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  • Molecular Sequence Data  (4)
  • Nature Publishing Group (NPG)  (4)
  • Copernicus
  • Wiley-Blackwell
  • Springer
  • American Physical Society (APS)
  • 1
    Publication Date: 2010-09-28
    Description: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" 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/PMC3010259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Filippakopoulos, Panagis -- Qi, Jun -- Picaud, Sarah -- Shen, Yao -- Smith, William B -- Fedorov, Oleg -- Morse, Elizabeth M -- Keates, Tracey -- Hickman, Tyler T -- Felletar, Ildiko -- Philpott, Martin -- Munro, Shonagh -- McKeown, Michael R -- Wang, Yuchuan -- Christie, Amanda L -- West, Nathan -- Cameron, Michael J -- Schwartz, Brian -- Heightman, Tom D -- La Thangue, Nicholas -- French, Christopher A -- Wiest, Olaf -- Kung, Andrew L -- Knapp, Stefan -- Bradner, James E -- 13058/Cancer Research UK/United Kingdom -- G0500905/Medical Research Council/United Kingdom -- G1000807/Medical Research Council/United Kingdom -- G9400953/Medical Research Council/United Kingdom -- K08 CA128972/CA/NCI NIH HHS/ -- K08 CA128972-03/CA/NCI NIH HHS/ -- T32-075762/PHS HHS/ -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Dec 23;468(7327):1067-73. doi: 10.1038/nature09504. Epub 2010 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20871596" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Azirines/chemical synthesis/chemistry/*pharmacology ; Binding Sites ; Carcinoma, Squamous Cell/physiopathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin/metabolism ; Dihydropyridines/chemical synthesis/chemistry/*pharmacology ; Female ; Humans ; Mice ; Mice, Nude ; *Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/*antagonists & inhibitors/*metabolism ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; Sequence Alignment ; Skin Neoplasms/physiopathology ; Stereoisomerism ; Transcription Factors/*antagonists & inhibitors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-08-24
    Description: A novel H7N9 influenza A virus first detected in March 2013 has since caused more than 130 human infections in China, resulting in 40 deaths. Preliminary analyses suggest that the virus is a reassortant of H7, N9 and H9N2 avian influenza viruses, and carries some amino acids associated with mammalian receptor binding, raising concerns of a new pandemic. However, neither the source populations of the H7N9 outbreak lineage nor the conditions for its genesis are fully known. Using a combination of active surveillance, screening of virus archives, and evolutionary analyses, here we show that H7 viruses probably transferred from domestic duck to chicken populations in China on at least two independent occasions. We show that the H7 viruses subsequently reassorted with enzootic H9N2 viruses to generate the H7N9 outbreak lineage, and a related previously unrecognized H7N7 lineage. The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at live poultry markets, which are thought to be the immediate source of human infections. Whether the H7N9 outbreak lineage has, or will, become enzootic in China and neighbouring regions requires further investigation. The discovery here of a related H7N7 influenza virus in chickens that has the ability to infect mammals experimentally, suggests that H7 viruses may pose threats beyond the current outbreak. The continuing prevalence of H7 viruses in poultry could lead to the generation of highly pathogenic variants and further sporadic human infections, with a continued risk of the virus acquiring human-to-human transmissibility.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801098/" 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/PMC3801098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Tommy Tsan-Yuk -- Wang, Jia -- Shen, Yongyi -- Zhou, Boping -- Duan, Lian -- Cheung, Chung-Lam -- Ma, Chi -- Lycett, Samantha J -- Leung, Connie Yin-Hung -- Chen, Xinchun -- Li, Lifeng -- Hong, Wenshan -- Chai, Yujuan -- Zhou, Linlin -- Liang, Huyi -- Ou, Zhihua -- Liu, Yongmei -- Farooqui, Amber -- Kelvin, David J -- Poon, Leo L M -- Smith, David K -- Pybus, Oliver G -- Leung, Gabriel M -- Shu, Yuelong -- Webster, Robert G -- Webby, Richard J -- Peiris, Joseph S M -- Rambaut, Andrew -- Zhu, Huachen -- Guan, Yi -- 092807/Wellcome Trust/United Kingdom -- 095831/Wellcome Trust/United Kingdom -- 260864/European Research Council/International -- BB/E009670/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- HHSN266200700005C/AI/NIAID NIH HHS/ -- HSN266200700005C/PHS HHS/ -- England -- Nature. 2013 Oct 10;502(7470):241-4. doi: 10.1038/nature12515. Epub 2013 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College, Shantou 515041, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23965623" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chickens ; China ; Ducks ; Genes, Viral/genetics ; Humans ; Influenza A Virus, H7N7 Subtype/classification/genetics ; Influenza A Virus, H9N2 Subtype/classification/genetics ; Influenza A virus/*classification/*genetics ; Influenza in Birds/transmission/virology ; Influenza, Human/transmission/*virology ; Molecular Sequence Data ; *Phylogeny ; Reassortant Viruses/classification/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-03-13
    Description: Since 2013 the occurrence of human infections by a novel avian H7N9 influenza virus in China has demonstrated the continuing threat posed by zoonotic pathogens. Although the first outbreak wave that was centred on eastern China was seemingly averted, human infections recurred in October 2013 (refs 3-7). It is unclear how the H7N9 virus re-emerged and how it will develop further; potentially it may become a long-term threat to public health. Here we show that H7N9 viruses have spread from eastern to southern China and become persistent in chickens, which has led to the establishment of multiple regionally distinct lineages with different reassortant genotypes. Repeated introductions of viruses from Zhejiang to other provinces and the presence of H7N9 viruses at live poultry markets have fuelled the recurrence of human infections. This rapid expansion of the geographical distribution and genetic diversity of the H7N9 viruses poses a direct challenge to current disease control systems. Our results also suggest that H7N9 viruses have become enzootic in China and may spread beyond the region, following the pattern previously observed with H5N1 and H9N2 influenza viruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Tommy Tsan-Yuk -- Zhou, Boping -- Wang, Jia -- Chai, Yujuan -- Shen, Yongyi -- Chen, Xinchun -- Ma, Chi -- Hong, Wenshan -- Chen, Yin -- Zhang, Yanjun -- Duan, Lian -- Chen, Peiwen -- Jiang, Junfei -- Zhang, Yu -- Li, Lifeng -- Poon, Leo Lit Man -- Webby, Richard J -- Smith, David K -- Leung, Gabriel M -- Peiris, Joseph S M -- Holmes, Edward C -- Guan, Yi -- Zhu, Huachen -- HHSN272201400006C/PHS HHS/ -- England -- Nature. 2015 Jun 4;522(7554):102-5. doi: 10.1038/nature14348. Epub 2015 Mar 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Emerging Infectious Diseases (HKU-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen 518112, China [2] Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College (SUMC), Shantou 515041, China [3] Centre of Influenza Research, School of Public Health, The University of Hong Kong (HKU), Hong Kong, China. ; State Key Laboratory of Emerging Infectious Diseases (HKU-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen 518112, China. ; 1] Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College (SUMC), Shantou 515041, China [2] Centre of Influenza Research, School of Public Health, The University of Hong Kong (HKU), Hong Kong, China. ; Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College (SUMC), Shantou 515041, China. ; Key Laboratory of Emergency Detection for Public Health of Zhejiang Province, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang 310051, China. ; 1] State Key Laboratory of Emerging Infectious Diseases (HKU-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen 518112, China [2] Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College (SUMC), Shantou 515041, China. ; 1] State Key Laboratory of Emerging Infectious Diseases (HKU-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen 518112, China [2] Centre of Influenza Research, School of Public Health, The University of Hong Kong (HKU), Hong Kong, China. ; Division of Virology, Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Centre of Influenza Research, School of Public Health, The University of Hong Kong (HKU), Hong Kong, China. ; Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762140" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chickens/*virology ; China/epidemiology ; Ecosystem ; *Evolution, Molecular ; Genotype ; Humans ; Influenza A Virus, H7N9 Subtype/classification/*genetics/*isolation & ; purification ; Influenza in Birds/*epidemiology/transmission/*virology ; Influenza, Human/epidemiology/transmission/virology ; Molecular Sequence Data ; Reassortant Viruses/genetics/isolation & purification ; Zoonoses/transmission/virology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-12-04
    Description: Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase sigma (PTPsigma), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPsigma has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPsigma wedge domain that binds to PTPsigma and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPsigma in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336236/" 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/PMC4336236/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lang, Bradley T -- Cregg, Jared M -- DePaul, Marc A -- Tran, Amanda P -- Xu, Kui -- Dyck, Scott M -- Madalena, Kathryn M -- Brown, Benjamin P -- Weng, Yi-Lan -- Li, Shuxin -- Karimi-Abdolrezaee, Soheila -- Busch, Sarah A -- Shen, Yingjie -- Silver, Jerry -- NS025713/NS/NINDS NIH HHS/ -- R01 EY024575/EY/NEI NIH HHS/ -- R01 NS025713/NS/NINDS NIH HHS/ -- R01 NS079432/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):404-8. doi: 10.1038/nature13974. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. ; Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210, USA. ; Regenerative Medicine Program and Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada. ; Baldwin Wallace University, Berea, Ohio 44017, USA. ; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA. ; Shriners Hospital's Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470046" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Chondroitin Sulfate Proteoglycans/*metabolism ; Extracellular Matrix/chemistry/drug effects/metabolism ; Female ; Growth Cones/drug effects/physiology ; Humans ; Mice ; Molecular Sequence Data ; *Nerve Regeneration/drug effects ; Protein Binding/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/antagonists & ; inhibitors/chemistry/*metabolism ; Spinal Cord Injuries/*metabolism/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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