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.

Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos.

Abstract: Dbl-homology guanine nucleotide exchange factors (DH-GEFs) regulate actin cytoskeletal reorganization, cell adhesion, and gene transcription via activation of Rho GTPases. However, little is known about the physiological role of mammalian DH-GEFs during development. The DH-GEF family member Trio is of particular interest because it is a multifunctional protein possessing two GEF domains, as well as a protein serine/threonine kinase domain, and trio-like genes in Caenorhabditis elegans and Drosophila were shown to function in neural migration and axon guidance. To determine the role of Trio during mammalian development, we generated a mouse trio loss-of-function mutation (trio−/−). Trio function is essential during late embryonic development as genotype analysis indicated that trio−/− embryos died between embryonic day (E)-15.5 and birth, or shortly thereafter. In the trio−/− embryos, primary skeletal myofibers were relatively normal at E14.5, but by E18.5 highly unusual spherical myofibers accumulated. Trio deficiency may cause a defect in secondary myogenesis, as the appearance of the abnormal trio−/− skeletal myofibers temporally coincided with the onset of secondary myogenesis, and smaller secondary myofibers located adjacent to the primary myofibers were absent. The proliferation of trio−/− secondary myoblasts appeared normal, suggesting that Trio may regulate secondary myoblast alignment or fusion. trio−/− embryos also displayed aberrant organization in several regions within the brain, including the hippocampal formation and olfactory bulb. We thus conclude that Trio is essential for late embryonic development, and that Trio functions in fetal skeletal muscle formation and in the organization of neural tissues.

A population-based study to investigate host genetic factors associated with hepatitis B infection and pathogenesis in the Chinese population

Abstract: Hepatitis B virus (HBV) infection is a significant public health problem that may lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 30% of the world's population has been infected with HBV and approximately 350 million (5–6%) are persistent carriers. More than 120 million Chinese are infected with HBV. The role of host genetic factors and their interactions with environmental factors leading to chronic HBV infection and its complications are not well understood. We believe that a better understanding of these factors and interactions will lead to more effective diagnostic and therapeutic options. This is a population-based, case-control study protocol to enroll 2200 Han Chinese from medical centers in northern and western China. Adult subjects in the following groups are being enrolled: healthy donors (n = 200), HBV infected persons achieving virus clearance (n = 400), asymptomatic HBV persistent carriers (n = 400), chronic hepatitis B cases (n = 400), decompensated liver cirrhosis with HBV infection cases (n = 400), and hepatocellular carcinoma with HBV infection cases (n = 400). In addition, for haplotype inference and quality control of sample handling and genotyping results, children of 1000 cases will be asked to provide a buccal sample for DNA extraction. With the exception of adult patients presenting with liver cirrhosis or HCC, all other cases and controls will be 40 years or older at enrollment. A questionnaire is being administered to capture dietary and environmental risk factors. Both candidate-gene and genome-wide association approaches will be used to assess the role of single genetic factors and higher order interactions with other genetic or environmental factors in HBV diseases. This study is designed and powered to detect single gene effects as well as gene-gene and environmental-gene interactions. The identification of allelic polymorphisms in genes involved in the pathway leading to chronic viral infection, liver cirrhosis and, ultimately, hepatocellular carcinoma would provide insights to those factors leading to HBV replication, liver inflammation, fibrosis, and the carcinogenic process. An understanding of the contribution of host genetic factors and their interactions may inform public health policy, improve diagnostics and clinical management, and provide targets for drug development.

Balanced polymorphism selected by genetic versus infectious human disease

Abstract: The polymorphisms within the human genome include several functional variants that cause debilitating inherited diseases. An elevated frequency of some of these deleterious mutations can be explained by a beneficial effect that confers a selective advantage owing to disease resistance in carriers of such mutations during an infectious disease outbreak. We here review plausible examples of balanced functional polymorphisms and their roles in the defense against pathogens. The genome organization of the chemokine receptor and HLA gene clusters and their influence on the HIV/AIDS epidemic provides compelling evidence for the interaction of infectious and genetic diseases in recent human history.

Outcomes of isolated type II SLAP lesions treated with arthroscopic fixation using a bioabsorbable tack.

Abstract: Purpose: The objective was to clinically evaluate the treatment of type II Slap lesions repaired surgically using a bioabsorbable device. Type of Study: Retrospective clinical follow-up study. Methods: Forty-one patients with isolated type II SLAP lesions who were treated with arthroscopic fixation were identified. Patients were excluded for rotator cuff tears, instability, or subacromial decompression. Patients completed the L'Insalata and the American Society of Shoulder and Elbow Surgeons (ASES) questionnaires, and underwent a thorough shoulder examination at a minimum of 2 years postoperatively. Results: At a mean of 3.7 years follow-up, 33 of 41 patients returned for physical examination and 6 others returned the L'Insalata questionnaire. The mean L'Insalata and ASES scores were 86.7 and 86.8, respectively; 27 patients reported their satisfaction as good to excellent but only 14 of the 29 athletes returned to their preinjury level of athletics. The average ASES scores were statistically different in patients who had their rotator cuff pierced versus those who did not ( P Conclusions: Despite high outcome scores, overall patient satisfaction was only 71%. In addition, up to 41% continued to experience some degree of night pain. Patients treated with a rotator cuff piercing had a significantly poorer outcome. Moreover, the patients who were athletes performed poorer on their outcomes evaluation than did their nonathletic counterparts. Whereas the outcome scores overall were high, this problem is still difficult to treat successfully. This may be because of the high demands of athletes. The data also suggest that placing portals through the rotator cuff may be associated with poorer surgical outcomes. Level of Evidence: Level III.

Clonal Variation of MCF-7 Breast Cancer Cells In Vitro and in Athymic Nude Mice

Abstract: The MCF-7 human breast cancer cell line and four derived variant sublines (R27, R3, R3–12, and R3–98), which were all estrogen receptor positive, as well as the receptor-deficient line, MDA-MB-231, were compared both in vitro and as heterotransplants into athymic nude mice. The cell lines and heterotransplanted tumors were evaluated in terms of growth, receptor status, morphology by light and electron microscopy, karyotype, and allozyme phenotype analyses. The R3 and R3–12 variant lines exhibited markedly retarded growth rates in vitro as compared with those of the MCF-7 parent line. The R3-12 line, which had the slowest growth rate in vitro as compared to those of the other cell lines, failed to produce tumors in nude mice after many attempts using various concentrations of tumor cell inocula. The MCF-7 and derived lines would not grow in oophorectomized animals without 17β-estradiol replacement, with one rare exception, while the MDA-MB-231 receptor-deficient line was able to grow in oophorectomized mice with and without 17β-estradiol replacement. Compared to the parent MCF-7 and R27 line in vivo and in vitro , the R3 line and its subclones had reduced progesterone receptor markedly. By light microscopy, all of the cell lines in vivo and in vitro could be identified as adenocarcinoma. Using electron microscopy, the MCF and variant lines showed better tissue organization and more squamous features in vivo than in vitro where glandular features were more prominent. The R27 line in vivo and in vitro showed the most cellular polarity and differentiation as compared to the MCF or R3 lines (R3, R3–12, and R3–98), while the R3 lines were the least differentiated of all the lines. The MDA-MB-231 line in vivo and in vitro had the most pronounced glandular features of all the lines and was not affected by changes in media additions of fetal calf serum, 17β-estradiol, or charcoal-treated calf serum as were the MCF-7- and MCF-7-derived lines. All the tumors in vivo and in vitro showed a human karyotype, and the MCF-7 and each of the derived lines showed both common and unique chromosome markers. The original cell line (MCF-7), the derived sublines (R27 and R3), and tumors derived in nude mice from these lines were typed for species identity using standard isozyme procedures and were found to be human. The allozyme phenotype at seven polymorphic human loci (allozyme genetic signature) demonstrated that the MCF-7 line and its derivatives were derived from the same individual and were distinct from the signatures of HeLa and a variety of other human breast cancer lines. This multifaceted study, using both in vivo and in vitro systems, may provide a model for better understanding the nature of tumor heterogeneity and its implications in therapeutic designs.

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.