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  • 1
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    Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-02-22
    Description: Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-alpha treatment can clear HBV but is limited by systemic side effects. We describe how interferon-alpha can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-beta receptor activation as a therapeutic alternative. Interferon-alpha and lymphotoxin-beta receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases-for example, by lymphotoxin-beta receptor activation-allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lucifora, Julie -- Xia, Yuchen -- Reisinger, Florian -- Zhang, Ke -- Stadler, Daniela -- Cheng, Xiaoming -- Sprinzl, Martin F -- Koppensteiner, Herwig -- Makowska, Zuzanna -- Volz, Tassilo -- Remouchamps, Caroline -- Chou, Wen-Min -- Thasler, Wolfgang E -- Huser, Norbert -- Durantel, David -- Liang, T Jake -- Munk, Carsten -- Heim, Markus H -- Browning, Jeffrey L -- Dejardin, Emmanuel -- Dandri, Maura -- Schindler, Michael -- Heikenwalder, Mathias -- Protzer, Ulrike -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1221-8. doi: 10.1126/science.1243462. Epub 2014 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Virology, Technische Universitat Munchen-Helmholtz Zentrum Munchen, 81675 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24557838" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal ; Antiviral Agents/*pharmacology/therapeutic use ; Cell Line ; Cell Nucleus/virology ; Cytidine/metabolism ; Cytidine Deaminase/biosynthesis ; DNA, Circular/*metabolism ; DNA, Viral/*metabolism ; Hepatitis B/*drug therapy ; Hepatitis B virus/*drug effects/metabolism ; Hepatocytes/*drug effects/metabolism/virology ; Humans ; Interferon-alpha/*pharmacology/therapeutic use ; Liver/drug effects/metabolism/virology ; Lymphotoxin beta Receptor/*agonists/antagonists & inhibitors ; Mice, SCID ; Proteins ; Up-Regulation
    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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    Structure and equilibria among silicate species in aqueous fluids in the upper mantle: Experimental SiO2-H2O and MgO-SiO2-H2O data recorded in-situ to 900˚C and 5.4 GPa (2013)
    Wiley
    Details
    Publication Date: 2013-12-05
    Description: [1]  Experiments to determine silicate structural species in silicate-saturated aqueous fluids in equilibrium with silica polymorphs (quartz and coesite), enstatite, and enstatite + forsterite in the SiO 2 -H 2 O and MgO-SiO 2 -H 2 O systems have been carried out in-situ in the 0.4-5.4 GPa and 700˚-900˚C pressure and temperature ranges, respectively. MicroRaman spectroscopy was the structural probe. In the SiO 2 -H 2 O system (1.6-5.4 GPa/700˚-900˚C), the detected silicate species are Q o (SiO 4 4- ), Q 1 (0.5 Si 2 O 7 6- ), and Q 2 (SiO 3 2- ). The expression, 2Q 1  ⇌ Q o  + Q 2 , describes the equilibrium among these species with ∆H and ∆V-values from the isochoric temperature- and isothermal pressure-dependence of its equilibrium constant, K = X Qo •X Q2 /(X Q1 ) 2 , range from −23 to −69 kJ/mol and −1 - -2 cm 3 /mol, respectively. In the system MgO-SiO 2 -H 2 O the calculated silica solubility, using literature algorithms, is approximately 50% of that in the SiO 2 -H 2 O system at similar temperature and pressure. Only Q 1 and Q o species were detected in the MgO-SiO 2 -H 2 O fluids, whether in equilibrium with enstatite + forsterite (P 〈 3 GPa) or enstatite only (P 〉 3 GPa). The temperature- and pressure-dependence of the equilibrium constant, K = X Q1 /X Qo , for this system yields average values of ∆H = 40 ± 5 kJ/mol and ∆V = −2.3 ± 0.4 cm 3 /mol. [2]  The speciation of silicate in aqueous fluids resembles that in hydrous melts as a function of temperature and pressure at deep crustal and upper mantle temperature and pressure conditions and they become increasingly similar with depth. As the silicate speciation and solubility in the aqueous fluid depend on silicate composition, the pressure and temperature at which complete miscibility occurs will also vary with silicate composition. The structural similarity between fluids and melts will also lead to fluid/melt element partition coefficients trending toward 1, and mineral/fluid partition coefficients trending toward mineral/melt values, in the upper mantle as the silicate-H 2 O systems approach complete miscibility with increasing temperature and pressure.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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