Biomedical subjects

John Watson

Publications and source records attributed to John Watson.

8 recordsLinked to original sources

PubMed2003

An ultra-HTS process for the identification of small molecule modulators of orphan G-protein-coupled receptors.

G-protein-coupled receptors (GPCRs) are the most successful target proteins for drug discovery research to date. More than 150 orphan GPCRs of potential therapeutic interest have been identified for which no activating ligands or biological functions are known. One of the greatest challenges in the pharmaceutical industry is to link these orphan GPCRs with human diseases. Highly automated parallel approaches that integrate ultra-high throughput and focused screening can be used to identify small molecule modulators of orphan GPCRs. These small molecules can then be employed as pharmacological tools to explore the function of orphan receptors in models of human disease. In this review, we describe methods that utilize powerful ultra-high-throughput screening technologies to identify surrogate ligands of orphan GPCRs.

Drug Design↗

PubMed2003

Evaluating subject specific preprocessing choices in multisubject fMRI data sets using data-driven performance metrics.

This study investigated the possible benefit of subject specific optimization of preprocessing strategies in functional magnetic resonance imaging (fMRI) experiments. The optimization was performed using the data-driven performance metrics developed recently [Neuroimage 15 (2002), 747]. We applied numerous preprocessing strategies and a multivariate statistical analysis to each of the 20 subjects in our two example fMRI data sets. We found that the optimal preprocessing strategy varied, in general, from subject to subject. For example, in one data set, optimum smoothing levels varied from 16 mm (4 subjects), 10 mm (5 subjects), to no smoothing at all (1 subject). This strongly suggests that group-specific preprocessing schemes may not give optimum results. For both studies, optimizing the preprocessing for each subject resulted in an increased number of suprathresholded voxels in within-subject analyses. Furthermore, we demonstrated that we were able to aggregate the optimized data with a random effects group analysis, resulting in improved sensitivity in one study and the detection of interesting, previously undetected results in the other.

Adult↗

PubMed2002

The heterogeneity of the glycosylation of alpha-1-acid glycoprotein between the sera and synovial fluid in rheumatoid arthritis.

Alpha-1-acid glycoprotein (AGP) is a plasma glycoprotein produced by the liver that undergoes increased production and altered glycosylation in several physiological and pathological conditions including rheumatoid arthritis. To date, although present in the synovial fluid of rheumatoid arthritis patients, there has been no evidence for the separate extra-hepatic production of AGP. This study indicates that there could be a localized production of AGP in rheumatoid synovial fluid by demonstrating that the glycosylation patterns of AGP differed between the serum and synovial fluid in the same rheumatoid patient. Serum AGP was largely composed of fucosylated tri- and tetra-antennary oligosaccharide chains while the synovial fluid contained mainly bi-antennary chains that were fucosylated to a lesser extent. This structural heterogeneity of glycosylation resulted in functional diversity; serum but not synovial AGP is able to inhibit binding to the cell adhesion molecule E-selectin through expression of antigen sialyl Lewis X.

Arthritis, Rheumatoid↗

PubMed2002

A preliminary evaluation of the functional significance of alpha-1-acid glycoprotein glycosylation on wound healing.

The laying down of collagen and fibrous tissue is a key process in wound healing, however excessive collagen (and glycoprotein) deposition causes hypertrophic and keloid scars, eg after burns. Collagen synthesis is increased in these scars compared with normal healing, as is collagenase activity, which controls the degradation pathway of collagen. The processes of wound healing are inextricably linked to those of the acute-phase response (APR): alpha-1-acid glycoprotein (AGP), a plasma glycoprotein that undergoes both an increase in concentration and an alteration in its glycosylation pattern during the APR. This study determined that AGP isolated from the plasma of burns patients was of an increased concentration and altered glycosylation pattern compared with normal plasma and was capable of directly interacting with type I collagen. It also had a profound effect on both collagen fibril formation and collagenase activity, to a degree dependent upon the percentage body surface area burned. Additionally, the results obtained provided the basis for predicting the formation of hypertrophic scars.

Burns↗

PubMed2002

Chapter three: methodology of exposure modeling.

In this chapter, the concept of exposure assessment and its evolution is introduced, and evaluated by critically appraising the pertinent literature as it applies to exposures to Particulate Matter (PM). Exposure measurement or estimation methodologies and models are reviewed. Three exposure/measurement methodologies are assessed. Estimation methods focus on source evaluation and attribution, sources include those outdoors and indoors as well as in occupational and in-transit environments. Fate and transport models and their inputs are addressed to estimate concentrations outdoors and indoors; source attribution techniques help focus on the contributing sources. Activity pattern techniques are also reviewed and their use in exposure models to estimate inhalation exposure to PM is presented. Deterministic, regression and other stochastic models of exposure to PM are reviewed and evaluated. Strengths, limitations, assumptions and affirmations of the use of exposure assessment as an integral component of risk assessment and risk management are discussed in the conclusions and discussions section of this work.

Air Pollutants↗

PubMed2002

Pneumocystis carinii: where are we now?

Pneumocystis carinii pneumonia (PCP) is still the commonest AIDS-defining condition in the UK, although absolute numbers have fallen since 1990 with the advent of prophylaxis and highly active antiretroviral therapy (HAART). Further decreases in its incidence are unlikely unless efforts are made to reduce late first presentations of HIV, improve retention of patients in care and improve adherence to P. carinii prophylaxis. The widespread development of key mutations in the P. carinii dihydropteroate synthase gene in the 1990's suggests that the organism is evolving under positive evolutionary pressure, possibly mediated by widespread use of co-trimoxazole and dapsone prophylaxis. It is not clear whether these mutants lead to treatment failure with co-trimoxazole, since most episodes are treated successfully and failure of prophylaxis is rare. Molecular diagnosis of PCP is restricted to research use, due to difficulties with sensitivity, specificity and turn-around times. Patients are infected with multiple P. carinii subtypes and re-infection from an environmental source is probably more important than re-activation of an existing infection. Person-to-person transmission does not appear to be a major source of infection in HIV-infected patients. Recent reports have highlighted the potential complications of initiating HAART during treatment of PCP.

AIDS-Related Opportunistic Infections↗

PubMed2002

From one well to 9000: using high-density streptavidin-coated membranes for kinase detection.

The study of kinases and their role in cellular regulation continues to expand as the human genome is sequenced and new kinases are identified as expression products of newly discovered genes. Reagents and assay systems that allow for sensitive, accurate, and high-throughput analysis of both purified kinases as well as crude extracts will enhance the characterization of these important cellular components and will speed the identification of appropriate therapeutic targets and the development of new and more effective treatments.

Autoradiography↗

PubMedDate not supplied

Immunohistochemical localization of the retinoic Acid receptors in human prostate.

Retinoic acid receptors (RARs) are nuclear transcription factors that mediate the effects of retinoids. Aberrant expression and regulation of RARs have been linked to various malignancies, including steroid-related breast and cervical cancers. Our previous results also suggest that prostate cancer is associated with altered RAR signaling. To understand the relationship between RAR signaling and prostate cancer, the current study examined the cellular distribution of RAR-alpha, -beta, and -gamma in human prostate tissues exhibiting different pathologic conditions. In histologically normal epithelium, both RAR-alpha and -gamma were present throughout the epithelium with minimal nuclear accumulation. RAR-beta was present only in basal epithelial nuclei. On the contrary, RAR-alpha was significantly increased in the nuclei of luminal epithelial cells, and both RAR-beta and -gamma were increased in basal and luminal epithelial nuclei in glands exhibiting benign prostatic hyperplasia (BPH). RAR-alpha was also increased in luminal epithelial nuclei in glands exhibiting prostatic intra-epithelial neoplasia (PIN). In these glands, RAR-beta was persisting in basal epithelial nuclei that were also RAR-gamma positive. In low- and intermediate-grade cancerous glands, RAR-alpha was also significantly increased in luminal epithelial nuclei, and a strong RAR-gamma signal was seen in some cells. RAR-beta was absent in these glands. Both RAR-alpha and -gamma were also increased in high-grade cancer cells. In conclusion, current results demonstrated changes in cellular distribution of RAR-alpha and -gamma in human prostate tissues exhibiting different pathologies. These results suggest links between altered RAR signaling and deregulated cell growth and/or tumorigenic transformation of prostate epithelial cells.

Humans↗