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  • Biodiversity Research  (14)
  • Linguistics  (14)
  • Natural Sciences  (14)
  • 1
    Online Resource
    Online Resource
    Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways
    American Association for the Advancement of Science (AAAS) ; 2015
    In:  Science Vol. 347, No. 6229 ( 2015-03-27), p. 1436-1441
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 347, No. 6229 ( 2015-03-27), p. 1436-1441
    Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaa3650
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 38 ( 2016-09-20), p. 10649-10654
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 38 ( 2016-09-20), p. 10649-10654
    Abstract: The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte–associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1605885113
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 3
    Online Resource
    Online Resource
    Specific hypomethylation programs underpin B cell activation in early multiple sclerosis
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 51 ( 2021-12-21)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 51 ( 2021-12-21)
    Abstract: Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2111920118
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    C9orf72 is required for proper macrophage and microglial function in mice
    American Association for the Advancement of Science (AAAS) ; 2016
    In:  Science Vol. 351, No. 6279 ( 2016-03-18), p. 1324-1329
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 351, No. 6279 ( 2016-03-18), p. 1324-1329
    Abstract: Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog ( 3110043O21Rik ) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaf1064
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2016
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  • 5
    Online Resource
    Online Resource
    Isolation of Substances That Stimulate RNA Synthesis from Red Kidney Bean: Their Activities in Lymphocytes and Escherichia coli
    Proceedings of the National Academy of Sciences ; 1973
    In:  Proceedings of the National Academy of Sciences Vol. 70, No. 2 ( 1973-02), p. 569-573
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 70, No. 2 ( 1973-02), p. 569-573
    Abstract: An extract from red kidney beans ( Phaseolus vulgaris ) was fractionated with respect to RNA synthesis-stimulating activity. The activity of the fractions was tested in chicken-spleen lymphocytes cultured in serum-free medium and in plasmolyzed E. coli cells. Lymphocyte -stimulating activity was found in a fraction called F III. This fraction contained protein and orcinol-positive carbohydrate. The protein (called F III p) responsible for the observed activity was separated from the contaminating carbohydrate by acid precipitation. F III p appears to belong to the group of well-known mitogens of high molecular weight present in red kidney beans. A bacteria -stimulating factor was found in a fraction called F V. This factor strongly stimulated RNA synthesis in the bacterial system, and had a weak stimulating effect in the lymphocyte system. In plasmolyzed E. coli cells, F V counteracted the inhibiting effect of rifampicin on RNA synthesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.70.2.569
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1973
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  • 6
    Online Resource
    Online Resource
    A conserved function of YidC in the biogenesis of respiratory chain complexes
    Proceedings of the National Academy of Sciences ; 2003
    In:  Proceedings of the National Academy of Sciences Vol. 100, No. 10 ( 2003-05-13), p. 5801-5806
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 100, No. 10 ( 2003-05-13), p. 5801-5806
    Abstract: The Escherichia coli inner membrane protein (IMP) YidC is involved in the membrane integration of IMPs both in concert with and independently from the Sec translocase. YidC seems to be dispensable for the assembly of Sec-dependent IMPs, and so far it has been shown to be essential only for the proper Sec-independent integration of some phage coat proteins. Here, we studied the physiological consequences of YidC depletion in an effort to understand the essential function of YidC. The loss of YidC rapidly and specifically induced the Psp stress response, which is accompanied by a reduction of the proton-motive force. This reduction is due to defects in the functional assembly of cytochrome o oxidase and the F 1 F o ATPase complex, which is reminiscent of the effects of mutations in the yidC homologue OXA1 in the yeast mitochondrial inner membrane. The integration of CyoA (subunit II of the cytochrome o oxidase) and F o c (membrane subunit of the F 1 F o ATPase) appeared exceptionally sensitive to depletion of YidC, suggesting that these IMPs are natural substrates of a membrane integration and assembly pathway in which YidC plays an exclusive or at least a pivotal role.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0636761100
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2003
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  • 7
    Online Resource
    Online Resource
    Pathways for Neoarchean pyrite formation constrained by mass-independent sulfur isotopes
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 44 ( 2013-10-29), p. 17638-17643
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 44 ( 2013-10-29), p. 17638-17643
    Abstract: It is generally thought that the sulfate reduction metabolism is ancient and would have been established well before the Neoarchean. It is puzzling, therefore, that the sulfur isotope record of the Neoarchean is characterized by a signal of atmospheric mass-independent chemistry rather than a strong overprint by sulfate reducers. Here, we present a study of the four sulfur isotopes obtained using secondary ion MS that seeks to reconcile a number of features seen in the Neoarchean sulfur isotope record. We suggest that Neoarchean ocean basins had two coexisting, significantly sized sulfur pools and that the pathways forming pyrite precursors played an important role in establishing how the isotopic characteristics of each of these pools was transferred to the sedimentary rock record. One of these pools is suggested to be a soluble (sulfate) pool, and the other pool (atmospherically derived elemental sulfur) is suggested to be largely insoluble and unreactive until it reacts with hydrogen sulfide. We suggest that the relative contributions of these pools to the formation of pyrite depend on both the accumulation of the insoluble pool and the rate of sulfide production in the pyrite-forming environments. We also suggest that the existence of a significant nonsulfate pool of reactive sulfur has masked isotopic evidence for the widespread activity of sulfate reducers in the rock record.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1218851110
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 8
    Online Resource
    Online Resource
    MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 15 ( 2019-04-09), p. 7533-7542
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 15 ( 2019-04-09), p. 7533-7542
    Abstract: Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1819085116
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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  • 9
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    Online Resource
    Rapid decay of tree-community composition in Amazonian forest fragments
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 50 ( 2006-12-12), p. 19010-19014
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 50 ( 2006-12-12), p. 19010-19014
    Abstract: Forest fragmentation is considered a greater threat to vertebrates than to tree communities because individual trees are typically long-lived and require only small areas for survival. Here we show that forest fragmentation provokes surprisingly rapid and profound alterations in Amazonian tree-community composition. Results were derived from a 22-year study of exceptionally diverse tree communities in 40 1-ha plots in fragmented and intact forests, which were sampled repeatedly before and after fragment isolation. Within these plots, trajectories of change in abundance were assessed for 267 genera and 1,162 tree species. Abrupt shifts in floristic composition were driven by sharply accelerated tree mortality and recruitment within ≈100 m of fragment margins, causing rapid species turnover and population declines or local extinctions of many large-seeded, slow-growing, and old-growth taxa; a striking increase in a smaller set of disturbance-adapted and abiotically dispersed species; and significant shifts in tree size distributions. Even among old-growth trees, species composition in fragments is being restructured substantially, with subcanopy species that rely on animal seed-dispersers and have obligate outbreeding being the most strongly disadvantaged. These diverse changes in tree communities are likely to have wide-ranging impacts on forest architecture, canopy-gap dynamics, plant–animal interactions, and forest carbon storage.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0609048103
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
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  • 10
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    Online Resource
    Discovery and validation of colonic tumor-associated proteins via metabolic labeling and stable isotopic dilution
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 40 ( 2009-10-06), p. 17235-17240
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 40 ( 2009-10-06), p. 17235-17240
    Abstract: The unique biology of a neoplasm is reflected by its distinct molecular profile compared with normal tissue. To understand tumor development better, we have undertaken a quantitative proteomic search for abnormally expressed proteins in colonic tumors from Apc Min /+ (Min) mice. By raising pairs of Min and wild-type mice on diets derived from natural-abundance or 15 N-labeled algae, we used metabolic labeling to compare protein levels in colonic tumor versus normal tissue. Because metabolic labeling allows internal control throughout sample preparation and analysis, technical error is minimized as compared with in vitro labeling. Several proteins displayed altered expression, and a subset was validated via stable isotopic dilution using synthetic peptide standards. We also compared gene and protein expression among tumor and nontumor tissue, revealing limited correlation. This divergence was especially pronounced for species showing biological change, highlighting the complementary perspectives provided by transcriptomics and proteomics. Our work demonstrates the power of metabolic labeling combined with stable isotopic dilution as an integrated strategy for the identification and validation of differentially expressed proteins using rodent models of human disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0909282106
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
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