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Biomedical subjects

T Sewell

Publications and source records attributed to T Sewell.

13 recordsLinked to original sources
PubMed1999

Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation.

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production.

Animals↗
PubMed1992

The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin.

FK-506 inhibits Ca(2+)-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.

Amino Acid Isomerases↗
PubMed1992

Growth and academic achievement in inner-city kindergarten children. The relationship of height, weight, cognitive ability, and neurodevelopmental level.

Measures of height, weight, nonverbal cognitive ability (Ravens progressive matrix), visual-motor-perceptual ability (Beery-Buktenica test of Visual Motor Integration [VMI]), the imitation-of-gestures technique, and academic achievement (Stanford Early Achievement) were obtained for a sample of 82 children from a poor inner-city community. In contrast to prior reports from the United States and about other developed countries, anthropometric measures were related both to academic achievement and to these measures of neurodevelopment. They were not consistently related to measures of nonverbal cognitive ability. Regression analyses revealed that general cognitive ability contributed more variance (39%) to predictions of achievement than all other variables, including weight for age (13%) and VMI (6%). Children with reduced somatic growth were likely to do poorly in school, but the data do not show that undernutrition causes learning failure. Rather, they suggest that environmental problems affecting the development of thought processes and nutrient intake precede both growth and learning failure.

Achievement↗
PubMed1977

X-ray analysis and circular dichroism of the acid protease from Endothia parasitica and chymosin.

The structure of an acid proteinase from Endothia parasitica has been solved by x-ray diffraction using multiple isomorphous replacement. A 3 A resolution map was interpreted in terms of a bilobal structure with a long 25 A cleft. The secondary structure is mostly distorted beta-sheet. The circular dichroism was measured and model curves for different secondary structures were fitted by least squares indicating a large component of beta-structure. The structure was seen to be homologous with that of the acid proteinase from R. Chinensis and hence with pepsin and chymosin. A rotation function against diffraction data from chymosin crystals confirm confirm this and suggested an approach to the solution of this structure.

Ascomycota↗
PubMed1977

American and British data on a three dimensional assessment of personality in college students.

Reported data on American and British college student samples for the new Psychoticism, Extraversion, and Neuroticism (PEN) Inventory. Descriptive statistics for PEN dimensions for five American female samples (total 492 subjects), five American male samples (total 399 subjects), one British female sample (700 subjects) and one British male sample (700 subjects) were summarized. Intercorrelations of PEN dimensions for most of the American samples were reported. The pattern of significant intercorrelations tended to be in accord with previous work on prior related inventories. Similarities and differences among the sample descriptive statistics were discussed.

Cross-Cultural Comparison↗