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  • 1
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    Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-11-23
    Description: Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for 〉99% of schistosomiasis cases worldwide.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136436/" 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/PMC4136436/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Valentim, Claudia L L -- Cioli, Donato -- Chevalier, Frederic D -- Cao, Xiaohang -- Taylor, Alexander B -- Holloway, Stephen P -- Pica-Mattoccia, Livia -- Guidi, Alessandra -- Basso, Annalisa -- Tsai, Isheng J -- Berriman, Matthew -- Carvalho-Queiroz, Claudia -- Almeida, Marcio -- Aguilar, Hector -- Frantz, Doug E -- Hart, P John -- LoVerde, Philip T -- Anderson, Timothy J C -- 098051/Wellcome Trust/United Kingdom -- 5R21-AI072704/AI/NIAID NIH HHS/ -- 5R21-AI096277/AI/NIAID NIH HHS/ -- C06 RR013556/RR/NCRR NIH HHS/ -- HHSN272201000005I/PHS HHS/ -- R01 AI097576/AI/NIAID NIH HHS/ -- R01-AI097576/AI/NIAID NIH HHS/ -- R21 AI072704/AI/NIAID NIH HHS/ -- R21 AI096277/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 13;342(6164):1385-9. doi: 10.1126/science.1243106. Epub 2013 Nov 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Biochemistry and Pathology, University of Texas Health Science Center, San Antonio, TX 78229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24263136" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Drug Resistance/*genetics ; Gene Knockdown Techniques ; Genetic Linkage ; Helminth Proteins/*genetics ; Humans ; Molecular Sequence Data ; Mutation ; Oxamniquine/*pharmacology ; Phylogeny ; Protein Conformation ; Quantitative Trait Loci ; RNA Interference ; Schistosoma mansoni/*drug effects/*genetics ; Schistosomicides/*pharmacology ; Sulfotransferases/chemistry/classification/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-02-09
    Description: HSP-100 protein machines, such as ClpB, play an essential role in reactivating protein aggregates that can otherwise be lethal to cells. Although the players involved are known, including the DnaK/DnaJ/GrpE chaperone system in bacteria, details of the molecular interactions are not well understood. Using methyl-transverse relaxation-optimized nuclear magnetic resonance spectroscopy, we present an atomic-resolution model for the ClpB-DnaK complex, which we verified by mutagenesis and functional assays. ClpB and GrpE compete for binding to the DnaK nucleotide binding domain, with GrpE binding inhibiting disaggregation. DnaK, in turn, plays a dual role in both disaggregation and subsequent refolding of polypeptide chains as they emerge from the aggregate. On the basis of a combined structural-biochemical analysis, we propose a model for the mechanism of protein aggregate reactivation by ClpB.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rosenzweig, Rina -- Moradi, Shoeib -- Zarrine-Afsar, Arash -- Glover, John R -- Kay, Lewis E -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 Mar 1;339(6123):1080-3. doi: 10.1126/science.1233066. Epub 2013 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. rina.rosenzweig@utoronto.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393091" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/genetics ; Adenosine Triphosphate/chemistry/metabolism ; Bacterial Proteins/chemistry ; Heat-Shock Proteins/*chemistry/genetics ; Hydrolysis ; *Models, Chemical ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Protein Interaction Domains and Motifs ; Protein Interaction Maps ; Protein Multimerization ; *Protein Refolding ; Protein Structure, Tertiary ; Protein Transport ; Thermus thermophilus
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-03-23
    Description: Glycosylated alpha-dystroglycan (alpha-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate alpha-DG, but many genes mutated in WWS remain unknown. To identify modifiers of alpha-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated alpha-DG to enter cells. In complementary screens, we profiled cells for absence of alpha-DG carbohydrate chains or biochemically related glycans. This revealed virus host factors and a suite of glycosylation units, including all known Walker-Warburg genes and five additional factors critical for the modification of alpha-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919138/" 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/PMC3919138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jae, Lucas T -- Raaben, Matthijs -- Riemersma, Moniek -- van Beusekom, Ellen -- Blomen, Vincent A -- Velds, Arno -- Kerkhoven, Ron M -- Carette, Jan E -- Topaloglu, Haluk -- Meinecke, Peter -- Wessels, Marja W -- Lefeber, Dirk J -- Whelan, Sean P -- van Bokhoven, Hans -- Brummelkamp, Thijn R -- AI057159/AI/NIAID NIH HHS/ -- AI081842/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 26;340(6131):479-83. doi: 10.1126/science.1233675. Epub 2013 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23519211" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Line ; Dystroglycans/*metabolism ; Female ; Glycosylation ; Haploidy ; Host-Pathogen Interactions/*genetics ; Humans ; Infant ; Lassa Fever/*genetics/virology ; Lassa virus/*physiology ; Male ; Membrane Proteins/*genetics ; Molecular Sequence Data ; Mutation ; Pedigree ; Proteome/*metabolism ; *Virus Internalization ; Walker-Warburg Syndrome/*genetics
    Print ISSN: 0036-8075
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  • 4
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    ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-05-21
    Description: Evidence for transcriptional feedback in circadian timekeeping is abundant, yet little is known about the mechanisms underlying translational control. We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in neurodegenerative disease, is a translational activator of the rate-limiting clock component PERIOD (PER) in Drosophila. ATX2 specifically interacted with TWENTY-FOUR (TYF), an activator of PER translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant ATX2 protein that does not associate with polyadenylate-binding protein (PABP) suppressed behavioral rhythms and decreased abundance of PER. Although ATX2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered TYF and disrupted the association between TYF and PABP. Thus, ATX2 coordinates an active translation complex important for PER expression and circadian rhythms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, Chunghun -- Allada, Ravi -- R01NS059042/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2013 May 17;340(6134):875-9. doi: 10.1126/science.1234785.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23687047" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxins ; Cell Line ; *Circadian Rhythm ; Drosophila Proteins/*biosynthesis/genetics/metabolism ; Drosophila melanogaster/metabolism/*physiology ; Mutation ; Nerve Tissue Proteins/genetics/*metabolism ; Period Circadian Proteins/*biosynthesis ; Poly(A)-Binding Proteins/metabolism ; Protein Biosynthesis ; RNA Interference
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  • 5
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    Microbiology. Eliminating malaria (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-07-03
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361224/" 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/PMC4361224/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fidock, David A -- R01 AI050234/AI/NIAID NIH HHS/ -- R01 AI079709/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Jun 28;340(6140):1531-3. doi: 10.1126/science.1240539.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology and Division of Infectious Diseases, Columbia University Medical Center, New York, NY 10032, USA. df2260@columbia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812705" target="_blank"〉PubMed〈/a〉
    Keywords: Antimalarials/*administration & dosage ; Artemisinins/*administration & dosage ; Child ; DNA Mismatch Repair/*genetics ; Disease Eradication/*methods ; Drug Resistance/*genetics ; Humans ; Malaria, Falciparum/parasitology/*prevention & control ; Mutation ; Plasmodium falciparum/drug effects/*genetics
    Print ISSN: 0036-8075
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  • 6
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    Epistasis among adaptive mutations in deer mouse hemoglobin (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-06-15
    Description: Epistatic interactions between mutant sites in the same protein can exert a strong influence on pathways of molecular evolution. We performed protein engineering experiments that revealed pervasive epistasis among segregating amino acid variants that contribute to adaptive functional variation in deer mouse hemoglobin (Hb). Amino acid mutations increased or decreased Hb-O2 affinity depending on the allelic state of other sites. Structural analysis revealed that epistasis for Hb-O2 affinity and allosteric regulatory control is attributable to indirect interactions between structurally remote sites. The prevalence of sign epistasis for fitness-related biochemical phenotypes has important implications for the evolutionary dynamics of protein polymorphism in natural populations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409680/" 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/PMC4409680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Natarajan, Chandrasekhar -- Inoguchi, Noriko -- Weber, Roy E -- Fago, Angela -- Moriyama, Hideaki -- Storz, Jay F -- HL087216-S1/HL/NHLBI NIH HHS/ -- R01 HL087216/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Jun 14;340(6138):1324-7. doi: 10.1126/science.1236862.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences, University of Nebraska, Lincoln, NE 68588, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23766324" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Biological/*genetics ; Alleles ; Animals ; *Epistasis, Genetic ; *Evolution, Molecular ; Exons ; Genetic Variation ; Hemoglobins/*chemistry/*genetics ; Hydrogen Bonding ; Mutation ; Oxygen/chemistry ; Peromyscus/genetics/*physiology ; Polymorphism, Genetic ; Protein Structure, Secondary ; alpha-Globins/chemistry/genetics ; beta-Globins/genetics
    Print ISSN: 0036-8075
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  • 7
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    2013 Runners-Up. Your microbes, your health (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-12-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉New York, N.Y. -- Science. 2013 Dec 20;342(6165):1440-1. doi: 10.1126/science.342.6165.1440-b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24357292" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/administration & dosage ; Fusobacterium/physiology ; Gastrointestinal Tract/*microbiology ; *Health ; Humans ; Infant ; Infant Formula/chemistry ; Kidney/metabolism ; Kidney Calculi/chemically induced/etiology ; Klebsiella/drug effects/metabolism ; Malnutrition/microbiology ; Neoplasms/microbiology ; Rats ; Triazines/metabolism/toxicity
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 8
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    Defining stem cell dynamics in models of intestinal tumor initiation (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-11-23
    Description: Cancer is a disease in which cells accumulate genetic aberrations that are believed to confer a clonal advantage over cells in the surrounding tissue. However, the quantitative benefit of frequently occurring mutations during tumor development remains unknown. We quantified the competitive advantage of Apc loss, Kras activation, and P53 mutations in the mouse intestine. Our findings indicate that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wild-type stem cells after biased, but still stochastic events. Furthermore, P53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene are favored. Our work confirms the previously theoretical notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vermeulen, Louis -- Morrissey, Edward -- van der Heijden, Maartje -- Nicholson, Anna M -- Sottoriva, Andrea -- Buczacki, Simon -- Kemp, Richard -- Tavare, Simon -- Winton, Douglas J -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2013 Nov 22;342(6161):995-8. doi: 10.1126/science.1243148.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24264992" target="_blank"〉PubMed〈/a〉
    Keywords: Adenomatous Polyposis Coli Protein/genetics ; Animals ; Cell Transformation, Neoplastic/*genetics/*pathology ; *Gene Expression Regulation, Neoplastic ; Intestinal Neoplasms/*genetics/*pathology ; Mice ; Mice, Mutant Strains ; Models, Biological ; Mutation ; Neoplastic Stem Cells/metabolism/*pathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Transcriptional Activation ; Tumor Suppressor Protein p53/genetics
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  • 9
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    2013 Runners-Up. Genetic microsurgery for the masses (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-12-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉New York, N.Y. -- Science. 2013 Dec 20;342(6165):1434-5. doi: 10.1126/science.342.6165.1434-a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24357285" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Proteins/genetics/metabolism ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; DNA/genetics ; Genetic Diseases, Inborn/*surgery ; Genetic Therapy/*methods ; Humans ; Mice ; Microsurgery/*methods ; *RNA Editing ; RNA, Guide/genetics/metabolism ; Rats
    Print ISSN: 0036-8075
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  • 10
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    Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-10-05
    Description: Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC(403/+) mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100553/" 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/PMC4100553/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Jianming -- Wakimoto, Hiroko -- Seidman, J G -- Seidman, Christine E -- R01 HL084553/HL/NHLBI NIH HHS/ -- R01HL084553/HL/NHLBI NIH HHS/ -- U01 HL066582/HL/NHLBI NIH HHS/ -- U01 HL098166/HL/NHLBI NIH HHS/ -- U01HL098166/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Oct 4;342(6154):111-4. doi: 10.1126/science.1236921.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24092743" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cardiomyopathy, Hypertrophic/*diagnosis/genetics/pathology ; Dependovirus ; Fibrosis ; Gene Silencing ; *Genetic Therapy ; HEK293 Cells ; Humans ; Mice ; Mutation ; Myosin Heavy Chains/*genetics ; *RNA Interference
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