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排序方式: 共有134条查询结果,搜索用时 218 毫秒
11.
Wan J Yourshaw M Mamsa H Rudnik-Schöneborn S Menezes MP Hong JE Leong DW Senderek J Salman MS Chitayat D Seeman P von Moers A Graul-Neumann L Kornberg AJ Castro-Gago M Sobrido MJ Sanefuji M Shieh PB Salamon N Kim RC Vinters HV Chen Z Zerres K Ryan MM Nelson SF Jen JC 《Nature genetics》2012,44(6):704-708
RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration. 相似文献
12.
Garcia-Gonzalo FR Corbit KC Sirerol-Piquer MS Ramaswami G Otto EA Noriega TR Seol AD Robinson JF Bennett CL Josifova DJ García-Verdugo JM Katsanis N Hildebrandt F Reiter JF 《Nature genetics》2011,43(8):776-784
Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies. 相似文献
13.
Gutiérrez-López MD Gilsanz A Yáñez-Mó M Ovalle S Lafuente EM Domínguez C Monk PN González-Alvaro I Sánchez-Madrid F Cabañas C 《Cellular and molecular life sciences : CMLS》2011,68(19):3275-3292
ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell
surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important
biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report
here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ
proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association
between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert
negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against
its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction,
negatively regulates the sheddase activity of ADAM17. 相似文献
14.
Rodríguez-Muñoz M Sánchez-Blázquez P Vicente-Sánchez A Bailón C Martín-Aznar B Garzón J 《Cellular and molecular life sciences : CMLS》2011,68(17):2933-2949
A series of pharmacological and physiological studies have demonstrated the functional cross-regulation between MOR and NMDAR.
These receptors coexist at postsynaptic sites in midbrain periaqueductal grey (PAG) neurons, an area implicated in the analgesic
effects of opioids like morphine. In this study, we found that the MOR-associated histidine triad nucleotide-binding protein
1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR. Morphine-induced analgesic tolerance is prevented
and even rescued by inhibiting PKC or by antagonizing NMDAR. However, in the absence of HINT1, the MOR becomes supersensitive
to morphine before suffering a profound and lasting desensitization that is refractory to PKC inhibition or NMDAR antagonism.
Thus, HINT1 emerges as a key protein that is critical for sustaining NMDAR-mediated regulation of MOR signaling strength.
Thus, HINT1 deficiency may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms
independent of NMDAR. 相似文献
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16.
Résumé Dans le rat, 1 h après la copulation, la concentration de l'MSH de l'hypophyse présente une diminution statistiquement significative, autant chez le mâle que chez la femelle. La stimulation vaginale avec une baguette de verre provoqua 60 et 120 min plus tard une diminution de la concentration de plus de 50% de l'MSH de l'hypophyse. Au bout de 30 min, on n'a observé aucun changement. On en déduit que la copulation ou la stimulation vaginale libère l'MSH.
This investigation was supported by grant No. NB 04732-03 from the NIH, US. Public health Service. 相似文献
This investigation was supported by grant No. NB 04732-03 from the NIH, US. Public health Service. 相似文献
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19.
OhnMarSan Van-NamHuynh YoshitexuNakamori 《系统科学与复杂性》2003,16(4):562-571
Most of the earlier work on clustering mainly focused on numeric data whose inherent geometric properties can be exploited to naturally define distance functions between data points. However, data mining applications frequently involve many datasets that also consists of mixed numeric and categorical attributes. In this paper we present a clustering algorithm which is based on the k-means algorithm. The algorithm clusters objects with numeric and categorical attributes in a way similar to k-means. The object similarity measure is derived from both numeric and categorical attributes. When applied to numeric data, the algorithm is identical to the k-means. The main result of this paper is to provide a method to update the “cluster centers“ of clustering objects described by mixed numeric and categorical attributes in the clustering process to minimise the clustering cost function. The clustering performance of the algorithm is demonstrated with the two well known data sets, namely credit approval and abalone databases. 相似文献
20.
A review of the literature suggests that the effects of nitric oxide (NO) on skeletal muscles fibers can be classified in
two groups. In the first, the effects of NO are direct, due to nitrosation or metal nitrosylation of target proteins: depression
of isometric force, shortening velocity of loaded or unloaded contractions, glycolysis and mitochondrial respiration. The
effect on calcium release channels varies, being inhibitory at low and stimulatory at high NO concentrations. The general
consequence of the direct effects of NO is to ‘brake’ the contraction and its associated metabolism. In the second group,
the effects of NO are mediated by cGMP: increase of the shortening velocity of loaded or unloaded contractions, maximal mechanical
power, initial rate of force development, frequency of tetanic fusion, glucose uptake, glycolysis and mitochondrial respiration;
decreases of half relaxation time of tetanus and twitch, twitch time-to-peak, force maintained during unfused tetanus and
of stimulus-associated calcium release. There is negligible effect on maximal force of isometric twitch and tetanus. The general
consequence of cGMP-mediated effects of NO is to improve mechanical and metabolic muscle power, similar to a transformation
of slow-twitch to fast-twitch muscle, an effect that we may summarize as a ‘slow-to-fast’ shift. 相似文献