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Gharavi AG Kiryluk K Choi M Li Y Hou P Xie J Sanna-Cherchi S Men CJ Julian BA Wyatt RJ Novak J He JC Wang H Lv J Zhu L Wang W Wang Z Yasuno K Gunel M Mane S Umlauf S Tikhonova I Beerman I Savoldi S Magistroni R Ghiggeri GM Bodria M Lugani F Ravani P Ponticelli C Allegri L Boscutti G Frasca G Amore A Peruzzi L Coppo R Izzi C Viola BF Prati E Salvadori M Mignani R Gesualdo L Bertinetto F Mesiano P Amoroso A Scolari F Chen N Zhang H Lifton RP 《Nature genetics》2011,43(4):321-327
We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10?2? and 4.84 × 10?? and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures. 相似文献
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Dave JR Connors RA Genovese RF Whipple RA Chen RW DeFord SM Moran AV Tortella EC 《Cellular and molecular life sciences : CMLS》2007,64(21):2823-2828
The objective of this study was to determine levels of DNA fragmentation in blood leukocytes and parietal cortex from guinea
pigs following repeated lowlevel exposure to the chemical warfare nerve agent (CWNA) sarin. Guinea pigs were injected (s.c.)
once a day for 10 days with saline, or 0.1, 0.2, or 0.4 LD50 (50% mean lethal dose) sarin dissolved in sterile physiological saline. Blood and parietal cortex was collected after injection
at 0, 3, and 17 days recovery and evaluated for DNA fragmentation using single-cell gel electrophoresis (Comet assay). Cells
were imaged using comet analysis software and three parameters of DNA fragmentation measured: tail length, percent DNA in
the tail, and tail moment arm. Repeated low-dose exposure to sarin produced a dose-dependent response in leukocytes at 0 and
3 days post-exposure. There was a significant increase in all measures of DNA fragmentation at 0.2 and 0.4 LD50, but not at 0.1 LD50. There was no significant increase in DNA fragmentation in any of the groups at 17 days post-exposure. Sarin did not produce
a systematic dose-dependent response in parietal cortex at any of the time points. However, significant increases in DNA fragmentation
at 0.1 and 0.4 LD50 were observed at 0 and 3 days post-exposure. All measures of DNA fragmentation in both leukocytes and neurons returned to
control levels by 17 days post-exposure, indicating a small and non-persistent increase in DNA fragmentation following repeated
low-level exposure to sarin.
Received 23 July 2007; received after revision 23 August 2007; accepted 3 September 2007
Research was conducted in compliance with the Animal Welfare Act, and other Federal statutes and regulation relating to animals
and experiments involving animals and adheres to the principles
stated in the Guide for the Care and Use of Laboratory Animals, NIH publication 85-23. The views of the authors do not purport
to reflect the position of the Department of the Army or the Department of Defense (para 4-3), AR 360–365. 相似文献
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FL Muller S Colla E Aquilanti VE Manzo G Genovese J Lee D Eisenson R Narurkar P Deng L Nezi MA Lee B Hu J Hu E Sahin D Ong E Fletcher-Sananikone D Ho L Kwong C Brennan YA Wang L Chin RA DePinho 《Nature》2012,488(7411):337-342
Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events. 相似文献
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Daniele Avitabile Licia Genovese Donatella Ponti Danilo Ranieri Salvatore Raffa Antonella Calogero Maria Rosaria Torrisi 《Cellular and molecular life sciences : CMLS》2014,71(13):2547-2559
In this work, we show for the first time that a second splicing variant of the core clock gene Period 2 (Per2), Per2S, is expressed at both the mRNA and protein levels in human keratinocytes and that it localizes in the nucleoli. Moreover, we show that a reversible perturbation of the nucleolar structure acts as a resetting stimulus for the cellular clock. Per2S expression and periodic oscillation upon dexamethasone treatment were assessed by qRT-PCR using specific primers. Western blot (WB) analysis using an antibody against the recombinant human PER2 (abRc) displayed an intense band at a molecular weight of ~55 kDa, close to the predicted size of Per2S, and a weaker band at the expected size of Per2 (~140 kDa). The antibody raised against PER2 pS662 (abS662), an epitope absent in PER2S, detected only the higher band. Immunolocalization studies with abRc revealed a peculiar nucleolar signal colocalizing with the nucleolar marker nucleophosmin, whereas with abS662 the signal was predominantly diffuse all over the nucleus and partially colocalized with abRc in the nucleolus. The analysis of cell fractions by WB confirmed the enrichment of PER2S and the presence of PER2 in the nucleolar compartment. Finally, a pulse (1 h) of actinomycin D (0.01 μg/ml) induced reversible nucleolar disruption, PER2S de-localization and circadian synchronization of clock and Per2S genes. Our work represents the first evidence that the Per2S splicing isoform is a clock component expressed in human cells localizing in the nucleolus. These results suggest a critical role for the nucleolus in the process of circadian synchronization in human keratinocytes. 相似文献
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