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  • 1
    Online-Ressource
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    A common glycan structure on immunoglobulin G for enhancement of effector functions
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 34 ( 2015-08-25), p. 10611-10616
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 34 ( 2015-08-25), p. 10611-10616
    Kurzfassung: Antibodies have been developed as therapeutic agents for the treatment of cancer, infection, and inflammation. In addition to binding activity toward the target, antibodies also exhibit effector-mediated activities through the interaction of the Fc glycan and the Fc receptors on immune cells. To identify the optimal glycan structures for individual antibodies with desired activity, we have developed an effective method to modify the Fc-glycan structures to a homogeneous glycoform. In this study, it was found that the biantennary N-glycan structure with two terminal alpha-2,6-linked sialic acids is a common and optimized structure for the enhancement of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antiinflammatory activities.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1513456112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2015
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
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    VEGF-A/VEGFR-2 Signaling Leading to cAMP Response Element-Binding Protein Phosphorylation Is a Shared Pathway Underlying the Protective Effect of Preconditioning on Neurons and Endothelial Cells
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 14 ( 2009-04-08), p. 4356-4368
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 14 ( 2009-04-08), p. 4356-4368
    Kurzfassung: Preconditioning protects endothelial cells as well as neurons from ischemic injury. In 7-d-old rat pups, ligating the carotid artery 1 h before hypoxia damaged the ipsilateral cerebral hemisphere; in contrast, ligating the artery 24 h before hypoxia provided complete neuroprotection. The protective effect of the 24 h artery ligation preconditioning model requires the activation of cAMP response element-binding protein (CREB). We tested the hypothesis that vascular endothelial growth factor (VEGF)-A/VEGF receptor-2 (VEGFR-2) signaling that leads to CREB activation is the shared pathway underlying the protective effect of preconditioning in neurons and endothelial cells. VEGF-A, VEGFR-1, or VEGFR-2 was inhibited by antisense oligodeoxynucleotides (ODNs) in vivo and by a VEGF-A neutralizing antibody or VEGFR-2 inhibitor in vitro . CREB phosphorylation (pCREB) and VEGF-A and VEGFR-2 expression were increased and colocalized in vascular endothelial cells and neurons in the ipsilateral cerebral cortex 24 h after ligation. The antisense ODN blockades of VEGF-A and VEGFR-2 decreased pCREB and reduced the protection of 24 h ligation preconditioning. Furthermore, oxygen-glucose deprivation (OGD) preconditioning upregulated VEGF-A, VEGFR-2, and pCREB levels and protected immortalized H19-7 neuronal cells and b.End3 vascular endothelial cells against 24 h OGD cell death. Blocking VEGF-A or VEGFR-2 reduced CREB activation and the effects of OGD preconditioning in neuronal cells and endothelial cells. Transfecting a serine-133 phosphorylation mutant CREB also inhibited the protective effect of OGD preconditioning. We conclude that VEGF-A/VEGFR-2 signaling leading to CREB phosphorylation is the shared pathway underlying the preconditioning-induced protective effect in neurons and vascular endothelial cells in the developing brain.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5497-08.2009
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2009
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Kurzfassung: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2020
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 47 ( 2015-11-24), p. 14670-14675
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 47 ( 2015-11-24), p. 14670-14675
    Kurzfassung: Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1518151112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2015
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Peta–electron volt gamma-ray emission from the Crab Nebula
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 373, No. 6553 ( 2021-07-23), p. 425-430
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 373, No. 6553 ( 2021-07-23), p. 425-430
    Kurzfassung: The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10 −4 to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10 36 ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg5137
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2021
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    Genomic Analyses of Visual Cognition: Perceptual Rivalry and Top-Down Control
    Society for Neuroscience ; 2018
    In:  The Journal of Neuroscience Vol. 38, No. 45 ( 2018-11-07), p. 9668-9678
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 38, No. 45 ( 2018-11-07), p. 9668-9678
    Kurzfassung: Visual cognition in humans has traditionally been studied with cognitive behavioral methods and brain imaging, but much less with genetic methods. Perceptual rivalry, an important phenomenon in visual cognition, is the spontaneous perceptual alternation that occurs between two distinct interpretations of a physically constant visual stimulus (e.g., binocular rivalry stimuli) or a perceptually ambiguous stimulus (e.g., the Necker cube). The switching rate varies dramatically across individuals and can be voluntarily modulated by observers. Here, we adopted a genomic approach to systematically investigate the genetics underlying binocular rivalry, Necker cube rivalry and voluntary modulation of Necker cube rivalry in young Chinese adults ( Homo sapiens , 81% female, 20 ± 1 years old) at multiple levels, including common single nucleotide polymorphism (SNP)-based heritability estimation, SNP-based genome-wide association study (GWAS), gene-based analysis, and pathway analysis. We performed a pilot GWAS in 2441 individuals and replicated it in an independent cohort of 943 individuals. Common SNP-based heritability was estimated to be 25% for spontaneous perceptual rivalry. SNPs rs184765639 and rs75595941 were associated with voluntary modulation, and imaging data suggested genotypic difference of rs184765639 in the surface area of the left caudal-middle frontal cortex. Additionally, converging evidence from multilevel analyses associated genes such as PRMT1 with perceptual switching rate, and MIR1178 with voluntary modulation strength. In summary, this study discovered specific genetic contributions to perceptual rivalry and its voluntary modulation in human beings. These findings may promote our understanding of psychiatric disorders, as perceptual rivalry is a potential psychiatric biomarker. SIGNIFICANCE STATEMENT Perceptual rivalry is an important visual phenomenon in which our perception of a physically constant visual input spontaneously switches between two different states. There are individual variations in perceptual switching rate and voluntary modulation strength. Our genomic analyses reveal several loci associated with these two kinds of variation. Because perceptual rivalry is thought to be relevant to and potentially an endophenotype for psychiatric disorders, these results may help understand not only visual cognition, but also psychiatric disorders.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.1970-17.2018
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t1-1
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t2-1
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t3-1
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t3-2
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t3-3
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t3-4
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t3-5
    DOI: 10.1523/JNEUROSCI.1970-17.2018.t3-6
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2018
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Insights into salt tolerance from the genome of Thellungiella salsuginea
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 30 ( 2012-07-24), p. 12219-12224
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 30 ( 2012-07-24), p. 12219-12224
    Kurzfassung: Thellungiella salsuginea, a close relative of Arabidopsis , represents an extremophile model for abiotic stress tolerance studies. We present the draft sequence of the T. salsuginea genome, assembled based on ∼134-fold coverage to seven chromosomes with a coding capacity of at least 28,457 genes. This genome provides resources and evidence about the nature of defense mechanisms constituting the genetic basis underlying plant abiotic stress tolerance. Comparative genomics and experimental analyses identified genes related to cation transport, abscisic acid signaling, and wax production prominent in T. salsuginea as possible contributors to its success in stressful environments.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1209954109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2012
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    The opportunistic marine pathogen Vibrio parahaemolyticus becomes virulent by acquiring a plasmid that expresses a deadly toxin
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 34 ( 2015-08-25), p. 10798-10803
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 34 ( 2015-08-25), p. 10798-10803
    Kurzfassung: Acute hepatopancreatic necrosis disease (AHPND) is a severe, newly emergent penaeid shrimp disease caused by Vibrio parahaemolyticus that has already led to tremendous losses in the cultured shrimp industry. Until now, its disease-causing mechanism has remained unclear. Here we show that an AHPND-causing strain of V. parahaemolyticus contains a 70-kbp plasmid (pVA1) with a postsegregational killing system, and that the ability to cause disease is abolished by the natural absence or experimental deletion of the plasmid-encoded homologs of the Photorhabdus insect-related (Pir) toxins PirA and PirB. We determined the crystal structure of the V. parahaemolyticus PirA and PirB (PirA vp and PirB vp ) proteins and found that the overall structural topology of PirA vp /PirB vp is very similar to that of the Bacillus Cry insecticidal toxin-like proteins, despite the low sequence identity ( 〈 10%). This structural similarity suggests that the putative PirAB vp heterodimer might emulate the functional domains of the Cry protein, and in particular its pore-forming activity. The gene organization of pVA1 further suggested that pirAB vp may be lost or acquired by horizontal gene transfer via transposition or homologous recombination.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1503129112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2015
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    A gender- and sexual orientation-dependent spatial attentional effect of invisible images
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 45 ( 2006-11-07), p. 17048-17052
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 45 ( 2006-11-07), p. 17048-17052
    Kurzfassung: Human observers are constantly bombarded with a vast amount of information. Selective attention helps us to quickly process what is important while ignoring the irrelevant. In this study, we demonstrate that information that has not entered observers' consciousness, such as interocularly suppressed (invisible) erotic pictures, can direct the distribution of spatial attention. Furthermore, invisible erotic information can either attract or repel observers' spatial attention depending on their gender and sexual orientation. While unaware of the suppressed pictures, heterosexual males' attention was attracted to invisible female nudes, heterosexual females' attention was attracted to invisible male nudes, gay males behaved similarly to heterosexual females, and gay/bisexual females performed in-between heterosexual males and females.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0605678103
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2006
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 49 ( 2015-12-08), p. 15084-15089
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 49 ( 2015-12-08), p. 15084-15089
    Kurzfassung: Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1521316112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2015
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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