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  • Male  (362)
  • Models, Molecular  (111)
  • Cell Line  (49)
  • Chemistry
  • Nature Publishing Group (NPG)  (503)
  • Dordrecht : Springer
  • Wiley-Blackwell
  • 2015-2019  (503)
  • 1
    Publication Date: 2015-04-23
    Description: The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467030/" 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/PMC4467030/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thi, Emily P -- Mire, Chad E -- Lee, Amy C H -- Geisbert, Joan B -- Zhou, Joy Z -- Agans, Krystle N -- Snead, Nicholas M -- Deer, Daniel J -- Barnard, Trisha R -- Fenton, Karla A -- MacLachlan, Ian -- Geisbert, Thomas W -- U19 AI109711/AI/NIAID NIH HHS/ -- U19AI109711/AI/NIAID NIH HHS/ -- England -- Nature. 2015 May 21;521(7552):362-5. doi: 10.1038/nature14442. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada. ; 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901685" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Disease Models, Animal ; Ebolavirus/classification/*drug effects/*genetics ; Female ; Hemorrhagic Fever, Ebola/pathology/prevention & control/*therapy/*virology ; Humans ; Macaca mulatta/virology ; Male ; Nanoparticles/*administration & dosage ; RNA, Small Interfering/*administration & dosage/pharmacology/*therapeutic use ; Survival Analysis ; Time Factors ; Treatment Outcome ; Viral Load/drug effects
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  • 2
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    Nature Publishing Group (NPG)
    Publication Date: 2015-06-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jun 4;522(7554):6. doi: 10.1038/522006a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040858" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; *Public Opinion ; Research Personnel/*ethics/standards ; Retraction of Publication as Topic ; Science/ethics/*standards ; Scientific Misconduct/*statistics & numerical data ; *Trust
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  • 3
    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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  • 4
    Publication Date: 2015-07-24
    Description: Bacteria secrete peptides and proteins to communicate, to poison competitors, and to manipulate host cells. Among the various protein-translocation machineries, the peptidase-containing ATP-binding cassette transporters (PCATs) are appealingly simple. Each PCAT contains two peptidase domains that cleave the secretion signal from the substrate, two transmembrane domains that form a translocation pathway, and two nucleotide-binding domains that hydrolyse ATP. In Gram-positive bacteria, PCATs function both as maturation proteases and exporters for quorum-sensing or antimicrobial polypeptides. In Gram-negative bacteria, PCATs interact with two other membrane proteins to form the type 1 secretion system. Here we present crystal structures of PCAT1 from Clostridium thermocellum in two different conformations. These structures, accompanied by biochemical data, show that the translocation pathway is a large alpha-helical barrel sufficient to accommodate small folded proteins. ATP binding alternates access to the transmembrane pathway and also regulates the protease activity, thereby coupling substrate processing to translocation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, David Yin-wei -- Huang, Shuo -- Chen, Jue -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 23;523(7561):425-30. doi: 10.1038/nature14623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Membrane Biology and Biophysics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA [2] Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA. ; Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26201595" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/metabolism ; Adenosine Triphosphate/deficiency/metabolism ; Clostridium thermocellum/*chemistry ; Crystallography, X-Ray ; Models, Molecular ; Peptides/*metabolism/secretion ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Structure-Activity Relationship
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  • 5
    Publication Date: 2015-05-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roth, Anna -- Diederichs, Sven -- England -- Nature. 2015 May 14;521(7551):170-1. doi: 10.1038/521170a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RNA Biology and Cancer Division, German Cancer Research Center, and at the Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25971508" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; *Gene Silencing ; Histone Deacetylases/*metabolism ; Male ; Mass Spectrometry/*methods ; Nuclear Proteins/*metabolism ; RNA, Long Noncoding/*metabolism ; Transcription, Genetic/*genetics ; X Chromosome/*genetics
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  • 6
    Publication Date: 2015-09-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geddes, Linda -- England -- Nature. 2015 Sep 24;525(7570):436-7. doi: 10.1038/525436a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26399806" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Brain/*growth & development ; Child ; Clinical Trials as Topic ; Electric Stimulation Therapy/*adverse effects ; Humans ; Learning ; Learning Disorders/*therapy ; Male ; Mathematics ; Risk Assessment ; Transcranial Direct Current Stimulation ; Transcranial Magnetic Stimulation ; Young Adult
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  • 7
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    Nature Publishing Group (NPG)
    Publication Date: 2015-11-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geddes, Linda -- England -- Nature. 2015 Nov 5;527(7576):22-5. doi: 10.1038/527022a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536940" target="_blank"〉PubMed〈/a〉
    Keywords: Attention Deficit Disorder with ; Hyperactivity/diagnosis/physiopathology/psychology ; Autism Spectrum Disorder/diagnosis/physiopathology/psychology ; Brain/blood supply/*growth & development/*physiology ; *Child Development ; Child, Preschool ; Electroencephalography ; Electromyography ; Eye Movements/physiology ; Female ; Humans ; Infant ; Infant Behavior/*physiology/*psychology ; *Laboratories ; London ; Magnetic Resonance Imaging ; Male ; Mirror Neurons ; Neuroimaging ; Personality ; Spectroscopy, Near-Infrared ; Time Factors
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  • 8
    Publication Date: 2015-06-25
    Description: In response to DNA damage, tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signalling pathways coordinate these processes, partly by propagating gene-expression-modulating signals. DNA damage influences not only the abundance of messenger RNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level. Our findings define R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells, and highlight a key role for spliceosome displacement in this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501432/" 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/PMC4501432/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tresini, Maria -- Warmerdam, Daniel O -- Kolovos, Petros -- Snijder, Loes -- Vrouwe, Mischa G -- Demmers, Jeroen A A -- van IJcken, Wilfred F J -- Grosveld, Frank G -- Medema, Rene H -- Hoeijmakers, Jan H J -- Mullenders, Leon H F -- Vermeulen, Wim -- Marteijn, Jurgen A -- 10-0594/Worldwide Cancer Research/United Kingdom -- 233424/European Research Council/International -- 340988/European Research Council/International -- P01 AG017242/AG/NIA NIH HHS/ -- England -- Nature. 2015 Jul 2;523(7558):53-8. doi: 10.1038/nature14512. Epub 2015 Jun 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands. ; Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. ; Department of Cell Biology, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands. ; Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands. ; Erasmus MC Proteomics Center, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands. ; Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26106861" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/physiology ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Cell Line ; Chromatin/metabolism ; DNA Damage/*physiology ; DNA-Directed RNA Polymerases/metabolism ; Enzyme Activation ; Humans ; *Signal Transduction ; Spliceosomes/*metabolism ; Ultraviolet Rays
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  • 9
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    Nature Publishing Group (NPG)
    Publication Date: 2015-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lynch, Michael -- England -- Nature. 2015 Jul 23;523(7561):414-6. doi: 10.1038/nature14634. Epub 2015 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Indiana University, Bloomington, Indiana 47405, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26176917" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arabidopsis/*genetics ; Bees/*genetics ; Female ; *Heterozygote ; Male ; Mutagenesis/*genetics ; *Mutation Rate ; Oryza/*genetics
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  • 10
    Publication Date: 2015-08-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Broadfoot, Marla -- England -- Nature. 2015 Aug 20;524(7565):275. doi: 10.1038/nature.2015.18187.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26289186" target="_blank"〉PubMed〈/a〉
    Keywords: *Data Collection ; Female ; Homophobia/psychology/statistics & numerical data ; Homosexuality/psychology/*statistics & numerical data ; Humans ; Job Satisfaction ; Laboratories/*manpower ; Male ; Research Personnel/psychology/*statistics & numerical data ; Science/*manpower ; Sex Ratio
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  • 11
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    Nature Publishing Group (NPG)
    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brody, Herb -- England -- Nature. 2015 Dec 17;528(7582):S117. doi: 10.1038/528S117a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672779" target="_blank"〉PubMed〈/a〉
    Keywords: Cancer Vaccines/economics/therapeutic use ; Cell Hypoxia/drug effects ; Humans ; Inflammation/complications ; Male ; Prostate-Specific Antigen/blood ; *Prostatic Neoplasms/complications/diagnosis/immunology/therapy ; Tissue Extracts/immunology/therapeutic use
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  • 12
    Publication Date: 2015-01-21
    Description: The regulated release of anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that alpha-MSH is an agonist that couples the receptor to the Galphas signalling pathway, while AgRP binds competitively to block alpha-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by alpha-MSH and AgRP can be mediated independently of Galphas signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of alpha-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383680/" 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/PMC4383680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ghamari-Langroudi, Masoud -- Digby, Gregory J -- Sebag, Julien A -- Millhauser, Glenn L -- Palomino, Rafael -- Matthews, Robert -- Gillyard, Taneisha -- Panaro, Brandon L -- Tough, Iain R -- Cox, Helen M -- Denton, Jerod S -- Cone, Roger D -- 5R01 DK082884-03/DK/NIDDK NIH HHS/ -- DK020593/DK/NIDDK NIH HHS/ -- F31 DK102343/DK/NIDDK NIH HHS/ -- P30 DK020593/DK/NIDDK NIH HHS/ -- R01 DK064265/DK/NIDDK NIH HHS/ -- R01 DK070332/DK/NIDDK NIH HHS/ -- R01DK064265/DK/NIDDK NIH HHS/ -- R01DK070332/DK/NIDDK NIH HHS/ -- R25 GM059994/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):94-8. doi: 10.1038/nature14051. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. ; Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA. ; 1] Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37208, USA. ; King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK. ; 1] Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600267" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Agouti-Related Protein/metabolism ; Animals ; Eating/genetics ; Energy Metabolism ; Female ; *GTP-Binding Protein alpha Subunits, Gs ; HEK293 Cells ; Homeostasis/genetics ; Humans ; Ligands ; Male ; Melanocortins/metabolism ; Mice ; Neurons/*metabolism ; Paraventricular Hypothalamic Nucleus/*cytology ; Potassium Channels, Inwardly Rectifying/*metabolism ; Receptor, Melanocortin, Type 4/genetics/*metabolism ; Signal Transduction/genetics ; alpha-MSH/metabolism
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  • 13
    Publication Date: 2015-03-25
    Description: Wing polyphenism is an evolutionarily successful feature found in a wide range of insects. Long-winged morphs can fly, which allows them to escape adverse habitats and track changing resources, whereas short-winged morphs are flightless, but usually possess higher fecundity than the winged morphs. Studies on aphids, crickets and planthoppers have revealed that alternative wing morphs develop in response to various environmental cues, and that the response to these cues may be mediated by developmental hormones, although research in this area has yielded equivocal and conflicting results about exactly which hormones are involved. As it stands, the molecular mechanism underlying wing morph determination in insects has remained elusive. Here we show that two insulin receptors in the migratory brown planthopper Nilaparvata lugens, InR1 and InR2, have opposing roles in controlling long wing versus short wing development by regulating the activity of the forkhead transcription factor Foxo. InR1, acting via the phosphatidylinositol-3-OH kinase (PI(3)K)-protein kinase B (Akt) signalling cascade, leads to the long-winged morph if active and the short-winged morph if inactive. InR2, by contrast, functions as a negative regulator of the InR1-PI(3)K-Akt pathway: suppression of InR2 results in development of the long-winged morph. The brain-secreted ligand Ilp3 triggers development of long-winged morphs. Our findings provide the first evidence of a molecular basis for the regulation of wing polyphenism in insects, and they are also the first demonstration--to our knowledge--of binary control over alternative developmental outcomes, and thus deepen our understanding of the development and evolution of phenotypic plasticity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Hai-Jun -- Xue, Jian -- Lu, Bo -- Zhang, Xue-Chao -- Zhuo, Ji-Chong -- He, Shu-Fang -- Ma, Xiao-Fang -- Jiang, Ya-Qin -- Fan, Hai-Wei -- Xu, Ji-Yu -- Ye, Yu-Xuan -- Pan, Peng-Lu -- Li, Qiao -- Bao, Yan-Yuan -- Nijhout, H Frederik -- Zhang, Chuan-Xi -- England -- Nature. 2015 Mar 26;519(7544):464-7. doi: 10.1038/nature14286. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Rice Biology and Ministry of Agriculture Key Laboratory of Agricultural Entomology, Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China. ; Department of Biology, Duke University, Durham, North Carolina 27708, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799997" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; Forkhead Transcription Factors/deficiency/metabolism ; Hemiptera/*anatomy & histology/enzymology/genetics/*metabolism ; Insulin/metabolism ; Male ; Molecular Sequence Data ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Insulin/deficiency/*metabolism ; Signal Transduction ; Wings, Animal/anatomy & histology/enzymology/*growth & development/*metabolism
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  • 14
    Publication Date: 2015-08-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zaret, Kenneth S -- England -- Nature. 2015 Aug 13;524(7564):165-6. doi: 10.1038/nature15201. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Regenerative Medicine and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245376" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axin Protein/*metabolism ; *Diploidy ; Female ; Hepatocytes/*cytology/*metabolism ; *Homeostasis ; Liver/*cytology ; Male
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  • 15
    Publication Date: 2015-08-01
    Description: Intracellular energy distribution has attracted much interest and has been proposed to occur in skeletal muscle via metabolite-facilitated diffusion; however, genetic evidence suggests that facilitated diffusion is not critical for normal function. We hypothesized that mitochondrial structure minimizes metabolite diffusion distances in skeletal muscle. Here we demonstrate a mitochondrial reticulum providing a conductive pathway for energy distribution, in the form of the proton-motive force, throughout the mouse skeletal muscle cell. Within this reticulum, we find proteins associated with mitochondrial proton-motive force production preferentially in the cell periphery and proteins that use the proton-motive force for ATP production in the cell interior near contractile and transport ATPases. Furthermore, we show a rapid, coordinated depolarization of the membrane potential component of the proton-motive force throughout the cell in response to spatially controlled uncoupling of the cell interior. We propose that membrane potential conduction via the mitochondrial reticulum is the dominant pathway for skeletal muscle energy distribution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Glancy, Brian -- Hartnell, Lisa M -- Malide, Daniela -- Yu, Zu-Xi -- Combs, Christian A -- Connelly, Patricia S -- Subramaniam, Sriram -- Balaban, Robert S -- Intramural NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):617-20. doi: 10.1038/nature14614.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26223627" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/biosynthesis/metabolism ; Animals ; Diffusion ; *Energy Metabolism ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Mitochondria, Muscle/*metabolism ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/*cytology/*metabolism ; Proton-Motive Force
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  • 16
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    Nature Publishing Group (NPG)
    Publication Date: 2015-11-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delude, Cathryn M -- England -- Nature. 2015 Nov 5;527(7576):S14-5. doi: 10.1038/527S14a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536218" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/genetics ; Cell Line ; Datasets as Topic ; Diabetes Mellitus/genetics ; Disease/*genetics ; Disease Models, Animal ; Genetics, Medical/*trends ; Genomics/trends ; Humans ; Mice ; Mice, Knockout ; Multifactorial Inheritance/genetics ; *Phenotype ; Precision Medicine/trends
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  • 17
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    Nature Publishing Group (NPG)
    Publication Date: 2015-11-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2015 Nov 19;527(7578):283-4. doi: 10.1038/527283a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26581268" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Migration/physiology ; Animals ; Circadian Rhythm/physiology ; Cryptochromes/metabolism ; Drosophila Proteins/chemistry/*metabolism ; Drosophila melanogaster/*physiology ; *Earth (Planet) ; Humans ; Iron/metabolism ; Iron-Sulfur Proteins/chemistry/*metabolism ; *Magnetic Fields ; Models, Molecular ; Protein Conformation ; Spatial Navigation/*physiology ; Whales/physiology
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  • 18
    Publication Date: 2015-07-07
    Description: Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance, while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation. Recently, stem cells have been shown to regulate themselves using an autocrine mechanism. The existence of a 'stem cell niche' was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells. Since then, an increasing body of work has focused on defining stem cell niches. Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells. Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells . Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521991/" 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/PMC4521991/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pardo-Saganta, Ana -- Tata, Purushothama Rao -- Law, Brandon M -- Saez, Borja -- Chow, Ryan Dz-Wei -- Prabhu, Mythili -- Gridley, Thomas -- Rajagopal, Jayaraj -- 5P30HL101287-02/HL/NHLBI NIH HHS/ -- R01 HL118185/HL/NHLBI NIH HHS/ -- R01HL118185/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):597-601. doi: 10.1038/nature14553. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA [2] Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; 1] Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, Massachusetts 02138, USA. ; Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147083" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Communication ; Cell Differentiation ; Cell Division ; Cilia/metabolism ; Female ; Male ; Membrane Proteins/metabolism ; Mice ; Receptor, Notch2/metabolism ; Signal Transduction ; Stem Cell Niche/*physiology ; Stem Cells/*cytology/metabolism/secretion ; Trachea/cytology
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  • 19
    Publication Date: 2015-03-26
    Description: Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383723/" 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/PMC4383723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Turner, Tychele N -- Sharma, Kamal -- Oh, Edwin C -- Liu, Yangfan P -- Collins, Ryan L -- Sosa, Maria X -- Auer, Dallas R -- Brand, Harrison -- Sanders, Stephan J -- Moreno-De-Luca, Daniel -- Pihur, Vasyl -- Plona, Teri -- Pike, Kristen -- Soppet, Daniel R -- Smith, Michael W -- Cheung, Sau Wai -- Martin, Christa Lese -- State, Matthew W -- Talkowski, Michael E -- Cook, Edwin -- Huganir, Richard -- Katsanis, Nicholas -- Chakravarti, Aravinda -- 1U24MH081810/MH/NIMH NIH HHS/ -- 5R25MH071584-07/MH/NIMH NIH HHS/ -- MH095867/MH/NIMH NIH HHS/ -- MH19961-14/MH/NIMH NIH HHS/ -- R00 MH095867/MH/NIMH NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 MH060007/MH/NIMH NIH HHS/ -- R01 MH074090/MH/NIMH NIH HHS/ -- R01MH074090/MH/NIMH NIH HHS/ -- R01MH081754/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):51-6. doi: 10.1038/nature14186. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA. ; Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; 1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, Yale University, New Haven, Connecticut 06511, USA. ; Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA. ; National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Autism &Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania 17837, USA. ; University of Illinois at Chicago, Chicago, Illinois 60608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807484" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/*genetics/*metabolism ; Brain/embryology/*metabolism ; Catenins/*deficiency/*genetics/metabolism ; Cells, Cultured ; Chromatin/genetics/metabolism ; DNA Copy Number Variations/genetics ; Embryo, Mammalian/cytology/metabolism ; Exome/genetics ; Female ; Gene Expression ; Gene Expression Regulation, Developmental ; Hippocampus/pathology ; Humans ; Male ; Mice ; Models, Genetic ; Multifactorial Inheritance/genetics ; Mutation, Missense ; Nerve Net ; Neurons/cytology/metabolism ; Sex Characteristics ; Zebrafish/embryology/genetics/metabolism
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  • 20
    Publication Date: 2015-02-06
    Description: Rising temperatures and lessening fresh water supplies are threatening agricultural productivity and have motivated efforts to improve plant water use and drought tolerance. During water deficit, plants produce elevated levels of abscisic acid (ABA), which improves water consumption and stress tolerance by controlling guard cell aperture and other protective responses. One attractive strategy for controlling water use is to develop compounds that activate ABA receptors, but agonists approved for use have yet to be developed. In principle, an engineered ABA receptor that can be activated by an existing agrochemical could achieve this goal. Here we describe a variant of the ABA receptor PYRABACTIN RESISTANCE 1 (PYR1) that possesses nanomolar sensitivity to the agrochemical mandipropamid and demonstrate its efficacy for controlling ABA responses and drought tolerance in transgenic plants. Furthermore, crystallographic studies provide a mechanistic basis for its activity and demonstrate the relative ease with which the PYR1 ligand-binding pocket can be altered to accommodate new ligands. Thus, we have successfully repurposed an agrochemical for a new application using receptor engineering. We anticipate that this strategy will be applied to other plant receptors and represents a new avenue for crop improvement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang-Youl -- Peterson, Francis C -- Mosquna, Assaf -- Yao, Jin -- Volkman, Brian F -- Cutler, Sean R -- England -- Nature. 2015 Apr 23;520(7548):545-8. doi: 10.1038/nature14123. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Plant Cell Biology and Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA [2] Institute for Integrative Genome Biology, Riverside, California 92521, USA. ; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652827" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Acclimatization/drug effects ; Agrochemicals/*pharmacology ; Amides/*pharmacology ; Arabidopsis/drug effects/genetics/metabolism ; Arabidopsis Proteins/*genetics/*metabolism ; Binding Sites ; Carboxylic Acids/*pharmacology ; Crystallography, X-Ray ; Droughts ; Genetic Engineering ; Genotype ; Ligands ; Lycopersicon esculentum/drug effects/genetics/metabolism ; Membrane Transport Proteins/*genetics/*metabolism ; Models, Molecular ; Plant Transpiration/drug effects ; Plants/*drug effects/genetics/*metabolism ; Plants, Genetically Modified ; Stress, Physiological/drug effects ; Structure-Activity Relationship ; Water/*metabolism
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  • 21
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    Nature Publishing Group (NPG)
    Publication Date: 2015-02-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Feb 26;518(7540):456. doi: 10.1038/518456b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719627" target="_blank"〉PubMed〈/a〉
    Keywords: Analgesics/pharmacology/therapeutic use ; Brain Mapping/*methods/psychology ; Chronic Pain/diagnosis/drug therapy/physiopathology/psychology ; Female ; Forensic Medicine/ethics/methods ; Humans ; Male ; Malingering/prevention & control ; Pain/*diagnosis/drug therapy/physiopathology/psychology ; Pain Measurement/ethics/*methods/psychology/standards ; Self Report
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  • 22
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    Nature Publishing Group (NPG)
    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bourzac, Katherine -- England -- Nature. 2015 Dec 17;528(7582):S134-6. doi: 10.1038/528S134a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672788" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cancer Vaccines/immunology/therapeutic use ; Drug Therapy, Combination ; Humans ; Immunotherapy/economics/methods ; Male ; Mice ; Precision Medicine/economics/methods ; Prostatic Neoplasms/genetics/*immunology/*therapy ; Survival Rate ; T-Lymphocytes/immunology ; Tissue Extracts/economics/immunology/therapeutic use
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  • 23
    Publication Date: 2015-11-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maheswaran, Shyamala -- Haber, Daniel A -- England -- Nature. 2015 Nov 26;527(7579):452-3. doi: 10.1038/nature16313. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560026" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Drug Resistance, Neoplasm/*drug effects ; *Epithelial-Mesenchymal Transition ; Female ; Lung Neoplasms/*pathology/*secondary ; Male ; Mammary Neoplasms, Experimental/*drug therapy/*pathology ; Neoplasm Metastasis/*pathology ; Pancreatic Neoplasms/*drug therapy/*pathology
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  • 24
    Publication Date: 2015-05-29
    Description: Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742237/" 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/PMC4742237/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Cheng-Zhong -- Spektor, Alexander -- Cornils, Hauke -- Francis, Joshua M -- Jackson, Emily K -- Liu, Shiwei -- Meyerson, Matthew -- Pellman, David -- GM083299-18/GM/NIGMS NIH HHS/ -- R01 GM061345/GM/NIGMS NIH HHS/ -- R01 GM083299/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 11;522(7555):179-84. doi: 10.1038/nature14493. Epub 2015 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [4] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [3] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017310" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Cell Survival ; *Chromosome Breakage ; Chromosome Segregation/genetics ; DNA Copy Number Variations/genetics ; *DNA Damage ; Gene Rearrangement/genetics ; Genomic Instability/genetics ; Humans ; *Micronuclei, Chromosome-Defective ; Mutation/genetics ; Neoplasms/genetics ; S Phase/genetics ; Single-Cell Analysis
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  • 25
    Publication Date: 2015-06-05
    Description: The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khaminets, Aliaksandr -- Heinrich, Theresa -- Mari, Muriel -- Grumati, Paolo -- Huebner, Antje K -- Akutsu, Masato -- Liebmann, Lutz -- Stolz, Alexandra -- Nietzsche, Sandor -- Koch, Nicole -- Mauthe, Mario -- Katona, Istvan -- Qualmann, Britta -- Weis, Joachim -- Reggiori, Fulvio -- Kurth, Ingo -- Hubner, Christian A -- Dikic, Ivan -- England -- Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498. Epub 2015 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ; Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany. ; 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands. ; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany. ; Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmuhlenweg 1, 07743 Jena, Germany. ; Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany. ; Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. ; 1] Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [2] Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany [3] Institute of Immunology, School of Medicine University of Split, Mestrovicevo setaliste bb, 21 000 Split, Croatia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040720" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis ; Autophagy/*physiology ; Biomarkers/metabolism ; Cell Line ; Endoplasmic Reticulum/chemistry/*metabolism ; Female ; Gene Deletion ; Humans ; Lysosomes/metabolism ; Male ; Membrane Proteins/deficiency/genetics/*metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Neoplasm Proteins/deficiency/genetics/*metabolism ; Phagosomes/metabolism ; Protein Binding ; Sensory Receptor Cells/metabolism/pathology
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  • 26
    Publication Date: 2015-11-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maillard, Ivan -- Saltiel, Alan R -- England -- Nature. 2015 Dec 3;528(7580):44-6. doi: 10.1038/nature15648. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Institute, the Division of Hematology/Oncology and Department of Internal Medicine, and the Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580010" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/*cytology/*immunology ; Aging/*immunology ; Animals ; Insulin Resistance/*immunology ; Male ; T-Lymphocytes, Regulatory/*cytology/*immunology
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  • 27
    Publication Date: 2015-09-17
    Description: Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced alphaMbeta2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712631/" 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/PMC4712631/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dachuan -- Chen, Grace -- Manwani, Deepa -- Mortha, Arthur -- Xu, Chunliang -- Faith, Jeremiah J -- Burk, Robert D -- Kunisaki, Yuya -- Jang, Jung-Eun -- Scheiermann, Christoph -- Merad, Miriam -- Frenette, Paul S -- R01 CA154947/CA/NCI NIH HHS/ -- R01 CA173861/CA/NCI NIH HHS/ -- R01 CA190400/CA/NCI NIH HHS/ -- R01 DK056638/DK/NIDDK NIH HHS/ -- R01 HL069438/HL/NHLBI NIH HHS/ -- R01 HL116340/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Sep 24;525(7570):528-32. doi: 10.1038/nature15367. Epub 2015 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA. ; The Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. ; The Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York 10029, USA. ; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26374999" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia, Sickle Cell/blood/microbiology/pathology ; Animals ; Cell Aging/*immunology ; Disease Models, Animal ; Erythrocytes, Abnormal/pathology ; Inflammation/immunology/pathology ; Macrophage-1 Antigen/metabolism ; Male ; Mice ; Microbiota/*immunology ; Myeloid Differentiation Factor 88/metabolism ; Neutrophils/*cytology/*immunology ; Shock, Septic/immunology/microbiology/pathology ; Signal Transduction ; Toll-Like Receptors/immunology
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  • 28
    Publication Date: 2015-04-23
    Description: Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 A, reaching 2.9 A resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRNA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal subunits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khatter, Heena -- Myasnikov, Alexander G -- Natchiar, S Kundhavai -- Klaholz, Bruno P -- England -- Nature. 2015 Apr 30;520(7549):640-5. doi: 10.1038/nature14427. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, 67404 Illkirch, France [2] Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France [3] Institut National de la Sante et de la Recherche Medicale (INSERM) U964, 67404 Illkirch, France [4] Universite de Strasbourg, 67081 Strasbourg, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901680" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Cryoelectron Microscopy ; Electrons ; Humans ; Models, Molecular ; RNA, Ribosomal/chemistry/metabolism/ultrastructure ; RNA, Transfer/chemistry/metabolism/ultrastructure ; Ribosomal Proteins/chemistry/metabolism/ultrastructure ; Ribosome Subunits/chemistry/metabolism/ultrastructure ; Ribosomes/*chemistry/metabolism/*ultrastructure
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  • 29
    Publication Date: 2015-02-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Patel, Sachin -- Cone, Roger D -- England -- Nature. 2015 Mar 5;519(7541):38-40. doi: 10.1038/nature14206. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vanderbilt University Medical Center, Department of Molecular Physiology and Biophysics, Nashville, Tennessee 37232-0615, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707800" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cannabinoids/*pharmacology ; Eating/*drug effects/*physiology ; Hypothalamus/*cytology ; Male ; Neurons/*drug effects/*metabolism ; Pro-Opiomelanocortin/*metabolism
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  • 30
    Publication Date: 2015-01-07
    Description: Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir, primarily in resting memory CD4(+) T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (〉98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406054/" 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/PMC4406054/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, Kai -- Pertea, Mihaela -- Rongvaux, Anthony -- Wang, Leyao -- Durand, Christine M -- Ghiaur, Gabriel -- Lai, Jun -- McHugh, Holly L -- Hao, Haiping -- Zhang, Hao -- Margolick, Joseph B -- Gurer, Cagan -- Murphy, Andrew J -- Valenzuela, David M -- Yancopoulos, George D -- Deeks, Steven G -- Strowig, Till -- Kumar, Priti -- Siliciano, Janet D -- Salzberg, Steven L -- Flavell, Richard A -- Shan, Liang -- Siliciano, Robert F -- 1U19AI096109/AI/NIAID NIH HHS/ -- AI096113/AI/NIAID NIH HHS/ -- K08 HL127269/HL/NHLBI NIH HHS/ -- P30 AI094189/AI/NIAID NIH HHS/ -- P30AI094189/AI/NIAID NIH HHS/ -- R01 AI043222/AI/NIAID NIH HHS/ -- R01 AI051178/AI/NIAID NIH HHS/ -- T32 AI007019/AI/NIAID NIH HHS/ -- T32 AI07019/AI/NIAID NIH HHS/ -- T32 HL007525/HL/NHLBI NIH HHS/ -- U19 AI096109/AI/NIAID NIH HHS/ -- U19 AI096113/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 15;517(7534):381-5. doi: 10.1038/nature14053. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA. ; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Deep Sequencing and Microarray Core, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA. ; Department of Medicine, University of California, San Francisco, San Francisco, California 94110, USA. ; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; 1] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA. ; 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Howard Hughes Medical Institute, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25561180" target="_blank"〉PubMed〈/a〉
    Keywords: Acute Disease/therapy ; Animals ; Anti-HIV Agents/administration & dosage/pharmacology/therapeutic use ; CD4-Positive T-Lymphocytes/cytology/immunology/virology ; Chronic Disease/drug therapy ; Epitopes, T-Lymphocyte/genetics/immunology ; Female ; Genes, Dominant/*genetics ; Genes, Viral/*genetics ; HIV Infections/blood/drug therapy/immunology/virology ; HIV-1/drug effects/*genetics/growth & development/*immunology ; Humans ; Male ; Mice ; Mutation/*genetics ; RNA, Viral/blood ; T-Lymphocytes, Cytotoxic/*immunology ; Viral Load/drug effects ; Virus Latency/genetics/*immunology ; Virus Replication/immunology ; gag Gene Products, Human Immunodeficiency Virus/genetics/immunology
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  • 31
    Publication Date: 2015-03-31
    Description: In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 A resolution, and with a non-nucleotide antagonist BPTU at 2.2 A resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" 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/PMC4408927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dandan -- Gao, Zhan-Guo -- Zhang, Kaihua -- Kiselev, Evgeny -- Crane, Steven -- Wang, Jiang -- Paoletta, Silvia -- Yi, Cuiying -- Ma, Limin -- Zhang, Wenru -- Han, Gye Won -- Liu, Hong -- Cherezov, Vadim -- Katritch, Vsevolod -- Jiang, Hualiang -- Stevens, Raymond C -- Jacobson, Kenneth A -- Zhao, Qiang -- Wu, Beili -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Z01 DK031116-21/Intramural NIH HHS/ -- Z01DK031116-26/DK/NIDDK NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA. ; Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA [2] Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822790" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/analogs & derivatives/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Deoxyadenine Nucleotides/*chemistry/*metabolism/pharmacology ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Purinergic P2Y Receptor Antagonists/*chemistry/metabolism/pharmacology ; Receptors, Purinergic P2Y1/*chemistry/*metabolism ; Thionucleotides/chemistry/metabolism ; Uracil/*analogs & derivatives/chemistry/metabolism/pharmacology
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  • 32
    Publication Date: 2015-08-11
    Description: G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca(2+)-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" 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/PMC4597782/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vafabakhsh, Reza -- Levitz, Joshua -- Isacoff, Ehud Y -- 2PN2EY018241/EY/NEI NIH HHS/ -- PN2 EY018241/EY/NEI NIH HHS/ -- England -- Nature. 2015 Aug 27;524(7566):497-501. doi: 10.1038/nature14679. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. ; Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258295" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Drug Partial Agonism ; *Fluorescence Resonance Energy Transfer ; Humans ; Ligands ; Models, Biological ; Models, Molecular ; Protein Binding ; Protein Conformation ; Rats ; Receptors, Metabotropic Glutamate/*chemistry/*classification/genetics/metabolism
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  • 33
    Publication Date: 2015-08-11
    Description: The plant hormone jasmonate plays crucial roles in regulating plant responses to herbivorous insects and microbial pathogens and is an important regulator of plant growth and development. Key mediators of jasmonate signalling include MYC transcription factors, which are repressed by jasmonate ZIM-domain (JAZ) transcriptional repressors in the resting state. In the presence of active jasmonate, JAZ proteins function as jasmonate co-receptors by forming a hormone-dependent complex with COI1, the F-box subunit of an SCF-type ubiquitin E3 ligase. The hormone-dependent formation of the COI1-JAZ co-receptor complex leads to ubiquitination and proteasome-dependent degradation of JAZ repressors and release of MYC proteins from transcriptional repression. The mechanism by which JAZ proteins repress MYC transcription factors and how JAZ proteins switch between the repressor function in the absence of hormone and the co-receptor function in the presence of hormone remain enigmatic. Here we show that Arabidopsis MYC3 undergoes pronounced conformational changes when bound to the conserved Jas motif of the JAZ9 repressor. The Jas motif, previously shown to bind to hormone as a partly unwound helix, forms a complete alpha-helix that displaces the amino (N)-terminal helix of MYC3 and becomes an integral part of the MYC N-terminal fold. In this position, the Jas helix competitively inhibits MYC3 interaction with the MED25 subunit of the transcriptional Mediator complex. Our structural and functional studies elucidate a dynamic molecular switch mechanism that governs the repression and activation of a major plant hormone pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567411/" 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/PMC4567411/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Feng -- Yao, Jian -- Ke, Jiyuan -- Zhang, Li -- Lam, Vinh Q -- Xin, Xiu-Fang -- Zhou, X Edward -- Chen, Jian -- Brunzelle, Joseph -- Griffin, Patrick R -- Zhou, Mingguo -- Xu, H Eric -- Melcher, Karsten -- He, Sheng Yang -- R01 AI068718/AI/NIAID NIH HHS/ -- R01 GM102545/GM/NIGMS NIH HHS/ -- R01AI060761/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 10;525(7568):269-73. doi: 10.1038/nature14661. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; DOE Plant Research Laboratory, Michigan State University, East Lansing, Michigan 48824, USA. ; College of Plant Protection, Nanjing Agricultural University, No. 1 Weigang, 210095, Nanjing, Jiangsu Province, China. ; Department of Biological Sciences, Western Michigan University, Kalamazoo, Michigan 49008, USA. ; Department of Plant Biology, Michigan State University, East Lansing, Michigan 48824, USA. ; Department of Molecular Therapeutics, Translational Research Institute, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. ; Department of Molecular Pharmacology and Biological Chemistry, Life Sciences Collaborative Access Team, Synchrotron Research Center, Northwestern University, Argonne, Illinois 60439, USA. ; Key Laboratory of Receptor Research, VARI-SIMM Center, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. ; Howard Hughes Medical Institute, Michigan State University, East Lansing, Michigan 48824, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258305" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Apoproteins/chemistry/metabolism ; *Arabidopsis/chemistry/metabolism ; Arabidopsis Proteins/*antagonists & inhibitors/*chemistry/genetics/*metabolism ; Binding, Competitive/genetics ; Crystallography, X-Ray ; Cyclopentanes/*metabolism ; Models, Molecular ; Nuclear Proteins/metabolism ; Oxylipins/*metabolism ; Plant Growth Regulators/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding/genetics ; Protein Conformation ; Repressor Proteins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Trans-Activators/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Ubiquitination
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  • 34
    Publication Date: 2015-06-18
    Description: Cell-to-cell variation is a universal feature of life that affects a wide range of biological phenomena, from developmental plasticity to tumour heterogeneity. Although recent advances have improved our ability to document cellular phenotypic variation, the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of mammalian DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells by assay for transposase-accessible chromatin using sequencing (ATAC-seq) integrated into a programmable microfluidics platform. Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provide insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type-specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signalling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome compartments de novo, linking single-cell accessibility variation to three-dimensional genome organization. Single-cell analysis of DNA accessibility provides new insight into cellular variation of the 'regulome'.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685948/" 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/PMC4685948/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buenrostro, Jason D -- Wu, Beijing -- Litzenburger, Ulrike M -- Ruff, Dave -- Gonzales, Michael L -- Snyder, Michael P -- Chang, Howard Y -- Greenleaf, William J -- 5U54HG00455805/HG/NHGRI NIH HHS/ -- P50 HG007735/HG/NHGRI NIH HHS/ -- P50HG007735/HG/NHGRI NIH HHS/ -- T32 HG000044/HG/NHGRI NIH HHS/ -- T32HG000044/HG/NHGRI NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19AI057266/AI/NIAID NIH HHS/ -- U54 HG004558/HG/NHGRI NIH HHS/ -- UH2 AR067676/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 23;523(7561):486-90. doi: 10.1038/nature14590. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Program in Epithelial Biology and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. ; Program in Epithelial Biology and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. ; Fluidigm Corporation, South San Francisco, California 94080, USA. ; 1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Applied Physics, Stanford University, Stanford, California 94025, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083756" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Compartmentation ; Cell Cycle/genetics ; Cell Line ; Cells/classification/*metabolism ; Chromatin/*genetics/*metabolism ; DNA/genetics/metabolism ; Epigenesis, Genetic ; *Epigenomics ; Genome, Human/genetics ; Humans ; Microfluidics ; Signal Transduction ; Single-Cell Analysis/*methods ; Transcription Factors/metabolism ; Transposases/metabolism
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  • 35
    Publication Date: 2015-04-10
    Description: The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to approximately 4 A resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409540/" 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/PMC4409540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paulsen, Candice E -- Armache, Jean-Paul -- Gao, Yuan -- Cheng, Yifan -- Julius, David -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01 NS055299/NS/NINDS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R01NS055299/NS/NINDS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 23;520(7548):511-7. doi: 10.1038/nature14367. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco, California 94158-2517, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA. ; 1] Department of Physiology, University of California, San Francisco, California 94158-2517, USA [2] Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855297" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Analgesics ; Ankyrin Repeat ; Anti-Inflammatory Agents ; Binding Sites ; Calcium Channels/*chemistry/metabolism/*ultrastructure ; *Cryoelectron Microscopy ; Cytosol/metabolism ; Humans ; Models, Molecular ; Nerve Tissue Proteins/antagonists & ; inhibitors/*chemistry/metabolism/*ultrastructure ; Polyphosphates/metabolism/pharmacology ; Protein Stability/drug effects ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Transient Receptor Potential Channels/antagonists & ; inhibitors/*chemistry/metabolism/*ultrastructure
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  • 36
    Publication Date: 2015-07-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bull, James J -- England -- Nature. 2015 Jul 2;523(7558):43-4. doi: 10.1038/523043a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cellular and Molecular Biology, the Center for Computational Biology and Bioinformatics and the Department of Integrative Biology, University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135445" target="_blank"〉PubMed〈/a〉
    Keywords: *Adaptation, Physiological ; Animals ; Female ; Male ; Sex Determination Processes/*physiology ; *Temperature
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  • 37
    Publication Date: 2015-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnorr, Stephanie L -- England -- Nature. 2015 Feb 26;518(7540):S14-5. doi: 10.1038/518S14a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Group on Plant Foods in Hominin Dietary Ecology at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715276" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; *Biodiversity ; Diet ; Dietary Fiber/metabolism/microbiology ; Feeding Behavior/*physiology ; Female ; Fertility ; Health ; Humans ; Intestines/*microbiology ; Male ; Microbiota/*physiology ; *Population Groups ; Seasons ; Sex Factors ; *Symbiosis ; Tanzania ; *Wilderness
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  • 38
    Publication Date: 2015-10-20
    Description: The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Lin -- Zhang, Siyuan -- Yao, Jun -- Lowery, Frank J -- Zhang, Qingling -- Huang, Wen-Chien -- Li, Ping -- Li, Min -- Wang, Xiao -- Zhang, Chenyu -- Wang, Hai -- Ellis, Kenneth -- Cheerathodi, Mujeeburahiman -- McCarty, Joseph H -- Palmieri, Diane -- Saunus, Jodi -- Lakhani, Sunil -- Huang, Suyun -- Sahin, Aysegul A -- Aldape, Kenneth D -- Steeg, Patricia S -- Yu, Dihua -- 5R00CA158066-05/CA/NCI NIH HHS/ -- P01-CA099031/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R00 CA158066/CA/NCI NIH HHS/ -- R01 CA194697/CA/NCI NIH HHS/ -- R01-CA112567-06/CA/NCI NIH HHS/ -- R01CA184836/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 5;527(7576):100-4. doi: 10.1038/nature15376. Epub 2015 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Cancer Biology Program, Graduate School of Biomedical Sciences, Houston, Texas 77030, USA. ; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA. ; Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Woman's Malignancies Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. ; The University of Queensland Centre for Clinical Research, Brisbane, Queensland 4029, Australia. ; The School of Medicine and Pathology Queensland, Brisbane, Queensland 4029, Australia. ; The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia. ; Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26479035" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/genetics ; Animals ; Astrocytes/cytology/metabolism ; Brain/metabolism/pathology ; Brain Neoplasms/metabolism/*pathology/*secondary ; Cell Proliferation/genetics ; Chemokine CCL2/secretion ; DNA-Binding Proteins/metabolism ; Down-Regulation/genetics ; Evolution, Molecular ; Exosomes/*genetics/metabolism/secretion ; Female ; *Gene Expression Regulation, Neoplastic ; *Gene Silencing ; Genes, Tumor Suppressor ; Humans ; Male ; Mice ; MicroRNAs/*genetics ; PTEN Phosphohydrolase/*deficiency/genetics ; RNA, Messenger/analysis/genetics ; *Tumor Microenvironment/genetics ; Tumor Suppressor Proteins/deficiency/genetics
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  • 39
    Publication Date: 2015-04-04
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544703/" 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/PMC4544703/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van der Lee, Sven J -- Holstege, Henne -- Wong, Tsz Hang -- Jakobsdottir, Johanna -- Bis, Joshua C -- Chouraki, Vincent -- van Rooij, Jeroen G J -- Grove, Megan L -- Smith, Albert V -- Amin, Najaf -- Choi, Seung-Hoan -- Beiser, Alexa S -- Garcia, Melissa E -- van IJcken, Wilfred F J -- Pijnenburg, Yolande A L -- Louwersheimer, Eva -- Brouwer, Rutger W W -- van den Hout, Mirjam C G N -- Oole, Edwin -- Eirkisdottir, Gudny -- Levy, Daniel -- Rotter, Jerome I -- Emilsson, Valur -- O'Donnell, Christopher J -- Aspelund, Thor -- Uitterlinden, Andre G -- Launer, Lenore J -- Hofman, Albert -- Boerwinkle, Eric -- Psaty, Bruce M -- DeStefano, Anita L -- Scheltens, Philip -- Seshadri, Sudha -- van Swieten, John C -- Gudnason, Vilmundur -- van der Flier, Wiesje M -- Ikram, M Arfan -- van Duijn, Cornelia M -- R01 HL105756/HL/NHLBI NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):E2-3. doi: 10.1038/nature14038.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; 1] Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands [2] Department of Clinical Genetics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands. ; Department of Neurology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; Icelandic Heart Association, Kopavogur 201, Iceland. ; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98101, USA. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland 20892, USA. ; Center for Biomics, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Boston University School of Medicine, Boston, Massachusetts 02118, USA [3] National Heart, Lung, and Blood Institute, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland [2] Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik 101, Iceland. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] National Heart, Lung, and Blood Institute, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland [2] Centre for Public Health, University of Iceland, Reykjavik 101, Iceland. ; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [3] Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden 2300 RC, The Netherlands. ; 1] School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98101, USA [2] Department of Epidemiology, University of Washington, Seattle, Washington 98101, USA [3] Group Health Research Institute, Seattle, Washington 98101-1448, USA. ; 1] Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands [2] Department of Neurology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; 1] Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands [2] Department of Epidemiology &Biostatistics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands. ; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Neurology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [3] Departments of Radiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25832410" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/*genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Humans ; Male ; Phospholipase D/*genetics
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  • 40
    Publication Date: 2015-01-30
    Description: The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311405/" 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/PMC4311405/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cancer Genome Atlas Network -- K08 DE024774/DE/NIDCR NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50CA097190/CA/NCI NIH HHS/ -- P50CA16672/CA/NCI NIH HHS/ -- R01 CA 095419/CA/NCI NIH HHS/ -- R01 DE023685/DE/NIDCR NIH HHS/ -- U24 CA143799/CA/NCI NIH HHS/ -- U24 CA143835/CA/NCI NIH HHS/ -- U24 CA143840/CA/NCI NIH HHS/ -- U24 CA143843/CA/NCI NIH HHS/ -- U24 CA143845/CA/NCI NIH HHS/ -- U24 CA143848/CA/NCI NIH HHS/ -- U24 CA143858/CA/NCI NIH HHS/ -- U24 CA143866/CA/NCI NIH HHS/ -- U24 CA143867/CA/NCI NIH HHS/ -- U24 CA143882/CA/NCI NIH HHS/ -- U24 CA143883/CA/NCI NIH HHS/ -- U24 CA144025/CA/NCI NIH HHS/ -- U24 CA180951/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- UL1 TR000433/TR/NCATS NIH HHS/ -- ZIA-DC-000016/DC/NIDCD NIH HHS/ -- ZIA-DC-000073/DC/NIDCD NIH HHS/ -- ZIA-DC-000074/DC/NIDCD NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Jan 29;517(7536):576-82. doi: 10.1038/nature14129.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25631445" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinoma, Squamous Cell/*genetics ; DNA Copy Number Variations/genetics ; DNA, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/*genetics ; *Genomics ; Head and Neck Neoplasms/*genetics ; Humans ; Male ; Molecular Targeted Therapy ; Mutation/genetics ; Oncogenes/genetics ; RNA, Neoplasm/genetics ; Signal Transduction/genetics ; Transcription Factors/metabolism
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  • 41
    Publication Date: 2015-09-08
    Description: During eukaryotic translation initiation, 43S complexes, comprising a 40S ribosomal subunit, initiator transfer RNA and initiation factors (eIF) 2, 3, 1 and 1A, attach to the 5'-terminal region of messenger RNA and scan along it to the initiation codon. Scanning on structured mRNAs also requires the DExH-box protein DHX29. Mammalian eIF3 contains 13 subunits and participates in nearly all steps of translation initiation. Eight subunits having PCI (proteasome, COP9 signalosome, eIF3) or MPN (Mpr1, Pad1, amino-terminal) domains constitute the structural core of eIF3, to which five peripheral subunits are flexibly linked. Here we present a cryo-electron microscopy structure of eIF3 in the context of the DHX29-bound 43S complex, showing the PCI/MPN core at approximately 6 A resolution. It reveals the organization of the individual subunits and their interactions with components of the 43S complex. We were able to build near-complete polyalanine-level models of the eIF3 PCI/MPN core and of two peripheral subunits. The implications for understanding mRNA ribosomal attachment and scanning are discussed.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719162/" 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/PMC4719162/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉des Georges, Amedee -- Dhote, Vidya -- Kuhn, Lauriane -- Hellen, Christopher U T -- Pestova, Tatyana V -- Frank, Joachim -- Hashem, Yaser -- R01 GM029169/GM/NIGMS NIH HHS/ -- R01 GM059660/GM/NIGMS NIH HHS/ -- R01 GM29169/GM/NIGMS NIH HHS/ -- R01 GM59660/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 24;525(7570):491-5. doi: 10.1038/nature14891. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HHMI, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. ; CNRS, Proteomic Platform Strasbourg - Esplanade, Strasbourg 67084, France. ; Department of Biological Sciences, Columbia University, New York, New York 10032, USA. ; CNRS, Architecture et Reactivite de l'ARN, Universite de Strasbourg, Strasbourg 67084, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344199" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Codon, Initiator/genetics ; Cryoelectron Microscopy ; Eukaryotic Initiation Factor-2/chemistry/metabolism ; Eukaryotic Initiation Factor-3/*chemistry/*metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism ; *Peptide Chain Initiation, Translational ; Peptide Initiation Factors/metabolism ; Protein Structure, Secondary ; Protein Subunits/chemistry/metabolism ; RNA Helicases/chemistry/metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Transfer, Met/metabolism ; Ribosome Subunits, Small, Eukaryotic/chemistry/metabolism ; Ribosomes/*chemistry/*metabolism
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  • 42
    Publication Date: 2015-06-18
    Description: The bacterial ubiD and ubiX or the homologous fungal fdc1 and pad1 genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone (also known as coenzyme Q) biosynthesis or microbial biodegradation of aromatic compounds, respectively. Despite biochemical studies on individual gene products, the composition and cofactor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear. Here we show that Fdc1 is solely responsible for the reversible decarboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesized by the associated UbiX/Pad1. Atomic resolution crystal structures reveal that two distinct isomers of the oxidized cofactor can be observed, an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with markedly altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor-cofactor adduct suggests that 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. Although 1,3-dipolar cycloaddition is commonly used in organic chemistry, we propose that this presents the first example, to our knowledge, of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc1/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de)carboxylation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Payne, Karl A P -- White, Mark D -- Fisher, Karl -- Khara, Basile -- Bailey, Samuel S -- Parker, David -- Rattray, Nicholas J W -- Trivedi, Drupad K -- Goodacre, Royston -- Beveridge, Rebecca -- Barran, Perdita -- Rigby, Stephen E J -- Scrutton, Nigel S -- Hay, Sam -- Leys, David -- BB/K017802/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/M/017702/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):497-501. doi: 10.1038/nature14560. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Synthetic Biology of Fine and Speciality Chemicals, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. ; Innovation/Biodomain, Shell International Exploration and Production, Westhollow Technology Center, 3333 Highway 6 South, Houston, Texas 77082-3101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083754" target="_blank"〉PubMed〈/a〉
    Keywords: Alkenes/chemistry/metabolism ; Aspergillus niger/enzymology/genetics ; *Biocatalysis ; Carboxy-Lyases/chemistry/genetics/*metabolism ; Crystallography, X-Ray ; *Cycloaddition Reaction ; Decarboxylation ; Escherichia coli Proteins/chemistry/genetics/metabolism ; Flavins/biosynthesis/chemistry/metabolism ; Isomerism ; Ligands ; Models, Molecular ; Ubiquinone/biosynthesis
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  • 43
    Publication Date: 2015-01-21
    Description: The gut microbiota plays a crucial role in the maturation of the intestinal mucosal immune system of its host. Within the thousand bacterial species present in the intestine, the symbiont segmented filamentous bacterium (SFB) is unique in its ability to potently stimulate the post-natal maturation of the B- and T-cell compartments and induce a striking increase in the small-intestinal Th17 responses. Unlike other commensals, SFB intimately attaches to absorptive epithelial cells in the ileum and cells overlying Peyer's patches. This colonization does not result in pathology; rather, it protects the host from pathogens. Yet, little is known about the SFB-host interaction that underlies the important immunostimulatory properties of SFB, because SFB have resisted in vitro culturing for more than 50 years. Here we grow mouse SFB outside their host in an SFB-host cell co-culturing system. Single-celled SFB isolated from monocolonized mice undergo filamentation, segmentation, and differentiation to release viable infectious particles, the intracellular offspring, which can colonize mice to induce signature immune responses. In vitro, intracellular offspring can attach to mouse and human host cells and recruit actin. In addition, SFB can potently stimulate the upregulation of host innate defence genes, inflammatory cytokines, and chemokines. In vitro culturing thereby mimics the in vivo niche, provides new insights into SFB growth requirements and their immunostimulatory potential, and makes possible the investigation of the complex developmental stages of SFB and the detailed dissection of the unique SFB-host interaction at the cellular and molecular levels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnupf, Pamela -- Gaboriau-Routhiau, Valerie -- Gros, Marine -- Friedman, Robin -- Moya-Nilges, Maryse -- Nigro, Giulia -- Cerf-Bensussan, Nadine -- Sansonetti, Philippe J -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 2;520(7545):99-103. doi: 10.1038/nature14027. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France [2] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France. ; 1] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France [2] Institut national de la recherche agronomique (INRA) Micalis UMR1319, 78350 Jouy-en-Josas, France [3] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France. ; 1] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France [2] Ecole Normale Superieure de Lyon, Department of Biology, 69007 Lyon, France. ; Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France. ; Imagopole, Ultrastructural Microscopy Platform, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France. ; 1] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France [2] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France. ; 1] Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France [2] Microbiologie et Maladies Infectieuses, College de France, 11 Marcelin Berthelot Square, 75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600271" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Animals ; Bacteria/cytology/*growth & development/*immunology ; Cell Line ; Coculture Techniques/*methods ; Escherichia coli/cytology/growth & development/immunology ; Feces/microbiology ; Female ; Germ-Free Life ; Humans ; Immunity, Mucosal/immunology ; Intestinal Mucosa/cytology/immunology/microbiology ; Intestines/cytology/*immunology/*microbiology ; Lymphocytes/cytology/*immunology ; Male ; Mice ; Microbial Viability ; Peyer's Patches/immunology ; Symbiosis/*immunology ; Th17 Cells/immunology
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  • 44
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    Nature Publishing Group (NPG)
    Publication Date: 2015-02-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goyal, Sidhartha -- Zandstra, Peter W -- England -- Nature. 2015 Feb 26;518(7540):488-90. doi: 10.1038/nature14203. Epub 2015 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, University of Toronto, Toronto, Ontario M5S 1A7, Canada. ; Institute of Biomaterials and Biomedical Engineering, University of Toronto, and at the Donnelly Centre for Cellular and Biomolecular Research, University of Toronto.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686602" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage/*physiology ; Female ; *Hematopoiesis ; Hematopoietic Stem Cells/*cytology ; Male ; Stem Cells/*cytology
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  • 45
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2015-12-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grafton, Anthony -- England -- Nature. 2015 Dec 3;528(7580):40. doi: 10.1038/528040a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princeton University in Princeton, New Jersey, USA. He collaborated extensively with Lisa Jardine.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632582" target="_blank"〉PubMed〈/a〉
    Keywords: Female ; Great Britain ; History, 15th Century ; History, 16th Century ; History, 17th Century ; History, 20th Century ; History, 21st Century ; Humans ; Knowledge ; Literature, Modern/*history ; Male ; Mitochondrial Replacement Therapy ; Science/*history ; Teaching/history ; Writing
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  • 46
    Publication Date: 2015-08-20
    Description: Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IkappaBzeta, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IkappaBzeta at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697747/" 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/PMC4697747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Qian -- Zhao, Kai -- Shen, Qicong -- Han, Yanmei -- Gu, Yan -- Li, Xia -- Zhao, Dezhi -- Liu, Yiqi -- Wang, Chunmei -- Zhang, Xiang -- Su, Xiaoping -- Liu, Juan -- Ge, Wei -- Levine, Ross L -- Li, Nan -- Cao, Xuetao -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 17;525(7569):389-93. doi: 10.1038/nature15252. Epub 2015 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China. ; National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China. ; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26287468" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Chromatin/chemistry/genetics/metabolism ; Colitis/enzymology/immunology/metabolism ; DNA Methylation ; DNA-Binding Proteins/deficiency/*metabolism ; Dendritic Cells/cytology/metabolism ; Down-Regulation/genetics ; Epigenesis, Genetic ; Female ; HEK293 Cells ; Histone Deacetylase 2/*metabolism ; Histones/chemistry/metabolism ; Humans ; I-kappa B Proteins/metabolism ; Inflammation/enzymology/immunology/*metabolism ; Interleukin-6/*antagonists & inhibitors/*biosynthesis/genetics/immunology ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic/genetics ; Proto-Oncogene Proteins/deficiency/*metabolism ; Transcription, Genetic
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  • 47
    Publication Date: 2015-02-25
    Description: V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" 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/PMC4342785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Min-Sung -- Lapkouski, Mikalai -- Yang, Wei -- Gellert, Martin -- Z01 DK036147-01/Intramural NIH HHS/ -- Z01 DK036147-02/Intramural NIH HHS/ -- Z01 DK036167-01/Intramural NIH HHS/ -- Z01 DK036167-02/Intramural NIH HHS/ -- ZIA DK036147-03/Intramural NIH HHS/ -- ZIA DK036147-04/Intramural NIH HHS/ -- ZIA DK036147-05/Intramural NIH HHS/ -- ZIA DK036147-06/Intramural NIH HHS/ -- ZIA DK036147-07/Intramural NIH HHS/ -- ZIA DK036147-08/Intramural NIH HHS/ -- ZIA DK036167-03/Intramural NIH HHS/ -- ZIA DK036167-04/Intramural NIH HHS/ -- ZIA DK036167-05/Intramural NIH HHS/ -- ZIA DK036167-06/Intramural NIH HHS/ -- ZIA DK036167-07/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):507-11. doi: 10.1038/nature14174. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707801" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Homeodomain Proteins/*chemistry/genetics/metabolism ; Humans ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Multimerization ; Protein Structure, Quaternary ; Severe Combined Immunodeficiency/genetics ; Transposases/chemistry ; VDJ Recombinases/*chemistry/metabolism ; X-Linked Combined Immunodeficiency Diseases/genetics
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  • 48
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    Nature Publishing Group (NPG)
    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeWeerdt, Sarah -- England -- Nature. 2015 Dec 17;528(7582):S124-5. doi: 10.1038/528S124a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672783" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Neoplasm/urine ; Biomarkers, Tumor/blood/urine ; Diagnostic Tests, Routine/*methods/trends ; Humans ; Male ; Oncogene Proteins, Fusion/urine ; Precision Medicine/*methods ; Prognosis ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/blood/*diagnosis/pathology/urine ; Risk Assessment
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  • 49
    Publication Date: 2015-12-10
    Description: Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-gamma (IFNgamma) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFNgamma elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFNgamma signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimmey, Jacqueline M -- Huynh, Jeremy P -- Weiss, Leslie A -- Park, Sunmin -- Kambal, Amal -- Debnath, Jayanta -- Virgin, Herbert W -- Stallings, Christina L -- GM007067/GM/NIGMS NIH HHS/ -- U19 AI109725/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):565-9. doi: 10.1038/nature16451. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649827" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics ; Dendritic Cells/immunology/metabolism ; Female ; Immunity, Innate/immunology ; Interferon-gamma/deficiency/immunology ; Macrophages, Alveolar/immunology/metabolism ; Male ; Mice ; Microtubule-Associated Proteins/deficiency/*metabolism ; *Mycobacterium tuberculosis/immunology/physiology ; Neutrophils/*immunology/metabolism ; Tuberculosis/*immunology/microbiology/*pathology
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  • 50
    Publication Date: 2015-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scholl, Benjamin -- Priebe, Nicholas J -- England -- Nature. 2015 Feb 19;518(7539):306-7. doi: 10.1038/nature14201. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, The University of Texas, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652821" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Excitatory Postsynaptic Potentials/*physiology ; Female ; Male ; Synapses/*physiology ; Visual Cortex/*cytology/*physiology
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  • 51
    Publication Date: 2015-10-28
    Description: Viruses in the Reoviridae, like the triple-shelled human rotavirus and the single-shelled insect cytoplasmic polyhedrosis virus (CPV), all package a genome of segmented double-stranded RNAs (dsRNAs) inside the viral capsid and carry out endogenous messenger RNA synthesis through a transcriptional enzyme complex (TEC). By direct electron-counting cryoelectron microscopy and asymmetric reconstruction, we have determined the organization of the dsRNA genome inside quiescent CPV (q-CPV) and the in situ atomic structures of TEC within CPV in both quiescent and transcribing (t-CPV) states. We show that the ten segmented dsRNAs in CPV are organized with ten TECs in a specific, non-symmetric manner, with each dsRNA segment attached directly to a TEC. The TEC consists of two extensively interacting subunits: an RNA-dependent RNA polymerase (RdRP) and an NTPase VP4. We find that the bracelet domain of RdRP undergoes marked conformational change when q-CPV is converted to t-CPV, leading to formation of the RNA template entry channel and access to the polymerase active site. An amino-terminal helix from each of two subunits of the capsid shell protein (CSP) interacts with VP4 and RdRP. These findings establish the link between sensing of environmental cues by the external proteins and activation of endogenous RNA transcription by the TEC inside the virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xing -- Ding, Ke -- Yu, Xuekui -- Chang, Winston -- Sun, Jingchen -- Zhou, Z Hong -- 1S10OD018111/OD/NIH HHS/ -- 1S10RR23057/RR/NCRR NIH HHS/ -- AI094386/AI/NIAID NIH HHS/ -- GM071940/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):531-4. doi: 10.1038/nature15767. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉California Nanosystems Institute, University of California, Los Angeles, California 90095, USA. ; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA. ; Bioengineering, University of California, Los Angeles, California 90095, USA. ; Subtropical Sericulture and Mulberry Resources Protection and Safety Engineering Research Center, Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503045" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid Proteins/chemistry/metabolism/ultrastructure ; Catalytic Domain ; Cryoelectron Microscopy ; *Genome, Viral/genetics ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism/*ultrastructure ; Nucleoside-Triphosphatase/metabolism/ultrastructure ; Protein Subunits/chemistry/metabolism ; RNA Replicase/chemistry/metabolism/*ultrastructure ; RNA, Double-Stranded/genetics/*ultrastructure ; RNA, Messenger/biosynthesis/genetics/ultrastructure ; RNA, Viral/biosynthesis/genetics/*ultrastructure ; Reoviridae/enzymology/genetics/*ultrastructure ; Templates, Genetic ; Transcription, Genetic
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  • 52
    Publication Date: 2015-02-18
    Description: Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or approximately 5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Busch, Katrin -- Klapproth, Kay -- Barile, Melania -- Flossdorf, Michael -- Holland-Letz, Tim -- Schlenner, Susan M -- Reth, Michael -- Hofer, Thomas -- Rodewald, Hans-Reimer -- England -- Nature. 2015 Feb 26;518(7540):542-6. doi: 10.1038/nature14242. Epub 2015 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; 1] Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium [2] Autoimmune Genetics Laboratory, VIB, B-3000 Leuven, Belgium. ; 1] BIOSS, Centre For Biological Signaling Studies, University of Freiburg, Schanzlestrasse 18, D-79104 Freiburg, Germany [2] Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg, and Max-Planck Institute of Immunobiology and Epigenetics, Stubeweg 51, D-79108 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686605" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Animals, Newborn ; Bone Marrow Transplantation ; Cell Lineage/*physiology ; Cell Proliferation ; Cell Tracking ; Female ; Fetus/cytology/embryology ; Fluorouracil ; *Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Male ; Mice ; Receptor, TIE-2/metabolism ; Stem Cells/*cytology/metabolism
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  • 53
    Publication Date: 2015-05-15
    Description: Eukaryotic vacuolar H(+)-ATPases (V-ATPases) are rotary enzymes that use energy from hydrolysis of ATP to ADP to pump protons across membranes and control the pH of many intracellular compartments. ATP hydrolysis in the soluble catalytic region of the enzyme is coupled to proton translocation through the membrane-bound region by rotation of a central rotor subcomplex, with peripheral stalks preventing the entire membrane-bound region from turning with the rotor. The eukaryotic V-ATPase is the most complex rotary ATPase: it has three peripheral stalks, a hetero-oligomeric proton-conducting proteolipid ring, several subunits not found in other rotary ATPases, and is regulated by reversible dissociation of its catalytic and proton-conducting regions. Studies of ATP synthases, V-ATPases, and bacterial/archaeal V/A-ATPases have suggested that flexibility is necessary for the catalytic mechanism of rotary ATPases, but the structures of different rotational states have never been observed experimentally. Here we use electron cryomicroscopy to obtain structures for three rotational states of the V-ATPase from the yeast Saccharomyces cerevisiae. The resulting series of structures shows ten proteolipid subunits in the c-ring, setting the ATP:H(+) ratio for proton pumping by the V-ATPase at 3:10, and reveals long and highly tilted transmembrane alpha-helices in the a-subunit that interact with the c-ring. The three different maps reveal the conformational changes that occur to couple rotation in the symmetry-mismatched soluble catalytic region to the membrane-bound proton-translocating region. Almost all of the subunits of the enzyme undergo conformational changes during the transitions between these three rotational states. The structures of these states provide direct evidence that deformation during rotation enables the smooth transmission of power through rotary ATPases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Jianhua -- Benlekbir, Samir -- Rubinstein, John L -- MOP 81294/Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 May 14;521(7551):241-5. doi: 10.1038/nature14365.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada [2] Department of Medical Biophysics, The University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada. ; Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada. ; 1] Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada [2] Department of Medical Biophysics, The University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada [3] Department of Biochemistry, The University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25971514" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Biocatalysis ; Cell Membrane/chemistry/enzymology/metabolism ; *Cryoelectron Microscopy ; Lipid Bilayers/metabolism ; Models, Molecular ; Pliability ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Protons ; *Rotation ; Saccharomyces cerevisiae/*enzymology ; Solubility ; Vacuolar Proton-Translocating ATPases/*chemistry/metabolism/*ultrastructure
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  • 54
    Publication Date: 2015-12-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 Dec 3;528(7580):20-1. doi: 10.1038/528020a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632570" target="_blank"〉PubMed〈/a〉
    Keywords: Anger ; Emigrants and Immigrants/psychology/statistics & numerical data ; Entrepreneurship/organization & administration ; Europe ; Humans ; Islam/*psychology ; Male ; Narcissism ; Prisoners/psychology/statistics & numerical data ; Prisons ; Terrorism/prevention & control/*psychology
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  • 55
    Publication Date: 2015-10-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grammer, Karl -- Sainani, Kristin Lynn -- England -- Nature. 2015 Oct 8;526(7572):S11. doi: 10.1038/526S11a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444367" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Anthropometry ; *Beauty ; *Biological Evolution ; *Courtship ; Cultural Characteristics ; Female ; Health ; Humans ; Male ; Odors ; Selection, Genetic ; Surgery, Plastic
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  • 56
    Publication Date: 2015-07-23
    Description: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. ; Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA. ; King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200341" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Amyloid/chemistry/drug effects/metabolism/ultrastructure ; Animals ; Base Sequence ; Cataract/congenital/*drug therapy/genetics/*metabolism/pathology ; Cell Line ; Child ; Crystallins/chemistry/genetics/metabolism/ultrastructure ; Dogs ; Female ; Humans ; Lanosterol/administration & dosage/*pharmacology/*therapeutic use ; Lens, Crystalline/drug effects/metabolism/pathology ; Male ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/genetics/metabolism/ultrastructure ; Pedigree ; Protein Aggregates/*drug effects ; Protein Aggregation, Pathological/*drug therapy/pathology
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  • 57
    Publication Date: 2015-08-11
    Description: The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Lan -- Oliver, Eduardo -- Maratou, Klio -- Atanur, Santosh S -- Dubois, Olivier D -- Cotroneo, Emanuele -- Chen, Chien-Nien -- Wang, Lei -- Arce, Cristina -- Chabosseau, Pauline L -- Ponsa-Cobas, Joan -- Frid, Maria G -- Moyon, Benjamin -- Webster, Zoe -- Aldashev, Almaz -- Ferrer, Jorge -- Rutter, Guy A -- Stenmark, Kurt R -- Aitman, Timothy J -- Wilkins, Martin R -- 098424/Wellcome Trust/United Kingdom -- 101033/Wellcome Trust/United Kingdom -- MR/J0003042/1/Medical Research Council/United Kingdom -- P01 HL014985/HL/NHLBI NIH HHS/ -- PG/04/035/16912/British Heart Foundation/United Kingdom -- PG/10/59/28478/British Heart Foundation/United Kingdom -- PG/12/61/29818/British Heart Foundation/United Kingdom -- PG/2000137/British Heart Foundation/United Kingdom -- PG/95170/British Heart Foundation/United Kingdom -- PG/98018/British Heart Foundation/United Kingdom -- RG/10/16/28575/British Heart Foundation/United Kingdom -- WT098424AIA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):356-60. doi: 10.1038/nature14620. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA. ; Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan. ; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258299" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Congenic ; Anoxia/genetics/*metabolism ; Arterioles/metabolism ; Cation Transport Proteins/deficiency/genetics/*metabolism ; Cattle ; Cell Hypoxia ; Cell Proliferation ; Cells, Cultured ; Chromosomes, Mammalian/genetics ; Chronic Disease ; Female ; Gene Knockdown Techniques ; Homeostasis ; Humans ; Hypertension, Pulmonary/genetics/*metabolism ; Intracellular Space/metabolism ; Male ; Muscle, Smooth, Vascular/cytology/*metabolism ; Rats ; Rats, Inbred F344 ; Rats, Inbred WKY ; Zinc/metabolism
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  • 58
    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graves, Jennifer A Marshall -- England -- Nature. 2015 Dec 17;528(7582):343-4. doi: 10.1038/528343a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Science, La Trobe University, Melbourne, Victoria 3086, Australia, and at the Research School of Biology, Australian National University, Canberra.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672550" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Evolution, Molecular ; Female ; *Genes, sry ; Humans ; Kruppel-Like Transcription Factors/genetics ; Male ; SOX9 Transcription Factor/metabolism ; Sex Determination Processes/*genetics ; Sex-Determining Region Y Protein/genetics/metabolism ; Testis/growth & development/metabolism ; X Chromosome/genetics ; Y Chromosome/*genetics
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  • 59
    Publication Date: 2015-06-23
    Description: Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1alpha) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1alpha is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific alpha myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimura, Wataru -- Xiao, Feng -- Canseco, Diana C -- Muralidhar, Shalini -- Thet, SuWannee -- Zhang, Helen M -- Abderrahman, Yezan -- Chen, Rui -- Garcia, Joseph A -- Shelton, John M -- Richardson, James A -- Ashour, Abdelrahman M -- Asaithamby, Aroumougame -- Liang, Hanquan -- Xing, Chao -- Lu, Zhigang -- Zhang, Cheng Cheng -- Sadek, Hesham A -- I01 BX000446/BX/BLRD VA/ -- R01 HL108104/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 9;523(7559):226-30. doi: 10.1038/nature14582. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan. ; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Medicine, VA North Texas Health Care System, 4600 South Lancaster Road, Dallas, Texas 75216, USA. ; 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098368" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Hypoxia ; Cell Proliferation/genetics ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Myocardium/*cytology ; Myocytes, Cardiac/*cytology/metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/genetics/*metabolism ; Recombinases/genetics/metabolism ; Signal Transduction ; Stem Cells/cytology/metabolism
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  • 60
    Publication Date: 2015-02-18
    Description: The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pemovska, Tea -- Johnson, Eric -- Kontro, Mika -- Repasky, Gretchen A -- Chen, Jeffrey -- Wells, Peter -- Cronin, Ciaran N -- McTigue, Michele -- Kallioniemi, Olli -- Porkka, Kimmo -- Murray, Brion W -- Wennerberg, Krister -- England -- Nature. 2015 Mar 5;519(7541):102-5. doi: 10.1038/nature14119. Epub 2015 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland. ; La Jolla Laboratories, Pfizer Worldwide Research &Development, San Diego, California 92121, USA. ; Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, 00290 Helsinki, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686603" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/chemistry/pharmacology/therapeutic use ; Cell Line ; Cell Proliferation/drug effects ; Crystallization ; Crystallography, X-Ray ; Drug Repositioning ; Drug Resistance, Neoplasm/genetics ; Drug Screening Assays, Antitumor ; Fusion Proteins, bcr-abl/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Humans ; Imidazoles/*chemistry/*pharmacology/therapeutic use ; Indazoles/*chemistry/*pharmacology/therapeutic use ; Kidney Neoplasms/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/metabolism ; Models, Molecular ; Molecular Conformation ; Phosphorylation/drug effects ; Protein Binding ; Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Proto-Oncogene Proteins c-abl/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Vascular Endothelial Growth Factor Receptor-2/antagonists & ; inhibitors/chemistry/metabolism
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  • 61
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    Nature Publishing Group (NPG)
    Publication Date: 2015-05-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gravitz, Lauren -- England -- Nature. 2015 May 21;521(7552):S60-1. doi: 10.1038/521S60a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992675" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bees/genetics/*physiology ; *Behavior, Animal ; DNA Methylation ; Epigenesis, Genetic/genetics/physiology ; Feeding Behavior ; Female ; Humans ; Instinct ; Male ; Models, Biological ; Reproduction/genetics/physiology ; Social Behavior
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 62
    Publication Date: 2015-01-13
    Description: Evolutionarily conserved SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors) proteins form a complex that drives membrane fusion in eukaryotes. The ATPase NSF (N-ethylmaleimide sensitive factor), together with SNAPs (soluble NSF attachment protein), disassembles the SNARE complex into its protein components, making individual SNAREs available for subsequent rounds of fusion. Here we report structures of ATP- and ADP-bound NSF, and the NSF/SNAP/SNARE (20S) supercomplex determined by single-particle electron cryomicroscopy at near-atomic to sub-nanometre resolution without imposing symmetry. Large, potentially force-generating, conformational differences exist between ATP- and ADP-bound NSF. The 20S supercomplex exhibits broken symmetry, transitioning from six-fold symmetry of the NSF ATPase domains to pseudo four-fold symmetry of the SNARE complex. SNAPs interact with the SNARE complex with an opposite structural twist, suggesting an unwinding mechanism. The interfaces between NSF, SNAPs, and SNAREs exhibit characteristic electrostatic patterns, suggesting how one NSF/SNAP species can act on many different SNARE complexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320033/" 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/PMC4320033/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Minglei -- Wu, Shenping -- Zhou, Qiangjun -- Vivona, Sandro -- Cipriano, Daniel J -- Cheng, Yifan -- Brunger, Axel T -- 5-U01AI082051-05/AI/NIAID NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- P50GM082250/GM/NIGMS NIH HHS/ -- R01 GM082893/GM/NIGMS NIH HHS/ -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01GM082893/GM/NIGMS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- R37MH63105/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 5;518(7537):61-7. doi: 10.1038/nature14148. Epub 2015 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA. ; 1] Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Department of Structural Biology, Department of Photon Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25581794" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Cricetulus ; Cryoelectron Microscopy ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism/ultrastructure ; N-Ethylmaleimide-Sensitive Proteins/chemistry/metabolism/ultrastructure ; Protein Binding ; Protein Structure, Tertiary ; Rats ; SNARE Proteins/*chemistry/*metabolism/ultrastructure ; Soluble N-Ethylmaleimide-Sensitive Factor Attachment ; Proteins/chemistry/metabolism/ultrastructure
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  • 63
    Publication Date: 2015-04-16
    Description: Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409554/" 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/PMC4409554/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marlin, Bianca J -- Mitre, Mariela -- D'amour, James A -- Chao, Moses V -- Froemke, Robert C -- DC009635/DC/NIDCD NIH HHS/ -- DC12557/DC/NIDCD NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R00 DC009635/DC/NIDCD NIH HHS/ -- R01 DC012557/DC/NIDCD NIH HHS/ -- T32 MH019524/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 23;520(7548):499-504. doi: 10.1038/nature14402. Epub 2015 Apr 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [5] Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA [6] Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA [5] Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA [6] Center for Neural Science, New York University, New York, New York 10003, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [5] Center for Neural Science, New York University, New York, New York 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25874674" target="_blank"〉PubMed〈/a〉
    Keywords: Acoustic Stimulation ; Animals ; Animals, Newborn ; Auditory Cortex/cytology/*physiology ; Auditory Perception/physiology ; Evoked Potentials, Auditory ; Female ; Male ; Maternal Behavior/*physiology ; Mice ; Mice, Inbred C57BL ; Neural Inhibition/*physiology ; Neuronal Plasticity ; Oxytocin/*metabolism ; Receptors, Oxytocin/metabolism ; Sexual Abstinence ; Vocalization, Animal
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  • 64
    Publication Date: 2015-06-23
    Description: Although CRISPR-Cas9 nucleases are widely used for genome editing, the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM). As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome-editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis. In addition, we identify and characterize another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGA PAMs and/or mismatched spacers. We also find that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540238/" 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/PMC4540238/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinstiver, Benjamin P -- Prew, Michelle S -- Tsai, Shengdar Q -- Topkar, Ved V -- Nguyen, Nhu T -- Zheng, Zongli -- Gonzales, Andrew P W -- Li, Zhuyun -- Peterson, Randall T -- Yeh, Jing-Ruey Joanna -- Aryee, Martin J -- Joung, J Keith -- DP1 GM105378/DP/NCCDPHP CDC HHS/ -- DP1 GM105378/GM/NIGMS NIH HHS/ -- R01 GM088040/GM/NIGMS NIH HHS/ -- R01 GM107427/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 23;523(7561):481-5. doi: 10.1038/nature14592. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [3] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden. ; 1] Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Broad Institute, Cambridge, Massachusetts 02142, USA. ; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098369" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution/genetics ; Animals ; CRISPR-Associated Proteins/*genetics/*metabolism ; CRISPR-Cas Systems ; Cell Line ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; Directed Molecular Evolution ; Genome/genetics ; Humans ; Mutation/genetics ; *Nucleotide Motifs ; Protein Engineering/*methods ; Staphylococcus aureus/enzymology ; Streptococcus pyogenes/*enzymology ; Streptococcus thermophilus/enzymology ; Substrate Specificity/genetics ; Zebrafish/embryology/genetics
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  • 65
    Publication Date: 2015-10-06
    Description: Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713039/" 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/PMC4713039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Tien -- Frank, David B -- Kadzik, Rachel S -- Morley, Michael P -- Rathi, Komal S -- Wang, Tao -- Zhou, Su -- Cheng, Lan -- Lu, Min Min -- Morrisey, Edward E -- HL087825/HL/NHLBI NIH HHS/ -- HL100405/HL/NHLBI NIH HHS/ -- HL110942/HL/NHLBI NIH HHS/ -- K08-HL121146/HL/NHLBI NIH HHS/ -- R01 HL087825/HL/NHLBI NIH HHS/ -- T32 HL007915/HL/NHLBI NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- U01 HL110942/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Oct 22;526(7574):578-82. doi: 10.1038/nature14984. Epub 2015 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26436454" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Proliferation ; Down-Regulation ; Epithelial Cells/cytology/metabolism/pathology ; Feedback, Physiological ; Hedgehog Proteins/deficiency/genetics/*metabolism ; Homeostasis ; Lung/*cytology/*metabolism/pathology ; Lung Injury/*metabolism/*pathology ; Male ; Mesoderm/cytology/metabolism ; Mice ; Paracrine Communication ; *Regeneration ; *Wound Healing
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  • 66
    Publication Date: 2015-11-19
    Description: Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals. In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain. Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map, with each taste quality encoded by distinct cortical fields. Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal's internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712381/" 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/PMC4712381/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Yueqing -- Gillis-Smith, Sarah -- Jin, Hao -- Trankner, Dimitri -- Ryba, Nicholas J P -- Zuker, Charles S -- DA035025/DA/NIDA NIH HHS/ -- R01 DA035025/DA/NIDA NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):512-5. doi: 10.1038/nature15763. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Departments of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Neuroscience, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; HHMI/Janelia Farm Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA. ; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580015" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Appetitive Behavior/*physiology/radiation effects ; Avoidance Learning/*physiology/radiation effects ; Brain Mapping ; Cerebral Cortex/*cytology/*physiology/radiation effects ; Discrimination (Psychology)/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Optogenetics ; Stereotaxic Techniques ; Taste/*physiology ; Taste Perception/*physiology/radiation effects ; Wakefulness/*physiology
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  • 67
    Publication Date: 2015-10-20
    Description: Anaerobic ammonium oxidation (anammox) has a major role in the Earth's nitrogen cycle and is used in energy-efficient wastewater treatment. This bacterial process combines nitrite and ammonium to form dinitrogen (N2) gas, and has been estimated to synthesize up to 50% of the dinitrogen gas emitted into our atmosphere from the oceans. Strikingly, the anammox process relies on the highly unusual, extremely reactive intermediate hydrazine, a compound also used as a rocket fuel because of its high reducing power. So far, the enzymatic mechanism by which hydrazine is synthesized is unknown. Here we report the 2.7 A resolution crystal structure, as well as biophysical and spectroscopic studies, of a hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis. The structure shows an elongated dimer of heterotrimers, each of which has two unique c-type haem-containing active sites, as well as an interaction point for a redox partner. Furthermore, a system of tunnels connects these active sites. The crystal structure implies a two-step mechanism for hydrazine synthesis: a three-electron reduction of nitric oxide to hydroxylamine at the active site of the gamma-subunit and its subsequent condensation with ammonia, yielding hydrazine in the active centre of the alpha-subunit. Our results provide the first, to our knowledge, detailed structural insight into the mechanism of biological hydrazine synthesis, which is of major significance for our understanding of the conversion of nitrogenous compounds in nature.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dietl, Andreas -- Ferousi, Christina -- Maalcke, Wouter J -- Menzel, Andreas -- de Vries, Simon -- Keltjens, Jan T -- Jetten, Mike S M -- Kartal, Boran -- Barends, Thomas R M -- P41-GM103311/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):394-7. doi: 10.1038/nature15517. Epub 2015 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany. ; Department of Microbiology, Institute for Water and Wetland Research, Radboud University Nijmegen, 6525 AJ Nijmegen, The Netherlands. ; Swiss Light Source, Paul Scherrer Institute, 5232 Villigen, Switzerland. ; Department of Biotechnology, Delft University of Technology, Delft, The Netherlands. ; Department of Biochemistry and Microbiology, Laboratory of Microbiology, Gent University, Gent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26479033" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Hydrazines/*metabolism ; Hydroxylamine/metabolism ; Metalloproteins/chemistry/metabolism ; Models, Molecular ; Multienzyme Complexes/*chemistry/*metabolism ; Nitric Oxide/metabolism ; Protein Multimerization
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  • 68
    Publication Date: 2015-05-21
    Description: The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre-lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458138/" 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/PMC4458138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klotz, Linda -- Norman, Sophie -- Vieira, Joaquim Miguel -- Masters, Megan -- Rohling, Mala -- Dube, Karina N -- Bollini, Sveva -- Matsuzaki, Fumio -- Carr, Carolyn A -- Riley, Paul R -- CH/11/1/28798/British Heart Foundation/United Kingdom -- PG/13/34/30216/British Heart Foundation/United Kingdom -- RG/08/003/25264/British Heart Foundation/United Kingdom -- RM/13/3/30159/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 Jun 4;522(7554):62-7.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992544" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Endothelial Cells/cytology/metabolism ; Female ; Heart/physiology/physiopathology ; Homeodomain Proteins/metabolism ; *Lymphangiogenesis ; Lymphatic Vessels/*cytology/*injuries/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Myocardial Infarction/metabolism/physiopathology ; Myocardium/*cytology/metabolism ; Proto-Oncogene Proteins c-vav/metabolism ; Receptor, Macrophage Colony-Stimulating Factor/metabolism ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptor, TIE-2/metabolism ; Spatio-Temporal Analysis ; Tumor Suppressor Proteins/deficiency/metabolism ; Vascular Endothelial Growth Factor C/metabolism ; Veins/cytology ; Yolk Sac/cytology
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  • 69
    Publication Date: 2015-06-02
    Description: Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499021/" 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/PMC4499021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schultz, Matthew D -- He, Yupeng -- Whitaker, John W -- Hariharan, Manoj -- Mukamel, Eran A -- Leung, Danny -- Rajagopal, Nisha -- Nery, Joseph R -- Urich, Mark A -- Chen, Huaming -- Lin, Shin -- Lin, Yiing -- Jung, Inkyung -- Schmitt, Anthony D -- Selvaraj, Siddarth -- Ren, Bing -- Sejnowski, Terrence J -- Wang, Wei -- Ecker, Joseph R -- F32 HL110473/HL/NHLBI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- K99 HL119617/HL/NHLBI NIH HHS/ -- K99 NS080911/NS/NINDS NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- R00 NS080911/NS/NINDS NIH HHS/ -- R00NS080911/NS/NINDS NIH HHS/ -- R01 ES024984/ES/NIEHS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 9;523(7559):212-6. doi: 10.1038/nature14465. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA [2] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. ; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Department of Cognitive Science, University of California, San Diego, La Jolla, California 92037, USA. ; Ludwig Institute for Cancer Research, La Jolla, California 92093, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, M-344 Stanford, California 94305, USA. ; Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St Louis, Missouri 63110, USA. ; Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Ludwig Institute for Cancer Research, La Jolla, California 92093, USA [2] University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, La Jolla, California 92093, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037, USA [3] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030523" target="_blank"〉PubMed〈/a〉
    Keywords: Age Factors ; Alleles ; Chromosome Mapping ; *DNA Methylation ; *Epigenesis, Genetic ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Genetic Variation ; Humans ; Male ; Organ Specificity
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  • 70
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2015-08-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Veiseh, Omid -- Langer, Robert -- England -- Nature. 2015 Aug 6;524(7563):39-40. doi: 10.1038/524039a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, and at the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA, and in the Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245577" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Glucose/*analysis ; Diabetes Mellitus, Experimental/*drug therapy ; Diabetes Mellitus, Type 1/*drug therapy ; Drug Delivery Systems/*methods ; Humans ; Insulin/*administration & dosage ; Male
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  • 71
    Publication Date: 2015-11-13
    Description: Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT). Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2, 3, 7-10). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear, and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Xiaofeng -- Carstens, Julienne L -- Kim, Jiha -- Scheible, Matthew -- Kaye, Judith -- Sugimoto, Hikaru -- Wu, Chia-Chin -- LeBleu, Valerie S -- Kalluri, Raghu -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA16672/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):525-30. doi: 10.1038/nature16064. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Bioengineering, Rice University, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560028" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/metabolism/pathology ; Animals ; Carcinoma, Pancreatic Ductal/drug therapy/metabolism/pathology ; Cell Proliferation/drug effects ; Deoxycytidine/analogs & derivatives/pharmacology/therapeutic use ; Disease Models, Animal ; Disease Progression ; Drug Resistance, Neoplasm/*drug effects ; *Epithelial-Mesenchymal Transition ; Female ; Male ; Mice ; Neoplasm Invasiveness/pathology ; Neoplasm Metastasis/*pathology ; Nucleoside Transport Proteins/metabolism ; Pancreatic Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Survival Analysis ; Transcription Factors/deficiency/genetics/metabolism ; Twist Transcription Factor/deficiency/genetics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 72
    Publication Date: 2015-01-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knott, Graham -- England -- Nature. 2015 Feb 12;518(7538):177-8. doi: 10.1038/nature14195. Epub 2015 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Life Sciences, EPFL, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25607369" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cold Temperature ; Cold-Shock Response/*physiology ; Male ; Neurodegenerative Diseases/*metabolism/*pathology ; *Neuronal Plasticity ; *Neuroprotective Agents ; RNA-Binding Proteins/*metabolism ; Synapses/*metabolism
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  • 73
    Publication Date: 2015-01-21
    Description: Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM(+)) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM(+) neurons in the CeL, and stimulation of PVT afferents facilitated SOM(+) neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM(+) CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM(+) CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376633/" 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/PMC4376633/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penzo, Mario A -- Robert, Vincent -- Tucciarone, Jason -- De Bundel, Dimitri -- Wang, Minghui -- Van Aelst, Linda -- Darvas, Martin -- Parada, Luis F -- Palmiter, Richard D -- He, Miao -- Huang, Z Josh -- Li, Bo -- R01 MH082808/MH/NIMH NIH HHS/ -- R01 MH094705/MH/NIMH NIH HHS/ -- R01 MH101214/MH/NIMH NIH HHS/ -- R01 NS082266/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 26;519(7544):455-9. doi: 10.1038/nature13978. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Ecole Normale Superieure de Cachan, 94230 Cachan, France. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Medical Scientist Training Program &Program in Neuroscience, Stony Brook University, Stony Brook, New York 11790, USA. ; CNRS, UMR-5203, INSERM U661, Institut de Genomique Fonctionnelle, 34090 Montpellier, France. ; Department of Pathology, University of Washington, Seattle, Washington 98104, USA. ; Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Howard Hughes Medical Institute; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600269" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Central Amygdaloid Nucleus/cytology/*physiology ; Conditioning (Psychology)/physiology ; Fear/*physiology/psychology ; Female ; Male ; Memory/physiology ; Mice ; Neural Pathways/cytology/*physiology ; Neuronal Plasticity ; Neurons/metabolism ; Receptor, trkB/metabolism ; Somatostatin/metabolism ; Thalamus/cytology/*physiology ; Time Factors
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  • 74
    Publication Date: 2015-10-13
    Description: The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine (m(6)A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m(6)A along mRNAs results in relatively less methylation in the 5' untranslated region (5'UTR) compared to other regions. However, whether and how 5'UTR methylation is regulated is poorly understood. Despite the crucial role of the 5'UTR in translation initiation, very little is known about whether m(6)A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5'UTR of newly transcribed mRNAs are preferentially methylated. We find that the dynamic 5'UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m(6)A 'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5'UTR methylation of stress-induced transcripts by limiting the m(6)A 'eraser' FTO from demethylation. Remarkably, the increased 5'UTR methylation in the form of m(6)A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m(6)A modification site in the 5'UTR enables translation initiation independent of the 5' end N(7)-methylguanosine cap. The elucidation of the dynamic features of 5'UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m(6)A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Jun -- Wan, Ji -- Gao, Xiangwei -- Zhang, Xingqian -- Jaffrey, Samie R -- Qian, Shu-Bing -- DA037150/DA/NIDA NIH HHS/ -- DP2OD006449/OD/NIH HHS/ -- R01AG042400/AG/NIA NIH HHS/ -- England -- Nature. 2015 Oct 22;526(7574):591-4. doi: 10.1038/nature15377. Epub 2015 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA. ; Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York City, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26458103" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Adenosine/*analogs & derivatives/metabolism ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Fibroblasts/cytology/metabolism ; *Gene Expression Regulation ; HSP70 Heat-Shock Proteins/genetics ; *Heat-Shock Response/genetics ; *Methylation ; Mice ; Mixed Function Oxygenases/antagonists & inhibitors/metabolism ; Oxo-Acid-Lyases/antagonists & inhibitors/metabolism ; *Peptide Chain Initiation, Translational ; RNA Caps/metabolism ; RNA, Messenger/genetics/*metabolism ; RNA-Binding Proteins/metabolism ; Transcription, Genetic/genetics
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  • 75
    Publication Date: 2015-02-25
    Description: Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide alpha-melanocyte-stimulating hormone, and the opioid peptide beta-endorphin. CB1R activation selectively increases beta-endorphin but not alpha-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496586/" 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/PMC4496586/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koch, Marco -- Varela, Luis -- Kim, Jae Geun -- Kim, Jung Dae -- Hernandez-Nuno, Francisco -- Simonds, Stephanie E -- Castorena, Carlos M -- Vianna, Claudia R -- Elmquist, Joel K -- Morozov, Yury M -- Rakic, Pasko -- Bechmann, Ingo -- Cowley, Michael A -- Szigeti-Buck, Klara -- Dietrich, Marcelo O -- Gao, Xiao-Bing -- Diano, Sabrina -- Horvath, Tamas L -- DP1 DK098058/DK/NIDDK NIH HHS/ -- DP1DK098058/DK/NIDDK NIH HHS/ -- P01 NS062686/NS/NINDS NIH HHS/ -- R01 AG040236/AG/NIA NIH HHS/ -- R01 DA023999/DA/NIDA NIH HHS/ -- R01AG040236/AG/NIA NIH HHS/ -- R01DK097566/DK/NIDDK NIH HHS/ -- R37 DK053301/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Mar 5;519(7541):45-50. doi: 10.1038/nature14260. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany. ; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Obesity &Diabetes Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. ; Division of Endocrinology &Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707796" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cannabinoids/*pharmacology ; Eating/*drug effects/*physiology ; Energy Metabolism/drug effects ; Hypothalamus/*cytology/drug effects/physiology ; Ion Channels/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/metabolism ; Mitochondrial Proteins/metabolism ; Naloxone/pharmacology ; Neurons/*drug effects/*metabolism ; Pro-Opiomelanocortin/*metabolism ; Receptor, Cannabinoid, CB1/agonists/metabolism ; Satiety Response/drug effects/physiology ; alpha-MSH/secretion ; beta-Endorphin/metabolism
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  • 76
    Publication Date: 2015-01-28
    Description: Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401560/" 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/PMC4401560/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marsolier, J -- Perichon, M -- DeBarry, J D -- Villoutreix, B O -- Chluba, J -- Lopez, T -- Garrido, C -- Zhou, X Z -- Lu, K P -- Fritsch, L -- Ait-Si-Ali, S -- Mhadhbi, M -- Medjkane, S -- Weitzman, J B -- 08-0111/Worldwide Cancer Research/United Kingdom -- R01 CA167677/CA/NCI NIH HHS/ -- R01CA167677/CA/NCI NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):378-82. doi: 10.1038/nature14044. Epub 2015 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Paris Diderot, Sorbonne Paris Cite, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France. ; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA. ; Universite Paris Diderot, Sorbonne Paris Cite, Molecules Therapeutiques in silico, INSERM UMR-S 973, 75013 Paris, France. ; 1] INSERM, UMR 866, Equipe labellisee Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, 21000 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 21000 Dijon, France. ; 1] INSERM, UMR 866, Equipe labellisee Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, 21000 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 21000 Dijon, France [3] Centre anticancereux George Francois Leclerc, CGFL, 21000 Dijon, France. ; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Laboratoire de Parasitologie, Ecole Nationale de Medecine Veterinaire, Universite de la Manouba, 2020 Sidi Thabet, Tunisia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25624101" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cattle ; Cell Line ; *Cell Transformation, Neoplastic/drug effects ; Drug Resistance/genetics ; *Host-Parasite Interactions ; Humans ; Leukocytes/drug effects/parasitology/*pathology ; Naphthoquinones/pharmacology ; Parasites/drug effects/enzymology/pathogenicity ; Peptidylprolyl Isomerase/antagonists & inhibitors/genetics/*metabolism/*secretion ; Protein Stability ; Proto-Oncogene Proteins c-jun/metabolism ; SKP Cullin F-Box Protein Ligases/metabolism ; Signal Transduction/drug effects ; Theileria/drug effects/*enzymology/genetics/*pathogenicity ; Transcription Factor AP-1/metabolism ; Ubiquitination ; Xenograft Model Antitumor Assays ; Zebrafish/embryology
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  • 77
    Publication Date: 2015-07-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marteau, Theresa M -- Mantzari, Eleni -- England -- Nature. 2015 Jul 2;523(7558):40-1. doi: 10.1038/523040a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Behaviour and Health Research Unit, University of Cambridge, Cambridge CB2 0SR, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135443" target="_blank"〉PubMed〈/a〉
    Keywords: Female ; Humans ; Male ; *Reward ; Smoking Cessation/*methods
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  • 78
    Publication Date: 2015-08-19
    Description: Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca(2+)- and Mg(2+)-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca(2+)-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca(2+)-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca(2+)-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca(2+) triggering, moves en bloc as Ca(2+) influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607316/" 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/PMC4607316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Qiangjun -- Lai, Ying -- Bacaj, Taulant -- Zhao, Minglei -- Lyubimov, Artem Y -- Uervirojnangkoorn, Monarin -- Zeldin, Oliver B -- Brewster, Aaron S -- Sauter, Nicholas K -- Cohen, Aina E -- Soltis, S Michael -- Alonso-Mori, Roberto -- Chollet, Matthieu -- Lemke, Henrik T -- Pfuetzner, Richard A -- Choi, Ucheor B -- Weis, William I -- Diao, Jiajie -- Sudhof, Thomas C -- Brunger, Axel T -- GM095887/GM/NIGMS NIH HHS/ -- GM102520/GM/NIGMS NIH HHS/ -- MH086403/MH/NIMH NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P50 MH086403/MH/NIMH NIH HHS/ -- R01 GM077071/GM/NIGMS NIH HHS/ -- R01 GM095887/GM/NIGMS NIH HHS/ -- R01 GM102520/GM/NIGMS NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- R37MH63105/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):62-7. doi: 10.1038/nature14975. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology, Stanford University, Stanford, California 94305, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; SLAC National Accelerator Laboratory, Stanford, California 94305, USA. ; Departments of Structural Biology, Molecular and Cellular Physiology, and Photon Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280336" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites/genetics ; Calcium/chemistry/metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Electrons ; *Exocytosis ; Hippocampus/cytology ; Lasers ; Magnesium/chemistry/metabolism ; Membrane Fusion ; Mice ; Models, Biological ; Models, Molecular ; Mutation/genetics ; Neurons/chemistry/cytology/*metabolism/secretion ; SNARE Proteins/*chemistry/genetics/*metabolism ; Synaptic Transmission ; Synaptic Vesicles/chemistry/metabolism/secretion ; Synaptotagmins/*chemistry/genetics/*metabolism
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  • 79
    facet.materialart.
    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yingying -- England -- Nature. 2015 Dec 17;528(7582):S170-3. doi: 10.1038/528S170a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26673023" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Science Disciplines ; Chemistry ; China ; Diffusion of Innovation ; Ecology ; Economic Recession ; Humans ; International Cooperation ; Nobel Prize ; Physics ; Research/economics/manpower/standards/*statistics & numerical data ; Research Personnel/education/standards/supply & distribution ; Time Factors
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  • 80
    Publication Date: 2015-08-13
    Description: The flipping of membrane-embedded lipids containing large, polar head groups is slow and energetically unfavourable, and is therefore catalysed by flippases, the mechanisms of which are unknown. A prominent example of a flipping reaction is the translocation of lipid-linked oligosaccharides that serve as donors in N-linked protein glycosylation. In Campylobacter jejuni, this process is catalysed by the ABC transporter PglK. Here we present a mechanism of PglK-catalysed lipid-linked oligosaccharide flipping based on crystal structures in distinct states, a newly devised in vitro flipping assay, and in vivo studies. PglK can adopt inward- and outward-facing conformations in vitro, but only outward-facing states are required for flipping. While the pyrophosphate-oligosaccharide head group of lipid-linked oligosaccharides enters the translocation cavity and interacts with positively charged side chains, the lipidic polyprenyl tail binds and activates the transporter but remains exposed to the lipid bilayer during the reaction. The proposed mechanism is distinct from the classical alternating-access model applied to other transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez, Camilo -- Gerber, Sabina -- Boilevin, Jeremy -- Bucher, Monika -- Darbre, Tamis -- Aebi, Markus -- Reymond, Jean-Louis -- Locher, Kaspar P -- England -- Nature. 2015 Aug 27;524(7566):433-8. doi: 10.1038/nature14953. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland. ; Department of Chemistry and Biochemistry, University of Berne, CH-3012 Berne, Switzerland. ; Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266984" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/*metabolism ; Adenosine Triphosphatases/chemistry/metabolism ; Adenosine Triphosphate/metabolism ; *Biocatalysis ; Campylobacter jejuni/cytology/*enzymology/metabolism ; Crystallography, X-Ray ; Hydrolysis ; Lipid Bilayers/metabolism ; Lipopolysaccharides/*metabolism ; Models, Molecular ; Protein Conformation ; Structure-Activity Relationship
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  • 81
    Publication Date: 2015-01-22
    Description: In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity. Reduction in synapse number is a consistent early feature of neurodegenerative diseases, suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders, how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338605/" 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/PMC4338605/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peretti, Diego -- Bastide, Amandine -- Radford, Helois -- Verity, Nicholas -- Molloy, Colin -- Martin, Maria Guerra -- Moreno, Julie A -- Steinert, Joern R -- Smith, Tim -- Dinsdale, David -- Willis, Anne E -- Mallucci, Giovanna R -- MC_U132692719/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Feb 12;518(7538):236-9. doi: 10.1038/nature14142. Epub 2015 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK. ; 1] Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK [2] Department of Clinical Neurosciences, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25607368" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism ; Animals ; Cold Shock Proteins and Peptides/metabolism ; *Cold Temperature ; Cold-Shock Response/*physiology ; Disease Models, Animal ; Hibernation/physiology ; Hippocampus/metabolism ; Male ; Mice ; Neurodegenerative Diseases/*metabolism/*pathology ; *Neuronal Plasticity ; *Neuroprotective Agents ; Prions/physiology ; RNA-Binding Proteins/genetics/*metabolism ; Regeneration ; Synapses/*metabolism
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  • 82
    Publication Date: 2015-09-17
    Description: It is commonly assumed, but has rarely been demonstrated, that sex differences in behaviour arise from sexual dimorphism in the underlying neural circuits. Parental care is a complex stereotypic behaviour towards offspring that is shared by numerous species. Mice display profound sex differences in offspring-directed behaviours. At their first encounter, virgin females behave maternally towards alien pups while males will usually ignore the pups or attack them. Here we show that tyrosine hydroxylase (TH)-expressing neurons in the anteroventral periventricular nucleus (AVPV) of the mouse hypothalamus are more numerous in mothers than in virgin females and males, and govern parental behaviours in a sex-specific manner. In females, ablating the AVPV TH(+) neurons impairs maternal behaviour whereas optogenetic stimulation or increased TH expression in these cells enhance maternal care. In males, however, this same neuronal cluster has no effect on parental care but rather suppresses inter-male aggression. Furthermore, optogenetic activation or increased TH expression in the AVPV TH(+) neurons of female mice increases circulating oxytocin, whereas their ablation reduces oxytocin levels. Finally, we show that AVPV TH(+) neurons relay a monosynaptic input to oxytocin-expressing neurons in the paraventricular nucleus. Our findings uncover a previously unknown role for this neuronal population in the control of maternal care and oxytocin secretion, and provide evidence for a causal relationship between sexual dimorphism in the adult brain and sex differences in parental behaviour.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scott, Niv -- Prigge, Matthias -- Yizhar, Ofer -- Kimchi, Tali -- England -- Nature. 2015 Sep 24;525(7570):519-22. doi: 10.1038/nature15378. Epub 2015 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26375004" target="_blank"〉PubMed〈/a〉
    Keywords: Aggression ; Animals ; Anterior Hypothalamic Nucleus/cytology/enzymology/physiology ; Dopaminergic Neurons/enzymology/metabolism ; Female ; Hypothalamus/*cytology/enzymology/*physiology ; Male ; Maternal Behavior/*physiology ; Mice ; Oxytocin/blood/*secretion ; Paraventricular Hypothalamic Nucleus/cytology/enzymology/physiology ; Postpartum Period ; *Sex Characteristics ; Synapses/metabolism ; Tyrosine 3-Monooxygenase/metabolism
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  • 83
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2015-03-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Mar 26;519(7544):397-8. doi: 10.1038/519397a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25810182" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Autopsy ; Case-Control Studies ; Diabetes Mellitus/*genetics/*pathology/veterinary ; *Disease Models, Animal ; Female ; Genetic Engineering ; Germany ; Humans ; Male ; Mice ; Sus scrofa/*genetics ; *Tissue Banks
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  • 84
    Publication Date: 2015-09-04
    Description: TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568559/" 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/PMC4568559/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Jiajun -- Sammons, Morgan A -- Donahue, Greg -- Dou, Zhixun -- Vedadi, Masoud -- Getlik, Matthaus -- Barsyte-Lovejoy, Dalia -- Al-awar, Rima -- Katona, Bryson W -- Shilatifard, Ali -- Huang, Jing -- Hua, Xianxin -- Arrowsmith, Cheryl H -- Berger, Shelley L -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- P30 ES013508/ES/NIEHS NIH HHS/ -- R01 CA078831/CA/NCI NIH HHS/ -- R01 GM069905/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 10;525(7568):206-11. doi: 10.1038/nature15251. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada. ; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. ; Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, Illinois 60611, USA. ; Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331536" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chromatin/chemistry/*genetics/*metabolism ; Female ; Genes, Tumor Suppressor ; Genome, Human/genetics ; Histone Acetyltransferases/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/metabolism ; Humans ; Male ; Mice ; Mutant Proteins/genetics/metabolism ; Mutation/*genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Neoplasms/*genetics/metabolism/*pathology ; Phenotype ; Protein Binding ; Protein Processing, Post-Translational ; Tumor Suppressor Protein p53/*genetics/*metabolism
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  • 85
    Publication Date: 2015-07-16
    Description: Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718588/" 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/PMC4718588/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kondo, Asami -- Shahpasand, Koorosh -- Mannix, Rebekah -- Qiu, Jianhua -- Moncaster, Juliet -- Chen, Chun-Hau -- Yao, Yandan -- Lin, Yu-Min -- Driver, Jane A -- Sun, Yan -- Wei, Shuo -- Luo, Man-Li -- Albayram, Onder -- Huang, Pengyu -- Rotenberg, Alexander -- Ryo, Akihide -- Goldstein, Lee E -- Pascual-Leone, Alvaro -- McKee, Ann C -- Meehan, William -- Zhou, Xiao Zhen -- Lu, Kun Ping -- P30 AG013846/AG/NIA NIH HHS/ -- P30AG13846/AG/NIA NIH HHS/ -- R01AG029385/AG/NIA NIH HHS/ -- R01AG046319/AG/NIA NIH HHS/ -- R01CA167677/CA/NCI NIH HHS/ -- R01HL111430/HL/NHLBI NIH HHS/ -- S10RR017927/RR/NCRR NIH HHS/ -- T32HD040128/HD/NICHD NIH HHS/ -- U01 NS086659/NS/NINDS NIH HHS/ -- U01NS086659-01/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Jul 23;523(7561):431-6. doi: 10.1038/nature14658. Epub 2015 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Emergency Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Alzheimer's Disease Center, CTE Program, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02130, USA. ; Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan. ; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Micheli Center for Sports Injury Prevention, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26176913" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/complications/prevention & control ; Animals ; Antibodies, Monoclonal/*immunology/*pharmacology/therapeutic use ; Antibody Affinity ; Axons/metabolism/pathology ; Brain/metabolism/pathology ; Brain Injuries/complications/metabolism/*pathology/*prevention & control ; Disease Models, Animal ; Epitopes/chemistry/immunology ; Female ; Humans ; Male ; Mice ; Phosphoproteins/antagonists & inhibitors/biosynthesis/immunology/toxicity ; Stress, Physiological ; Tauopathies/complications/metabolism/pathology/*prevention & control ; tau Proteins/*antagonists & ; inhibitors/biosynthesis/*chemistry/immunology/toxicity
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  • 86
    Publication Date: 2015-04-22
    Description: Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome. The most recently acquired human ERV is HERVK(HML-2), which repeatedly infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor. Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins. However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection. Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503379/" 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/PMC4503379/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grow, Edward J -- Flynn, Ryan A -- Chavez, Shawn L -- Bayless, Nicholas L -- Wossidlo, Mark -- Wesche, Daniel J -- Martin, Lance -- Ware, Carol B -- Blish, Catherine A -- Chang, Howard Y -- Pera, Renee A Reijo -- Wysocka, Joanna -- 1F30CA189514-01/CA/NCI NIH HHS/ -- 1S10RR02678001/RR/NCRR NIH HHS/ -- 1S10RR02933801/RR/NCRR NIH HHS/ -- DP2 AI112193/AI/NIAID NIH HHS/ -- DP2AI11219301/AI/NIAID NIH HHS/ -- F30 CA189514/CA/NCI NIH HHS/ -- P01GM099130/GM/NIGMS NIH HHS/ -- P50-HG007735/HG/NHGRI NIH HHS/ -- R01 GM112720/GM/NIGMS NIH HHS/ -- T32 HG000044/HG/NHGRI NIH HHS/ -- U01 HL100397/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 11;522(7555):221-5. doi: 10.1038/nature14308. Epub 2015 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. ; Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [2] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, Beaverton, Oregon 97006, USA. ; Stanford Immunology, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA. ; Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA. ; Department of Comparative Medicine, University of Washington, Seattle, Washington 98195-8056, USA. ; Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [4] Department of Cell Biology and Neurosciences, Montana State University, Bozeman, Montana 59717, USA. ; 1] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [2] Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA [3] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25896322" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Differentiation/metabolism ; Blastocyst/cytology/metabolism/*virology ; Cell Line ; DNA Methylation ; Endogenous Retroviruses/genetics/*metabolism ; Female ; Gene Products, gag/metabolism ; Humans ; Male ; Octamer Transcription Factor-3/metabolism ; Open Reading Frames/genetics ; Pluripotent Stem Cells/cytology/metabolism/*virology ; RNA, Messenger/genetics/metabolism ; Ribosomes/genetics/metabolism ; Terminal Repeat Sequences/genetics ; Transcription, Genetic/genetics ; Transcriptional Activation ; Viral Envelope Proteins/genetics/metabolism ; *Virus Activation
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  • 87
    Publication Date: 2015-01-21
    Description: Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376623/" 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/PMC4376623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Do-Monte, Fabricio H -- Quinones-Laracuente, Kelvin -- Quirk, Gregory J -- G12 MD007600/MD/NIMHD NIH HHS/ -- K99 MH105549/MH/NIMH NIH HHS/ -- P50 MH086400/MH/NIMH NIH HHS/ -- P50-MH086400/MH/NIMH NIH HHS/ -- R01-MH058883/MH/NIMH NIH HHS/ -- R25 GM061838/GM/NIGMS NIH HHS/ -- R25-GM061838/GM/NIGMS NIH HHS/ -- R37 MH058883/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Mar 26;519(7544):460-3. doi: 10.1038/nature14030. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Psychiatry, University of Puerto Rico School of Medicine, PO Box 365067, San Juan 00936, Puerto Rico [2] Department of Anatomy &Neurobiology, University of Puerto Rico School of Medicine, P.O. Box 365067, San Juan 00936, Puerto Rico.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600268" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/cytology/physiology ; Animals ; Conditioning (Psychology)/physiology ; Fear/*physiology ; Male ; Memory/*physiology ; Neural Pathways/cytology/*physiology ; Neurons/physiology ; Optogenetics ; Prefrontal Cortex/cytology/physiology ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Rats, Sprague-Dawley ; Thalamus/cytology/physiology ; Time Factors
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  • 88
    facet.materialart.
    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2015-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Feb 5;518(7537):24-6. doi: 10.1038/518024a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nature's senior European correspondent.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652979" target="_blank"〉PubMed〈/a〉
    Keywords: Brain/blood supply/embryology/*growth & development/*physiology ; Cognition/physiology ; Cognition Disorders/genetics/*physiopathology/psychology ; Erythropoietin/metabolism/therapeutic use ; Genetic Testing ; Humans ; Infant, Newborn ; Infant, Premature/growth & development/*physiology/*psychology ; Magnetic Resonance Imaging ; Male ; Randomized Controlled Trials as Topic
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  • 89
    facet.materialart.
    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2015-01-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scudellari, Megan -- England -- Nature. 2015 Jan 22;517(7535):426-9. doi: 10.1038/517426a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25612035" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*blood ; Alzheimer Disease/blood/therapy ; Animals ; Blood Component Removal ; Blood Transfusion ; Bone Morphogenetic Proteins/pharmacology ; Caloric Restriction ; Clinical Trials as Topic ; Female ; Geriatrics/*methods ; Growth Differentiation Factors/pharmacology ; Humans ; Longevity/drug effects ; Male ; Memory/drug effects ; Mice ; Myoblasts, Skeletal/cytology/drug effects ; Neuronal Plasticity/drug effects ; Neurons/cytology/drug effects ; Oxytocin/metabolism/pharmacology ; Plasma/chemistry/physiology ; Rats ; Rejuvenation/*physiology ; Sirolimus/adverse effects/pharmacology
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  • 90
    Publication Date: 2015-07-16
    Description: Recent studies into the global causes of severe diarrhoea in young children have identified the protozoan parasite Cryptosporidium as the second most important diarrhoeal pathogen after rotavirus. Diarrhoeal disease is estimated to be responsible for 10.5% of overall child mortality. Cryptosporidium is also an opportunistic pathogen in the contexts of human immunodeficiency virus (HIV)-caused AIDS and organ transplantation. There is no vaccine and only a single approved drug that provides no benefit for those in gravest danger: malnourished children and immunocompromised patients. Cryptosporidiosis drug and vaccine development is limited by the poor tractability of the parasite, which includes a lack of systems for continuous culture, facile animal models, and molecular genetic tools. Here we describe an experimental framework to genetically modify this important human pathogen. We established and optimized transfection of C. parvum sporozoites in tissue culture. To isolate stable transgenics we developed a mouse model that delivers sporozoites directly into the intestine, a Cryptosporidium clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, and in vivo selection for aminoglycoside resistance. We derived reporter parasites suitable for in vitro and in vivo drug screening, and we evaluated the basis of drug susceptibility by gene knockout. We anticipate that the ability to genetically engineer this parasite will be transformative for Cryptosporidium research. Genetic reporters will provide quantitative correlates for disease, cure and protection, and the role of parasite genes in these processes is now open to rigorous investigation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640681/" 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/PMC4640681/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vinayak, Sumiti -- Pawlowic, Mattie C -- Sateriale, Adam -- Brooks, Carrie F -- Studstill, Caleb J -- Bar-Peled, Yael -- Cipriano, Michael J -- Striepen, Boris -- R01 AI112427/AI/NIAID NIH HHS/ -- R01AI112427/AI/NIAID NIH HHS/ -- T32 AI060546/AI/NIAID NIH HHS/ -- T32AI060546/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jul 23;523(7561):477-80. doi: 10.1038/nature14651. Epub 2015 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Tropical and Emerging Global Diseases, University of Georgia, Paul D. Coverdell Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, USA. ; 1] Center for Tropical and Emerging Global Diseases, University of Georgia, Paul D. Coverdell Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, USA [2] Department of Cellular Biology, University of Georgia, Paul D. Coverdell Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26176919" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoglycosides/pharmacology ; Animals ; Antimalarials/pharmacology ; CRISPR-Cas Systems ; Cell Line ; Cryptosporidiosis/complications/*parasitology ; Cryptosporidium parvum/enzymology/*genetics/growth & development ; Diarrhea/complications/*parasitology ; Drug Evaluation, Preclinical ; Drug Resistance ; Female ; Gene Deletion ; Gene Knockout Techniques ; Genes, Reporter ; Genetic Engineering/*methods ; Humans ; Intestines/parasitology ; Mice ; Models, Animal ; Sporozoites ; Thymidine Kinase/deficiency/genetics ; Transfection/methods ; Trimethoprim/pharmacology
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  • 91
    Publication Date: 2015-09-30
    Description: Haematopoietic stem cells (HSCs) reside in a perivascular niche but the specific location of this niche remains controversial. HSCs are rare and few can be found in thin tissue sections or upon live imaging, making it difficult to comprehensively localize dividing and non-dividing HSCs. Here, using a green fluorescent protein (GFP) knock-in for the gene Ctnnal1 in mice (hereafter denoted as alpha-catulin(GFP)), we discover that alpha-catulin(GFP) is expressed by only 0.02% of bone marrow haematopoietic cells, including almost all HSCs. We find that approximately 30% of alpha-catulin-GFP(+)c-kit(+) cells give long-term multilineage reconstitution of irradiated mice, indicating that alpha-catulin-GFP(+)c-kit(+) cells are comparable in HSC purity to cells obtained using the best markers currently available. We optically cleared the bone marrow to perform deep confocal imaging, allowing us to image thousands of alpha-catulin-GFP(+)c-kit(+) cells and to digitally reconstruct large segments of bone marrow. The distribution of alpha-catulin-GFP(+)c-kit(+) cells indicated that HSCs were more common in central marrow than near bone surfaces, and in the diaphysis relative to the metaphysis. Nearly all HSCs contacted leptin receptor positive (Lepr(+)) and Cxcl12(high) niche cells, and approximately 85% of HSCs were within 10 mum of a sinusoidal blood vessel. Most HSCs, both dividing (Ki-67(+)) and non-dividing (Ki-67(-)), were distant from arterioles, transition zone vessels, and bone surfaces. Dividing and non-dividing HSCs thus reside mainly in perisinusoidal niches with Lepr(+)Cxcl12(high) cells throughout the bone marrow.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Acar, Melih -- Kocherlakota, Kiranmai S -- Murphy, Malea M -- Peyer, James G -- Oguro, Hideyuki -- Inra, Christopher N -- Jaiyeola, Christabel -- Zhao, Zhiyu -- Luby-Phelps, Katherine -- Morrison, Sean J -- HL097760/HL/NHLBI NIH HHS/ -- R01 DK100848/DK/NIDDK NIH HHS/ -- S10 RR029731/RR/NCRR NIH HHS/ -- S10RR029731/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Oct 1;526(7571):126-30. doi: 10.1038/nature15250. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416744" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arterioles/metabolism ; Biomarkers/analysis/metabolism ; Bone Marrow/*anatomy & histology ; Cell Division ; Cell Lineage ; Chemokine CXCL12/metabolism ; Diaphyses/cytology/metabolism ; Female ; Hematopoietic Stem Cells/cytology/*metabolism ; Image Processing, Computer-Assisted ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; *Molecular Imaging ; Proto-Oncogene Proteins c-kit/metabolism ; Receptors, Leptin/metabolism ; Stem Cell Niche ; Tibia/anatomy & histology/blood supply/cytology ; alpha Catenin/analysis/metabolism
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  • 92
    Publication Date: 2015-06-11
    Description: Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome. How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location +/-3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530500/" 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/PMC4530500/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maskell, Daniel P -- Renault, Ludovic -- Serrao, Erik -- Lesbats, Paul -- Matadeen, Rishi -- Hare, Stephen -- Lindemann, Dirk -- Engelman, Alan N -- Costa, Alessandro -- Cherepanov, Peter -- P50 GM082251-06/GM/NIGMS NIH HHS/ -- R01 AI070042/AI/NIAID NIH HHS/ -- R01 AI070042-08/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):366-9. doi: 10.1038/nature14495. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK. ; 1] Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] National Institute for Biological Standards and Control, Microscopy and Imaging, Blanche Lane, South Mimms EN6 3QG, UK. ; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. ; NeCEN, Gorlaeus Laboratory, Einsteinweg 55, Leiden, 2333, the Netherlands. ; Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK. ; Institute of Virology, Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. ; Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK. ; 1] Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061770" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Binding Sites/genetics ; Cryoelectron Microscopy ; DNA/genetics/metabolism/ultrastructure ; Genome/genetics ; Histones/chemistry/metabolism/ultrastructure ; Integrases/metabolism ; Models, Molecular ; Nucleosomes/*chemistry/genetics/ultrastructure/*virology ; Protein Multimerization ; Recombination, Genetic ; Spumavirus/chemistry/genetics/*metabolism/ultrastructure ; *Virus Integration
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  • 93
    Publication Date: 2015-04-02
    Description: Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413032/" 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/PMC4413032/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gundem, Gunes -- Van Loo, Peter -- Kremeyer, Barbara -- Alexandrov, Ludmil B -- Tubio, Jose M C -- Papaemmanuil, Elli -- Brewer, Daniel S -- Kallio, Heini M L -- Hognas, Gunilla -- Annala, Matti -- Kivinummi, Kati -- Goody, Victoria -- Latimer, Calli -- O'Meara, Sarah -- Dawson, Kevin J -- Isaacs, William -- Emmert-Buck, Michael R -- Nykter, Matti -- Foster, Christopher -- Kote-Jarai, Zsofia -- Easton, Douglas -- Whitaker, Hayley C -- ICGC Prostate UK Group -- Neal, David E -- Cooper, Colin S -- Eeles, Rosalind A -- Visakorpi, Tapio -- Campbell, Peter J -- McDermott, Ultan -- Wedge, David C -- Bova, G Steven -- 077012/Wellcome Trust/United Kingdom -- A12758/Cancer Research UK/United Kingdom -- A14835/Cancer Research UK/United Kingdom -- CA92234/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):353-7. doi: 10.1038/nature14347. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium [3] Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; 1] Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK [2] The Genome Analysis Centre, Norwich NR4 7UH, UK. ; Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere FI-33520, Finland. ; The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA. ; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Maryland 20892, USA. ; University of Liverpool and HCA Pathology Laboratories, London WC1E 6JA, UK. ; Division of Genetics and Epidemiology, The Institute Of Cancer Research, London SW7 3RP, UK. ; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK. ; Uro-oncology Research Group, Cancer Research UK Cambridge Institute, Cambridge CB2 0RE, UK. ; 1] Uro-oncology Research Group, Cancer Research UK Cambridge Institute, Cambridge CB2 0RE, UK [2] Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. ; 1] Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK [2] Division of Genetics and Epidemiology, The Institute Of Cancer Research, London SW7 3RP, UK. ; 1] Division of Genetics and Epidemiology, The Institute Of Cancer Research, London SW7 3RP, UK [2] Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; and Sutton SM2 5PT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830880" target="_blank"〉PubMed〈/a〉
    Keywords: Androgens/deficiency ; *Cell Lineage/genetics ; Clone Cells/metabolism/pathology ; DNA Mutational Analysis ; Disease Progression ; Epigenesis, Genetic ; Genes, Tumor Suppressor ; Humans ; Male ; Neoplasm Metastasis/genetics/*pathology ; Prostatic Neoplasms/genetics/metabolism/*pathology ; Receptors, Androgen/metabolism ; Signal Transduction/genetics
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  • 94
    Publication Date: 2015-08-27
    Description: Methane-oxidizing bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase. Certain methanotrophs are also able to switch to using the iron-containing soluble methane monooxygenase to catalyse methane oxidation, with this switchover regulated by copper. Methane monooxygenases are nature's primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and methane monooxygenases have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. Here we discover and characterize a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for particulate methane monooxygenase. Csp1 is a tetramer of four-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realized. Cytosolic homologues of Csp1 are present in diverse bacteria, thus challenging the dogma that such organisms do not use copper in this location.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561512/" 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/PMC4561512/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vita, Nicolas -- Platsaki, Semeli -- Basle, Arnaud -- Allen, Stephen J -- Paterson, Neil G -- Crombie, Andrew T -- Murrell, J Colin -- Waldron, Kevin J -- Dennison, Christopher -- 098375/Z/12/Z/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Sep 3;525(7567):140-3. doi: 10.1038/nature14854. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. ; Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK. ; School of Environmental Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308900" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Bacterial Proteins/*chemistry/*metabolism ; Copper/*metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Methane/chemistry/*metabolism ; Methylosinus trichosporium/*chemistry/enzymology ; Models, Molecular ; Oxidation-Reduction ; Oxygenases/metabolism ; Protein Folding ; Protein Structure, Secondary
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  • 95
    Publication Date: 2015-12-18
    Description: Tandem repeat proteins, which are formed by repetition of modular units of protein sequence and structure, play important biological roles as macromolecular binding and scaffolding domains, enzymes, and building blocks for the assembly of fibrous materials. The modular nature of repeat proteins enables the rapid construction and diversification of extended binding surfaces by duplication and recombination of simple building blocks. The overall architecture of tandem repeat protein structures--which is dictated by the internal geometry and local packing of the repeat building blocks--is highly diverse, ranging from extended, super-helical folds that bind peptide, DNA, and RNA partners, to closed and compact conformations with internal cavities suitable for small molecule binding and catalysis. Here we report the development and validation of computational methods for de novo design of tandem repeat protein architectures driven purely by geometric criteria defining the inter-repeat geometry, without reference to the sequences and structures of existing repeat protein families. We have applied these methods to design a series of closed alpha-solenoid repeat structures (alpha-toroids) in which the inter-repeat packing geometry is constrained so as to juxtapose the amino (N) and carboxy (C) termini; several of these designed structures have been validated by X-ray crystallography. Unlike previous approaches to tandem repeat protein engineering, our design procedure does not rely on template sequence or structural information taken from natural repeat proteins and hence can produce structures unlike those seen in nature. As an example, we have successfully designed and validated closed alpha-solenoid repeats with a left-handed helical architecture that--to our knowledge--is not yet present in the protein structure database.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727831/" 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/PMC4727831/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Doyle, Lindsey -- Hallinan, Jazmine -- Bolduc, Jill -- Parmeggiani, Fabio -- Baker, David -- Stoddard, Barry L -- Bradley, Philip -- R01 GM049857/GM/NIGMS NIH HHS/ -- R01 GM115545/GM/NIGMS NIH HHS/ -- R01GM49857/GM/NIGMS NIH HHS/ -- R21 GM106117/GM/NIGMS NIH HHS/ -- R21GM106117/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 24;528(7583):585-8. doi: 10.1038/nature16191. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98109, USA. ; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA. ; Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA. ; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98019, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675735" target="_blank"〉PubMed〈/a〉
    Keywords: *Amino Acid Motifs ; *Bioengineering ; *Computer Simulation ; Crystallography, X-Ray ; Databases, Protein ; Models, Molecular ; *Protein Structure, Secondary ; Proteins/*chemistry ; Reproducibility of Results
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  • 96
    Publication Date: 2015-03-25
    Description: Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-beta1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to beta1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, alpha5beta1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vitorino, Philip -- Yeung, Stacey -- Crow, Ailey -- Bakke, Jesse -- Smyczek, Tanya -- West, Kristina -- McNamara, Erin -- Eastham-Anderson, Jeffrey -- Gould, Stephen -- Harris, Seth F -- Ndubaku, Chudi -- Ye, Weilan -- England -- Nature. 2015 Mar 26;519(7544):425-30. doi: 10.1038/nature14323. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Chemical Biology and Therapeutics Department, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Pathology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Structural Biology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Discovery Chemistry Department, Genentech, Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799996" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Antigens, CD29/chemistry/drug effects/metabolism ; Cell Membrane/drug effects/metabolism ; *Cell Movement ; Cell Shape/drug effects ; Endothelial Cells/*cytology/drug effects/*metabolism ; Epistasis, Genetic ; Focal Adhesions/metabolism ; Humans ; Integrin alpha1/drug effects/metabolism ; Integrins/drug effects/*metabolism ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Male ; Mice ; Microfilament Proteins/deficiency/genetics/metabolism ; Neovascularization, Pathologic ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Talin/chemistry/metabolism
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  • 97
    Publication Date: 2015-07-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kornberg, Thomas B -- Gilboa, Lilach -- England -- Nature. 2015 Jul 16;523(7560):292-3. doi: 10.1038/nature14631. Epub 2015 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26131936" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Drosophila melanogaster/*cytology ; Male ; Microtubules/*chemistry/*metabolism ; *Nanotubes ; *Signal Transduction ; Stem Cell Niche/*physiology ; Testis/*cytology
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  • 98
    Publication Date: 2015-08-19
    Description: Phosphorus is required for all life and microorganisms can extract it from their environment through several metabolic pathways. When phosphate is in limited supply, some bacteria are able to use phosphonate compounds, which require specialized enzymatic machinery to break the stable carbon-phosphorus (C-P) bond. Despite its importance, the details of how this machinery catabolizes phosphonates remain unknown. Here we determine the crystal structure of the 240-kilodalton Escherichia coli C-P lyase core complex (PhnG-PhnH-PhnI-PhnJ; PhnGHIJ), and show that it is a two-fold symmetric hetero-octamer comprising an intertwined network of subunits with unexpected self-homologies. It contains two potential active sites that probably couple phosphonate compounds to ATP and subsequently hydrolyse the C-P bond. We map the binding site of PhnK on the complex using electron microscopy, and show that it binds to a conserved insertion domain of PhnJ. Our results provide a structural basis for understanding microbial phosphonate breakdown.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617613/" 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/PMC4617613/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seweryn, Paulina -- Van, Lan Bich -- Kjeldgaard, Morten -- Russo, Christopher J -- Passmore, Lori A -- Hove-Jensen, Bjarne -- Jochimsen, Bjarne -- Brodersen, Ditlev E -- MC_U105192715/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 3;525(7567):68-72. doi: 10.1038/nature14683. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10c, DK-8000 Aarhus C, Denmark. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280334" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Binding Sites ; Biocatalysis ; Carbon/chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Escherichia coli/*enzymology ; Escherichia coli Proteins/*chemistry/*metabolism/ultrastructure ; Hydrolysis ; Iron/chemistry/metabolism ; Lyases/*chemistry/*metabolism/ultrastructure ; Microscopy, Electron ; Models, Molecular ; Organophosphonates/metabolism ; Phosphorus/chemistry/metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Sulfur/chemistry/metabolism
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  • 99
    Publication Date: 2015-07-07
    Description: During fertilization, an egg and a sperm fuse to form a new embryo. Eggs develop from oocytes in a process called meiosis. Meiosis in human oocytes is highly error-prone, and defective eggs are the leading cause of pregnancy loss and several genetic disorders such as Down's syndrome. Which genes safeguard accurate progression through meiosis is largely unclear. Here we develop high-content phenotypic screening methods for the systematic identification of mammalian meiotic genes. We targeted 774 genes by RNA interference within follicle-enclosed mouse oocytes to block protein expression from an early stage of oocyte development onwards. We then analysed the function of several genes simultaneously by high-resolution imaging of chromosomes and microtubules in live oocytes and scored each oocyte quantitatively for 50 phenotypes, generating a comprehensive resource of meiotic gene function. The screen generated an unprecedented annotated data set of meiotic progression in 2,241 mammalian oocytes, which allowed us to analyse systematically which defects are linked to abnormal chromosome segregation during meiosis, identifying progression into anaphase with misaligned chromosomes as well as defects in spindle organization as risk factors. This study demonstrates how high-content screens can be performed in oocytes, and allows systematic studies of meiosis in mammals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538867/" 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/PMC4538867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pfender, Sybille -- Kuznetsov, Vitaliy -- Pasternak, Michal -- Tischer, Thomas -- Santhanam, Balaji -- Schuh, Melina -- 337415/European Research Council/International -- MC_U105185859/Medical Research Council/United Kingdom -- MC_U105192711/Medical Research Council/United Kingdom -- England -- Nature. 2015 Aug 13;524(7564):239-42. doi: 10.1038/nature14568. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147080" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase/genetics ; Aneuploidy ; Animals ; Chromosome Segregation/genetics ; Chromosomes/genetics/metabolism ; Dual-Specificity Phosphatases/genetics ; Female ; Genomic Instability/genetics ; Male ; Meiosis/*genetics ; Mice ; Microtubule-Associated Proteins/genetics ; Microtubules/genetics/metabolism ; Oocytes/*cytology/*metabolism ; Ovarian Follicle/cytology ; Phenotype ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases/genetics ; *RNA Interference ; Spindle Apparatus/genetics/metabolism
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  • 100
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    Nature Publishing Group (NPG)
    Publication Date: 2015-02-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Feb 12;518(7538):145-6. doi: 10.1038/518145a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25673389" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Clinical Trials as Topic/legislation & jurisprudence ; Embryo Research/ethics/*legislation & jurisprudence ; Female ; Fertilization in Vitro/ethics/*legislation & jurisprudence/*methods ; Great Britain ; Humans ; Male ; United States ; United States Food and Drug Administration/legislation & jurisprudence
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