Stephen J. O'Brien

Bio: Stephen J. O'Brien is an academic researcher from Saint Petersburg State University of Information Technologies, Mechanics and Optics. The author has contributed to research in topics: Population & Gene. The author has an hindex of 153, co-authored 1062 publications receiving 93025 citations. Previous affiliations of Stephen J. O'Brien include University College Cork & QIMR Berghofer Medical Research Institute.

Glomerulopathy in the KK.Cg-Ay/J Mouse Reflects the Pathology of Diabetic Nephropathy

Abstract: The KK.Cg-Ay/J (KK-Ay) mouse strain is a previously described model of type 2 diabetes with renal impairment. In the present study, female KK-Ay mice received an elevated fat content diet (24% of calories), and a cohort was uninephrectomized (Unx) to drive renal disease severity. Compared to KK-a/a controls, 26-week-old KK-Ay mice had elevated HbA1c, insulin, leptin, triglycerides, and cholesterol, and Unx further elevated these markers of metabolic dysregulation. Unx KK-Ay mice also exhibited elevated serum BUN and reduced glomerular filtration, indicating that reduction in renal mass leads to more severe impairment in renal function. Glomerular hypertrophy and hypercellularity, mesangial matrix expansion, podocyte effacement, and basement membrane thickening were present in both binephric and uninephrectomized cohorts. Glomerular size was increased in both groups, but podocyte density was reduced only in the Unx animals. Consistent with functional and histological evidence of increased injury, fibrotic (fibronectin 1, MMP9, and TGFβ1) and inflammatory (IL-6, CD68) genes were markedly upregulated in Unx KK-Ay mice, while podocyte markers (nephrin and podocin) were significantly decreased. These data suggest podocyte injury developing into glomerulopathy in KK-Ay mice. The addition of uninephrectomy enhances renal injury in this model, resulting in a disease which more closely resembles human diabetic nephropathy.

AIDS: a role for host genes.

Abstract: Suspicion that human genes affect the natural history of AIDS has been confirmed by discoveries of three such genes, one of which confers near-total immunity in about 1% of Caucasians. The findings suggest a novel therapeutic target: not HIV but the host's cooperation with it. They also herald an era in which genomes are seen as having been shaped by the evolutionary pressures of infection, and may thus hold evolution-tested therapies.

Marker of proliferation Ki-67 expression is associated with transforming growth factor beta 1 and can predict the prognosis of patients with hepatic B virus-related hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver. Transforming growth factor beta 1 (TGFB1) and marker of proliferation Ki-67 (MKI67) regulate cell proliferation, differentiation, and growth. The association between MKI67 and TGFB1 expression and its clinical implications in HCC remain unknown. Methods Public databases were used to analyze TGFB1 and MKI67 expression in different pathologic grades/stages and tissue types of HCC. The association between MKI67 and TGFB1 expression was explored using pathway analysis and in a HepG2 cell line treated with TGFB1. Survival analysis was performed to evaluate the prognostic value of TGFB1 and MKI67 expression in patients with hepatitis B virus (HBV)-related HCC. Results We identified that MKI67 expression was upregulated in liver cancer tissues. MKI67 and TGFB1 expression levels were different in various stages and tissue types of liver cancer. Furthermore, MKI67 expression was associated with TGFB1 expression in liver cancer tissues and HepG2 cells. Patients with HBV-related HCC and a higher level of MKI67 expression had a worse prognosis. Moreover, a nomogram was conducted to predict the clinical outcomes of patients with HBV-related HCC. Conclusion MKI67 expression level was associated with TGFB1 expression in liver cancer tissues and a HepG2 cell line. MKI67 expression level can predict the clinical outcomes of patients with HBV-related HCC.

Initial sequencing and analysis of the human genome.

Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.