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.

The role and function of IκKα/β in monocyte impairment

Abstract: Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/β, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/β complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naive monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/β with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1β, TNF-β, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/β activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκKα/β is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/β function to restore monocyte function in this clinically important problem.

Open-Access Video-Based Orthopaedic Instructional Content is Inaccurate:

Abstract: Objectives:The internet has an increasing role in both patient and physician education. While several recent studies critically appraised the quality and accuracy of web-based written information available to patients, no studies have evaluated such parameters for open access video content designed for provider use. The present study sought to determine utilization of video resources by orthopaedic residents and assess the quality and accuracy of their contentMethods:Surveys were distributed to orthopaedic surgery residents to to determine their use of open access instructional video content. An assessment of quality and accuracy of said video content was performed using the basic shoulder examination as a suragate for the “best-case scenario” due to its widely accepted components that are stable over time. Three search terms (“shoulder”, “examination” and “shoulder exam”) were entered into the four online video resources most commonly accessed by orthopaedic surgery residents (VuMedi, G9MD, Orthobullets,...

Parallels of Genomic Organization and of Endogenous Retrovirus Organization in Cat and Man

Abstract: A combination of technical advances (most notably heterologous cell fusion, high resolution G-banding, and molecular cloning) has contributed to an accelerated advance in genetic analysis in mammals. The present human genetic map contains over 400 gene assignments and the map is growing rapidly as each new molecular clone or immunological reagent is developed. In our laboratory, we have developed a panel of rodent X human somatic cell hybrids that have been utilized in chromosome assignment of several classes of genes including oncogenes (ras, raf) and endogenous human retroviral sequences (ERVL, 2, etc). Using similar techniques, a biochemical genetic map of the domestic cat has been derived. The cat has 19 chromosome pairs and, to date, 40 genes have been mapped to 16 linkage or syntenic groups. Comparison of linkage relationships between homologous enzymes has revealed a striking conversation of chromosomal linkage association between cat and man. A comparison of syntenically homologous, highly extended high resoultion G-banded chromosomes between the two mammalian families revealed that 20–25%, by length, of the human karyotype can be precisely aligned (chromomere to chromomere) between cats and man despite the evolutionary divergence of the species nearly 80 million years ago. Moderately repetitive families of retrovirus-related DNAs exist within the feline and the human genomes. We have isolated molecular clones of several members of the feline RD-114 retrovirus family from a genomic library of normal cat cellular DNA. The endogenous sequences analyzed were similar to each other in that they were colinear with RD-114 proviral DNA, were bounded by long terminal redundancies, and conserved many restriction sites in the gag and pol regions. Several sequences were apparently deleted, relative to the previously characterized inducible RD-114 genome. The env regions of a number of endogenous RD-114 sequences examined were substantially deleted or diverged; a subset of these sequences contained information at the position of the env region that was not homologous to inducible RD-114. The RD-114 virogenes were dispersed to several cat chrosomes that were localized using a panel of rodent x cat somatic cell hybrids. A comparison of the genetic properties of endogenous human retroviral sequences revealed several similarities between the human and feline status of endogenous retroviruses.

Signal localization: a new approach in signal discovery.

Abstract: A new approach for statistical association signal identification is developed in this paper. We consider a strategy for nonprecise signal identification by extending the well-known signal detection and signal identification methods applicable to the multiple testing problem. Collection of statistical instruments under the presented approach is much broader than under the traditional signal identification methods, allowing more efficient signal discovery. Further assessments of maximal value and average statistics in signal discovery are improved. While our method does not attempt to detect individual predictors, it instead detects sets of predictors that are jointly associated with the outcome. Therefore, an important application would be in genome wide association study (GWAS), where it can be used to detect genes which influence the phenotype but do not contain any individually significant single nucleotide polymorphism (SNP). We compare power of the signal identification method based on extremes of single p-values with the signal localization method based on average statistics for logarithms of p-values. A simulation analysis informs the application of signal localization using the average statistics for wide signals discovery in Gaussian white noise process. We apply average statistics and the localization method to GWAS to discover better gene influences of regulating loci in a Chinese cohort developed for risk of nasopharyngeal carcinoma (NPC).

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.