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21.
Matthew R. Cohen William M. Johnson Jennifer M. Pilat Janna Kiselar Alicia DeFrancesco-Lisowitz Richard E. Zigmond Vera Y. Moiseenkova-Bell 《Molecular and cellular biology》2015,35(24):4238-4252
Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca2+-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca2+-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca2+ signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca2+ signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function. 相似文献
22.
Pablo Moreno Stephan Beisken Bhavana Harsha Venkatesh Muthukrishnan Ilinca Tudose Adriano Dekker Stefanie Dornfeldt Franziska Taruttis Ivo Grosse Janna Hastings Steffen Neumann Christoph Steinbeck 《BMC bioinformatics》2015,16(1)
Background
Ontology-based enrichment analysis aids in the interpretation and understanding of large-scale biological data. Ontologies are hierarchies of biologically relevant groupings. Using ontology annotations, which link ontology classes to biological entities, enrichment analysis methods assess whether there is a significant over or under representation of entities for ontology classes. While many tools exist that run enrichment analysis for protein sets annotated with the Gene Ontology, there are only a few that can be used for small molecules enrichment analysis.Results
We describe BiNChE, an enrichment analysis tool for small molecules based on the ChEBI Ontology. BiNChE displays an interactive graph that can be exported as a high-resolution image or in network formats. The tool provides plain, weighted and fragment analysis based on either the ChEBI Role Ontology or the ChEBI Structural Ontology.Conclusions
BiNChE aids in the exploration of large sets of small molecules produced within Metabolomics or other Systems Biology research contexts. The open-source tool provides easy and highly interactive web access to enrichment analysis with the ChEBI ontology tool and is additionally available as a standalone library.Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0486-3) contains supplementary material, which is available to authorized users. 相似文献23.
Gutnick A Blechman J Kaslin J Herwig L Belting HG Affolter M Bonkowsky JL Levkowitz G 《Developmental cell》2011,21(4):642-654
The hypothalamo-neurohypophyseal system (HNS) is?the neurovascular structure through which the hypothalamic neuropeptides oxytocin and arginine-vasopressin exit the brain into the bloodstream, where they go on to affect peripheral physiology. Here, we investigate the molecular cues that regulate the neurovascular contact between hypothalamic axons and neurohypophyseal capillaries of the zebrafish. We developed a transgenic system in which both hypothalamic axons and neurohypophyseal vasculature can be analyzed in?vivo. We identified the cellular organization of the zebrafish HNS as well as the dynamic processes that contribute to formation of the HNS neurovascular interface. We show that formation of this interface is regulated during development by local release of oxytocin, which affects endothelial morphogenesis. This cell communication process is essential for the establishment of a tight axovasal interface between the neurons and blood vessels of the HNS. We present a unique example of axons affecting endothelial morphogenesis through secretion of a neuropeptide. 相似文献
24.
Bouman HJ Schömig E van Werkum JW Velder J Hackeng CM Hirschhäuser C Waldmann C Schmalz HG ten Berg JM Taubert D 《Nature medicine》2011,17(1):110-116
Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel. 相似文献
25.
Kotzsch M Dorn J Doetzer K Schmalfeldt B Krol J Baretton G Kiechle M Schmitt M Magdolen V 《Biological chemistry》2011,392(11):1047-1051
High tumor tissue mRNA expression of the tumor biological factors uPAR, uPAR-del4/5, or rab31 is associated with shorter distant metastasis-free and overall survival in breast cancer patients. To evaluate whether these factors are also clinically relevant in ovarian cancer, we quantified the respective mRNA levels in primary tumor tissue of advanced ovarian cancer patients (n=103) and evaluated their association with clinicopathological parameters and patients' prognosis. mRNA expression levels of all three markers did not show any significant association with overall or progression-free survival, demonstrating that these factors have no prognostic value in advanced ovarian cancer. 相似文献
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29.
Janna L. Fierst Thomas F. Hansen 《Evolution; international journal of organic evolution》2010,64(3):675-693
The Bateson–Dobzhansky–Muller model predicts that postzygotic isolation evolves due to the accumulation of incompatible epistatic interactions, but few studies have quantified the relationship between genetic architecture and patterns of reproductive divergence. We examined how the direction and magnitude of epistatic interactions in a polygenic trait under stabilizing selection influenced the evolution of hybrid incompatibilities. We found that populations evolving independently under stabilizing selection experienced suites of compensatory allelic changes that resulted in genetic divergence between populations despite the maintenance of a stable, high‐fitness phenotype. A small number of loci were then incompatible with multiple alleles in the genetic background of the hybrid and the identity of these incompatibility loci changed over the evolution of the populations. For F1 hybrids, reduced fitness evolved in a window of intermediate strengths of epistatic interactions, but F2 and backcross hybrids evolved reduced fitness across weak and moderate strengths of epistasis due to segregation variance. Strong epistatic interactions constrained the allelic divergence of parental populations and prevented the development of reproductive isolation. Because many traits with varying genetic architectures must be under stabilizing selection, our results indicate that polygenetic drift is a plausible hypothesis for the evolution of postzygotic reproductive isolation. 相似文献
30.
This year, 2011, the Department of Pharmacology at the University of Alberta celebrated its 50th anniversary. This timeframe covers nearly the entire history of Cys-loop pentameric ligand-gated ion channel (pLGIC) research. In this review we consider how major technological advancements affected our current understanding of pLGICs, and highlight the contributions made by members of our department. The individual at the center of our story is Susan Dunn; her passing earlier this year has robbed the Department of Pharmacology and the research community of a most insightful colleague. Her dissection of ligand interactions with the nAChR, together with their interpretation, was the hallmark of her extensive collaborations with Michael Raftery. Here, we highlight some electrophysiological studies from her laboratory over the last few years, using the technique that she introduced to the department in Edmonton, the 2-electrode voltage-clamp of Xenopus oocytes. Finally, we discuss some single-channel studies of the anionic GlyR and GABA(A)R that prefaced the introduction of this technique to her laboratory. 相似文献