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31.
Proteins with polyglutamine (polyQ) expansions accumulate in the nucleus and affect gene expression. The mechanism by which mutant huntingtin (htt) accumulates intranuclearly is not known; wild-type htt, a 350-kDa protein of unknown function, is normally found in the cytoplasm. N-terminal fragments of mutant htt, which contain a polyQ expansion (>37 glutamines), have no conserved nuclear localization sequences or nuclear export sequences but can accumulate in the nucleus and cause neurological problems in transgenic mice. Here we report that N-terminal htt shuttles between the cytoplasm and nucleus in a Ran GTPase-independent manner. Small N-terminal htt fragments interact with the nuclear pore protein translocated promoter region (Tpr), which is involved in nuclear export. PolyQ expansion and aggregation decrease this interaction and increase the nuclear accumulation of htt. Reducing the expression of Tpr by RNA interference or deletion of ten amino acids of N-terminal htt, which are essential for the interaction of htt with Tpr, increased the nuclear accumulation of htt. These results suggest that Tpr has a role in the nuclear export of N-terminal htt and that polyQ expansion reduces this nuclear export to cause the nuclear accumulation of htt. 相似文献
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Ross AJ May-Simera H Eichers ER Kai M Hill J Jagger DJ Leitch CC Chapple JP Munro PM Fisher S Tan PL Phillips HM Leroux MR Henderson DJ Murdoch JN Copp AJ Eliot MM Lupski JR Kemp DT Dollfus H Tada M Katsanis N Forge A Beales PL 《Nature genetics》2005,37(10):1135-1140
The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation. Here we show that mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles. Furthermore, we identify genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. We also show that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggest that cilia are intrinsically involved in PCP processes. 相似文献
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Summary Continuous exposure of golden hamsters to nitrous fumes (40 ppm NO2+20 ppm NO) for up to 16 months revealed no carcinogenic action of nitrogen oxides in the lung nor in other organs. 相似文献
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Résumé L'épreuvein vivo classique pour MSH implique l'injection dans le sac lymphatique dorsal. Sa sensibilité peut être doublée par injection dans le tronc aortique de la manière décrite, tout en gardant une précision et simplicité suffisante. 相似文献
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A pessimistic strain of thought is fomenting in the health studies literature regarding the status of medicine. Ioannidis’s (2005) now famous finding that “most published research findings are false” and Stegenga’s (2018) book-length argument for medical nihilism are examples of this. In this paper, we argue that these positions are incorrect insofar as they rest on an untenable account of the nature of facts. Proper attention to fallibilism and the social organization of knowledge, as well as Bayesian probabilities in medical reasoning, prompt us to ask why the cynics expect the results of quantitative studies to be incontrovertibly true in the first place. While we agree with Ioannidis and others’ identified flaws in the medical research enterprise, and encourage rectification, we conclude that medical nihilism is not the natural outcome of the current state of research. 相似文献