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  • Linguistik  (352)
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  • 1
    Online-Ressource
    Online-Ressource
    Identification of Sodium- and Chloride-Sensitive Sites in the Slack Channel
    Society for Neuroscience ; 2023
    In:  The Journal of Neuroscience Vol. 43, No. 15 ( 2023-04-12), p. 2665-2681
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 43, No. 15 ( 2023-04-12), p. 2665-2681
    Kurzfassung: The Slack channel (KCNT1, Slo2.2) is a sodium-activated and chloride-activated potassium channel that regulates heart rate and maintains the normal excitability of the nervous system. Despite intense interest in the sodium gating mechanism, a comprehensive investigation to identify the sodium-sensitive and chloride-sensitive sites has been missing. In the present study, we identified two potential sodium-binding sites in the C-terminal domain of the rat Slack channel by conducting electrophysical recordings and systematic mutagenesis of cytosolic acidic residues in the rat Slack channel C terminus. In particular, by taking advantage of the M335A mutant, which results in the opening of the Slack channel in the absence of cytosolic sodium, we found that among the 92 screened negatively charged amino acids, E373 mutants could completely remove sodium sensitivity of the Slack channel. In contrast, several other mutants showed dramatic decreases in sodium sensitivity but did not abolish it altogether. Furthermore, molecular dynamics (MD) simulations performed at the hundreds of nanoseconds timescale revealed one or two sodium ions at the E373 position or an acidic pocket composed of several negatively charged residues. Moreover, the MD simulations predicted possible chloride interaction sites. By screening predicted positively charged residues, we identified R379 as a chloride interaction site. Thus, we conclude that the E373 site and the D863/E865 pocket are two potential sodium-sensitive sites, while R379 is a chloride interaction site in the Slack channel. SIGNIFICANCE STATEMENT The research presented here identified two distinct sodium and one chloride interaction sites located in the intracellular C-terminal domain of the Slack (Slo2.2, KCNT1) channel. Identification of the sites responsible for the sodium and chloride activation of the Slack channel sets its gating property apart from other potassium channels in the BK channel family. This finding sets the stage for future functional and pharmacological studies of this channel.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1365-22.2023
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2023
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 9 ( 2020-03-03), p. 4770-4780
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 9 ( 2020-03-03), p. 4770-4780
    Kurzfassung: Recurrence and metastasis remain the major obstacles to successful treatment of hepatocellular carcinoma (HCC). Chromatin remodeling factor ARID2 is commonly mutated in HCC, indicating its important role in cancer development. However, its role in HCC metastasis is largely elusive. In this study, we find that ARID2 expression is significantly decreased in metastatic HCC tissues, showing negative correlation with pathological grade, organ metastasis and positive association with survival of HCC patients. ARID2 inhibits migration and invasion of HCC cells in vitro and metastasis in vivo. Moreover, ARID2 knockout promotes pulmonary metastasis in different HCC mouse models. Mechanistic study reveals that ARID2 represses epithelial–mesenchymal transition (EMT) of HCC cells by recruiting DNMT1 to Snail promoter, which increases promoter methylation and inhibits Snail transcription. In addition, we discover that ARID2 mutants with disrupted C2H2 domain lose the metastasis suppressor function, exhibiting a positive association with HCC metastasis and poor prognosis. In conclusion, our study reveals the metastasis suppressor role as well as the underlying mechanism of ARID2 in HCC and provides a potential therapeutic target for ARID2-deficient HCC.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1914937117
    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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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 8 ( 2023-08-01), p. 3373-3391
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 8 ( 2023-08-01), p. 3373-3391
    Kurzfassung: GGC repeat expansion in the 5′ untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.
    Materialart: Online-Ressource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad058
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2023
    ZDB Id: 1474117-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Upregulation of the E3 ligase NEDD4-1 by Oxidative Stress Degrades IGF-1 Receptor Protein in Neurodegeneration
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 32 ( 2012-08-08), p. 10971-10981
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 32 ( 2012-08-08), p. 10971-10981
    Kurzfassung: The importance of ubiquitin E3 ligases in neurodegeneration is being increasingly recognized. The crucial role of NEDD4-1 in neural development is well appreciated; however, its role in neurodegeneration remains unexplored. Herein, we report increased NEDD4-1 expression in the degenerated tissues of several major neurodegenerative diseases. Moreover, its expression is upregulated in cultured neurons in response to various neurotoxins, including zinc and hydrogen superoxide, via transcriptional activation likely mediated by the reactive oxygen species (ROS)-responsive FOXM1B. Reduced protein levels of the insulin-like growth factor receptor (IGF-1Rβ) were observed as a consequence of upregulated NEDD4-1 via the ubiquitin-proteasome system. Overexpression of a familial mutant form of superoxide dismutase 1 (SOD1) (G93A) in neuroblastoma cells resulted in a similar reduction of IGF-1Rβ protein. This inverse correlation between NEDD4-1 and IGF-1Rβ was also observed in the cortex and spinal cords of mutant (G93A) SOD1 transgenic mice at a presymptomatic age, which was similarly induced by in vivo -administered zinc in wild-type C57BL/6 mice. Furthermore, histochemistry reveals markedly increased NEDD4-1 immunoreactivity in the degenerating/degenerated motor neurons in the lumbar anterior horn of the spinal cord, suggesting a direct causative role for NEDD4-1 in neurodegeneration. Indeed, downregulation of NEDD4-1 by shRNA or overexpression of a catalytically inactive form rescued neurons from zinc-induced cell death. Similarly, neurons with a NEDD4-1 haplotype are more resistant to apoptosis, largely due to expression of higher levels of IGF-1Rβ.Together, our work identifies a novel molecular mechanism for ROS-upregulated NEDD4-1 and the subsequently reduced IGF-1Rβ signaling in neurodegeneration.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1836-12.2012
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2012
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 5
    Online-Ressource
    Online-Ressource
    AGRP Neurons Project to the Medial Preoptic Area and Modulate Maternal Nest-Building
    Society for Neuroscience ; 2019
    In:  The Journal of Neuroscience Vol. 39, No. 3 ( 2019-01-16), p. 456-471
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 39, No. 3 ( 2019-01-16), p. 456-471
    Kurzfassung: AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ∼30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP→mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger. SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP→mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0958-18.2018
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2019
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    Hsp90 Chaperone Inhibitor 17-AAG Attenuates Aβ-Induced Synaptic Toxicity and Memory Impairment
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 7 ( 2014-02-12), p. 2464-2470
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 7 ( 2014-02-12), p. 2464-2470
    Kurzfassung: The excessive accumulation of soluble amyloid peptides (Aβ) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. Here, we report that Hsp90 inhibition by 17-AAG elicited not only a heat shock-like response but also upregulated presynaptic and postsynaptic proteins, such as synapsin I, synaptophysin, and PSD95 in neurons. 17-AAG treatment enhanced high-frequency stimulation-evoked LTP and protected neurons from synaptic damage induced by soluble Aβ. In AD transgenic mice, the daily administration of 17-AAG over 7 d resulted in a marked increase in PSD95 expression in hippocampi. 17-AAG treatments in wild-type C57BL/6 mice challenged by soluble Aβ significantly improved contextual fear memory. Further, we demonstrate that 17-AAG activated synaptic protein expression via transcriptional mechanisms through the heat shock transcription factor HSF1. Together, our findings identify a novel function of Hsp90 inhibition in regulating synaptic plasticity, in addition to the known neuroprotective effects of the chaperones against Aβ and tau toxicity, thus further supporting the potential of Hsp90 inhibitors in treating neurodegenerative diseases.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0151-13.2014
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2014
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 7
    Online-Ressource
    Online-Ressource
    Soluble cpg15 from Astrocytes Ameliorates Neurite Outgrowth Recovery of Hippocampal Neurons after Mouse Cerebral Ischemia
    Society for Neuroscience ; 2017
    In:  The Journal of Neuroscience Vol. 37, No. 6 ( 2017-02-08), p. 1628-1647
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 37, No. 6 ( 2017-02-08), p. 1628-1647
    Kurzfassung: The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody. Furthermore, lentivirus-delivered knockdown of cpg15 expression in mouse hippocampal astrocytes diminishes the dendritic branches and exacerbates injury of neurons in CA1 region after TGI. In addition, treatment with inhibitors of MEK1/2, PI3K, and TrkA decreases, whereas overexpression of p-CREB, but not dp-CREB, increases the expression of cpg15 in U118 or primary cultured astrocytes. Also, it is observed that the Flag-tagged soluble cpg15 from the astrocytes transfected with Flag-tagged cpg15-expressing plasmids adheres to the surface of neuronal bodies and the neurites. In conclusion, our results suggest that the soluble cpg15 from astrocytes induced by ischemia could ameliorate the recovery of the ischemic-injured hippocampal neurons via adhering to the surface of neurons. The upregulated expression of cpg15 in astrocytes may be activated via MAPK and PI3K signal pathways, and regulation of CREB phosphorylation. SIGNIFICANCE STATEMENT Neuronal plasticity plays a crucial role in the amelioration of neurological recovery of ischemic injured brain, which remains a challenge for clinic treatment of cerebral ischemia. cpg15 as a synaptic plasticity-related factor may participate in promoting the recovery process; however, the underlying mechanisms are still largely unknown. The objective of this study is to reveal the function and mechanism of neuronal-specific cpg15 expressed in astrocytes after ischemia induction, in promoting the recovery of injured neurons. Our findings provided new mechanistic insight into the neurological recovery, which might help develop novel therapeutic options for cerebral ischemia via astrocytic-targeting interference of gene expression.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1611-16.2016
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2017
    ZDB Id: 1475274-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Online-Ressource
    Online-Ressource
    A strategy learning framework for particle swarm optimization algorithm
    Elsevier BV ; 2023
    In:  Information Sciences Vol. 619 ( 2023-01), p. 126-152
    Details
    In: Information Sciences, Elsevier BV, Vol. 619 ( 2023-01), p. 126-152
    Materialart: Online-Ressource
    ISSN: 0020-0255
    URL: Article
    DOI: 10.1016/j.ins.2022.10.069
    RVK:
    SA 5420
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2023
    ZDB Id: 218760-7
    ZDB Id: 1478990-5
    SSG: 24,1
    SSG: 7,11
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 9
    Online-Ressource
    Online-Ressource
    Comprehensive functional genomic resource and integrative model for the human brain
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 362, No. 6420 ( 2018-12-14)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6420 ( 2018-12-14)
    Kurzfassung: Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with 〉 88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aat8464
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2018
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 10
    Online-Ressource
    Online-Ressource
    Integrative functional genomic analysis of human brain development and neuropsychiatric risks
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Vol. 362, No. 6420 ( 2018-12-14)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 362, No. 6420 ( 2018-12-14)
    Kurzfassung: To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type–specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C , SATB2 , SOX5 , TCF4 , and TSHZ3 ) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aat7615
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2018
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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