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Articles by B Xie
Total Records ( 2 ) for B Xie
  J. B Li , Y Gao , J Aach , K Zhang , G. V Kryukov , B Xie , A Ahlford , J. K Yoon , A. M Rosenbaum , A. W Zaranek , E LeProust , S. R Sunyaev and G. M. Church
 

Utilizing the full power of next-generation sequencing often requires the ability to perform large-scale multiplex enrichment of many specific genomic loci in multiple samples. Several technologies have been recently developed but await substantial improvements. We report the 10,000-fold improvement of a previously developed padlock-based approach, and apply the assay to identifying genetic variations in hypermutable CpG regions across human chromosome 21. From ~3 million reads derived from a single Illumina Genome Analyzer lane, ~94% (~50,500) target sites can be observed with at least one read. The uniformity of coverage was also greatly improved; up to 93% and 57% of all targets fell within a 100- and 10-fold coverage range, respectively. Alleles at >400,000 target base positions were determined across six subjects and examined for single nucleotide polymorphisms (SNPs), and the concordance with independently obtained genotypes was 98.4%–100%. We detected >500 SNPs not currently in dbSNP, 362 of which were in targeted CpG locations. Transitions in CpG sites were at least 13.7 times more abundant than non-CpG transitions. Fractions of polymorphic CpG sites are lower in CpG-rich regions and show higher correlation with human–chimpanzee divergence within CpG versus non-CpG sites. This is consistent with the hypothesis that methylation rate heterogeneity along chromosomes contributes to mutation rate variation in humans. Our success suggests that targeted CpG resequencing is an efficient way to identify common and rare genetic variations. In addition, the significantly improved padlock capture technology can be readily applied to other projects that require multiplex sample preparation.

  M. Q Zheng , K Tang , M. C Zimmerman , L Liu , B Xie and G. J. Rozanski
 

-Glutamyl transpeptidase (-GT) is a key enzyme in GSH metabolism that regulates intracellular GSH levels in response to extracellular GSH (GSHo). The objective of this study was to identify the role of -GT in reversing pathogenic K+ channel remodeling in the diseased heart. Chronic ventricular dysfunction was induced in rats by myocardial infarction (MI), and studies were done after 6–8 wk. Biochemical assays of tissue extracts from post-MI hearts revealed significant increases in -GT activity in left ventricle (47%) and septum (28%) compared with sham hearts, which paralleled increases in protein abundance and mRNA. Voltage-clamp studies of isolated left ventricular myocytes from post-MI hearts showed that downregulation of transient outward K+ current (Ito) was reversed after 4–5 h by 10 mmol/l GSHo or N-acetylcysteine (NACo), and that the effect of GSHo but not NACo was blocked by the -GT inhibitors, acivicin or S-hexyl-GSH. Inhibition of -glutamylcysteine synthetase by buthionine sulfoximine did not prevent upregulation of Ito by GSHo, suggesting that intracellular synthesis of GSH was not directly involved. However, pretreatment of post-MI myocytes with an SOD mimetic [manganese (III) tetrapyridylporphyrin] and catalase completely blocked recovery of Ito by GSHo. Confocal microscopy using the fluorogenic dye 2',7'-dichlorodihydrofluorescein diacetate confirmed that GSHo increased reactive oxygen species (ROS) generation by post-MI myocytes and to a lesser extent in myocytes from sham hearts. Furthermore, GSHo-mediated upregulation of Ito was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, and AG1024) and thioredoxin reductase (auranofin and 13-cis-retinoic acid). These data suggest that GSHo elicits -GT- and ROS-dependent transactivation of tyrosine kinase signaling that upregulates K+ channel activity or expression via redox-mediated mechanisms. The signaling events stimulated by -GT catalysis of GSHo may be a therapeutic target to reverse pathogenic electrical remodeling of the failing heart.

 
 
 
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