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  • 1
    Online Resource
    Online Resource
    Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 19 ( 2013-05-07)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 19 ( 2013-05-07)
    Abstract: The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1220523110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 2
    Online Resource
    Online Resource
    Clonal precursor of bone, cartilage, and hematopoietic niche stromal cells
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 31 ( 2013-07-30), p. 12643-12648
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 31 ( 2013-07-30), p. 12643-12648
    Abstract: Organs are composites of tissue types with diverse developmental origins, and they rely on distinct stem and progenitor cells to meet physiological demands for cellular production and homeostasis. How diverse stem cell activity is coordinated within organs is not well understood. Here we describe a lineage-restricted, self-renewing common skeletal progenitor (bone, cartilage, stromal progenitor; BCSP) isolated from limb bones and bone marrow tissue of fetal, neonatal, and adult mice. The BCSP clonally produces chondrocytes (cartilage-forming) and osteogenic (bone-forming) cells and at least three subsets of stromal cells that exhibit differential expression of cell surface markers, including CD105 (or endoglin), Thy1 [or CD90 (cluster of differentiation 90)], and 6C3 [ENPEP glutamyl aminopeptidase (aminopeptidase A)] . These three stromal subsets exhibit differential capacities to support hematopoietic (blood-forming) stem and progenitor cells. Although the 6C3-expressing subset demonstrates functional stem cell niche activity by maintaining primitive hematopoietic stem cell (HSC) renewal in vitro, the other stromal populations promote HSC differentiation to more committed lines of hematopoiesis, such as the B-cell lineage. Gene expression analysis and microscopic studies further reveal a microenvironment in which CD105-, Thy1-, and 6C3-expressing marrow stroma collaborate to provide cytokine signaling to HSCs and more committed hematopoietic progenitors. As a result, within the context of bone as a blood-forming organ, the BCSP plays a critical role in supporting hematopoiesis through its generation of diverse osteogenic and hematopoietic-promoting stroma, including HSC supportive 6C3(+) niche cells.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1310212110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 3
    Online Resource
    Online Resource
    Failure to Confirm XMRV/MLVs in the Blood of Patients with Chronic Fatigue Syndrome: A Multi-Laboratory Study
    American Association for the Advancement of Science (AAAS) ; 2011
    In:  Science Vol. 334, No. 6057 ( 2011-11-11), p. 814-817
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 334, No. 6057 ( 2011-11-11), p. 814-817
    Abstract: Murine leukemia viruses (MLVs), including xenotropic-MLV–related virus (XMRV), have been controversially linked to chronic fatigue syndrome (CFS). To explore this issue in greater depth, we compiled coded replicate samples of blood from 15 subjects previously reported to be XMRV/MLV–positive (14 with CFS) and from 15 healthy donors previously determined to be negative for the viruses. These samples were distributed in a blinded fashion to nine laboratories, which performed assays designed to detect XMRV/MLV nucleic acid, virus replication, and antibody. Only two laboratories reported evidence of XMRV/MLVs; however, replicate sample results showed disagreement, and reactivity was similar among CFS subjects and negative controls. These results indicate that current assays do not reproducibly detect XMRV/MLV in blood samples and that blood donor screening is not warranted.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1213841
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2011
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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  • 4
    Online Resource
    Online Resource
    Relating Self-Concept Consistency to Hedonic and Eudaimonic Well-Being in Eight Cultures
    SAGE Publications ; 2014
    In:  Journal of Cross-Cultural Psychology Vol. 45, No. 5 ( 2014-06), p. 695-712
    Details
    In: Journal of Cross-Cultural Psychology, SAGE Publications, Vol. 45, No. 5 ( 2014-06), p. 695-712
    Abstract: Western theories suggest that self-concept consistency is important for well-being, but cultural psychologists have proposed that this relationship may be weaker in collectivistic or dialectical cultures. Hypotheses regarding the ability of self-concept (cross-role) consistency and short-term stability to predict hedonic and eudaimonic well-being across cultures were tested. College students in the United States, Australia, Mexico, Venezuela, the Philippines, Malaysia, China, and Japan rated their traits in various roles at test and retest and completed measures of hedonic and eudaimonic well-being. In all cultures, cross-role consistency and short-term stability were inversely associated with negative affect, an aspect of hedonic well-being, and positively associated with Big Five Emotional Stability. In contrast, cross-role consistency and short-term stability were related to eudaimonic well-being more reliably in individualistic cultures than in collectivistic cultures, although the results in China only partially conformed to this pattern. We concluded that cross-role variability and short-term instability of self-concepts have a significant temperamental or affective basis, and this temperamental basis is a cultural universal. In addition, cultural psychology predictions of a weaker relationship between self-concept consistency and well-being in collectivistic cultures, as compared with individualistic cultures, were largely supported for eudaimonic well-being.
    Type of Medium: Online Resource
    ISSN: 0022-0221 , 1552-5422
    URL: Article
    DOI: 10.1177/0022022114527347
    RVK:
    CL 1000
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
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  • 5
    Online Resource
    Online Resource
    Need Satisfaction and Well-Being : Testing Self-Determination Theory in Eight Cultures
    SAGE Publications ; 2013
    In:  Journal of Cross-Cultural Psychology Vol. 44, No. 4 ( 2013-05), p. 507-534
    Details
    In: Journal of Cross-Cultural Psychology, SAGE Publications, Vol. 44, No. 4 ( 2013-05), p. 507-534
    Abstract: According to Self-Determination Theory (SDT), satisfaction of needs for autonomy, competence, and relatedness is a universal requirement for psychological well-being. We tested this hypothesis with college students in the United States, Australia, Mexico, Venezuela, the Philippines, Malaysia, China, and Japan. Participants rated the extent to which these needs, plus needs for self-actualization and pleasure-stimulation, were satisfied in various roles and reported their general hedonic (i.e., positive and negative affect) and eudaimonic (e.g., meaning in life, personal growth) well-being. Asian participants averaged lower than non-Asian participants in perceived satisfaction of autonomy, competence, and self-actualization needs and in most aspects of eudaimonic well-being, and these differences were partially accounted for by differences in dialecticism and independent self-construals. Nonetheless, perceived need satisfaction predicted overall well-being to a similar degree in all cultures and in most cultures provided incremental prediction beyond the Big Five traits. Perceived imbalance in the satisfaction of different needs also modestly predicted well-being, particularly negative affect. The study extended support for the universal importance of SDT need satisfaction to several new cultures.
    Type of Medium: Online Resource
    ISSN: 0022-0221 , 1552-5422
    URL: Article
    DOI: 10.1177/0022022112466590
    RVK:
    CL 1000
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2013
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  • 6
    Online Resource
    Online Resource
    Toward discovery science of human brain function
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 10 ( 2010-03-09), p. 4734-4739
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 10 ( 2010-03-09), p. 4734-4739
    Abstract: Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency ( 〈 0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's “functional connectome.” Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain–behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/ .
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0911855107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 7
    Online Resource
    Online Resource
    Electroencephalogram signatures of loss and recovery of consciousness from propofol
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 12 ( 2013-03-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 12 ( 2013-03-19)
    Abstract: Unconsciousness is a fundamental component of general anesthesia (GA), but anesthesiologists have no reliable ways to be certain that a patient is unconscious. To develop EEG signatures that track loss and recovery of consciousness under GA, we recorded high-density EEGs in humans during gradual induction of and emergence from unconsciousness with propofol. The subjects executed an auditory task at 4-s intervals consisting of interleaved verbal and click stimuli to identify loss and recovery of consciousness. During induction, subjects lost responsiveness to the less salient clicks before losing responsiveness to the more salient verbal stimuli; during emergence they recovered responsiveness to the verbal stimuli before recovering responsiveness to the clicks. The median frequency and bandwidth of the frontal EEG power tracked the probability of response to the verbal stimuli during the transitions in consciousness. Loss of consciousness was marked simultaneously by an increase in low-frequency EEG power ( 〈 1 Hz), the loss of spatially coherent occipital alpha oscillations (8–12 Hz), and the appearance of spatially coherent frontal alpha oscillations. These dynamics reversed with recovery of consciousness. The low-frequency phase modulated alpha amplitude in two distinct patterns. During profound unconsciousness, alpha amplitudes were maximal at low-frequency peaks, whereas during the transition into and out of unconsciousness, alpha amplitudes were maximal at low-frequency nadirs. This latter phase–amplitude relationship predicted recovery of consciousness. Our results provide insights into the mechanisms of propofol-induced unconsciousness, establish EEG signatures of this brain state that track transitions in consciousness precisely, and suggest strategies for monitoring the brain activity of patients receiving GA.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1221180110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 8
    Online Resource
    Online Resource
    Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 12 ( 2010-03-23), p. 5587-5592
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 12 ( 2010-03-23), p. 5587-5592
    Abstract: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is epidemic in the United States, even rivaling HIV/AIDS in its public health impact. The pandemic clone USA300, like other CA-MRSA strains, expresses Panton-Valentine leukocidin (PVL), a pore-forming toxin that targets polymorphonuclear leukocytes (PMNs). PVL is thought to play a key role in the pathogenesis of necrotizing pneumonia, but data from rodent infection models are inconclusive. Rodent PMNs are less susceptible than human PMNs to PVL-induced cytolysis, whereas rabbit PMNs, like those of humans, are highly susceptible to PVL-induced cytolysis. This difference in target cell susceptibility could affect results of experimental models. Therefore, we developed a rabbit model of necrotizing pneumonia to compare the virulence of a USA300 wild-type strain with that of isogenic PVL-deletion mutant and -complemented strains. PVL enhanced the capacity of USA300 to cause severe lung necrosis, pulmonary edema, alveolar hemorrhage, hemoptysis, and death, hallmark clinical features of fatal human necrotizing pneumonia. Purified PVL instilled directly into the lung caused lung inflammation and injury by recruiting and lysing PMNs, which damage the lung by releasing cytotoxic granule contents. These findings provide insights into the mechanism of PVL-induced lung injury and inflammation and demonstrate the utility of the rabbit for studying PVL-mediated pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0912403107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 9
    Online Resource
    Online Resource
    Crystallographic basis for calcium regulation of sodium channels
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 9 ( 2012-02-28), p. 3558-3563
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 9 ( 2012-02-28), p. 3558-3563
    Abstract: Voltage-gated sodium channels underlie the rapid regenerative upstroke of action potentials and are modulated by cytoplasmic calcium ions through a poorly understood mechanism. We describe the 1.35 Å crystal structure of Ca 2+ -bound calmodulin (Ca 2+ /CaM) in complex with the inactivation gate (DIII-IV linker) of the cardiac sodium channel (Na V 1.5). The complex harbors the positions of five disease mutations involved with long Q-T type 3 and Brugada syndromes. In conjunction with isothermal titration calorimetry, we identify unique inactivation-gate mutations that enhance or diminish Ca 2+ /CaM binding, which, in turn, sensitize or abolish Ca 2+ regulation of full-length channels in electrophysiological experiments. Additional biochemical experiments support a model whereby a single Ca 2+ /CaM bridges the C-terminal IQ motif to the DIII-IV linker via individual N and C lobes, respectively. The data suggest that Ca 2+ /CaM destabilizes binding of the inactivation gate to its receptor, thus biasing inactivation toward more depolarized potentials.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1114748109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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