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  • Cells, Cultured  (1,353)
  • ASTROPHYSICS
  • Chemical Engineering
  • American Association for the Advancement of Science (AAAS)  (1,358)
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  • 1
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    Designer protein delivery: From natural to engineered affinity-controlled release systems (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-19
    Description: Exploiting binding affinities between molecules is an established practice in many fields, including biochemical separations, diagnostics, and drug development; however, using these affinities to control biomolecule release is a more recent strategy. Affinity-controlled release takes advantage of the reversible nature of noncovalent interactions between a therapeutic protein and a binding partner to slow the diffusive release of the protein from a vehicle. This process, in contrast to degradation-controlled sustained-release formulations such as poly(lactic-co-glycolic acid) microspheres, is controlled through the strength of the binding interaction, the binding kinetics, and the concentration of binding partners. In the context of affinity-controlled release--and specifically the discovery or design of binding partners--we review advances in in vitro selection and directed evolution of proteins, peptides, and oligonucleotides (aptamers), aided by computational design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pakulska, Malgosia M -- Miersch, Shane -- Shoichet, Molly S -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):aac4750. doi: 10.1126/science.aac4750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, and Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. ; Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, and Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26989257" target="_blank"〉PubMed〈/a〉
    Keywords: Chemical Engineering ; Combinatorial Chemistry Techniques ; Delayed-Action Preparations/*chemistry ; Directed Molecular Evolution ; *Drug Design ; Humans ; Lactic Acid/*chemistry ; Microspheres ; Polyglycolic Acid/*chemistry ; Proteins/*administration & dosage
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Voltage-gated CaV1.2 channels (L-type calcium channel alpha1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VDeltaC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VDeltaC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VDeltaC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VDeltaC by 10 to 20 seconds. CaV1.2 VDeltaC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VDeltaC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VDeltaC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Boxing -- Tadross, Michael R -- Tsien, Richard W -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):863-7. doi: 10.1126/science.aad3647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. ; Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. tadrossm@janelia.hhmi.org. ; Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912895" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/genetics/metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/chemistry/*metabolism ; *Calcium Signaling ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Gene Expression Regulation ; HEK293 Cells ; Hippocampus/cytology ; Humans ; Long QT Syndrome/genetics/metabolism ; Neuronal Plasticity/*genetics ; Neurons/drug effects/*metabolism ; Nimodipine/pharmacology ; Protein Conformation/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Synapses/metabolism ; Syndactyly/genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-23
    Description: Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucie, Erinn L -- Weng, Ziming -- Geirsdottir, Laufey -- Molawi, Kaaweh -- Maurizio, Julien -- Fenouil, Romain -- Mossadegh-Keller, Noushine -- Gimenez, Gregory -- VanHille, Laurent -- Beniazza, Meryam -- Favret, Jeremy -- Berruyer, Carole -- Perrin, Pierre -- Hacohen, Nir -- Andrau, J-C -- Ferrier, Pierre -- Dubreuil, Patrice -- Sidow, Arend -- Sieweke, Michael H -- P01AG036695/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):aad5510. doi: 10.1126/science.aad5510. Epub 2016 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Universite Aix-Marseille (UM105), Marseille, France. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu. ; Department of Pathology, Stanford University, Stanford, CA 94305-5324, USA. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, 10 Robert-Rossle-Strasse, 13125 Berlin, Germany. ; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Institut de Genetique Moleculaire de Montpellier, CNRS UMR 5535, 1919 Route de Mende, 34293 Montpellier, France. ; Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Universite Aix-Marseille (UM105), Marseille, France. ; Department of Pathology, Stanford University, Stanford, CA 94305-5324, USA. Department of Genetics, Stanford University, Stanford, CA 94305, USA. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, 10 Robert-Rossle-Strasse, 13125 Berlin, Germany. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26797145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/*genetics ; Cell Lineage/*genetics ; Cell Proliferation ; Cells, Cultured ; Down-Regulation ; Embryonic Stem Cells/*cytology ; Enhancer Elements, Genetic/*physiology ; *Gene Expression Regulation ; Gene Regulatory Networks ; Macrophages/*cytology ; MafB Transcription Factor/metabolism ; Mice ; Proto-Oncogene Proteins c-maf/metabolism ; Single-Cell Analysis ; Transcriptional Activation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Distinct routes of lineage development reshape the human blood hierarchy across ontogeny (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-11-07
    Description: In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34(+) cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead, only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult "two-tier" hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Notta, Faiyaz -- Zandi, Sasan -- Takayama, Naoya -- Dobson, Stephanie -- Gan, Olga I -- Wilson, Gavin -- Kaufmann, Kerstin B -- McLeod, Jessica -- Laurenti, Elisa -- Dunant, Cyrille F -- McPherson, John D -- Stein, Lincoln D -- Dror, Yigal -- Dick, John E -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2016 Jan 8;351(6269):aab2116. doi: 10.1126/science.aab2116. Epub 2015 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. ; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. ; Wellcome Trust, Medical Research Council Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, Cambridge, UK. ; Ecole Polytechnique Federale de Lausanne, LMC, Station 12, Lausanne, CH-1015, Switzerland. ; Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. ; The Hospital for Sick Children Research Institute, University of Toronto, Ontario, Canada. ; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. jdick@uhnres.utoronto.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26541609" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Antigens, CD34/analysis ; Cell Lineage/genetics/*physiology ; Cell Separation ; Cells, Cultured ; Erythroid Cells/*cytology ; Fetal Blood/cytology ; Gene Expression Profiling ; Hematopoiesis/genetics/*physiology ; Humans ; Liver/cytology/embryology ; Megakaryocyte Progenitor Cells/*cytology ; Megakaryocytes/*cytology ; Multipotent Stem Cells/cytology ; Myeloid Cells/*cytology ; Transcription, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 5
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    The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-26
    Description: Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-kappaB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Chanhee -- Xu, Qikai -- Martin, Timothy D -- Li, Mamie Z -- Demaria, Marco -- Aron, Liviu -- Lu, Tao -- Yankner, Bruce A -- Campisi, Judith -- Elledge, Stephen J -- AG009909/AG/NIA NIH HHS/ -- AG017242/AG/NIA NIH HHS/ -- AG046174/AG/NIA NIH HHS/ -- DP1 OD006849/OD/NIH HHS/ -- DP1OD006849/OD/NIH HHS/ -- GM44664/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 25;349(6255):aaa5612. doi: 10.1126/science.aaa5612.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. ; Buck Institute for Research on Aging, Novato, CA 94945, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. selledge@genetics.med.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26404840" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*genetics/metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Autophagy/*genetics ; Brain/metabolism ; Cell Aging/*genetics ; Cell Cycle/genetics ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16 ; *DNA Damage ; Fibroblasts ; GATA4 Transcription Factor/genetics/*metabolism ; Gene Expression Profiling ; Humans ; Inflammation/*genetics ; Interleukin-1alpha/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; MicroRNAs/genetics/metabolism ; NF-kappa B/metabolism ; Phenotype ; Promoter Regions, Genetic ; Tumor Necrosis Factor Receptor-Associated Peptides and ; Proteins/genetics/metabolism ; Tumor Suppressor Protein p53/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 6
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    Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-05
    Description: Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)-rich environment with protection has remained elusive. Here we show that chronic exposure to low-dose endotoxin or farm dust protects mice from developing house dust mite (HDM)-induced asthma. Endotoxin reduced epithelial cell cytokines that activate dendritic cells (DCs), thus suppressing type 2 immunity to HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished the protective effect. A single-nucleotide polymorphism in the gene encoding A20 was associated with allergy and asthma risk in children growing up on farms. Thus, the farming environment protects from allergy by modifying the communication between barrier epithelial cells and DCs through A20 induction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schuijs, Martijn J -- Willart, Monique A -- Vergote, Karl -- Gras, Delphine -- Deswarte, Kim -- Ege, Markus J -- Madeira, Filipe Branco -- Beyaert, Rudi -- van Loo, Geert -- Bracher, Franz -- von Mutius, Erika -- Chanez, Pascal -- Lambrecht, Bart N -- Hammad, Hamida -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1106-10. doi: 10.1126/science.aac6623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium. Department of Internal Medicine, Ghent University, Ghent, Belgium. ; Department of Respiratory Medicine, Assistance Publique Hopitaux de Marseille, UMR INSERM U1067 CNRS 7333, Aix Marseille University, Marseille, France. ; Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universitat, Munich, Germany. ; Unit of Molecular Signal Transduction, VIB Inflammation Research Center, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. ; Center for Drug Research, Department of Pharmacy, Ludwig Maximilians University, Butenandtstrasse 5-13, D-81377 Munich, Germany. ; Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium. Department of Internal Medicine, Ghent University, Ghent, Belgium. Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, Netherlands. hamida.hammad@ugent.be bart.lambrecht@ugent.be. ; Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium. Department of Internal Medicine, Ghent University, Ghent, Belgium. hamida.hammad@ugent.be bart.lambrecht@ugent.be.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26339029" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asthma/immunology/prevention & control ; Cells, Cultured ; Child ; DNA-Binding Proteins/*biosynthesis ; Dairying ; Dendritic Cells/immunology ; Dust/*immunology ; Female ; Humans ; Hygiene Hypothesis ; Hypersensitivity/enzymology/immunology/*prevention & control ; Inhalation Exposure ; Intracellular Signaling Peptides and Proteins/*biosynthesis ; Lipopolysaccharides/*immunology ; Lung/*enzymology/immunology ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins/*biosynthesis ; Pyroglyphidae/*immunology ; Respiratory Mucosa/*enzymology/immunology
    Print ISSN: 0036-8075
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  • 7
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    HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-01
    Description: Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618316/" 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/PMC4618316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hinson, John T -- Chopra, Anant -- Nafissi, Navid -- Polacheck, William J -- Benson, Craig C -- Swist, Sandra -- Gorham, Joshua -- Yang, Luhan -- Schafer, Sebastian -- Sheng, Calvin C -- Haghighi, Alireza -- Homsy, Jason -- Hubner, Norbert -- Church, George -- Cook, Stuart A -- Linke, Wolfgang A -- Chen, Christopher S -- Seidman, J G -- Seidman, Christine E -- EB017103/EB/NIBIB NIH HHS/ -- HG005550/HG/NHGRI NIH HHS/ -- HL007374/HL/NHLBI NIH HHS/ -- HL115553/HL/NHLBI NIH HHS/ -- HL125807/HL/NHLBI NIH HHS/ -- K08 HL125807/HL/NHLBI NIH HHS/ -- T32 HL007208/HL/NHLBI NIH HHS/ -- Department of Health/United Kingdom -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):982-6. doi: 10.1126/science.aaa5458.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu. ; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ; Department of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56 D-44780, Bochum, Germany. ; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Cardiovascular and Metabolic Sciences, Max Delbruck Center for Molecular Medicine, Berlin, Germany. ; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. ; Cardiovascular and Metabolic Sciences, Max Delbruck Center for Molecular Medicine, Berlin, Germany. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. ; National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease at Royal Brompton and Harefield National Health Service (NHS) Foundation Trust, Imperial College London, London, UK. National Heart Centre and Duke-National University, Singapore, Singapore. ; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315439" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-Agonists/pharmacology ; Cardiomyopathy, Dilated/*genetics/pathology/*physiopathology ; Cells, Cultured ; Connectin/chemistry/*genetics/*physiology ; Heart Rate ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Isoproterenol/pharmacology ; Mutant Proteins/chemistry/physiology ; *Mutation, Missense ; Myocardial Contraction ; Myocytes, Cardiac/*physiology ; RNA/genetics/metabolism ; Sarcomeres/*physiology/ultrastructure ; Sequence Analysis, RNA ; Signal Transduction ; Stress, Physiological
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-08
    Description: Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ling, Jonathan P -- Pletnikova, Olga -- Troncoso, Juan C -- Wong, Philip C -- P50AG05146/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):650-5. doi: 10.1126/science.aab0983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. wong@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26250685" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Base Sequence ; Cells, Cultured ; Cysteine Endopeptidases/genetics ; DNA-Binding Proteins/genetics/*physiology ; Embryonic Stem Cells ; Exons/*genetics ; Frontotemporal Dementia/*genetics ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Mice ; Molecular Sequence Data ; Protein Isoforms/genetics ; *RNA Splicing ; RNA Stability ; RNA, Messenger/metabolism ; Sequence Analysis, DNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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    Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-07-18
    Description: Secretion of the cytokine interleukin-1beta (IL-1beta) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1beta, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1beta for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1beta transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1beta production. Cholesterol crystals triggered neutrophils to release neutrophil extracellular traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with neutrophils.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warnatsch, Annika -- Ioannou, Marianna -- Wang, Qian -- Papayannopoulos, Venizelos -- MC_UP_1202/13/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):316-20. doi: 10.1126/science.aaa8064. Epub 2015 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK. ; Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK. veni.p@crick.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26185250" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins E/genetics ; Atherosclerosis/*immunology ; Cells, Cultured ; Cholesterol/chemistry/immunology ; Disease Models, Animal ; Extracellular Traps/*immunology ; Humans ; Inflammasomes/immunology ; Inflammation/immunology ; Interleukin-1beta/*biosynthesis/genetics ; Macrophages/*immunology ; Mice ; Mice, Mutant Strains ; Neutrophils/*immunology ; Signal Transduction ; Th17 Cells/immunology ; Transcription, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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    Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-20
    Description: The inactive X chromosome (Xi) serves as a model to understand gene silencing on a global scale. Here, we perform "identification of direct RNA interacting proteins" (iDRiP) to isolate a comprehensive protein interactome for Xist, an RNA required for Xi silencing. We discover multiple classes of interactors-including cohesins, condensins, topoisomerases, RNA helicases, chromatin remodelers, and modifiers-that synergistically repress Xi transcription. Inhibiting two or three interactors destabilizes silencing. Although Xist attracts some interactors, it repels architectural factors. Xist evicts cohesins from the Xi and directs an Xi-specific chromosome conformation. Upon deleting Xist, the Xi acquires the cohesin-binding and chromosomal architecture of the active X. Our study unveils many layers of Xi repression and demonstrates a central role for RNA in the topological organization of mammalian chromosomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Minajigi, Anand -- Froberg, John E -- Wei, Chunyao -- Sunwoo, Hongjae -- Kesner, Barry -- Colognori, David -- Lessing, Derek -- Payer, Bernhard -- Boukhali, Myriam -- Haas, Wilhelm -- Lee, Jeannie T -- R01-DA-38695/DA/NIDA NIH HHS/ -- R03-MH97478/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 17;349(6245). pii: aab2276. doi: 10.1126/science.aab2276. Epub 2015 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. ; Massachusetts General Hospital Cancer Center, Charlestown, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA, USA. ; Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. lee@molbio.mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089354" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Animals ; Cell Cycle Proteins/*metabolism ; Cells, Cultured ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA-Binding Proteins/metabolism ; Embryonic Stem Cells/metabolism ; Fibroblasts/metabolism ; Gene Knockdown Techniques ; Gene Silencing ; Mice ; Multiprotein Complexes/metabolism ; Nucleic Acid Conformation ; Proteomics ; RNA Helicases/metabolism ; RNA, Long Noncoding/*metabolism ; X Chromosome/chemistry/genetics/*metabolism ; *X Chromosome Inactivation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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