Biomedical subjects

Michael J Clark

Publications and source records attributed to Michael J Clark.

6 recordsLinked to original sources

PubMed2006

The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.

OBJECTIVE: Oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine (oxPAPC) accumulates in atherosclerotic lesions and in vitro studies suggest that it mediates chronic inflammatory response in endothelial cells (ECs). The goal of our studies was to identify pathways mediating the induction of inflammatory genes by oxPAPC. METHODS AND RESULTS: Using expression arrays, quantitative polymerase chain reaction (PCR), and immunoblotting we demonstrate that oxPAPC leads to endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in human aortic ECs. Immunohistochemistry analysis of human atherosclerotic lesions indicated that UPR is induced in areas containing oxidized phospholipids. Using the UPR inducing agent tunicamycin and selective siRNA targeting of the ATF4 and XBP1 branches of the UPR, we demonstrate that these transcription factors are essential mediators of IL8, IL6, and MCP1 expression in human aortic ECs required for maximal inflammatory gene expression in the basal state and after oxPAPC treatment. We also identify a novel oxPAPC-induced chemokine, the CXC motif ligand 3 (CXCL3), and show that its expression requires XBP1. CONCLUSIONS: These data suggest that the UPR pathway is a general mediator of vascular inflammation and EC dysfunction in atherosclerosis, and, likely, other inflammatory disorders.

Activating Transcription Factor 4↗

PubMed2006

Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.

Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.

Activating Transcription Factor 4↗

PubMed2006

Confronting flood risk: implications for insurance and risk transfer.

The UK floods in late 2000 reinforced an emerging awareness which questioned the long-term sustainability of an exclusive reliance on hard-engineered flood defences to protect the UK population against increased flood risk. The debate has subsequently focused on a broader interpretation of the risks associated with flooding. This paper explores the notion that, although social and technical issues are already being integrated to understand and manage flood, practitioners are now realising the importance of accommodating public hazard understanding and perception of risk into their management models, and there remains a need to fit such ideas to the insurance-based system of flood management in the UK.

Community Participation↗

PubMed2005

Autopsy.

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Autopsy↗

PubMed2002

The effects of training history, player position, and body composition on exercise performance in collegiate football players.

Performance data for 261 NCAA Division 1A collegiate football players were analyzed to determine if player position, body weight, body fat, and training time were correlated with changes in performance in the following events: power clean (PC), bench press (BP), squat (SQ), vertical jump (VJ), 40-yd dash (40yd), and 20-yd shuttle (20yd). Individual positions were combined into the following groups: (A) wide receivers, defensive backs, and running backs, (B) linebackers, kickers, tight ends, quarterbacks, and specialists, and (C) linemen. Increases in body weight were positively correlated with increases in BP and PC performance for all groups. Increases in body fat were negatively correlated with performance in the PC and VJ for all groups. For group C, increases in body fat were also negatively correlated with performance in the 40yd and 20yd. Group and training time exhibited no linear relationship with performance in any of the tested events. No linear relationships were observed between the independent variables and performance in the SQ. When individual training data were analyzed longitudinally, a nonlinear increase in performance in the PC, BP, and SQ was observed as training time increased, with the greatest rate of change occurring between the first and second semesters of training.

Adolescent↗

PubMedDate not supplied

Forensic.

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Forensic Medicine↗