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Biomedical subjects

Stephen Harris

Publications and source records attributed to Stephen Harris.

14 recordsLinked to original sources
PubMed2006

PRISM/PRDM6, a transcriptional repressor that promotes the proliferative gene program in smooth muscle cells.

Smooth muscle cells (SMCs) display remarkable phenotypic diversity and plasticity and can readily switch between proliferative and differentiated states in response to extracellular cues. In an effort to identify novel transcriptional regulators of smooth muscle phenotypes, we compared the gene expression profiles of arterial and venous SMCs by microarray-based transcriptional profiling. Among numerous genes displaying distinct expression patterns in these two SMC types, we discovered an expressed sequence tag encoding a previously uncharacterized zinc finger protein belonging to the PRDM (PRDI-BF1 and RIZ homology domain) family of chromatin-remodeling proteins and named it PRISM (PR domain in smooth muscle). PRISM is expressed in a variety of smooth muscle-containing tissues and displays especially robust expression in the cardiac outflow tract and descending aorta during embryogenesis. PRISM is localized to the nucleus and contains an amino-terminal PR domain and four Krüppel-like zinc fingers at the carboxy terminus. We show that PRISM acts as a transcriptional repressor by interacting with class I histone deacetylases and the G9a histone methyltransferase, thereby identifying PRISM as a novel SMC-restricted epigenetic regulator. Overexpression of PRISM in cultured primary SMCs induces genes associated with the proliferative smooth muscle phenotype while repressing regulators of differentiation, including myocardin and GATA-6. Conversely, small interfering RNA-mediated knockdown of PRISM slows cell growth and induces myocardin, GATA-6, and markers of SMC differentiation. We conclude that PRISM acts as a novel epigenetic regulator of SMC phenotypic plasticity by suppressing differentiation and maintaining the proliferative potential of vascular SMCs.

Amino Acid Sequence↗
PubMed2005

Clinical pharmacology and pharmacokinetics of once-daily hydromorphone hydrochloride extended-release capsules.

Hydromorphone hydrochloride extended release (HHER) is a multiparticulate melt-extrusion pellet capsule formulation administered q24h. Study 1 investigated the bioavailability of 24-mg HHER fed, as well as 24-mg and 12-mg HHER and 8-mg hydromorphone hydrochloride immediate-release (HHIR) tablets fasting. No clinically significant food effect was observed on hydromorphone C(max) or AUC for the 24-mg HHER, and dose proportionality (AUC) was demonstrated between 12- and 24-mg HHER. Study 2 demonstrated dose strength proportionality for 3 x 12-mg HHER versus 1 x 32-mg HHER. Study 3 evaluated 12-mg HHER q24h versus 3-mg HHIR q6h at steady state. HHER produced relatively constant steady-state concentrations over 24 hours. HHER and HHIR were equivalent for AUC(ss). C(ssmax) was 26% lower for HHER than HHIR, C(ssmin) was 43% higher for HHER, and peak-to-trough fluctuation was 126% for HHER versus 328% for HHIR, which are ideal attributes of a once-daily oral extended-release dosage form. HHER administration resulted in fewer adverse events than HHIR in study 3.

Adult↗
PubMed2004

Development of public toxicogenomics software for microarray data management and analysis.

A robust bioinformatics capability is widely acknowledged as central to realizing the promises of toxicogenomics. Successful application of toxicogenomic approaches, such as DNA microarray, inextricably relies on appropriate data management, the ability to extract knowledge from massive amounts of data and the availability of functional information for data interpretation. At the FDA's National Center for Toxicological Research (NCTR), we are developing a public microarray data management and analysis software, called ArrayTrack. ArrayTrack is Minimum Information About a Microarray Experiment (MIAME) supportive for storing both microarray data and experiment parameters associated with a toxicogenomics study. A quality control mechanism is implemented to assure the fidelity of entered expression data. ArrayTrack also provides a rich collection of functional information about genes, proteins and pathways drawn from various public biological databases for facilitating data interpretation. In addition, several data analysis and visualization tools are available with ArrayTrack, and more tools will be available in the next released version. Importantly, gene expression data, functional information and analysis methods are fully integrated so that the data analysis and interpretation process is simplified and enhanced. ArrayTrack is publicly available online and the prospective user can also request a local installation version by contacting the authors.

Databases, Genetic↗
PubMed2004

Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans.

A previous study revealed that the difference in susceptibility to atherosclerotic lesions between inbred mouse strains SM/J and NZB/BlNJ was determined by one major locus (Ath8). In this study a (SM/J x NZB/BlNJ) F(1) x SM/J backcross localized Ath8 by quantitative trait locus mapping to chromosome 4 with a suggestive LOD score of 2.7. This quantitative trait locus (QTL) was confirmed using an (SM/J x NZB/BlNJ) intercross; Ath8 mapped to a 23cM region with a significant LOD score of 3.6. The genes for toll-like receptor 4 (T1r4), arachidonic acid epoxygenase (Cyp2j5), and angiopoietin-like protein 3 (Angptl3) map to this region. These candidate genes were analyzed for expression and sequence differences in the mouse and for associations with cardiovascular traits in human. Sequence analysis of Angptl3 shows a base pair substitution in SM, the susceptible strain, giving rise to an amino acid change in the fibrinogen homology domain of the protein. We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angptl3 is involved in atherosclerosis susceptibility in both mouse and human.

Animals↗
PubMed2004

Modelling the costs of fox predation and preventive measures on sheep farms in Britain.

Economic analysis is a useful tool to aid decisions on what to do about wildlife impacts, such as those of vertebrate predators on livestock farmers. The case-study of lamb predation by foxes in Britain is used to develop a theoretical economic model, with the aim of determining a financially optimal solution to minimise the total costs of livestock predation at the farm-level. Total costs include output losses and expenditure on preventive and control measures, in this case indoor housing and lethal fox control. The model is tested empirically with data from a questionnaire survey of sheep farmers and field data on fox population densities in Britain. Regression analyses are used to determine the relationships between lamb losses and expenditure on indoor housing, fox population density and other non-management characteristics. The effect of fox abundance on the cost of fox control is also assessed. Marginal analysis is used to determine the total cost-minimising solution from the farmer's point-of-view, in terms of how many ewes should be housed indoors and for how long, as well as how many foxes should be killed in addition to any lethal control already carried out. Optimal solutions vary according to farm characteristics, including flock size and the regional location of farms. In all cases, to minimise the costs of predation, as many ewes as possible should be housed. However, it is not worthwhile housing them for more than a day after lambing. Efficient fox predation management does not necessarily mean that lamb losses should be reduced to zero, and additional fox control is not worthwhile on the majority of farms. The analysis provides a framework for future evaluations of wildlife impacts and cost-effective management of these problems.

Animal Husbandry↗
PubMed2003

Identification of the haematopoietic stem cell niche and control of the niche size.

Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche'--the in vivo regulatory microenvironment where HSCs reside--and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+CD45- osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and beta-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.

Animals↗
PubMed2003

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases.

Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.

Bone Neoplasms↗
PubMed2003

Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci.

Mapping quantitative trait loci (QTLs) with high resolution facilitates identification and positional cloning of the underlying genes. The novel approach of advanced intercross lines (AILs) generates many more recombination events and thus can potentially narrow QTLs significantly more than do conventional backcrosses and F2 intercrosses. In this study, we carried out QTL analyses in (C57BL/6J x NZB/BlNJ) x C57BL/6J backcross progeny fed either chow or an atherogenic diet to detect QTLs that regulate high-density lipoprotein cholesterol (HDL)concentrations, and in (C57BL/6J x NZB/BlNJ) F11 AIL progeny to confirm and narrow those QTLs. QTLs for HDL concentrations were found on chromosomes 1, 5, and 16. AIL not only narrowed the QTLs significantly more than did a conventional backcross but also resolved a chromosome 5 QTL identified in the backcross into two QTLs, the peaks of both being outside the backcross QTL region. We tested 27 candidate genes and found significant mRNA expression differences for 12 (Nr1i3, Apoa2, Sap, Tgfb2, Fgfbp1, Prom, Ppargc1, Tcf1, Ncor2, Srb1, App, and Ifnar). Some of these underlay the same QTL, indicating that expression differences are common and not sufficient to identify QTL genes. All the major HDL QTLs in our study had homologous counterparts in humans, implying that their underlying genes regulate HDL in humans.

Animals↗
PubMed2003

The current and future management of wild mammals hunted with dogs in England and Wales.

There is increasing concern about the use of lethal methods to control wild mammal populations, especially those methods that may have significant impacts on animal welfare. The continued use of dogs to hunt wild mammals in England and Wales, principally foxes (Vulpes vulpes), red deer (Cervus elaphus), brown hares (Lepus europaeus) and mink (Mustela vison), has become a focus for political debate and has been the subject of a recent UK government inquiry. This paper reports the results of a questionnaire study to quantify the use, effectiveness and acceptability of the different methods currently used to manage these four species, and future changes in management following a possible ban on hunting with dogs. There was no straightforward relationship between culling pressure and perceived pest status of the different species from the questionnaire data. For foxes and brown hares, the proportion of land managers (practitioners) carrying out lethal control was higher than that considering these species to be pests. However, the reverse was the case for mink. The most frequently used and effective control methods, which were most acceptable to practitioners and public alike, were various forms of shooting. The general public perceived hunting with dogs as one of the least acceptable means of control for all four species. Practitioners thought that hunting with dogs for red deer and the use of terriers against foxes were among the least acceptable forms of control, but considered hunting with dogs in other situations and for other species to be relatively acceptable. Most practitioners said a ban on hunting with dogs would make no difference to their management of the four species. A ban on hunting with dogs would have minimal impact on populations of foxes, red deer and mink, but it may be of conservation benefit to hares.

Animal Husbandry↗
PubMed2003

ArrayTrack--supporting toxicogenomic research at the U.S. Food and Drug Administration National Center for Toxicological Research.

The mapping of the human genome and the determination of corresponding gene functions, pathways, and biological mechanisms are driving the emergence of the new research fields of toxicogenomics and systems toxicology. Many technological advances such as microarrays are enabling this paradigm shift that indicates an unprecedented advancement in the methods of understanding the expression of toxicity at the molecular level. At the National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration, core facilities for genomic, proteomic, and metabonomic technologies have been established that use standardized experimental procedures to support centerwide toxicogenomic research. Collectively, these facilities are continuously producing an unprecedented volume of data. NCTR plans to develop a toxicoinformatics integrated system (TIS) for the purpose of fully integrating genomic, proteomic, and metabonomic data with the data in public repositories as well as conventional (Italic)in vitro(/Italic) and (Italic)in vivo(/Italic) toxicology data. The TIS will enable data curation in accordance with standard ontology and provide or interface a rich collection of tools for data analysis and knowledge mining. In this article the design, practical issues, and functions of the TIS are discussed through presenting its prototype version, ArrayTrack, for the management and analysis of DNA microarray data. ArrayTrack is logically constructed of three linked components: a) a library (LIB) that mirrors critical data in public databases; b) a database (MicroarrayDB) that stores microarray experiment information that is Minimal Information About a Microarray Experiment (MIAME) compliant; and c) tools (TOOL) that operate on experimental and public data for knowledge discovery. Using ArrayTrack, we can select an analysis method from the TOOL and apply the method to selected microarray data stored in the MicroarrayDB; the analysis results can be linked directly to gene information in the LIB.

Databases, Factual↗
PubMed2002

Effect of British hunting ban on fox numbers.

Pressure to ban the hunting of foxes with hounds in Britain has fuelled debate about its contribution to the control of fox populations. We took advantage of a nationwide one-year ban on fox-hunting during the outbreak of foot-and-mouth disease (FMD) in 2001 to examine this issue and found that the ban had no measurable impact on fox numbers in randomly selected areas. Our results argue against suggestions that fox populations would increase markedly in the event of a permanent ban on hunting.

Animals↗
PubMed2002

Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice.

To investigate the quantitative trait loci (QTL) regulating plasma cholesterol, the female progeny of an (SMxNZB/ B1NJ)xNZB/B1NJ backcross were fed an atherogenic diet. After 18 wk, plasma total cholesterol and high-density lipoprotein cholesterol (HDL-C) was measured. HDL-C concentrations were greater in NZB than in SM mice. For standard chow-fed mice, QTL were found near D5Mit370 and D18Mit34. For mice fed an atherogenic diet, a QTL was found near D5Mit239. The QTL for chow-fed and atherogenic-fed mice on chromosome 5 seem to be two different loci. We used a multitrait analysis to rule out pleiotropy in favor of a two-QTL hypothesis. Furthermore, the HDL-C in these strains was induced by the high-fat diet. For inducible HDL-C, one significant locus was found near D15Mit39. The gene for an HDL receptor, Srb1, maps close to the HDL-C QTL at D5Mit370, but the concentrations of Srb1 mRNA and SR-B1 protein and the gene sequence of NZB/B1NJ and SM/J did not support Srb1 as a candidate gene. With these QTL, we have identified chromosomal regions that affect lipoprotein profiles in these strains.

Animals↗
PubMedDate not supplied

Models of steroid binding based on the minimum deviation of structurally assigned 13C NMR spectra analysis (MiDSASA).

This paper develops a quantitative k-nearest neighbors modeling technique. The technique is used to demonstrate that a compound's biological binding activity to a receptor can be calculated from the minimum of the square root of the sum of squared deviations (SSSD) of a structurally assigned chemical shift on a template between the unknown compound to be predicted and a set of known compounds with known activities. When building models of biological activity, nonlinear relationships are built into the input training data. If a model is developed by selecting only compounds with minimum structurally assigned chemical shift deviations from the unknown compound, some of the nonlinear relationships can be removed. The smaller the total chemical shift deviation between a compound with known activity and another compound with unknown activity, the more likely it will have similar biological, chemical, and physical properties. This means that a model can be produced without rigorous statistics or neural networks. This technique is similar to structure-activity relationship (SAR) modeling, but instead of relying on substructure fragments to produce a model, this new model is based on minimum chemical shift differences on those substructure fragments. We refer to this method as minimum deviation of structurally assigned spectra analysis (MiDSASA) modeling. Modeling by the minimum deviation concept can be applied to other chemoinformatic data analyses such as metabolite concentrations in metabolic pathways for metabolomics research. A MiDSASA template model for 30 steroids binding the corticosterone binding globulin based on the activity factors of the two nearest compounds had a correlation of 0.88. A MiDSASA template model for 50 steroids binding the aromatse enzyme based on the average activity of the four nearest compounds had a correlation of 0.71.

Aromatase↗