Regulation of transforming growth factor-beta 1 gene expression by glucocorticoids in normal human T lymphocytes.

Glucocorticoids (GC) modulate immune function in a number of ways, including suppression of T cell proliferation and other IL-2-mediated T cell functions. These inhibitory effects are similar to those induced by transforming growth factor-beta 1 (TGF-beta 1), a cytokine with potent T cell inhibiting activities. We examined the hypothesis that GC effects may be at least partially achieved through modulation of the expression of the TGF-beta 1 gene in activated T cells. Normal T cells were cultured with or without purified phytohemagglutinin (PHA-p) and 4 beta-phorbol 12-myristate 13-acetate (PMA) in the presence or absence of the synthetic GC, dexamethasone (100-200 micrograms/ml). The production of latent and active forms of TGF beta by these cells were analyzed by immunoblotting and bioassays. The steady-state levels of TGF-beta 1 mRNA were analyzed in total RNA from these cells by Northern hybridizations using a human TGF-beta 1 cDNA. The results showed that dexamethasone caused an increase in TGF beta production and a dose-dependent two to fourfold increase in TGF-beta 1 mRNA in activated as well as in unstimulated T cells, 1 h after exposure of the cultures to the steroid. The increase in TGF-beta 1 mRNA levels by dexamethasone was further potentiated two to threefold by cycloheximide, suggesting that the steroid effect may be due to inhibition of the synthesis of proteins that decrease TGF-beta 1 gene transcription or the stability of its transcripts. Finally, in vitro nuclear transcription studies indicated the dexamethasone effects on TGF-beta 1 gene expression to be largely transcriptional

Epidermal growth factor coordinately regulates the expression of prostaglandin G/H synthase and cytosolic phospholipase A2 genes in embryonic mouse cells.

Confluent, primary cultures of mouse embryo palate mesenchyme (MEPM) cells are refractory to activation of phospholipase A2 (PLA2) by the calcium ionophore A23187. However, treatment of these cultures with epidermal growth factor (EGF) permits the cells to activate PLA2 in response to A23187. We have developed this finding by exploring molecular mechanisms by which growth factors modulate mobilization and metabolism of arachidonic acid. We found chronic treatment (\u3e 6 h) of confluent MEPM cells with EGF (a) increases their ability to metabolize exogenous arachidonic acid to prostaglandin E2 (PGE2) and (b) stimulated constitutive expression of activities of PLA2 and cyclooxygenase (CyOx). Immunoprecipitation of [35S]proteins and Western blot analysis revealed EGF treatment stimulated synthesis and accumulation of PLA2c, CyOx-1, and CyOx-2. Northern hybridization analysis revealed EGF increased the steady-state levels of a transcript for the high molecular weight, cytosolic PLA2 (PLA2c), and both the 2.8- and 4.2-kb transcripts for CyOx-1 and CyOx-2, respectively. In vitro nuclear transcription assays showed a parallel increase in the transcription rate of the genes corresponding to CyOx-1 and PLA2c, but not CyOx-2, in response to EGF. Treatment with EGF had no effect on either synthesis of the low molecular weight, group II PLA2, accumulation of its transcript, or the transcription rate of its gene. Coordinate regulation of activities of PLA2 and CyOx in response to EGF did not parallel the mitogenic effects of EGF on confluent MEPM cells

Duality theory and slackness conditions in multiobjective linear programming

AbstractThe aim of this paper is to develop a duality theory for linear multiobjective programming verifying similar properties as in the scalar case. We use the so-called “strongly proper optima” and we characterize such optima and its associated dual solutions by means of some complementary slackness conditions. Moreover, the dual solutions can measure the sensitivity of the primal optima

Tiltrotor CFD part II: aerodynamic optimisation of tiltrotor blades

This paper presents aerodynamic optimisation of tiltrotor blades with high-fidelity computational fluid dynamics. The employed optimisation framework is based on a quasi-Newton method, and the required high-fidelity flow gradients were computed using a discrete adjoint solver. Single-point optimisations were first performed, to highlight the contrasting requirements of the helicopter and aeroplane flight regimes. It is then shown how a trade-off blade design can be obtained using a multi-point optimisation strategy. The parametrisation of the blade shape allowed to modify the twist and chord distributions, and to introduce a swept tip. The work shows how these main blade shape parameters influence the optimal performance of the tiltrotor in helicopter and aeroplane modes, and how a compromise blade shape can increase the overall tiltrotor performance. Moreover, in all the presented cases, the accuracy of the adjoint gradients resulted in a small number of flow evaluations for finding the optimal solution, thus indicating gradient-based optimisation as a viable tool for modern tiltrotor design

Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis