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  • 1
    Online Resource
    Online Resource
    Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 8 ( 2010-02-23), p. 3728-3733
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 8 ( 2010-02-23), p. 3728-3733
    Abstract: p53, apoptosis, and senescence are frequently activated in preneoplastic lesions and are barriers to progression to malignancy. These barriers have been suggested to result from an ATM-mediated DNA damage response (DDR), which may follow oncogene-induced hyperproliferation and ensuing DNA replication stress. To elucidate the currently untested role of DDR in breast cancer initiation, we examined the effect of oncogene expression in several murine models of breast cancer. We did not observe a detectable DDR in early hyperplastic lesions arising in transgenic mice expressing several different oncogenes. However, DDR signaling was strongly induced in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2 . Thus, activation of an oncogene after normal tissue development causes a DDR. Furthermore, in this somatic ErbB2 tumor model, ATM, and thus DDR, is required for p53 stabilization, apoptosis, and senescence. In palpable tumors in this model, p53 stabilization and apoptosis are lost, but unexpectedly senescence remains in many tumor cells. Thus, this murine model fully recapitulates early DDR signaling; the eventual suppression of its endpoints in tumorigenesis provides compelling evidence that ErbB2-induced aberrant mammary cell proliferation leads to an ATM-mediated DDR that activates apoptosis and senescence, and at least the former must be overcome to progress to malignancy. This in vivo study also uncovers an unexpected effect of ErbB2 activation previously known for its prosurvival roles, and suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be important in breast cancer prevention.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0910665107
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 2
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    Disruption of the petal identity gene APETALA3-3 is highly correlated with loss of petals within the buttercup family (Ranunculaceae)
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 13 ( 2013-03-26), p. 5074-5079
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 13 ( 2013-03-26), p. 5074-5079
    Abstract: Absence of petals, or being apetalous, is usually one of the most important features that characterizes a group of flowering plants at high taxonomic ranks (i.e., family and above). The apetalous condition, however, appears to be the result of parallel or convergent evolution with unknown genetic causes. Here we show that within the buttercup family (Ranunculaceae), apetalous genera in at least seven different lineages were all derived from petalous ancestors, indicative of parallel petal losses. We also show that independent petal losses within this family were strongly associated with decreased or eliminated expression of a single floral organ identity gene, APETALA3-3 ( AP3-3 ) , apparently owing to species-specific molecular lesions. In an apetalous mutant of Nigella , insertion of a transposable element into the second intron has led to silencing of the gene and transformation of petals into sepals. In several naturally occurring apetalous genera, such as Thalictrum , Beesia , and Enemion , the gene has either been lost altogether or disrupted by deletions in coding or regulatory regions. In Clematis , a large genus in which petalous species evolved secondarily from apetalous ones, the gene exhibits hallmarks of a pseudogene. These results suggest that, as a petal identity gene, AP3-3 has been silenced or down-regulated by different mechanisms in different evolutionary lineages. This also suggests that petal identity did not evolve many times independently across the Ranunculaceae but was lost in numerous instances. The genetic mechanisms underlying the independent petal losses, however, may be complex, with disruption of AP3-3 being either cause or effect.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1219690110
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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  • 3
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    A New Boson with a Mass of 125 GeV Observed with the CMS Experiment at the Large Hadron Collider
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Vol. 338, No. 6114 ( 2012-12-21), p. 1569-1575
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 338, No. 6114 ( 2012-12-21), p. 1569-1575
    Abstract: The Higgs boson was postulated nearly five decades ago within the framework of the standard model of particle physics and has been the subject of numerous searches at accelerators around the world. Its discovery would verify the existence of a complex scalar field thought to give mass to three of the carriers of the electroweak force—the W + , W – , and Z 0 bosons—as well as to the fundamental quarks and leptons. The CMS Collaboration has observed, with a statistical significance of five standard deviations, a new particle produced in proton-proton collisions at the Large Hadron Collider at CERN. The evidence is strongest in the diphoton and four-lepton (electrons and/or muons) final states, which provide the best mass resolution in the CMS detector. The probability of the observed signal being due to a random fluctuation of the background is about 1 in 3 × 10 6 . The new particle is a boson with spin not equal to 1 and has a mass of about 125 giga–electron volts. Although its measured properties are, within the uncertainties of the present data, consistent with those expected of the Higgs boson, more data are needed to elucidate the precise nature of the new particle.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1230816
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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    detail.hit.zdb_id: 2066996-3
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  • 4
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    Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 38 ( 2014-09-23), p. 13990-13995
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 38 ( 2014-09-23), p. 13990-13995
    Abstract: Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1403493111
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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  • 5
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    Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory loss
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 41 ( 2012-10-09), p. 16743-16748
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 41 ( 2012-10-09), p. 16743-16748
    Abstract: Current understanding of amyloid-β (Aβ) metabolism and toxicity provides an extensive list of potential targets for developing drugs for treating Alzheimer’s disease. We took two independent approaches, including synaptic-plasticity–based analysis and behavioral screening of synthetic compounds, for identifying single compounds that are capable of rescuing the Aβ-induced memory loss in both transgenic fruit fly and transgenic mouse models. Two clinically available drugs and three synthetic compounds not only showed positive effects in behavioral tests but also antagonized the Aβ oligomers-induced activation of the epidermal growth factor receptor (EGFR). Such surprising converging outcomes from two parallel approaches lead us to conclude that EGFR is a preferred target for treating Aβ-induced memory loss.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1208011109
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 6
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    Virus infection triggers widespread silencing of host genes by a distinct class of endogenous siRNAs in Arabidopsis
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 40 ( 2014-10-07), p. 14613-14618
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 40 ( 2014-10-07), p. 14613-14618
    Abstract: Antiviral immunity controlled by RNA interference (RNAi) in plants and animals is thought to specifically target only viral RNAs by the virus-derived small interfering RNAs (siRNAs). Here we show that activation of antiviral RNAi in Arabidopsis plants is accompanied by the production of an abundant class of endogenous siRNAs mapped to the exon regions of more than 1,000 host genes and rRNA. These virus-activated siRNAs (vasiRNAs) are predominantly 21 nucleotides long with an approximately equal ratio of sense and antisense strands. Genetically, vasiRNAs are distinct from the known plant endogenous siRNAs characterized to date and instead resemble viral siRNAs by requiring Dicer-like 4 and RNA-dependent RNA polymerase 1 (RDR1) for biogenesis. However, loss of EXORIBONUCLEASE4/THYLENE-INSENSITIVE5 enhances vasiRNA biogenesis and virus resistance without altering the biogenesis of viral siRNAs. We show that vasiRNAs are active in directing widespread silencing of the target host genes and that Argonaute-2 binds to and is essential for the silencing activity of vasiRNAs. Production of vasiRNAs is readily detectable in Arabidopsis after infection by viruses from two distinct supergroups of plant RNA virus families and is targeted for inhibition by the silencing suppressor protein 2b of Cucumber mosaic virus. These findings reveal RDR1 production of Arabidopsis endogenous siRNAs and identify production of vasiRNAs to direct widespread silencing of host genes as a conserved response of plants to infection by diverse viruses. A possible function for vasiRNAs to confer broad-spectrum antiviral activity distinct to the virus-specific antiviral RNAi by viral siRNAs is discussed.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1407131111
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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    SSG: 11
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  • 7
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    Process-based network decomposition reveals backbone motif structure
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 23 ( 2010-06-08), p. 10478-10483
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 23 ( 2010-06-08), p. 10478-10483
    Abstract: A central challenge in systems biology today is to understand the network of interactions among biomolecules and, especially, the organizing principles underlying such networks. Recent analysis of known networks has identified small motifs that occur ubiquitously, suggesting that larger networks might be constructed in the manner of electronic circuits by assembling groups of these smaller modules. Using a unique process-based approach to analyzing such networks, we show for two cell-cycle networks that each of these networks contains a giant backbone motif spanning all the network nodes that provides the main functional response. The backbone is in fact the smallest network capable of providing the desired functionality. Furthermore, the remaining edges in the network form smaller motifs whose role is to confer stability properties rather than provide function. The process-based approach used in the above analysis has additional benefits: It is scalable, analytic (resulting in a single analyzable expression that describes the behavior), and computationally efficient (all possible minimal networks for a biological process can be identified and enumerated).
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0914180107
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 8
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    Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 8 ( 2012-02-21), p. 3149-3154
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 8 ( 2012-02-21), p. 3149-3154
    Abstract: With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2–mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE 2 ) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with K B 2–20 nM in Schild regression analysis and 268- to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1120195109
    RVK:
    TA 1000
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 9
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    Feature-specific cortical plasticity after rapid perceptual learning during speech segregation: a MEG study
    Acoustical Society of America (ASA) ; 2012
    In:  The Journal of the Acoustical Society of America Vol. 131, No. 4_Supplement ( 2012-04-01), p. 3388-3388
    Details
    In: The Journal of the Acoustical Society of America, Acoustical Society of America (ASA), Vol. 131, No. 4_Supplement ( 2012-04-01), p. 3388-3388
    Abstract: This study examined whether 1-hour perceptual training could elicit feature-specific improvement of performance and corresponding cortical plasticity in humans during speech segregation by using magnetoencephalography (MEG). One group of participants learned to segregate concurrent vowels by using difference in fundamental frequency (f0) while the other group learned to use difference in sound location. MEG recordings were conducted after the training and required participants to identify the two different vowels, which may have the same f0 and location or differ in f0 only, location only or both f0 and location. Compared to Control Group who didn't receive pre-scan training, the trained groups showed behavioral improvements specific to the trained cues which were paralleled by feature-specific changes on brain activities. That is, f0-difference-induced changes in dipole source-waveforms in auditory cortex were only modulated in Frequency Group, while location-difference-induced changes were only modulated in Location Group. Furthermore, Frequency Group showed stronger activations in auditory “what” pathway than Location Group when processing f0-difference, while Location Group revealed stronger activation in auditory “where” pathway than Frequency Group when processing location-difference. The double-disassociation in both behaviors and neuromagnetic responses indicates that rapid perceptual learning could elicit highly feature-specific plasticity in human cortex during speech segregation.
    Type of Medium: Online Resource
    ISSN: 0001-4966 , 1520-8524
    URL: Article
    DOI: 10.1121/1.4708779
    RVK:
    EQ 1000
    Language: English
    Publisher: Acoustical Society of America (ASA)
    Publication Date: 2012
    detail.hit.zdb_id: 1461063-2
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  • 10
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    Differentially Organized Top-Down Modulation of Prepulse Inhibition of Startle
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 38 ( 2011-09-21), p. 13644-13653
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 38 ( 2011-09-21), p. 13644-13653
    Abstract: Prepulse inhibition (PPI) of startle is the suppression of the startle reflex when a weaker sensory stimulus (the prepulse) shortly precedes the startling stimulus. PPI can be attentionally enhanced in both humans and laboratory animals. This study investigated whether the following three forebrain structures, which are critical for initial cortical processing of auditory signals, auditory fear conditioning/memories, and spatial attention, respectively, play a role in the top-down modulation of PPI in rats: the primary auditory cortex (A1), lateral nucleus of the amygdala (LA), and posterior parietal cortex (PPC). The results show that, under the noise-masking condition, PPI was enhanced by fear conditioning of the prepulse in a prepulse-specific manner, and the conditioning-induced PPI enhancement was further increased by perceptual separation between the conditioned prepulse and the noise masker. Reversibly blocking glutamate receptors in the A1 with 2 m m kynurenic acid eliminated both the conditioning-induced and perceptual separation-induced PPI enhancements. Blocking the LA eliminated the conditioning-induced but not the perceptual separation-induced PPI enhancement, and blocking the PPC specifically eliminated the perceptual separation-induced PPI enhancement. The two types of PPI enhancements were also eliminated by the extinction manipulation. Thus, the top-down modulation of PPI is differentially organized and depends on operations of various forebrain structures. Due to the fine-tuned modulation by higher-order cognitive processes, functions of PPI can be more flexible to complex environments. The top-down enhancements of PPI in rats are also useful for modeling some mental disorders, such as schizophrenia, attention deficit/hyperactivity disorder, and posttraumatic stress disorder.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1292-11.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
    detail.hit.zdb_id: 1475274-8
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