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  • 1
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    Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-05-16
    Description: The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692360/" 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/PMC4692360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chew, Jeannie -- Gendron, Tania F -- Prudencio, Mercedes -- Sasaguri, Hiroki -- Zhang, Yong-Jie -- Castanedes-Casey, Monica -- Lee, Chris W -- Jansen-West, Karen -- Kurti, Aishe -- Murray, Melissa E -- Bieniek, Kevin F -- Bauer, Peter O -- Whitelaw, Ena C -- Rousseau, Linda -- Stankowski, Jeannette N -- Stetler, Caroline -- Daughrity, Lillian M -- Perkerson, Emilie A -- Desaro, Pamela -- Johnston, Amelia -- Overstreet, Karen -- Edbauer, Dieter -- Rademakers, Rosa -- Boylan, Kevin B -- Dickson, Dennis W -- Fryer, John D -- Petrucelli, Leonard -- P01 NS084974/NS/NINDS NIH HHS/ -- P01NS084974/NS/NINDS NIH HHS/ -- P50 AG016574/AG/NIA NIH HHS/ -- P50AG016574/AG/NIA NIH HHS/ -- R01 NS077402/NS/NINDS NIH HHS/ -- R01ES20395/ES/NIEHS NIH HHS/ -- R01NS063964/NS/NINDS NIH HHS/ -- R01NS077402/NS/NINDS NIH HHS/ -- R01NS088689/NS/NINDS NIH HHS/ -- R21 NS084528/NS/NINDS NIH HHS/ -- R21NS079807/NS/NINDS NIH HHS/ -- R21NS084528/NS/NINDS NIH HHS/ -- R21NS089979/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1151-4. doi: 10.1126/science.aaa9344. Epub 2015 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ; Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ; German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. petrucelli.leonard@mayo.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25977373" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Antisocial Personality Disorder/genetics/pathology ; Cerebral Cortex/metabolism/pathology ; DNA-Binding Proteins/*genetics ; Dependovirus ; Dipeptides/metabolism ; *Disease Models, Animal ; Frontotemporal Dementia/*genetics/pathology ; Gene Transfer Techniques ; HEK293 Cells ; Humans ; *Mice ; Proteins/*genetics ; Purkinje Cells/metabolism/pathology ; RNA, Nuclear/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Persistent HIV-1 replication maintains the tissue reservoir during therapy (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-01-28
    Description: Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lorenzo-Redondo, Ramon -- Fryer, Helen R -- Bedford, Trevor -- Kim, Eun-Young -- Archer, John -- Kosakovsky Pond, Sergei L -- Chung, Yoon-Seok -- Penugonda, Sudhir -- Chipman, Jeffrey G -- Fletcher, Courtney V -- Schacker, Timothy W -- Malim, Michael H -- Rambaut, Andrew -- Haase, Ashley T -- McLean, Angela R -- Wolinsky, Steven M -- AI1074340/AI/NIAID NIH HHS/ -- DA033773/DA/NIDA NIH HHS/ -- G1000196/Medical Research Council/United Kingdom -- GM110749/GM/NIGMS NIH HHS/ -- R01 DA033773/DA/NIDA NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2016 Feb 4;530(7588):51-6. doi: 10.1038/nature16933. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60011, USA. ; Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK. ; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Centro de Investigacao em Biodiversidade e Recursos Geneticos Universidade do Porto, 4485-661 Vairao, Portugal. ; Department of Medicine, University of California, San Diego, California 92093, USA. ; Division of AIDS, Center for Immunology and Pathology, Korea National Institutes of Health, Chungju-si, Chungcheongbuk-do, 28159, South Korea. ; Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Antiviral Pharmacology Laboratory, University of Nebraska Medical Center, College of Pharmacy, Omaha, Nebraska 68198, USA. ; Division of Infectious Diseases, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Department of Infectious Diseases, King's College London, Guy's Hospital, London SE21 7DN, UK. ; Centre for Immunology, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, UK. ; Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814962" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-HIV Agents/administration & dosage/pharmacology/therapeutic use ; Carrier State/blood/*drug therapy/*virology ; Drug Resistance, Viral/drug effects ; HIV Infections/blood/*drug therapy/*virology ; HIV-1/drug effects/genetics/*growth & development/isolation & purification ; Haplotypes/drug effects ; Humans ; Lymph Nodes/drug effects/virology ; Models, Biological ; Molecular Sequence Data ; Phylogeny ; Selection, Genetic/drug effects ; Sequence Analysis, DNA ; Spatio-Temporal Analysis ; Time Factors ; *Viral Load/drug effects ; *Virus Replication/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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