排序方式: 共有16条查询结果,搜索用时 15 毫秒
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Onouchi Y Gunji T Burns JC Shimizu C Newburger JW Yashiro M Nakamura Y Yanagawa H Wakui K Fukushima Y Kishi F Hamamoto K Terai M Sato Y Ouchi K Saji T Nariai A Kaburagi Y Yoshikawa T Suzuki K Tanaka T Nagai T Cho H Fujino A Sekine A Nakamichi R Tsunoda T Kawasaki T Nakamura Y Hata A 《Nature genetics》2008,40(1):35-42
Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis. 相似文献
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A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage 总被引:18,自引:0,他引:18
Tanaka H Arakawa H Yamaguchi T Shiraishi K Fukuda S Matsui K Takei Y Nakamura Y 《Nature》2000,404(6773):42-49
The p53 gene is frequently inactivated in human cancers. Here we have isolated a p53-inducible gene, p53R2, by using differential display to examine messenger RNAs in a cancer-derived human cell line carrying a highly regulated wild-type p53 expression system. p53R2 contains a p53-binding sequence in intron 1 and encodes a 351-amino-acid peptide with striking similarity to the ribonucleotide reductase small subunit (R2), which is important in DNA synthesis during cell division. Expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wild-type p53-dependent manner. Induction of p53R2 in p53-deficient cells caused G2/M arrest and prevented cells from death in response to adriamycin. Inhibition of endogenous p53R2 expression in cells that have an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair and cell survival after exposure to various genotoxins. Our results indicate that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA. The discovery of p53R2 clarifies a relationship between a ribonucleotide reductase activity involved in repair of damaged DNA and tumour suppression by p53. 相似文献
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Jin D Liu HX Hirai H Torashima T Nagai T Lopatina O Shnayder NA Yamada K Noda M Seike T Fujita K Takasawa S Yokoyama S Koizumi K Shiraishi Y Tanaka S Hashii M Yoshihara T Higashida K Islam MS Yamada N Hayashi K Noguchi N Kato I Okamoto H Matsushima A Salmina A Munesue T Shimizu N Mochida S Asano M Higashida H 《Nature》2007,446(7131):41-45
CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders. 相似文献
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Onouchi Y Ozaki K Burns JC Shimizu C Terai M Hamada H Honda T Suzuki H Suenaga T Takeuchi T Yoshikawa N Suzuki Y Yasukawa K Ebata R Higashi K Saji T Kemmotsu Y Takatsuki S Ouchi K Kishi F Yoshikawa T Nagai T Hamamoto K Sato Y Honda A Kobayashi H Sato J Shibuta S Miyawaki M Oishi K Yamaga H Aoyagi N Iwahashi S Miyashita R Murata Y Sasago K Takahashi A Kamatani N Kubo M Tsunoda T Hata A Nakamura Y Tanaka T;Japan Kawasaki Disease Genome Consortium;US Kawasaki Disease Genetics Consortium 《Nature genetics》2012,44(5):517-521
We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease. 相似文献
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T. Sakata K. Fukagawa K. Fujimoto H. Yoshimatsu T. Shiraishi H. Wada 《Cellular and molecular life sciences : CMLS》1988,44(3):216-218
Summary Histamine antagonists were infused into the third ventricle of the cerebrum in rats. All the H1-, but none of the H2-antagonists tested, induced initial feeding during the early portion of the light phase when histamine level was highest. No periprandial drinking was observed. Ambulation increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early portion of the dark phase, or was decreased by -fluoromethylhistidine. Hypothalamic neuronal histamine may suppress food intake through H1-receptors, and diurnal fluctuations of food intake may mirror neuronal histamine levels. 相似文献
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This paper discusses the asymptotic efficiency of estimators for optimal portfolios when returns are vector‐valued non‐Gaussian stationary processes. We give the asymptotic distribution of portfolio estimators ? for non‐Gaussian dependent return processes. Next we address the problem of asymptotic efficiency for the class of estimators ?. First, it is shown that there are some cases when the asymptotic variance of ? under non‐Gaussianity can be smaller than that under Gaussianity. The result shows that non‐Gaussianity of the returns does not always affect the efficiency badly. Second, we give a necessary and sufficient condition for ? to be asymptotically efficient when the return process is Gaussian, which shows that ? is not asymptotically efficient generally. From this point of view we propose to use maximum likelihood type estimators for g, which are asymptotically efficient. Furthermore, we investigate the problem of predicting the one‐step‐ahead optimal portfolio return by the estimated portfolio based on ? and examine the mean squares prediction error. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
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Yoshida K Sanada M Shiraishi Y Nowak D Nagata Y Yamamoto R Sato Y Sato-Otsubo A Kon A Nagasaki M Chalkidis G Suzuki Y Shiosaka M Kawahata R Yamaguchi T Otsu M Obara N Sakata-Yanagimoto M Ishiyama K Mori H Nolte F Hofmann WK Miyawaki S Sugano S Haferlach C Koeffler HP Shih LY Haferlach T Chiba S Nakauchi H Miyano S Ogawa S 《Nature》2011,478(7367):64-69
Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (~45 to ~85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia. 相似文献
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Izuhara K Ohta S Kanaji S Shiraishi H Arima K 《Cellular and molecular life sciences : CMLS》2008,65(16):2541-2553
The inhibitory mechanism against proteases is important in the maintenance of homeostasis or health in the body. The human ovalbumin serpin (ovserpin)/ clade B serpin family is one group of the human serpins, a family of serine protease inhibitors. They have acquired diversity in the profiles of target proteases, inhibitory mechanisms, and localization patterns during their evolution. Most serpins target serine proteases, however, some ov-serpins target only cysteine proteases or both serine and cysteine proteases and furthermore, several ov-serpins do not possess inhibitory activities. Although the ov-serpins act primarily as intracellular serpins, some show extracellular and nuclear localizations. Such diversity enables the ov-serpins to play multiple physiological roles in the body. Recent analyses have revealed that the functions of human ov-serpins are more diversified than we previously knew. In this article, we describe recent progress in our understanding of how the human ov-serpin/clade B serpin family demonstrates diversity. 相似文献