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  • 1
    Online Resource
    Online Resource
    Allelic Exclusion in Transgenic Mice That Express the Membrane form of Immunoglobulin μ
    American Association for the Advancement of Science (AAAS) ; 1987
    In:  Science Vol. 236, No. 4803 ( 1987-05-15), p. 816-819
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 236, No. 4803 ( 1987-05-15), p. 816-819
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.3107126
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 1987
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  • 2
    Online Resource
    Online Resource
    Development of autoimmunity in mice lacking DNA topoisomerase 3β
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 22 ( 2007-05-29), p. 9242-9247
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 22 ( 2007-05-29), p. 9242-9247
    Abstract: Mice lacking DNA topoisomerase 3β are predisposed to a shortened lifespan, infertility, and lesions in multiple organs resulting from inflammatory responses. Examination of the immune system of 6- and 52-week-old top3 β −/− mice revealed no significant aberrations in their central and peripheral tolerance or in T lymphocyte activation. However, the older but not the younger cohort shows a high incidence of serum autoantibodies relative to their TOP3 β +/+ age-mates. The mutant mice also show an increase in numerical aberrations of chromosomes in splenocytes and bone marrow cells, as well as an increase in apoptotic cells in the thymus. Thus, it appears plausible that the inflammatory lesions in top3 β −/− mice are caused by the development of autoimmunity as they age: Chromosomal abnormalities in top3 β −/− mice might lead to a persistent increase in apoptotic cells, which might in turn lead to the progression of autoimmunity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0703587104
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
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  • 3
    Online Resource
    Online Resource
    Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease
    American Association for the Advancement of Science (AAAS) ; 2016
    In:  Science Vol. 352, No. 6284 ( 2016-04-22), p. 463-466
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 352, No. 6284 ( 2016-04-22), p. 463-466
    Abstract: Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1 -intact mice with weakened resistance due to deficiencies in Mavs and Tlr7 , we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaf3926
    RVK:
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2016
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  • 4
    Online Resource
    Online Resource
    Atomic-level characterization of protein–protein association
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 10 ( 2019-03-05), p. 4244-4249
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 10 ( 2019-03-05), p. 4244-4249
    Abstract: Despite the biological importance of protein–protein complexes, determining their structures and association mechanisms remains an outstanding challenge. Here, we report the results of atomic-level simulations in which we observed five protein–protein pairs repeatedly associate to, and dissociate from, their experimentally determined native complexes using a molecular dynamics (MD)–based sampling approach that does not make use of any prior structural information about the complexes. To study association mechanisms, we performed additional, conventional MD simulations, in which we observed numerous spontaneous association events. A shared feature of native association for these five structurally and functionally diverse protein systems was that if the proteins made contact far from the native interface, the native state was reached by dissociation and eventual reassociation near the native interface, rather than by extensive interfacial exploration while the proteins remained in contact. At the transition state (the conformational ensemble from which association to the native complex and dissociation are equally likely), the protein–protein interfaces were still highly hydrated, and no more than 20% of native contacts had formed.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1815431116
    RVK:
    TA 1000
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 5
    Online Resource
    Online Resource
    Pathway and mechanism of drug binding to G-protein-coupled receptors
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 32 ( 2011-08-09), p. 13118-13123
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 32 ( 2011-08-09), p. 13118-13123
    Abstract: How drugs bind to their receptors—from initial association, through drug entry into the binding pocket, to adoption of the final bound conformation, or “pose”—has remained unknown, even for G-protein-coupled receptor modulators, which constitute one-third of all marketed drugs. We captured this pharmaceutically critical process in atomic detail using the first unbiased molecular dynamics simulations in which drug molecules spontaneously associate with G-protein-coupled receptors to achieve final poses matching those determined crystallographically. We found that several beta blockers and a beta agonist all traverse the same well-defined, dominant pathway as they bind to the β 1 - and β 2 -adrenergic receptors, initially making contact with a vestibule on each receptor’s extracellular surface. Surprisingly, association with this vestibule, at a distance of 15 Å from the binding pocket, often presents the largest energetic barrier to binding, despite the fact that subsequent entry into the binding pocket requires the receptor to deform and the drug to squeeze through a narrow passage. The early barrier appears to reflect the substantial dehydration that takes place as the drug associates with the vestibule. Our atomic-level description of the binding process suggests opportunities for allosteric modulation and provides a structural foundation for future optimization of drug–receptor binding and unbinding rates.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1104614108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Defective signal transduction in B lymphocytes lacking presenilin proteins
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 3 ( 2008-01-22), p. 979-984
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 3 ( 2008-01-22), p. 979-984
    Abstract: The mammalian presenilin (PS) proteins mediate the posttranslational cleavage of several protein substrates, including amyloid precursor protein, Notch family members, and CD44, but they have also been suggested to function in diverse cellular processes, including calcium-dependent signaling and apoptosis. We carried out an integrative computational study of multiple genomic datasets, including RNA expression, protein interaction, and pathway analyses, which implicated PS proteins in Toll-like receptor signaling. To test these computational predictions, we analyzed mice carrying a conditional allele of PS1 and a germ line-inactivating allele of PS2 , together with Cre site-specific recombinase expression under the influence of CD19 control sequences. Notably, B cells deficient in both PS1 and PS2 function have an unexpected and substantial deficit in both lipopolysaccharide and B cell antigen receptor-induced proliferation and signal transduction events, including a defect in anti-IgM-mediated calcium flux. Taken together, these results demonstrate a fundamental and unanticipated role for PS proteins in B cell function and emphasize the potency of (systems level) integrative analysis of whole-genome datasets in identifying novel biologic signal transduction relationships. Our findings also suggest that pharmacologic inhibition of PS for the treatment of conditions such as Alzheimer's disease may have potential consequences for immune system function.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0707755105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 19 ( 2019-05-07), p. 9390-9399
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 19 ( 2019-05-07), p. 9390-9399
    Abstract: Bruton’s tyrosine kinase (Btk) is critical for B cell proliferation and activation, and the development of Btk inhibitors is a vigorously pursued strategy for the treatment of various B cell malignancies. A detailed mechanistic understanding of Btk activation has, however, been lacking. Here, inspired by a previous suggestion that Btk activation might depend on dimerization of its lipid-binding PH–TH module on the cell membrane, we performed long-timescale molecular dynamics simulations of membrane-bound PH–TH modules and observed that they dimerized into a single predominant conformation. We found that the phospholipid PIP 3 stabilized the dimer allosterically by binding at multiple sites, and that the effects of PH–TH mutations on dimer stability were consistent with their known effects on Btk activity. Taken together, our simulation results strongly suggest that PIP 3 -mediated dimerization of Btk at the cell membrane is a critical step in Btk activation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1819301116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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    SSG: 11
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Defective p53 engagement after the induction of DNA damage in cells deficient in topoisomerase 3β
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 13 ( 2008-04), p. 5063-5068
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 13 ( 2008-04), p. 5063-5068
    Abstract: The type IA topoisomerases have been implicated in the repair of dsDNA breaks by homologous recombination and in the resolution of stalled or damaged DNA replication forks; thus, these proteins play important roles in the maintenance of genomic stability. We studied the functions of one of the two mammalian type IA enzymes, Top3β, using murine embryonic fibroblasts (MEFs) derived from top3 β −/− embryos. top3 β −/− MEFs proliferated more slowly than TOP3 β +/+ control MEFs, demonstrated increased sensitivity to DNA-damaging agents such as ionizing and UV radiation, and had increased DNA double-strand breaks as manifested by increased γ-H2-AX phosphorylation. However, incomplete enforcement of the G 1 –S cell cycle checkpoint was observed in top3 β −/− MEFs. Notably, ataxia-telangiectasia, mutated (ATM)/ATM and Rad3-related (ATR)-dependent substrate phosphorylation after UV-B and ionizing radiation was impaired in top3 β −/− versus TOP3 β +/+ control MEFs, and impaired up-regulation of total and Ser-18-phosphorylated p53 was observed in top3 β −/− cells. Taken together, these results suggest an unanticipated role for Top3β beyond DNA repair in the activation of cellular responses to DNA damage.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0801235105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 9
    Online Resource
    Online Resource
    American Bibliography for 1927
    Modern Language Association (MLA) ; 1928
    In:  PMLA/Publications of the Modern Language Association of America Vol. 43, No. 1 ( 1928-03), p. 1-78
    Details
    In: PMLA/Publications of the Modern Language Association of America, Modern Language Association (MLA), Vol. 43, No. 1 ( 1928-03), p. 1-78
    Type of Medium: Online Resource
    ISSN: 0030-8129 , 1938-1530
    URL: Article
    DOI: 10.1632/S0030812900206275
    RVK:
    EA 1000
    Language: English
    Publisher: Modern Language Association (MLA)
    Publication Date: 1928
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    detail.hit.zdb_id: 209526-9
    detail.hit.zdb_id: 2066864-8
    SSG: 7,11
    SSG: 7,24
    SSG: 7,12
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  • 10
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    Online Resource
    Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS)
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 33 ( 2017-08-15), p. 8770-8775
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 33 ( 2017-08-15), p. 8770-8775
    Abstract: Fibrils and oligomers are the aggregated protein agents of neuronal dysfunction in ALS diseases. Whereas we now know much about fibril architecture, atomic structures of disease-related oligomers have eluded determination. Here, we determine the corkscrew-like structure of a cytotoxic segment of superoxide dismutase 1 (SOD1) in its oligomeric state. Mutations that prevent formation of this structure eliminate cytotoxicity of the segment in isolation as well as cytotoxicity of the ALS-linked mutants of SOD1 in primary motor neurons and in a Danio rerio (zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Our work adds to evidence that the toxic oligomeric entities in protein aggregation diseases contain antiparallel, out-of-register β-sheet structures and identifies a target for structure-based therapeutics in ALS.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1705091114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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