Differential activity of GSK-3 isoforms regulates NF-kappa B and TRAIL- or TNF alpha induced apoptosis in pancreatic cancer cells

While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3 alpha or GSK-3 beta. In contrast, depletion of GSK-3 beta, but not GSK-3 alpha, sensitized PDA cell lines to TNF alpha-induced cell death. Further experiments demonstrated that TNF alpha-stimulated I kappa B alpha phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3 beta-deficient MEFs. Nonetheless, inhibition of GSK-3 beta function in MEFs or PDA cell lines impaired the expression of the NF-kappa B target genes Bcl-xL and cIAP2, but not I kappa B alpha. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3 beta targeted to the nucleus but not GSK-3 beta targeted to the cytoplasm, suggesting that GSK-3 beta regulates NF-kappa B function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3 beta overexpression and nuclear localization contribute to TNF alpha and TRAIL resistance via anti-apoptotic NF-kappa B genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

Approximate Solutions by Truncated Taylor Series Expansions of Nonlinear Differential Equations and Related Shadowing Property with Applications

This paper investigates the errors of the solutions as well as the shadowing property of a class of nonlinear differential equations which possess unique solutions on a certain interval for any admissible initial condition. The class of differential equations is assumed to be approximated by well-posed truncated Taylor series expansions up to a certain order obtained about certain, in general nonperiodic, sampling points t(i) is an element of [t(0), t(J)] for i = 0, 1, . . . , J of the solution. Two examples are provided.

Variation in trawl geometry due to unequal warp length

Survey standardization procedures can reduce the variability in trawl catch efficiency thus producing more precise estimates of biomass. One such procedure, towing with equal amounts of trawl warp on both sides of the net, was experimentally investigated for its importance in determining optimal trawl geometry and for evaluating the effectiveness of the recent National Oceanic and Atmospheric Administration (NOAA) national protocol on accurate measurement of trawl warps. This recent standard for measuring warp length requires that the difference between warp lengths can be no more than 4% of the distance between the otter doors measured along the bridles and footrope. Trawl performance data from repetitive towing with warp differentials of 0, 3, 5, 7, 9, 11, and 20 m were analyzed for their effect on three determinants of flatfish catch efficiency: footrope distance off-bottom, bridle length in contact with the bottom, and area swept by the net. Our results indicated that the distortion of the trawl caused by asymmetry in trawl warp length could have a negative inf luence on flatfish catch efficiency. At a difference of 7 m in warp length, the NOAA 4% threshold value for the 83112 Eastern survey trawl used in our study, we found no effect on the acous-tic-based measures of door spread, wing spread, and headrope height off-bottom. However, the sensitivity of the trawl to 7 m of warp offset could be seen as footrope distances off-bottom increased slightly (particularly in the center region of the net where flatfish escapement is highest), and as the width of the bridle path responsible for flatfish herding, together with the effective net width, was reduced. For this survey trawl, a NOAA threshold value of 4% should be considered a maximum. A more conservative value (less than 4%) would likely reduce potential bias in estimates of relative abundance caused by large differences in warp length approaching 7 m.

Distribution theory and fundamental solutions of differential operators

The objective of this dissertation is to study the theory of distributions and some of its applications. Certain concepts which we would include in the theory of distributions nowadays have been widely used in several fields of mathematics and physics. It was Dirac who first introduced the delta function as we know it, in an attempt to keep a convenient notation in his works in quantum mechanics. Their work contributed to open a new path in mathematics, as new objects, similar to functions but not of their same nature, were being used systematically. Distributions are believed to have been first formally introduced by the Soviet mathematician Sergei Sobolev and by Laurent Schwartz. The aim of this project is to show how distribution theory can be used to obtain what we call fundamental solutions of partial differential equations.

Uso de espinores na investigação do limite de Karlhede para ondas pp

Neste trabalho foi feito um estudo do limite de Karlhede para ondas pp. Para este fim, uma revisão rigorosa de Geometria Diferencial foi apresentada numa abordagem independente de sistemas de coordenadas. Além da abordagem usual, a curvatura de uma variedade riemanniana foi reescrita usando os formalismos de referenciais, formas diferenciais e espinores do grupo de Lorentz. O problema de equivalência para geometrias riemannianas foi formulado e as peculiaridades de sua aplicação é a Relatividade Geral são delineadas. O limite teórico de Karlhede para espaços-tempo de vácuo de tipo Petrov N foi apresentado. Esse limite é estudado na prática usando técnicas espinores e as condições para sua existência são resolvidas sem a introdução de sistemas de coordenadas.

Cálculo no ensino médio: uma proposta para o ensino de derivada na primeira série

Este trabalho traz uma proposta de atividades, a serem desenvolvidas em sala de aula, com o objetivo de introduzir o conceito de derivadas para os alunos da primeira série do Ensino Médio. Antes das atividades, estão presentes algumas breves pesquisas. O histórico da presença de tópicos do Cálculo Diferencial e Integral no Ensino Médio no Brasil, assim como a análise de alguns livros didáticos, serve para mostrar como o assunto já foi e está sendo tratado no país. Também são exibidos aspectos sobre o Ensino Médio na Alemanha e nos Estados Unidos, países onde o cálculo está presente na Escola Secundária, embora de formas bastante diferentes. Um capítulo sobre a preparação adequada para as aulas também foi incluído, uma vez que a simples inserção da derivada poderia causar problemas de tempo para o cumprimento do cronograma e não trazer os resultados esperados. São necessários algum grau de adequação dos conteúdos ministrados e de cooperação com professores de Física. As atividades visando o ensino dos conceitos iniciais de derivada são motivadas por um problema físico de movimento. O foco é dado na intuição e na visualização de gráficos, para que haja uma melhor compreensão dos conceitos envolvidos. A utilização de um software de geometria dinâmica é requerida em boa parte do tempo, como importante ferramenta de apoio pedagógico