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4 results on '"Departments of pharmacology and molecular biophysics and biochemistry [New Haven]"'

1. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia

Author

Tamas L. Horvath, Maria Teresa Dell’Anno, Xiao-Bing Gao, Naoki Nakagawa, Anze Testen, Yalan Zhang, Tianliuyun Gao, Mihovil Pletikos, Candace Bichsel, Nenad Sestan, Mingfeng Li, Sirisha Pochareddy, Brett D. Lindenbach, Leonard K. Kaczmarek, Zhen Li, Wenqi Han, Forrest O. Gulden, Fuchen Liu, André M. M. Sousa, Stephen M. Strittmatter, Andrew T.N. Tebbenkamp, Marco Onorati, Steven Lisgo, Jernej Mlakar, Marie Flamand, Mara Popović, Eva S. Anton, Luis Varela, Klara Szigeti-Buck, Ying Zhu, Department of Neuroscience [New Haven], Yale University School of Medicine-Kavli Institute for Neuroscience [New Haven], Department of Cell Biology and Physiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience [New Haven], Yale University School of Medicine, Section of Comparative Medicine [New Haven], Institute of Genetic Medicine, Newcastle University [Newcastle], Departments of pharmacology and molecular biophysics and biochemistry [New Haven], University of Ljubljana, Département de Virologie - Department of Virology, Institut Pasteur [Paris], Departments of Internal Medicine, Cellular & Molecular Physiology, Departments of Medicine and Cell Biology & Physiology, Department of Microbial Pathogenesis, Reproductive Neuroscience Unit, Department of Obstetrics and Gynecology and Department of Neurobiology, Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, Kavli Institute for Neuroscience [New Haven], Departments of Psychiatry and Genetics, This work was supported by grants NS076503, MH103339, MH105972, MH106934, MH060929, NS080388, AG034924, AG047270, DC01919, AI120113, and AI089826 from the NIH, SFARI 307705 from the Simons Foundation, and 15-RMA-YALE-31 from Connecticut Innovations’ Regenerative Medicine Research Fund. The Laboratory of Developmental Biology at the University of Washington, Seattle, and Human Developmental Biology Resource were supported by NIH award number HD0008836 and the Joint MRC/Wellcome Trust grant 099175/Z/12/Z, respectively. Additional support was provided by the Kavli Foundation and the Falk Medical Research Trust., Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP), Kavli Institute for Neuroscience, Yale School of Medicine, and Yale School of Medicine [New Haven, Connecticut] (YSM)-Yale School of Medicine [New Haven, Connecticut] (YSM)

Subjects
Genetics and Molecular Biology (all), Microcephaly, Transcription, Genetic, Neocortex, MESH: Neuroepithelial Cells/ultrastructure, Biochemistry, environment and public health, MESH: Brain/virology, Neural Stem Cells, MESH: Centrosome/drug effects, MESH: Mitochondria/metabolism, lcsh:QH301-705.5, Neurons, MESH: Protein-Serine-Threonine Kinases/metabolism, Zika Virus Infection, Brain, MESH: Neurons/virology, MESH: Neural Stem Cells/virology, MESH: Neural Stem Cells/immunology, Nucleosides, MESH: Zika Virus/physiology, MESH: Virus Replication/drug effects, Neural stem cell, 3. Good health, Cell biology, Neuroepithelial cell, MESH: Brain/pathology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Spinal Cord, MESH: Neocortex/pathology, MESH: Neuroepithelial Cells/immunology, Neuroglia, MESH: Receptor Protein-Tyrosine Kinases/metabolism, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Protein Kinase Inhibitors/pharmacology, 03 medical and health sciences, MESH: Gene Expression Profiling, Fetus, Humans, MESH: Phosphorylation/drug effects, Mitosis, MESH: Neural Stem Cells/ultrastructure, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Receptor Protein-Tyrosine Kinases, MESH: Zika Virus/pathogenicity, medicine.disease, Immunity, Innate, MESH: Mitosis/drug effects, 030104 developmental biology, MESH: Neuroprotective Agents/pharmacology, MESH: Mitochondria/drug effects, MESH: Spinal Cord/pathology, MESH: Neuroglia/ultrastructure, 0301 basic medicine, MESH: Fetus/virology, viruses, [SDV]Life Sciences [q-bio], Neuroepithelial Cells, MESH: Zika Virus/ultrastructure, Virus Replication, MESH: Neurons/drug effects, MESH: Neuroepithelial Cells/drug effects, MESH: Zika Virus Infection/pathology, MESH: Neurons/pathology, MESH: Immunity, Innate/drug effects, Phosphorylation, Genetics, Cell Death, MESH: Transcription, Genetic/drug effects, MESH: Neuroglia/virology, MESH: Nucleosides/pharmacology, Mitochondria, Neuroprotective Agents, MESH: Neuroglia/pathology, lipids (amino acids, peptides, and proteins), MESH: Zika Virus Infection/virology, Stem cell, Programmed cell death, MESH: Centrosome/metabolism, MESH: Brain/embryology, Protein Serine-Threonine Kinases, Biology, Proto-Oncogene Proteins, MESH: Microcephaly/pathology, medicine, MESH: Zika Virus/drug effects, Protein Kinase Inhibitors, Centrosome, MESH: Neural Stem Cells/enzymology, Gene Expression Profiling, MESH: Proto-Oncogene Proteins/metabolism, Zika Virus, Axl Receptor Tyrosine Kinase, MESH: Microcephaly/virology, Gene expression profiling, MESH: Cell Death/drug effects, lcsh:Biology (General), MESH: Neuroepithelial Cells/virology
Abstract

SummaryThe mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment.

Published
2016
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2. Data publication with the structural biology data grid supports live analysis

Author

Emil F. Pai, Qing R. Fan, Yousif Shamoo, Kevin D. Corbett, Dominika Borek, Tom Kirchhausen, James S. Fraser, Elizabeth Ransey, Stephanie M. Socias, Peter A. Meyer, Enrico Di Cera, Oleg V. Tsodikov, Jason S. McLellan, C. S. Raman, James Withrow, Mercè Crosas, Karen S. Anderson, Carlo Petosa, Filipe R. N. C. Maia, Gabrielle Rudenko, Yorgo Modis, Peng Gong, Walter J. Chazin, Zongchao Jia, Zbyszek Otwinowski, Adrian R. Ferré-D'Amaré, Yunsun Nam, Stephen C. Harrison, Sirano Dhe-Paganon, Joseph Schlessinger, Catherine L. Drennan, Kenneth D. Westover, Holger Sondermann, Richard H. G. Baxter, Marc Kvansakul, Ekaterina E. Heldwein, J. Christopher Fromme, Sean Crosson, Michael K. Rosen, Antonina Roll-Mecak, Robert J. Keenan, Tamir Gonen, Andrew C. Kruse, Ian Foster, Kanagalaghatta R. Rajashankar, Titus J. Boggon, Ming Lei, K. Christopher Garcia, Alexandre M. J. J. Bonvin, Michael S. Cosgrove, Amedeo Caflisch, Michael J. Eck, Brandt F. Eichman, Thomas U. Schwartz, Chung-I Chang, Rachelle Gaudet, Yizhi Jane Tao, Emily C. Tjon, Pedro Pereira, Jason Key, David B. Neau, Stephen C. Blacklow, Kay Diederichs, Hao Wu, Tom A. Rapoport, Alejandro Buschiazzo, Tom J. Brett, Piotr Sliz, Chris Botka, Niraj H. Tolia, Department of Biological Chemistry and Molecular Pharmacology [Boston] (DBCMP), Harvard Medical School [Boston] (HMS), Laboratory of molecular and structural microbiology, Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Shanghai Institutes for Biological Sciences (Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences [Beijing] (CAS), NE-CAT and department of chemistry and chemical biology [Argonne], Cornell University, Departments of pharmacology and molecular biophysics and biochemistry [New Haven], Yale University School of Medicine, Department of Chemistry and Molecular Biophysics & Biochemistry [New Haven], Yale University [New Haven], Bijovet center [Utrecht], Utrecht University [Utrecht], Department of Biophysics and Biochemistry [Dallas], University of Texas Southwestern Medical Center [Dallas], Department of Internal Medicine [St Louis], Washington University School of Medicine, Department of Biochemistry [Zurich], University of Zürich [Zürich] (UZH), Institute of Biological Chemistry (IBC Sinica), Academia Sinica, Departments of biochemistry and chemistry [Nashville], Vanderbilt University [Nashville], Ludwig Institute for Cancer Research, University of California [San Diego] (UC San Diego), University of California, SUNY Upstate Medical University, State University of New York (SUNY), University of Chicago, Dana-Farber Cancer Institute [Boston], Saint Louis University School of Medicine [St Louis], Massachusetts Institute of Technology (MIT), Department of Biological Chemistry and Molecular Pharmacology (DBCMP), Columbia University [New York], National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Weill Institute for Cell and Molecular Biology, Howard Hughes Medical Institute [Stanford], Stanford University School of Medicine [CA, USA], Harvard University [Cambridge], Wuhan Institute of Virology, Howard Hughes Medical Institute [Boston], Tufts University School of Medicine [Boston], Queen's University [Kingston], La Trobe University [Melbourne], Geisel School of Medicine at Dartmouth, University of Cambridge [UK] (CAM), University of Texas at Dallas [Richardson] (UT Dallas), Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Instituto de Biologia Molecular e Celular (IBMC), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), University of Maryland [Baltimore County] (UMBC), University of Maryland System, National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch (UTMB), Rice University [Houston], University of Washington School of Medicine, University of Kentucky, Boston Children's Hospital, Department of Computer Science, University of Chicago, University of California [San Francisco] (UCSF), Uppsala University, Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Howard Hughes Medical Institute [Ashburn], Fachbereich Biologie, University of Konstanz, Institute for Quantitative Social Sciences, Development of the Structural Biology Data Grid is funded by The Leona M. and Harry B. Helmsley Charitable Trust 2016PG-BRI002 to PS and MC. Development of citation workflows is supported NSF 1448069 (to PS). DAA is being developed as a pilot project of the National Data Service, with additional funds to support storage and technology development, including NIH P41 GM103403 (NE-CAT) and 1S10RR028832 (HMS) and DOE DE-AC02-06CH11357, NIH 1U54EB020406-01, Big Data for Discovery Science Center, and NIST 60NANB15D077 (Globus Project), Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemistry, Drennan, Catherine L., Schwartz, Thomas, Sub NMR Spectroscopy, NMR Spectroscopy, Instituto de Investigação e Inovação em Saúde, Molecular and structural microbiology / Microbiología Molecular y Estructural [Montevideo], Cornell University [New York], Universität Zürich [Zürich] = University of Zurich (UZH), Howard Hughes Medical Institute (HHMI), Queen's University [Kingston, Canada], Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), University of Zurich, Sliz, Piotr, Yale School of Medicine [New Haven, Connecticut] (YSM), University of California (UC), Harvard University, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Kentucky (UK), University of California [San Francisco] (UC San Francisco), Harrison, Seamus Conor [0000-0003-1480-1143], Modis, Yorgo [0000-0002-6084-0429], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Chemistry(all), Experiences, General Physics and Astronomy, computer.software_genre, Crystallography, X-Ray, Biochemistry, Software, Structural Biology, Databases, Genetic, Structure models, Macromolecular crystallography, media_common, Strukturbiologi, Uncategorized, Multidisciplinary, Crystallography, Data grid, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Publications, X-ray scattering, 1.5 Resources and infrastructure (underpinning), 3100 General Physics and Astronomy, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Networking and Information Technology R&D, Networking and Information Technology R&D (NITRD), The Internet, Data mining, Macromolecular Substances, media_common.quotation_subject, Science, 610 Medicine & health, 1600 General Chemistry, Biology, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Synchrotron, 03 medical and health sciences, Databases, Genetic, Underpinning research, 1300 General Biochemistry, Genetics and Molecular Biology, ddc:570, 10019 Department of Biochemistry, Quality (business), Internet, business.industry, Biochemistry, Genetics and Molecular Biology(all), Data quality, Experimental data, General Chemistry, Data science, 030104 developmental biology, Data access, Protein data-bank, Paradigm shift, X-Ray, 570 Life sciences, biology, Resolution, business, computer, Department of Biochemistry, Genetics and Molecular Biology(all)
Abstract

Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis., The validation and analysis of X-ray crystallographic data is essential for reproducibility and the development of crystallographic methods. Here, the authors describe a repository for crystallographic datasets and demonstrate some of the ways it could serve the crystallographic community.

Published
2016
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3. Data publication with the structural biology data grid supports live analysis

Author

Pa, Meyer, Socias S, Key J, Ransey E, Ec, Tjon, Alejandro Buschiazzo, Lei M, Botka C, Withrow J, Neau D, Rajashankar K, Ks, Anderson, Rh, Baxter, Sc, Blacklow, Tj, Boggon, Am, Bonvin, Borek D, Tj, Brett, Caflisch A, Ci, Chang, Department of Biological Chemistry and Molecular Pharmacology [Boston] (DBCMP), Harvard Medical School [Boston] (HMS), Molecular and structural microbiology = Microbiología Molecular y Estructural [Montevideo], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Shanghai Institutes for Biological Sciences (Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences [Beijing] (CAS), NE-CAT and department of chemistry and chemical biology [Argonne], Cornell University, Departments of pharmacology and molecular biophysics and biochemistry [New Haven], Yale University School of Medicine, Department of Chemistry and Molecular Biophysics & Biochemistry [New Haven], Yale University [New Haven], Bijovet center [Utrecht], Utrecht University [Utrecht], Department of Biophysics and Biochemistry [Dallas], University of Texas Southwestern Medical Center [Dallas], Department of Internal Medicine [St Louis], Washington University School of Medicine, Department of Biochemistry [Zurich], University of Zürich [Zürich] (UZH), Institute of Biological Chemistry (IBC Sinica), Academia Sinica, Departments of biochemistry and chemistry [Nashville], Vanderbilt University [Nashville], Ludwig Institute for Cancer Research, University of California [San Diego] (UC San Diego), University of California, SUNY Upstate Medical University, State University of New York (SUNY), University of Chicago, Dana-Farber Cancer Institute [Boston], Saint Louis University School of Medicine [St Louis], Massachusetts Institute of Technology (MIT), Department of Biological Chemistry and Molecular Pharmacology (DBCMP), Columbia University [New York], National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Weill Institute for Cell and Molecular Biology, Howard Hughes Medical Institute [Stanford], Stanford University School of Medicine [CA, USA], Harvard University [Cambridge], Wuhan Institute of Virology, Howard Hughes Medical Institute [Boston], Tufts University School of Medicine [Boston], Queen's University [Kingston], La Trobe University [Melbourne], Geisel School of Medicine at Dartmouth, University of Cambridge [UK] (CAM), University of Texas at Dallas [Richardson] (UT Dallas), Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Instituto de Biologia Molecular e Celular (IBMC), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), University of Maryland [Baltimore County] (UMBC), University of Maryland System, National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch (UTMB), Rice University [Houston], University of Washington School of Medicine, University of Kentucky, Boston Children's Hospital, Department of Computer Science, University of Chicago, University of California [San Francisco] (UCSF), Uppsala University, Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Howard Hughes Medical Institute [Ashburn], Fachbereich Biologie, University of Konstanz, Institute for Quantitative Social Sciences, Development of the Structural Biology Data Grid is funded by The Leona M. and Harry B. Helmsley Charitable Trust 2016PG-BRI002 to PS and MC. Development of citation workflows is supported NSF 1448069 (to PS). DAA is being developed as a pilot project of the National Data Service, with additional funds to support storage and technology development, including NIH P41 GM103403 (NE-CAT) and 1S10RR028832 (HMS) and DOE DE-AC02-06CH11357, NIH 1U54EB020406-01, Big Data for Discovery Science Center, and NIST 60NANB15D077 (Globus Project), Department of Biological Chemistry and Molecular Pharmacology [Boston] ( DBCMP ), Harvard Medical School [Boston] ( HMS ), Laboratory of molecular and structural microbiology, Institut Pasteur Montevideo-Réseau International des Instituts Pasteur ( RIIP ), Shanghai Institutes for Biological Sciences ( Institute of Biochemistry and Cell Biology ), Chinese Academy of Sciences [Beijing] ( CAS ), Yale University, Faculty of Science, Utrecht University, University of Zürich [Zürich] ( UZH ), Institute of Biological Chemistry ( IBC Sinica ), Vanderbilt University of Nashville, University of California [San Diego] ( UC San Diego ), Massachusetts Institute of Technology ( MIT ), Department of Biological Chemistry and Molecular Pharmacology ( DBCMP ), National Heart, Lung, and Blood Institute [Bethesda] ( NHLBI ), Stanford University School of Medicine, Havard Medical School, University of Cambridge [UK] ( CAM ), University of Texas at Dallas [Richardson] ( UT Dallas ), Instituto de Biologia Molecular e Celular ( IBMC ), Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), University of Maryland Baltimore County [Baltimore] ( UMBC ), National Institute of Neurological Disorders and Stroke [Bethesda] ( NINDS ), National Institutes of Health [Bethesda] ( NIH ), The University of Texas Medical Branch ( UTMB ), Yale School of Medicine, University of California [San Francisco] ( UCSF ), Lawrence Berkeley National Laboratory [Berkeley] ( LBNL ), Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemistry, Drennan, Catherine L., Schwartz, Thomas, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), and Instituto de Investigação e Inovação em Saúde

Subjects
Data set, Data quality, General Physics and Astronomy, Experimental data, General Chemistry, Data grid, General Biochemistry, Genetics and Molecular Biology, Data science, Genetics, Paradigm shift, Data access, Data mining, Biology, The Internet
Abstract

The validation and analysis of X-ray crystallographic data is essential for reproducibility and the development of crystallographic methods. Here, the authors describe a repository for crystallographic datasets and demonstrate some of the ways it could serve the crystallographic community., Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis.

Published
2016
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4. Human Slack potassium channel mutations increase positive cooperativity between individual channels

Author

Jenny C. Taylor, Laurence Colleaux, Leonard K. Kaczmarek, Giulia Barcia, Hilary C. Martin, Jack Kronengold, Rima Nabbout, Imran H. Quraishi, Grace Kim, Edward Blair, Olivier Dulac, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, University of Oxford [Oxford], Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departments of pharmacology and molecular biophysics and biochemistry [New Haven], Yale University School of Medicine, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]

Subjects
Potassium Channels, Mutant, Mutation, Missense, Gene Expression, Nerve Tissue Proteins, Gating, Potassium Channels, Sodium-Activated, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, Xenopus laevis, medicine, Animals, Humans, Point Mutation, lcsh:QH301-705.5, Ion channel, Cells, Cultured, Genetics, Mutation, Epilepsy, Chemistry, Point mutation, Infant, Newborn, Cooperative binding, Infant, Potassium channel, Rats, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Biophysics, Communication channel
Abstract

Summary: Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na+-activated K+ channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions. : Slack KCNT1 channels regulate how neurons respond to sustained stimulation. Kim et al. characterized nine KCNT1 mutations found in epilepsy patients with severe intellectual disabilities and showed that, in isolation, channel behavior is unaltered. However, in groups, mutant channels interact with each other abnormally, increasing current that flows through the channels.

Published
2014
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