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61.
Chang YP Kim JD Schwander K Rao DC Miller MB Weder AB Cooper RS Schork NJ Province MA Morrison AC Kardia SL Quertermous T Chakravarti A 《European journal of human genetics : EJHG》2006,14(4):469-477
The application of genome-wide linkage scans to uncover susceptibility loci for complex diseases offers great promise for the risk assessment, treatment, and understanding of these diseases. However, for most published studies, linkage signals are typically modest and vary considerably from one study to another. The multicenter Family Blood Pressure Program has analyzed genome-wide linkage scans of over 12 000 individuals. Based on this experience, we developed a protocol for large linkage studies that reduces two sources of data error: pedigree structure and marker genotyping errors. We then used the linkage signals, before and after data cleaning, to illustrate the impact of missing and erroneous data. A comprehensive error-checking protocol is an important part of complex disease linkage studies and enhances gene mapping. The lack of significant and reproducible linkage findings across studies is, in part, due to data quality. 相似文献
62.
Zhou W Han WF Landree LE Thupari JN Pinn ML Bililign T Kim EK Vadlamudi A Medghalchi SM El Meskini R Ronnett GV Townsend CA Kuhajda FP 《Cancer research》2007,67(7):2964-2971
Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation. 相似文献
63.
D'Avila A Aryana A Thiagalingam A Holmvang G Schmidt E Gutierrez P Ruskin JN Reddy VY 《Pacing and clinical electrophysiology : PACE》2008,31(10):1322-1331
Background: This study of a chronic porcine postinfarction model examined whether linear epicardial cryoablation was capable of creating large, homogenous lesions in regions of the myocardium including scarred ventricle. Endocardial and epicardial focal cryolesions were also compared to determine if there were significant differences in lesion characteristics. Methods: Eighty focal endocardial and 28 focal epicardial cryoapplications were delivered to eight normal caprine and four normal porcine ventricular myocardium, and 21 linear cryolesions were applied along the border of infarcted epicardial tissue in a chronic porcine infarct model in six swines. Results: Focal endocardial cryolesions in normal animals measured 9.7±0.4 mm (length) by 7.3±1.4 mm (width) by 4.8±0.2 mm (depth), while epicardial lesions measured 10.2±1.4 mm (length) by 7.7±2 mm (width) by 4.6±0.9 mm (depth); P > 0.05. Linear epicardial cryolesions in the chronic porcine infarct model measured 36.5±7.8 mm (length) by 8.2±1.3 mm (width) by 6.0±1.2 mm (depth). The mean depth of linear cryolesions applied to the border of the infarct scar was 7±0.7 mm, as measured by magnetic resonance imaging. Conclusions: Cryoablation can create deep lesions when delivered to the ventricular epicardium. Endocardial and epicardial cryolesions created by a focal cryoablation catheter are similar in size and depth. The ability to rapidly create deep linear cryolesions may prove to be beneficial in substrate‐based catheter ablation of ventricular arrhythmias. 相似文献
64.
Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis 总被引:4,自引:0,他引:4
Blackman SM Deering-Brose R McWilliams R Naughton K Coleman B Lai T Algire M Beck S Hoover-Fong J Hamosh A Fallin MD West K Arking DE Chakravarti A Cutler DJ Cutting GR 《Gastroenterology》2006,131(4):1030-1039
BACKGROUND & AIMS: Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF. METHODS: A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage. RESULTS: Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 x 10(-5)), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 x 10(-4)). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI. CONCLUSIONS: The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors. 相似文献
65.
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67.
Marth G Schuler G Yeh R Davenport R Agarwala R Church D Wheelan S Baker J Ward M Kholodov M Phan L Czabarka E Murvai J Cutler D Wooding S Rogers A Chakravarti A Harpending HC Kwok PY Sherry ST 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(1):376-381
Single-nucleotide polymorphisms (SNPs) constitute the great majority of variations in the human genome, and as heritable variable landmarks they are useful markers for disease mapping and resolving population structure. Redundant coverage in overlaps of large-insert genomic clones, sequenced as part of the Human Genome Project, comprises a quarter of the genome, and it is representative in terms of base compositional and functional sequence features. We mined these regions to produce 500,000 high-confidence SNP candidates as a uniform resource for describing nucleotide diversity and its regional variation within the genome. Distributions of marker density observed at different overlap length scales under a model of recombination and population size change show that the history of the population represented by the public genome sequence is one of collapse followed by a recent phase of mild size recovery. The inferred times of collapse and recovery are Upper Paleolithic, in agreement with archaeological evidence of the initial modern human colonization of Europe. 相似文献
68.
Stephen P. Daiger Aravinda Chakravarti John M. Opitz 《American journal of medical genetics. Part A》1983,14(1):43-48
Deletion of a chromosome region containing a polymorphic marker may result in apparent parental exclusion at that locus. We present a general method for calculating the probability that deletion at a specific locus would have such an effect. For many autosomal loci this probability is substantial, justifying attempts at deletion mapping in most cases. This method may be especially valuable in assigning DNA restriction fragment polymorphisms to chromosome regions. 相似文献
69.
Jason M Laramie Jemma B Wilk Steven C Hunt R Curtis Ellison Aravinda Chakravarti Eric Boerwinkle Richard H Myers 《BMC medical genetics》2006,7(1):17-11
Background
Elevated resting heart rate has been shown in multiple studies to be a strong predictor of cardiovascular disease. Previous family studies have shown a significant heritable component to heart rate with several groups conducting genomic linkage scans to identify quantitative trait loci. 相似文献70.
Joël Zlotogora Yasir Hujerat Luci Zalman Saleh Barges Dori Filon Ariel Koren Stavit A. Shalev Aravinda Chakravarti 《American journal of human biology》2005,17(5):659-661
In Israel, as in several countries of the Mediterranean basin, beta-thalassemia is frequent among Arabs, and many different mutations in the beta globin gene have been identified. In a single Arab village, three different thalassemia mutations, as well as the sickle-cell mutation, were characterized. Using genealogical data as well as the results of screening in the village population, we were able to demonstrate/speculate on how mutations were introduced into the village and how they later expanded. The sickle-cell mutation became particularly prevalent in the village as the result of a founder effect due to a preference for consanguineous marriages. 相似文献