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  • 1
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    ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links (2017)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2017-09-30
    Description: Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a "split-SIM" SUMO2 engagement platform. These findings uncover a ZATT-TDP2–catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.
    Keywords: Molecular Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , 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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    Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma (2014)
    Oxford University Press
    Details
    Publication Date: 2014-11-21
    Description: Gain-of-function mutations in the olfactomedin domain of the MYOC gene facilitate the toxic accumulation of amyloid-containing myocilin aggregates, hastening the onset of the prevalent ocular disorder primary open-angle glaucoma. Aggregation of wild-type myocilin has been reported in other glaucoma subtypes, suggesting broader relevance of misfolded myocilin across the disease spectrum, but the absence of myocilin does not cause disease. Thus, strategies aimed at eliminating myocilin could be therapeutically relevant for glaucoma. Here, a novel and selective Grp94 inhibitor reduced the levels of several mutant myocilin proteins as well as wild-type myocilin when forced to misfold in cells. This inhibitor rescued mutant myocilin toxicity in primary human trabecular meshwork cells. Mechanistically, in vitro kinetics studies demonstrate that Grp94 recognizes on-pathway aggregates of the myocilin olfactomedin domain (myoc-OLF), accelerates rates of aggregation and co-precipitates with myoc-OLF. These results indicate that aberrant myocilin quaternary structure drives Grp94 recognition, rather than peptide motifs exposed by unfolded protein. Inhibition of Grp94 ameliorates the effects of Grp94-accelerated myoc-OLF aggregation, and Grp94 remains in solution. In cells, when wild-type myocilin is driven to misfold and aggregate, it becomes a client of Grp94 and sensitive to Grp94 inhibition. Taken together, the interaction of Grp94 with myocilin aggregates can be manipulated by cellular environment and genetics; this process can be exploited with Grp94 inhibitors to promote the clearance of toxic forms of myocilin.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Whither or wither microbicides? (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-07-26
    Description: After disappointing results from all efficacy trials conducted to date, the field of microbicides research now faces substantial challenges. Poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies have hampered progress and created mistrust about the use of microbicides as a method to prevent HIV-1 sexual transmission. Although new promising strategies are available, there will need to be serious reappraisals of how decisions are made to advance the next generations of candidates into clinical trials, and the use of appropriate animal models in this process will be critical.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835691/" 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/PMC2835691/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grant, Robert M -- Hamer, Dean -- Hope, Thomas -- Johnston, Rowena -- Lange, Joep -- Lederman, Michael M -- Lieberman, Judy -- Miller, Christopher J -- Moore, John P -- Mosier, Donald E -- Richman, Douglas D -- Schooley, Robert T -- Springer, Marty S -- Veazey, Ronald S -- Wainberg, Mark A -- U19 AI076981/AI/NIAID NIH HHS/ -- U19 AI076981-01/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2008 Jul 25;321(5888):532-4. doi: 10.1126/science.1160355.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉J. David Gladstone Institutes, University of California-San Francisco, San Francisco, CA 94518, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18653884" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Intravaginal ; Animals ; Anti-HIV Agents/*administration & dosage/pharmacology/therapeutic use ; Anti-Infective Agents, Local/*administration & dosage/pharmacology/therapeutic ; use ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Female ; HIV Infections/drug therapy/*prevention & control/transmission ; HIV-1/*drug effects ; Humans ; Male ; Patient Compliance ; Polymers/*administration & dosage/pharmacology/therapeutic use ; Primates ; Reverse Transcriptase Inhibitors/*administration & ; dosage/pharmacology/therapeutic use ; Vaginal Diseases/drug therapy/*prevention & control
    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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  • 4
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    Human conflict: pacifists at heart (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-07-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lieberman, E James -- New York, N.Y. -- Science. 2012 Jul 20;337(6092):290-1. doi: 10.1126/science.337.6092.290-c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22822131" target="_blank"〉PubMed〈/a〉
    Keywords: *Conflict (Psychology) ; Humans ; *Population Groups ; *Social Behavior ; *Violence ; *Warfare
    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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  • 5
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    Public health. A sound rationale needed for phase III HIV-1 vaccine trials (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2004-01-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burton, Dennis R -- Desrosiers, Ronald C -- Doms, Robert W -- Feinberg, Mark B -- Gallo, Robert C -- Hahn, Beatrice -- Hoxie, James A -- Hunter, Eric -- Korber, Bette -- Landay, Alan -- Lederman, Michael M -- Lieberman, Judy -- McCune, Joseph M -- Moore, John P -- Nathanson, Neal -- Picker, Louis -- Richman, Douglas -- Rinaldo, Charles -- Stevenson, Mario -- Watkins, David I -- Wolinsky, Steven M -- Zack, Jerome A -- New York, N.Y. -- Science. 2004 Jan 16;303(5656):316.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Scripps Research Institute, La Jolla, California, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14726576" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/*immunology ; *Clinical Trials, Phase III as Topic/economics ; Costs and Cost Analysis ; HIV Envelope Protein gp120/*immunology ; HIV Infections/*immunology/prevention & control/therapy ; HIV-1/*immunology ; Humans ; Immunization Schedule ; Immunization, Secondary ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; Thailand ; United States ; Vaccines, Synthetic/immunology
    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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  • 6
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    Identification of host proteins required for HIV infection through a functional genomic screen (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-01-12
    Description: HIV-1 exploits multiple host proteins during infection. We performed a large-scale small interfering RNA screen to identify host factors required by HIV-1 and identified more than 250 HIV-dependency factors (HDFs). These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle. Further analysis revealed previously unknown roles for retrograde Golgi transport proteins (Rab6 and Vps53) in viral entry, a karyopherin (TNPO3) in viral integration, and the Mediator complex (Med28) in viral transcription. Transcriptional analysis revealed that HDF genes were enriched for high expression in immune cells, suggesting that viruses evolve in host cells that optimally perform the functions required for their life cycle. This effort illustrates the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brass, Abraham L -- Dykxhoorn, Derek M -- Benita, Yair -- Yan, Nan -- Engelman, Alan -- Xavier, Ramnik J -- Lieberman, Judy -- Elledge, Stephen J -- AI052014/AI/NIAID NIH HHS/ -- AI062773/AI/NIAID NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- U19-AI056900/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2008 Feb 15;319(5865):921-6. doi: 10.1126/science.1152725. Epub 2008 Jan 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Center for Genetics and Genomics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18187620" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Computational Biology ; Cytoskeletal Proteins/genetics/physiology ; Genomics ; HIV Infections/genetics/metabolism/*virology ; HIV-1/genetics/pathogenicity/*physiology ; Host-Pathogen Interactions ; Human Immunodeficiency Virus Proteins/physiology ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/physiology ; Karyopherins/genetics/physiology ; Mediator Complex ; Proteins/*physiology ; RNA Interference ; RNA, Small Interfering ; Transcription, Genetic ; Vesicular Transport Proteins/genetics/physiology ; Virus Integration ; Virus Internalization ; Virus Replication ; rab GTP-Binding Proteins/genetics/physiology
    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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  • 7
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    Epithelial nitration by a peroxidase/NOX5 system mediates mosquito antiplasmodial immunity (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-01-28
    Description: Plasmodium ookinetes traverse midgut epithelial cells before they encounter the complement system in the mosquito hemolymph. We identified a heme peroxidase (HPX2) and NADPH oxidase 5 (NOX5) as critical mediators of midgut epithelial nitration and antiplasmodial immunity that enhance nitric oxide toxicity in Anopheles gambiae. We show that the two immune mechanisms that target ookinetes-epithelial nitration and thioester-containing protein 1 (TEP1)-mediated lysis-work sequentially, and we propose that epithelial nitration works as an opsonization-like system that promotes activation of the mosquito complement cascade.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444286/" 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/PMC3444286/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oliveira, Giselle de Almeida -- Lieberman, Joshua -- Barillas-Mury, Carolina -- ZIA AI000947-08/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2012 Feb 17;335(6070):856-9. doi: 10.1126/science.1209678. Epub 2012 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Rockville, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22282475" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles gambiae/genetics/*immunology/physiology ; Complement System Proteins/metabolism ; Female ; Gene Silencing ; Intestinal Mucosa/immunology ; Malaria/immunology ; Mice ; Mice, Inbred BALB C ; NADPH Oxidase/genetics/*metabolism ; Nitrogen/*metabolism ; Peroxidases/genetics/*metabolism ; Plasmodium berghei/*immunology/physiology
    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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  • 8
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    Neural response to eudaimonic and hedonic rewards [Psychological and Cognitive Sciences] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-05-07
    Description: The pursuit of happiness and reward is an impetus for everyday human behavior and the basis of well-being. Although optimal well-being may be achieved through eudaimonic activities (e.g., meaning and purpose), individuals tend to orient toward hedonic activities (e.g., pleasure seeking), potentially placing them at risk for ill-being. We implemented...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
    Electronic Resource
    Electronic Resource
    Inhibition of trypsin by deoxyribonucleic acid
    Amsterdam : Elsevier
    Archives of Biochemistry and Biophysics 110 (1965), S. 601-610 
    Details
    ISSN: 0003-9861
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0003-9861(65)90456-X
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  • 10
    Electronic Resource
    Electronic Resource
    Regularization of the stress-energy tensor for vector and scalar particles propagating in a general background metric
    Amsterdam : Elsevier
    Annals of Physics 106 (1977), S. 279-321 
    Details
    ISSN: 0003-4916
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0003-4916(77)90313-X
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