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  • 1
    Online Resource
    Online Resource
    Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE
    American Association for the Advancement of Science (AAAS) ; 2010
    In:  Science Vol. 330, No. 6012 ( 2010-12-24), p. 1787-1797
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 330, No. 6012 ( 2010-12-24), p. 1787-1797
    Abstract: To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1198374
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2010
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  • 2
    Online Resource
    Online Resource
    Control of NMDA Receptor Function by the NR2 Subunit Amino-Terminal Domain
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 39 ( 2009-09-30), p. 12045-12058
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 39 ( 2009-09-30), p. 12045-12058
    Abstract: NMDA receptors comprised of different NR2 subunits exhibit strikingly unique biophysical and pharmacological properties. Here, we report that the extracellular amino-terminal domain (ATD) of the NR2 subunit controls pharmacological and kinetic properties of recombinant NMDA receptors, such as agonist potency, deactivation time course, open probability ( P OPEN ), and mean open/shut duration. Using ATD deletion mutants of NR2A, NR2B, NR2C, NR2D, and chimeras of NR2A and NR2D with interchanged ATD [NR2A-(2D-ATD) and NR2D-(2A-ATD)], we show that the ATD contributes to the low glutamate potency of NR2A-containing NMDA receptors and the high glutamate potency of NR2D-containing receptors. The ATD influences the deactivation time courses of NMDA receptors, as removal of the ATD from NR2A slows the deactivation rate, while removal of the ATD from NR2B, NR2C and NR2D accelerates the deactivation rate. Open probability also is influenced by the ATD. Removal of the ATD from NR2A or replacement of the NR2A-ATD with that of NR2D decreases P OPEN in single-channel recordings from outside-out patches of HEK 293 cells. In contrast, deletion of the ATD from NR2D or replacement of the NR2D ATD with that of NR2A increases P OPEN and mean open duration. These data demonstrate the modular nature of NMDA receptors, and show that the ATD of the different NR2 subunits plays an important role in fine-tuning the functional properties of the individual NMDA receptor subtypes.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1365-09.2009
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2009
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  • 3
    Online Resource
    Online Resource
    Cell type–specific genetic regulation of gene expression across human tissues
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 369, No. 6509 ( 2020-09-11)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 369, No. 6509 ( 2020-09-11)
    Abstract: The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type–interaction QTLs for seven cell types and show that cell type–interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type–interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaz8528
    RVK:
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    Early human dispersals within the Americas
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 362, No. 6419 ( 2018-12-07)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6419 ( 2018-12-07)
    Abstract: Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are ≥10,000 years old (up to ~18× coverage). All are most closely related to Native Americans, including those from an Ancient Beringian individual and two morphologically distinct “Paleoamericans.” We found evidence of rapid dispersal and early diversification that included previously unknown groups as people moved south. This resulted in multiple independent, geographically uneven migrations, including one that provides clues of a Late Pleistocene Australasian genetic signal, as well as a later Mesoamerican-related expansion. These led to complex and dynamic population histories from North to South America.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aav2621
    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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    detail.hit.zdb_id: 2066996-3
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  • 5
    Online Resource
    Online Resource
    Structural and Mechanistic Determinants of a Novel Site for Noncompetitive Inhibition of GluN2D-Containing NMDA Receptors
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 10 ( 2011-03-09), p. 3650-3661
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 10 ( 2011-03-09), p. 3650-3661
    Abstract: NMDA receptors are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in several neurological diseases. We have evaluated the mechanism of action of a class of novel subunit-selective NMDA receptor antagonists, typified by (E)-4-(6-methoxy-2-(3-nitrostyryl)-4-oxoquinazolin-3(4H)-yl)-benzoic acid (QNZ46). We found that QNZ46 inhibits NMDA receptor function in a noncompetitive and voltage-independent manner by an unconventional mechanism that requires binding of glutamate to the GluN2 subunit, but not glycine binding to the GluN1 subunit. This dependency of antagonist association on glutamate binding to GluN2 renders these compounds nominally use-dependent, since inhibition will rely on synaptic release of glutamate. Evaluation of the structural determinants responsible for the subunit-selectivity of QNZ46 revealed that these compounds act at a new site that has not previously been described. Residues residing in the part of the agonist binding domain immediately adjacent to the transmembrane helices appear to control selectivity of QNZ46 for GluN2C- and GluN2D-containing receptors. These residues are well-positioned to sense glutamate binding to GluN2 and thus to mediate glutamate-dependent actions. This new class of noncompetitive antagonists could provide an opportunity for the development of pharmacological tools and therapeutic agents that target NMDA receptors at a new site and modulate function by a novel mechanism.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5565-10.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
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  • 6
    Online Resource
    Online Resource
    Social environment is associated with gene regulatory variation in the rhesus macaque immune system
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 17 ( 2012-04-24), p. 6490-6495
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 17 ( 2012-04-24), p. 6490-6495
    Abstract: Variation in the social environment is a fundamental component of many vertebrate societies. In humans and other primates, adverse social environments often translate into lasting physiological costs. The biological mechanisms associated with these effects are therefore of great interest, both for understanding the evolutionary impacts of social behavior and in the context of human health. However, large gaps remain in our understanding of the mechanisms that mediate these effects at the molecular level. Here we addressed these questions by leveraging the power of an experimental system that consisted of 10 social groups of female macaques, in which each individual's social status (i.e., dominance rank) could be experimentally controlled. Using this paradigm, we show that dominance rank results in a widespread, yet plastic, imprint on gene regulation, such that peripheral blood mononuclear cell gene expression data alone predict social status with 80% accuracy. We investigated the mechanistic basis of these effects using cell type-specific gene expression profiling and glucocorticoid resistance assays, which together contributed to rank effects on gene expression levels for 694 (70%) of the 987 rank-related genes. We also explored the possible contribution of DNA methylation levels to these effects, and identified global associations between dominance rank and methylation profiles that suggest epigenetic flexibility in response to status-related behavioral cues. Together, these results illuminate the importance of the molecular response to social conditions, particularly in the immune system, and demonstrate a key role for gene regulation in linking the social environment to individual physiology.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1202734109
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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  • 7
    Online Resource
    Online Resource
    Ionotropic glutamate-like receptor δ2 binds d -serine and glycine
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 35 ( 2007-08-28), p. 14116-14121
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 35 ( 2007-08-28), p. 14116-14121
    Abstract: The orphan glutamate-like receptor GluRδ2 is predominantly expressed in Purkinje cells of the central nervous system. The classification of GluRδ2 to the ionotropic glutamate receptor family is based on sequence similarities, because GluRδ2 does not form functional homomeric glutamate-gated ion channels in transfected cells. Studies in GluRδ2 −/− knockout mice as well as in mice with naturally occurring mutations in the GluRδ2 gene have demonstrated an essential role of GluRδ2 in cerebellar long-term depression, motor learning, motor coordination, and synaptogenesis. However, the lack of a known agonist has hampered investigations on the function of GluRδ2. In this study, the ligand-binding core of GluRδ2 (GluRδ2–S1S2) was found to bind neutral amino acids such as d -serine and glycine, as demonstrated by isothermal titration calorimetry. Direct evidence for binding of d -serine and structural rearrangements in the binding cleft of GluRδ2–S1S2 is provided by x-ray structures of GluRδ2–S1S2 in its apo form and in complex with d -serine. Functionally, d -serine and glycine were shown to inactivate spontaneous ion-channel conductance in GluRδ2 containing the lurcher mutation (EC 50 values, 182 and 507 μM, respectively). These data demonstrate that the GluRδ2 ligand-binding core is capable of binding ligands and that cleft closure of the ligand-binding core can induce conformational changes that alter ion permeation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0703718104
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
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  • 8
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    Online Resource
    Engineering of a membrane-triggered activity switch in coagulation factor VIIa
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 47 ( 2017-11-21), p. 12454-12459
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 47 ( 2017-11-21), p. 12454-12459
    Abstract: Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa-M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1618713114
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
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  • 9
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    Transcriptomic signatures across human tissues identify functional rare genetic variation
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 369, No. 6509 ( 2020-09-11)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 369, No. 6509 ( 2020-09-11)
    Abstract: Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaz5900
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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  • 10
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    Determinants of telomere length across human tissues
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 369, No. 6509 ( 2020-09-11)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 369, No. 6509 ( 2020-09-11)
    Abstract: Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing 〉 20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaz6876
    RVK:
    TA 1000
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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