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  • 1
    Online-Ressource
    Online-Ressource
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 372, No. 6537 ( 2021-04-02), p. 81-84
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 372, No. 6537 ( 2021-04-02), p. 81-84
    Kurzfassung: Pesticide impacts are usually discussed in the context of applied amounts while disregarding the large but environmentally relevant variations in substance-specific toxicity. Here, we systemically interpret changes in the use of 381 pesticides over 25 years by considering 1591 substance-specific acute toxicity threshold values for eight nontarget species groups. We find that the toxicity of applied insecticides to aquatic invertebrates and pollinators has increased considerably—in sharp contrast to the applied amount—and that this increase has been driven by highly toxic pyrethroids and neonicotinoids, respectively. We also report increasing applied toxicity to aquatic invertebrates and pollinators in genetically modified (GM) corn and to terrestrial plants in herbicide-tolerant soybeans since approximately 2010. Our results challenge the claims of a decrease in the environmental impacts of pesticide use.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    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
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 17 ( 2008-04-23), p. 4488-4500
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 17 ( 2008-04-23), p. 4488-4500
    Kurzfassung: Stromal-cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) play a well-established role during embryonic development of dentate gyrus granule cells. However, little is known about the regulation and function of CXCR4 in the postnatal dentate gyrus. Here, we identify a striking mismatch between intense CXCR4 mRNA and limited CXCR4 protein expression in adult rat subgranular layer (SGL) neurons. We demonstrate that CXCR4 protein expression in SGL neurons is progressively lost during postnatal day 15 (P15) to P21. This loss of CXCR4 protein expression was paralleled by a reduction in the number of SDF-1-responsive SGL neurons and a massive upregulation of SDF-1 mRNA in granule cells. Intraventricular infusion of the CXCR4-antagonist AMD3100 dramatically increased CXCR4 protein expression in SGL neurons, suggesting that CXCR4 is tonically activated and downregulated by endogenous SDF-1. Infusion of AMD3100 also facilitated detection of CXCR4 protein in bromodeoxyuridine-, nestin-, and doublecortin-labeled cells and showed that the vast majority of adult-born granule cells transiently expressed CXCR4. Chronic AMD3100 administration impaired formation of new granule cells as well as neurogenesis-dependent long-term recognition of novel objects. Therefore, our findings suggest that tonic activation of CXCR4 in newly formed granule cells by endogenous SDF-1 is essential for neurogenesis-dependent long-term memory in the adult hippocampus.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2008
    ZDB Id: 1475274-8
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 3
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 22, No. 14 ( 2002-07-15), p. 5865-5878
    Kurzfassung: The chemoattractant stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) are key modulators of immune function. In the developing brain, SDF-1 is crucial for neuronal guidance; however, cerebral functions of SDF-1/CXCR4 in adulthood are unclear. Here, we examine the cellular expression of SDF-1 isoforms and CXCR4 in the brain of mice receiving systemic lipopolysaccharide (LPS) or permanent focal cerebral ischemia. CXCR4 mRNA was constitutively expressed in cortical and hippocampal neurons and ependymal cells. Hippocampal neurons targeted the CXCR4 receptor to their somatodendritic and axonal compartments. In cortex and hippocampus, CXCR4-expressing neurons exhibited an overlapping distribution with neurons expressing SDF-1 transcripts. Although neurons synthesized SDF-1α mRNA, the SDF-1β isoform was selectively expressed by endothelial cells of cerebral microvessels. LPS stimulation dramatically decreased endothelial SDF-1β mRNA expression throughout the forebrain but did not affect neuronal SDF-1α. After focal cerebral ischemia, SDF-1β expression was selectively increased in endothelial cells of penumbral blood vessels and decreased in endothelial cells of nonlesioned brain areas. In the penumbra, SDF-1β upregulation was associated with a concomitant infiltration of CXCR4-expressing peripheral blood cells, including macrophages. Neuronal SDF-1α was transiently downregulated and neuronal CXCR4 was transiently upregulated in the nonlesioned cerebral cortex in response to ischemia. Although endothelial SDF-1β may control cerebral infiltration of CXCR4-carrying leukocytes during cerebral ischemia, the neuronal SDF-1α/CXCR4 system may contribute to ischemia-induced neuronal plasticity. Thus, the isoform-specific regulation of SDF-1 expression modulates neurotransmission and cerebral infiltration via distinct CXCR4-dependent pathways.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2002
    ZDB Id: 1475274-8
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 4
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 28 ( 2013-07-09), p. 11451-11456
    Kurzfassung: Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy ( 〉 20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate-binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1–mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2013
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 5
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 39 ( 2011-09-28), p. 13890-13896
    Kurzfassung: Morphine is one of the most potent analgesic drugs. However, the utility of morphine in the management of chronic pain is limited by its rapid development of tolerance. Morphine exerts all of its pharmacological effects via the μ-opioid receptor. In many systems, tolerance is associated with phosphorylation and desensitization of G-protein-coupled receptors (GPCRs). In case of the μ-opioid receptor, phosphorylation occurs in an agonist-selective manner. High-efficacy agonists such as [ d -Ala 2 -MePhe 4 -Gly-ol]enkephalin (DAMGO), fentanyl, or etonitazene stimulate the phosphorylation of both C-terminal threonine 370 (T370) and serine 375 (S375). In contrast, morphine promotes the phosphorylation of S375 but fails to stimulate T370 phosphorylation. Here, we have assessed the contribution of S375 phosphorylation to the development of antinociceptive tolerance to high- and low-efficacy μ agonists in vivo . We show that S375 phosphorylation of the μ-opioid receptor occurs in intact mouse brain in a dose-dependent manner after administration of morphine, fentanyl, or etonitazene. In knock-in mice expressing the phosphorylation-deficient S375A mutant of the μ-opioid receptor, morphine and fentanyl exhibited greater dose-dependent antinociceptive responses than in wild-type mice. However, acute and chronic tolerance to morphine was retained in S375A mutant mice. In contrast, antinociceptive tolerance after repeated subcutaneous application of etonitazene or repeated intracerebroventricular application of DAMGO was diminished. Thus, tolerance to μ agonists with different efficacies develops through distinct pathways. Whereas tolerance induced by DAMGO or etonitazene requires agonist-driven phosphorylation of S375, the development and maintenance of antinociceptive tolerance to morphine occurs independent of S375 phosphorylation.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2011
    ZDB Id: 1475274-8
    SSG: 12
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  • 6
    Online-Ressource
    Online-Ressource
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 18 ( 2015-05-05), p. 5750-5755
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 18 ( 2015-05-05), p. 5750-5755
    Kurzfassung: Compared with nutrient levels and habitat degradation, the importance of agricultural pesticides in surface water may have been underestimated due to a lack of comprehensive quantitative analysis. Increasing pesticide contamination results in decreasing regional aquatic biodiversity, i.e., macroinvertebrate family richness is reduced by ∼30% at pesticide concentrations equaling the legally accepted regulatory threshold levels (RTLs). This study provides a comprehensive metaanalysis of 838 peer-reviewed studies ( 〉 2,500 sites in 73 countries) that evaluates, for the first time to our knowledge on a global scale, the exposure of surface waters to particularly toxic agricultural insecticides. We tested whether measured insecticide concentrations (MICs; i.e., quantified insecticide concentrations) exceed their RTLs and how risks depend on insecticide development over time and stringency of environmental regulation. Our analysis reveals that MICs occur rarely (i.e., an estimated 97.4% of analyses conducted found no MICs) and there is a complete lack of scientific monitoring data for ∼90% of global cropland. Most importantly, of the 11,300 MICs, 52.4% (5,915 cases; 68.5% of the sites) exceeded the RTL for either surface water (RTL SW ) or sediments. Thus, the biological integrity of global water resources is at a substantial risk. RTL SW exceedances depend on the catchment size, sampling regime, and sampling date; are significantly higher for newer-generation insecticides (i.e., pyrethroids); and are high even in countries with stringent environmental regulations. These results suggest the need for worldwide improvements to current pesticide regulations and agricultural pesticide application practices and for intensified research efforts on the presence and effects of pesticides under real-world conditions.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2015
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
    Online-Ressource
    Online-Ressource
    Society for Neuroscience ; 2004
    In:  The Journal of Neuroscience Vol. 24, No. 50 ( 2004-12-15), p. 11404-11415
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 24, No. 50 ( 2004-12-15), p. 11404-11415
    Kurzfassung: Somatostatin receptor 2 (SSTR2) mediates neuromodulatory signals of somatostatin and cortistatin in the cerebral cortex. Recently, SSTR2 has been shown to enhance conserved death ligand- and mitochondria-mediated apoptotic pathways in non-neuronal cells. Whether somatostatin receptors are activated in cerebrocortical neurons and contribute to neurodegeneration after experimental focal ischemia was unknown until now. Here we examined internalization of SSTR2 in a rat model of middle cerebral artery occlusion (MCAO) by confocal microscopy. At 3 and 6 hr after MCAO, SSTR2 was internalized excessively in cerebrocortical neurons adjacent to the infarct, which was prevented by intracerebroventricular application of the SSTR2-selective antagonist BIM-23627. SSTR2 internalization was associated with a transient depletion of somatostatin from axonal terminals and increased expression of SSTR2 mRNA. The initial loss of somatostatin was followed by an increase in somatostatin mRNA levels, whereas cortistatin mRNA expression was decreased. In SSTR2-deficient mice with lacZ under the control of the SSTR2 promoter, MCAO-induced upregulation of SSTR2 gene expression was less pronounced than in wild types. SSTR2-deficient mice exhibited a 40% reduction of infarct size after permanent distal MCAO and a 63% reduction after transient proximal MCAO. In summary, we provide direct evidence for activation of SSTR2 by an endogenous ligand after focal ischemia. Activation of functional SSTR2 receptors contributes to increased SSTR2 gene expression and postischemic neurodegeneration.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2004
    ZDB Id: 1475274-8
    SSG: 12
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  • 8
    Online-Ressource
    Online-Ressource
    Society for Neuroscience ; 2003
    In:  The Journal of Neuroscience Vol. 23, No. 12 ( 2003-06-15), p. 5123-5130
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 23, No. 12 ( 2003-06-15), p. 5123-5130
    Kurzfassung: The chemotactic factors directing interneuron migration during cerebrocortical development are essentially unknown. Here we identify the CXC chemokine receptor 4 (CXCR4) in interneuron precursors migrating from the basal forebrain to the neocortex and demonstrate that stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for isolated striatal precursors. In addition, we show that CXCR4 is present in early generated Cajal-Retzius cells of the cortical marginal zone. In mice with a null mutation in CXCR4 or SDF-1, interneurons were severely underrepresented in the superficial layers and ectopically placed in the deep layers of the neocortex. In contrast, the submeningeal positioning of Cajal-Retzius cells was unaffected. Thus, our findings suggest that SDF-1, which is highly expressed in the embryonic leptomeninx, selectively regulates migration and layer-specific integration of CXCR4-expressing interneurons during neocortical development.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2003
    ZDB Id: 1475274-8
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 9
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 13 ( 2020-03-31), p. 7140-7149
    Kurzfassung: The recognition of cis -regulatory RNA motifs in human transcripts by RNA binding proteins (RBPs) is essential for gene regulation. The molecular features that determine RBP specificity are often poorly understood. Here, we combined NMR structural biology with high-throughput iCLIP approaches to identify a regulatory mechanism for U2AF2 RNA recognition. We found that the intrinsically disordered linker region connecting the two RNA recognition motif (RRM) domains of U2AF2 mediates autoinhibitory intramolecular interactions to reduce nonproductive binding to weak Py-tract RNAs. This proofreading favors binding of U2AF2 at stronger Py-tracts, as required to define 3′ splice sites at early stages of spliceosome assembly. Mutations that impair the linker autoinhibition enhance the affinity for weak Py-tracts result in promiscuous binding of U2AF2 along mRNAs and impact on splicing fidelity. Our findings highlight an important role of intrinsically disordered linkers to modulate RNA interactions of multidomain RBPs.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2020
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 10
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 30 ( 2021-07-27)
    Kurzfassung: Cyclic nucleotide-gated (CNG) ion channels of olfactory neurons are tetrameric membrane receptors that are composed of two A2 subunits, one A4 subunit, and one B1b subunit. Each subunit carries a cyclic nucleotide-binding domain in the carboxyl terminus, and the channels are activated by the binding of cyclic nucleotides. The mechanism of cooperative channel activation is still elusive. Using a complete set of engineered concatenated olfactory CNG channels, with all combinations of disabled binding sites and fit analyses with systems of allosteric models, the thermodynamics of microscopic cooperativity for ligand binding was subunit- and state-specifically quantified. We show, for the closed channel, that preoccupation of each of the single subunits increases the affinity of each other subunit with a Gibbs free energy ( ΔΔG ) of ∼−3.5 to ∼−5.5 kJ ⋅ mol −1 , depending on the subunit type, with the only exception that a preoccupied opposite A2 subunit has no effect on the other A2 subunit. Preoccupation of two neighbor subunits of a given subunit causes the maximum affinity increase with ΔΔG of ∼−9.6 to ∼−9.9 kJ ⋅ mol −1 . Surprisingly, triple preoccupation leads to fewer negative ΔΔG values for a given subunit as compared to double preoccupation. Channel opening increases the affinity of all subunits. The equilibrium constants of closed–open isomerizations systematically increase with progressive liganding. This work demonstrates, on the example of the heterotetrameric olfactory CNG channel, a strategy to derive detailed insights into the specific mutual control of the individual subunits in a multisubunit membrane receptor.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2021
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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