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Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies 总被引:1,自引:0,他引:1
Adaikalavan Ramasamy Daniah Trabzuni J. Raphael Gibbs Allissa Dillman Dena G. Hernandez Sampath Arepalli Robert Walker Colin Smith Gigaloluwa Peter Ilori Andrey A. Shabalin Yun Li Andrew B. Singleton Mark R. Cookson for NABEC John Hardy for UKBEC Mina Ryten Michael E. Weale 《Nucleic acids research》2013,41(7):e88
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Nalls MA Couper DJ Tanaka T van Rooij FJ Chen MH Smith AV Toniolo D Zakai NA Yang Q Greinacher A Wood AR Garcia M Gasparini P Liu Y Lumley T Folsom AR Reiner AP Gieger C Lagou V Felix JF Völzke H Gouskova NA Biffi A Döring A Völker U Chong S Wiggins KL Rendon A Dehghan A Moore M Taylor K Wilson JG Lettre G Hofman A Bis JC Pirastu N Fox CS Meisinger C Sambrook J Arepalli S Nauck M Prokisch H Stephens J Glazer NL Cupples LA Okada Y Takahashi A Kamatani Y Matsuda K Tsunoda T Tanaka T Kubo M 《PLoS genetics》2011,7(6):e1002113
White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds. 相似文献
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S. K. Arepalli V. Sridhar J. Venkateswara Rao P. Kavin Kennady Y. Venkateswarlu 《Apoptosis : an international journal on programmed cell death》2009,14(5):729-740
Bioassay directed fractionation and purification led to the successful isolation of a furano sesquiterpene, Methyl 5-[(1E,5E)-2,6-Dimethyl
octa-1,5,7-trienyl] furan-3-carboxylate (MDTFC), a bioactive component from a soft coral, Sinularia kavarittiensis. Its structure was determined by analyzing 1H, 13C NMR and FAB-MS. The results show that MDTFC could efficiently and selectively inhibit the proliferation of several human
cancer cell lines. Among all the cell lines, THP-1 was found to be most sensitive (IC50 29.59 μM), whereas the peripheral blood mononuclear cells were least effected (IC50 464.16 μM). The molecular mechanism of MDTFC mediated apoptosis was investigated for the first time. Induction of apoptosis
in THP-1 cells was characterized by cell membrane blebbing, chromatin condensation, DNA fragmentation, and decrease in level
of pro-caspases 3, 9 and increase in Bax/Bcl-2 ratio. Our results were further strengthened through cleavage of poly (ADP-ribose)
polymerase, reduction of mitochondrial membrane potential (Ψm) and cytosolic release of cytochrome c, which are key events during apoptosis. Moreover, phosphatidyl serine exposure and appearance of sub-G1 peak also demonstrated
cell death, when analyzed by flow cytometry. DNA fragmentation was prevented moderately when pretreated with caspase-9 inhibitor
(Z-LEHD-FMK) and largely with caspase-3 inhibitor (Z-DEVD-FMK). In summary, MDTFC mediated apoptosis involves mitochondria-dependent
pathway and the present compound of marine origin might have a therapeutic value against human cancer cell lines and especially
on leukemia cells. 相似文献
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Nirogi RV Kambhampati R Kothmirkar P Konda J Bandyala TR Gudla P Arepalli S Gangadasari NP Shinde AK Deshpande AD Dwarampudi A Chindhe AK Dubey PK 《Journal of enzyme inhibition and medicinal chemistry》2012,27(3):443-450
5-Hydroxytryptamine 6 receptors (5-HT(6)R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure-activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT(6) receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT(6)R with the K(i) of 23.4 and 20.5?nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze. 相似文献
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Starting from methyl β-D-galactofuranoside, 3,5,6-tri-O-methyl-D-galactose (9) and 2,5,6-tri-O-methyl-D-galactose (16) were synthesized. The alditol acetates were prepared from 9 and 16, and their behavior in g.l.c. was compared. Mass spectra of the alditol acetates from 9 and 16 showed that these compounds gave fragmentations as expected. The alditol acetate from 16 was also prepared by an alternative route. 相似文献
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Reiner AP Lettre G Nalls MA Ganesh SK Mathias R Austin MA Dean E Arepalli S Britton A Chen Z Couper D Curb JD Eaton CB Fornage M Grant SF Harris TB Hernandez D Kamatini N Keating BJ Kubo M LaCroix A Lange LA Liu S Lohman K Meng Y Mohler ER Musani S Nakamura Y O'Donnell CJ Okada Y Palmer CD Papanicolaou GJ Patel KV Singleton AB Takahashi A Tang H Taylor HA Taylor K Thomson C Yanek LR Yang L Ziv E Zonderman AB Folsom AR Evans MK Liu Y Becker DM Snively BM Wilson JG 《PLoS genetics》2011,7(6):e1002108
Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10(-8)). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS. 相似文献
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Johnson JO Mandrioli J Benatar M Abramzon Y Van Deerlin VM Trojanowski JQ Gibbs JR Brunetti M Gronka S Wuu J Ding J McCluskey L Martinez-Lage M Falcone D Hernandez DG Arepalli S Chong S Schymick JC Rothstein J Landi F Wang YD Calvo A Mora G Sabatelli M Monsurrò MR Battistini S Salvi F Spataro R Sola P Borghero G;ITALSGEN Consortium Galassi G Scholz SW Taylor JP Restagno G Chiò A Traynor BJ 《Neuron》2010,68(5):857-864
Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in?families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ~1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration. 相似文献