ; *Gene Knockdown Techniques ; Genes, Duplicate/*genetics ; Humans ; Integrases/genetics/metabolism ; Mental Retardation, X-Linked/*genetics/physiopathology ; Methyl-CpG-Binding Protein 2/*genetics/metabolism ; Mice ; Mice, Transgenic ; Oligonucleotides, Antisense/*genetics ; *Phenotype
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  • 10
    Publication Date: 2016-03-10
    Description: Many biopolymers, including polysaccharides, must be translocated across at least one membrane to reach their site of biological function. Cellulose is a linear glucose polymer synthesized and secreted by a membrane-integrated cellulose synthase. Here, in crystallo enzymology with the catalytically active bacterial cellulose synthase BcsA-BcsB complex reveals structural snapshots of a complete cellulose biosynthesis cycle, from substrate binding to polymer translocation. Substrate- and product-bound structures of BcsA provide the basis for substrate recognition and demonstrate the stepwise elongation of cellulose. Furthermore, the structural snapshots show that BcsA translocates cellulose via a ratcheting mechanism involving a 'finger helix' that contacts the polymer's terminal glucose. Cooperating with BcsA's gating loop, the finger helix moves 'up' and 'down' in response to substrate binding and polymer elongation, respectively, thereby pushing the elongated polymer into BcsA's transmembrane channel. This mechanism is validated experimentally by tethering BcsA's finger helix, which inhibits polymer translocation but not elongation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843519/" 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/PMC4843519/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morgan, Jacob L W -- McNamara, Joshua T -- Fischer, Michael -- Rich, Jamie -- Chen, Hong-Ming -- Withers, Stephen G -- Zimmer, Jochen -- 1R01GM101001/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM101001/GM/NIGMS NIH HHS/ -- S10 RR029205/RR/NCRR NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):329-34. doi: 10.1038/nature16966. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Virginia School of Medicine, Center for Membrane Biology, Molecular Physiology and Biological Physics, 480 Ray C. Hunt Drive, Charlottesville, Virginia 22908, USA. ; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958837" target="_blank"〉PubMed〈/a〉
    Keywords: Cellulose/*biosynthesis/chemistry/*metabolism ; Crystallography, X-Ray ; Glucose/metabolism ; Glucosyltransferases/*chemistry/*metabolism ; Intracellular Membranes/chemistry/*metabolism ; Models, Molecular ; Movement ; Protein Structure, Secondary ; Proteolipids/chemistry/metabolism ; Rhodobacter sphaeroides/enzymology ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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