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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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  • 3
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    Ti-44 Gamma-Ray Emission Lines from SN1987A Reveal an Asymmetric Explosion (2015)
    In:  Other Sources
    Details
    Publication Date: 2019-07-13
    Description: In core-collapse supernovae, titanium-44 (Ti-44) is produced in the innermost ejecta, in the layer of material directly on top of the newly formed compact object. As such, it provides a direct probe of the supernova engine. Observations of supernova 1987A (SN1987A) have resolved the 67.87- and 78.32-kilo-electron volt emission lines from decay of Ti-44 produced in the supernova explosion. These lines are narrow and redshifted with a Doppler velocity of ~700 kilometers per second, direct evidence of large-scale asymmetry in the explosion.
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN34983 , Science Magazine (e-ISSN 1095-9203); 348; 6235; 670-671
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  • 4
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    Energetic Particles of Cosmic Accelerators II: Active Galactic Nuclei and Gamma-ray Bursts (2019)
    In:  CASI
    Details
    Publication Date: 2019-07-20
    Description: The high-energy universe has revealed that energetic particles are ubiquitous in the cosmos and play a vital role in the cultivation of cosmic environments on all scales. Our pursuit of more than a century to uncover the origins and fate of these cosmic energetic particles has given rise to some of the most interesting and challenging questions in astrophysics. Within our own galaxy, we have seen that energetic particles engage in a complex interplay with the galactic environment and even drive many of its key characteristics (for more information, see the first white paper in this series). On cosmological scales, the energetic particles supplied by the jets of active galactic nuclei (AGN) are an important source of energy for the intracluster and intergalactic media, providing a mechanism for regulating star formation and black hole growth and cultivating galaxy evolution (AGN feedback). Gamma-ray burst (GRB) afterglows encode information about their circumburst environment, which has implications for massive stellar winds during previous epochs over the stellar lifecycle. As such, GRB afterglows provide a means for studying very high-redshift galaxies since GRBs can be detected even if their host galaxy cannot. It has even been suggest that GRB could be used to measure cosmological distance scales if they could be shown to be standard candles. Though they play a key role in cultivating the cosmological environment and/or enabling our studies of it, there is still much we do not know about AGNs and GRBs, particularly the avenue in which and through which they supply radiation and energetic particles, namely their jets. Despite the enormous progress in particle-in-cell and magnetohydrodynamic simulations, we have yet to pinpoint the processes involved in jet formation and collimation and the conditions under which they can occur. For that matter, we have yet to identify the mechanism(s) through which the jet accelerates energetic particles is it the commonly invoked diffusive shock acceleration process or is another mechanism, such as magnetic reconnection, required? Do AGNs and GRBs accelerate hadrons, and if so, do they accelerate them to ultra-high energies and are there high-energy neutrinos associated with them? MeV gamma-ray astronomy, enabled by technological advances that will be realized in the coming decade, will provide a unique and indispensable perspective on the persistent mysteries of the energetic universe. This White Paper is the second of a two-part series highlighting the most well-known high-energy cosmic accelerators and contributions that MeV gamma-ray astronomy will bring to understanding their energetic particle phenomena. Specifically, MeV astronomy will: 1. Determine whether AGNs accelerate CRs to ultra-high energies; 2. Provide the missing pieces for the physics of the GRB prompt emission; 3. Measure magnetization in cosmic accelerators and search for acceleration via reconnection.
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN66972
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  • 5
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    Transient Astrophysics Probe: White Paper (2019)
    In:  CASI
    Details
    Publication Date: 2019-07-30
    Description: The Transient Astrophysics Probe (TAP) is a wide-field multi-wavelength transient mission proposed for flight starting in the late 2020s. The mission instruments include unique ``Lobster-eye'' imaging soft X-ray optics that allow an approximately 1600-degrees-squared Field of View (FoV); a high sensitivity, 1-degree-squared FoV soft X-ray telescope; a 1-degree-squared FoV Infrared telescope with bandpass 0.6 to 3 microns; and a set of 8 NaI gamma-ray detectors. TAP's most exciting capability will be the observation of tens per year of X-ray and Infrared counterparts of gravitational waves (GWs) involving stellar-mass black holes and neutron stars detected by LIGO (Laser Interferometer Gravitational-Wave Observatory ) / Virgo / KAGRA (Kamioka (Japan) Gravitational Wave Detector) / LIGO-India, and possibly several per year X-ray counterparts of GWs from supermassive black holes, detected by LISA (Laser Interferometer Space Antenna) and Pulsar Timing Arrays. TAP will also discover hundreds of X-ray transients related to compact objects, including tidal disruption events, supernova shock breakouts, and Gamma-Ray Bursts from the epoch of reionization.
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN70871
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  • 6
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    Swift and NuSTAR Observations of GW170817: Detection of a Blue Kilonova (2017)
    In:  Other Sources
    Details
    Publication Date: 2019-07-13
    Description: With the first direct detection of merging black holes in 2015, the era of gravitational wave (GW) astrophysics began. A complete picture of compact object mergers, however, requires the detection of an electromagnetic (EM) counterpart. We report ultraviolet (UV) and x-ray observations by Swift and the Nuclear Spectroscopic Telescope Array of the EM counter part of the binary neutron star merger GW170817.The bright, rapidly fading UV emission indicates a high mass (0.03 solar masses) wind-driven outflow with moderate electron fraction (Ye 0.27). Combined with the x-ray limits, we favor an observer viewing angle of 30 away from the orbital rotation axis, which avoids both obscuration from the heaviest elements in the orbital plane and a direct view of any ultra relativistic, highly collimated ejecta (a gamma-ray burst afterglow).
    Keywords: Astrophysics
    Type: GSFC-E-DAA-TN67019 , Science (ISSN 0036-8075) (e-ISSN 1095-9203); 358; 6370; 1565-1570
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