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61.
Giardine B Borg J Higgs DR Peterson KR Philipsen S Maglott D Singleton BK Anstee DJ Basak AN Clark B Costa FC Faustino P Fedosyuk H Felice AE Francina A Galanello R Gallivan MV Georgitsi M Gibbons RJ Giordano PC Harteveld CL Hoyer JD Jarvis M Joly P Kanavakis E Kollia P Menzel S Miller W Moradkhani K Old J Papachatzopoulou A Papadakis MN Papadopoulos P Pavlovic S Perseu L Radmilovic M Riemer C Satta S Schrijver I Stojiljkovic M Thein SL Traeger-Synodinos J Tully R Wada T Waye JS Wiemann C 《Nature genetics》2011,43(4):295-301
We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases. 相似文献
62.
V. Le Fourn K. Gaplovska-Kysela B. Guhl R. Santimaria C. Zuber J. Roth 《Cellular and molecular life sciences : CMLS》2009,66(8):1434-1445
Little is known about the fate of machinery proteins of the protein quality control and endoplasmic reticulum(ER)-associated
degradation (ERAD). We investigated the degradation of the ERAD component EDEM1, which directs overexpressed misfolded glycoproteins
to degradation. Endogenous EDEM1 was studied since EDEM1 overexpression not only resulted in inappropriate occurrence throughout
the ER but also caused cytotoxic effects. Proteasome inhibitors had no effect on the clearance of endogenous EDEM1 in non-starved
cells. However, EDEM1 could be detected by immunocytochemistry in autophagosomes and biochemically in LC3 immuno-purified
autophagosomes. Furthermore, influencing the lysosome-autophagy pathway by vinblastine or pepstatin A/E64d and inhibiting
autophagosome formation by 3-methyladenine or ATGs short interfering RNA knockdown stabilized EDEM1. Autophagic degradation
involved removal of cytosolic Triton X-100-insoluble deglycosylated EDEM1, but not of EDEM1-containing ER cisternae. Our studies
demonstrate that endogenous EDEM1 in cells not stressed by the expression of a transgenic misfolded protein reaches the cytosol
and is degraded by basal autophagy.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 15 January 2009; received after revision 16 February 2009; accepted 17 February 2009
V. Le Fourn, K. Gaplovska-Kysela: These authors equally contributed to this work. 相似文献
63.
目的观察金丝桃素对慢性病毒性心肌炎(VMC)小鼠心肌细胞凋亡及Fas/FasL蛋白表达的影响。方法Balb/C小鼠多次接种心肌柯萨奇段病毒复制慢性VMC模型,首次感染病毒45天后将存活小鼠分为模型组、金丝桃素组及氯沙坦组,同时设正常对照组.分别给予相应药物干预30天,采用原位末端标记法检测心肌细胞凋亡及免疫组化方法检测Fas/FasL蛋白表达。结果模型组心肌细胞凋亡率较正常组显著增加(P〈0.05),金丝桃素组和氯沙坦组凋亡率较模型组显著降低(P〈0.05)。模型组Fas/FasL蛋白表达较正常组显著增多(P〈0.01),金丝桃素组和氯沙坦组较模型组显著降低(P〈0.01)。结论金丝桃素保护心肌细胞与抑制VMC心肌细胞的凋亡.下调Fas/FasL蛋白表达有关。 相似文献
64.
Benoît Le Tallec Stéphane Koundrioukoff Therese Wilhelm Anne Letessier Olivier Brison Michelle Debatisse 《Cellular and molecular life sciences : CMLS》2014,71(23):4489-4494
Common fragile sites (CFSs) are large chromosomal regions long identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs came from their key role in the formation of DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was notably correlated with the appearance of genome instability in precancerous lesions and during tumor progression. Identification of the molecular mechanisms responsible for their instability therefore represents a major challenge. A number of data show that breaks result from mitotic entry before replication completion but the mechanisms responsible for such delayed replication of CFSs and relaxed checkpoint surveillance are still debated. In addition, clues to the molecular events leading to breakage just start to emerge. We present here the results of recent reports addressing these questions. 相似文献
65.
Kerkel K Spadola A Yuan E Kosek J Jiang L Hod E Li K Murty VV Schupf N Vilain E Morris M Haghighi F Tycko B 《Nature genetics》2008,40(7):904-908
Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen--the vanin and CYP2A6-CYP2A7 gene clusters--both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes. 相似文献
66.
Amundadottir LT Sulem P Gudmundsson J Helgason A Baker A Agnarsson BA Sigurdsson A Benediktsdottir KR Cazier JB Sainz J Jakobsdottir M Kostic J Magnusdottir DN Ghosh S Agnarsson K Birgisdottir B Le Roux L Olafsdottir A Blondal T Andresdottir M Gretarsdottir OS Bergthorsson JT Gudbjartsson D Gylfason A Thorleifsson G Manolescu A Kristjansson K Geirsson G Isaksson H Douglas J Johansson JE Bälter K Wiklund F Montie JE Yu X Suarez BK Ober C Cooney KA Gronberg H Catalona WJ Einarsson GV 《Nature genetics》2006,38(6):652-658
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry. 相似文献
67.
南京地铁6号线万寿村站至燕尧路站区间深部主要为灰岩,盾构隧洞贯通后,深部岩体对隧洞维护起至关重要的作用,为了对该地铁深部稳定性提供理论指导,利用MTS815试验机对灰岩在经历干湿循环后进行了常规三轴压缩试验,研究了灰岩在不同次数干湿循环作用下和不同围压下的力学特性,结果表明:(1)受干湿循环作用前后试件的应力—应变曲线... 相似文献
68.
黄仂 《萍乡高等专科学校学报》2012,29(5):1-4
毛泽东从1921年9月到1930年9月先后8次来到安源,开创、领导了闻名天下的安源工人革命运动,安源成为毛泽东在江西伟大革命实践的第一站,成为毛泽东实现早期革命生涯重大飞跃的地方,成为毛泽东缔造新型人民军队的地方,成为毛泽东早期革命思想初步形成的地方。近十年的安源革命运动展示了毛泽东非凡的领导方略和策略思想,这笔宝贵的精神财富,对党的各级领导干部在新的历史时期从容应对复杂局面,创造性地开展各项工作,努力践行党的宗旨,仍然具有重要的现实启示意义。 相似文献
69.
王乐 《鞍山科技大学学报》2010,(4)
为提高成人钢琴教学效果,用问卷调查的方法分析了成人学习钢琴的优势和劣势,就提高专业素养、修身养性、圆儿时之梦和陪学需要等成人学习钢琴动机进行了探讨。针对成人特点,提出了小组学习、集体学习、多媒体以及一对一教学等成人钢琴教学模式。 相似文献
70.
结合连铸坯凝固规律及轻压下技术改善铸坯中心偏析的冶金原理,建立宽板坯轻压下率理论模型。根据某厂连铸宽板坯实际生产条件,以传热模型计算的铸坯凝固温度数据作为轻压下率模型计算条件,分析拉速、浇注温度、坯壳凝固收缩特性对铸坯轻压下率的影响规律。结果表明,在相同的拉速和浇注温度条件下,铸坯轻压下率沿拉坯方向的分布总体呈减小趋势;拉速较高时的起始轻压下率小于拉速较低时对应的起始轻压下率;拉速与平均轻压下率呈线性递减关系:拉速每升高0.1m/min,平均轻压下率减小0.015mm/m;浇注温度越低,轻压下区起始轻压下率的值越高;浇注温度对平均轻压下率的影响较小,浇注温度每升高10℃,平均轻压下率仅减小0.002 5mm/m;铸坯外部凝固坯壳的收缩对整个轻压下区平均轻压下率的贡献量为20.4%~22.3%。 相似文献