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41.
Neurotoxicity induces cleavage of p35 to p25 by calpain 总被引:52,自引:0,他引:52
Cyclin-dependent kinase 5 (cdk5) and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Conversion of p35 to p25 causes prolonged activation and mislocalization of cdk5. Consequently, the p25/cdk5 kinase hyperphosphorylates tau, disrupts the cytoskeleton and promotes the death (apoptosis) of primary neurons. Here we describe the mechanism of conversion of p35 to p25. In cultured primary cortical neurons, excitotoxins, hypoxic stress and calcium influx induce the production of p25. In fresh brain lysates, addition of calcium can stimulate cleavage of p35 to p25. Specific inhibitors of calpain, a calcium-dependent cysteine protease, effectively inhibit the calcium-induced cleavage of p35. In vitro, calpain directly cleaves p35 to release a fragment with relative molecular mass 25,000. The sequence of the calpain cleavage product corresponds precisely to that of p25. Application of the amyloid beta-peptide A beta(1-42) induces the conversion of p35 to p25 in primary cortical neurons. Furthermore, inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease. 相似文献
42.
Th. F. Spande J. W. Daly D. J. Hart Y-M. Tsai T. L. Macdonald 《Cellular and molecular life sciences : CMLS》1981,37(12):1242-1245
Summary The structure 3-butyl-5-propylindolizidine (2), tentatively assigned to a minor alkaloid in skin extracts from a number of poison frogs of the Neotropical genusDendrobates, has been confirmed and its stereochemistry determined as 5E, 9E (2d) by comparison on GC and GC-MS with the four synthetic diastereomers2a-2d. 相似文献
43.
DNA replication sites within nuclei of mammalian cells 总被引:12,自引:0,他引:12
44.
Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura 总被引:114,自引:0,他引:114
45.
The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice. 总被引:2,自引:0,他引:2
J Bressler T F Tsai M Y Wu S F Tsai M A Ramirez D Armstrong A L Beaudet 《Nature genetics》2001,28(3):232-240
In mice and humans, the locus encoding the gene for small nuclear ribonucleoprotein N (SNRPN/Snrpn), as well as other loci in the region are subject to genomic imprinting. The SNRPN promoter is embedded in a maternally methylated CpG island, is expressed only from the paternal chromosome and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. We show here that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited. 相似文献
46.
介绍东经 12 0°低纬电离层CT实验及CT重建结果 .提出一种改进的电离层CT算法 .该算法通过联合使用差分Doppler相位和差分Doppler频率数据 ,把相位积分常数估算融入重建过程之中 .CT重建结果发现 ,赤道异常峰电子密度等值线沿磁力线倾斜 ;峰位置逐日变化时 ,倾斜程度也随之改变 ,使峰电子密度等值线仍沿磁力线 ;峰朝赤道的运动通常伴随峰区展宽 .此外 ,对一次中等强度磁暴期间电离层响应的分析发现 ,在赤道异常峰区 ,磁暴急始之后 2 0min出现电子密度的深度耗空 ,这种耗空遍及从底到顶的整个F区 .结果表明 ,电离层CT技术在研究电离层赤道异常的动力过程、电离层行扰和不规则结构的时空演变以及暴时电离层响应等方面具有重要的应用价值与前景 . 相似文献
47.
Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis
Lee YC Kuo HC Chang JS Chang LY Huang LM Chen MR Liang CD Chi H Huang FY Lee ML Huang YC Hwang B Chiu NC Hwang KP Lee PC Chang LC Liu YM Chen YJ Chen CH;Taiwan Pediatric ID Alliance Chen YT Tsai FJ Wu JY 《Nature genetics》2012,44(5):522-525
To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10(-8)). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis. 相似文献
48.
Y Okada X Sim MJ Go JY Wu D Gu F Takeuchi A Takahashi S Maeda T Tsunoda P Chen SC Lim TY Wong J Liu TL Young T Aung M Seielstad YY Teo YJ Kim JY Lee BG Han D Kang CH Chen FJ Tsai LC Chang SJ Fann H Mei DC Rao JE Hixson S Chen T Katsuya M Isono T Ogihara JC Chambers W Zhang JS Kooner;KidneyGen Consortium;CKDGen Consortium E Albrecht;GUGC consortium K Yamamoto M Kubo Y Nakamura N Kamatani N Kato J He YT Chen YS Cho ES Tai T Tanaka 《Nature genetics》2012,44(8):904-909
Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ~110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function. 相似文献
49.
Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells 总被引:154,自引:0,他引:154
Genes expressed in erythroid cells contain binding sites for a cell-specific factor believed to be an important regulator for this haematopoietic lineage. Using high-level transient expression in mammalian cells, we have identified complementary DNA encoding the murine protein. The factor, a new member of the zinc-finger family of DNA-binding proteins, is restricted to erythroid cells at the level of RNA expression and is closely homologous between mouse and man. 相似文献
50.
Increased gamma-globin expression in a nondeletion HPFH mediated by an erythroid-specific DNA-binding factor 总被引:63,自引:0,他引:63
In man, a shift from gamma- to beta-globin gene expression in erythroblasts underlies a switch from fetal to adult haemoglobin during development. In hereditary persistence of fetal haemoglobin (HPFH), inappropriately high gamma-globin expression in adult life is associated with deletions in the beta-globin cluster or with single-base changes upstream of the gamma-globin genes. To account for enhanced gamma-gene expression in HPFH of the non-deletion type, we tested the nuclear proteins of human erythroleukaemia cells that bind gamma-promoter sequences in vitro by correlating specific mutations in their binding sites with promoter activity. An erythroid-specific factor (GF-1) binds as a single molecule to the -195 to -170 region and contacts two TATCT(AGATA) motifs, but not the conserved octamer (ATGCAAAT) that separates them. We observe that a single change (at -175, T----C) found in HPFH leads to increased promoter activity only in erythroid cells. This effect is mediated by GF-1, the human counterpart of the chicken erythroid factor Eryf 1. The form of HPFH we studied here is an inherited disorder which can be ascribed to the action of a cell-specific DNA-binding factor on a mutant promoter. 相似文献