Cardioprotective Effect of Nicorandil, a Mitochondrial ATP-Sensitive Potassium Channel Opener, Prolongs Survival in HSPB5 R120G Transgenic Mice

BACKGROUND: Transgenic (TG) mice with overexpression of an arg120gly (R120G) missense mutation in HSPB5 display desmin-related cardiomyopathy, which is characterized by formation of aggresomes. It is also known that progressive mitochondrial abnormalities and apoptotic cell death occur in the hearts of R120G TG mice. The role of mitochondrial dysfunction and apoptosis in disease progression, however, remains uncertain. METHODS AND RESULTS: Mitochondrial abnormalities and apoptotic cell death induced by overexpression of HSPB5 R120G were analyzed in neonatal rat cardiomyocytes. Overexpression of mutant HSPB5 led to development of aggresomes with a concomitant reduction in cell viability in the myocytes. Overexpression of mutant HSPB5 induced a reduction in the cytochrome c level in the mitochondrial fraction and a corresponding increase in the cytoplasmic fraction in the myocytes. Down-regulation of BCL2 and up-regulation of BAX were detected in the myocytes expressing the mutant HSPB5. Concomitant with mitochondrial abnormality, the activation of caspase-3 and increased apoptotic cell death was observed. Cell viability was dose-dependently recovered in myocytes overexpressing HSPB5 R120G by treatment with nicorandil a mitochondrial ATP-sensitive potassium channel opener. Nicorandil treatment also inhibited the increase in BAX, the decrease in BCL2, activation of caspase-3 and apoptotic cell death by mutant HSPB5. To confirm the results of the in-vitro study, we analyzed the effect of nicorandil in HSPB5 R120G TG mice. Nicorandil treatment appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in HSPB5 R120G TG mice. CONCLUSIONS: Nicorandil may prolong survival in HSPB5 R120G TG mice by protecting against mitochondrial impairments

Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy

An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain.In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice.Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM

Régua de cálculo: uma contribuição de William Oughtred para a matemática

Esta pesquisa aborda obras de William Oughtred (1574-1660), clérigo britânico e instrutor de matemática, a quem se atribui o projeto da primeira régua de cálculo logarítmica linear na Europa no século XVII, quando a elaboração de tabelas astronômicas e calendários utilizados, por exemplo, para orientar navegações, demandava meios para que o cálculo de números extremamente pequenos ou extremamente grandes fosse realizado rapidamente. A criação e o uso de réguas de cálculo logarítmicas foram aqui estudados pela análise dos textos The Circles of Proportion and The Horizontal Instrument (1633), New Artificial Gauging Line or Rod (1633) e The Description and Use of the Double Horizontal Dial (1653), escritos por William Oughtred. Outras obras desse estudioso foram examinadas para mostrar a sua contribuição para o ensino da Matemática, como os textos Clavis Mathematicae, que foi utilizado por mais de 70 anos, e Mathematical Recreations traduzido para o inglês e incrementado por ele com os textos The Description and Use of the Double Horizontal Dial e Horological Ring publicados como apêndices de Mathematical Recreations, em 1653The present research covers the works of William Oughtred (1574-1660), a British cleric and instructor of mathematics, to whom is attributed the project of the first slide linear log rule in Europe in the seventeenth century when drawing up tables and astronomical calendars, used to guide sailing for example, demanded means for the calculation of numbers, very small or very large, to be carried out quickly. The creation and use of logarithmic rules for calculating will be studied here by the analysis of texts written by William Oughtred: The Circles of Proportion and The Horizontal Instrument (1633), New Line or Artificial Gauging Rod (1633) and The description and Use of the Double Horizontal Dial (1653). Other works of this scholar were examined to show their contribution to the teaching of Mathematics, as the texts Clavis Mathematicae, which was used by more than 70 years, and Mathematical Recreations translated into English and combined by him with other texts, such as: The description and Use of the Double Horizontal Dial and Horological Ring published as appendages of Mathematical Recreations in 165

O ensino da escrita japonesa : um estudo terminológico bilíngüe (japonês-português)

Dissertação (mestrado)—Universidade de Brasília, Instituto de Letras, Departamento de Línguas Estrangeiras e Tradução, 2006.Esta pesquisa tem por finalidade investigar as características do ensino da escrita japonesa por meio da análise de sua linguagem de especialidade em textos especializados. Para a coleta de unidades terminológicas relevantes para a pesquisa foi utilizado um corpus selecionado e delimitado entre textos especializados relativos ao ensino da escrita japonesa. A categorização dessas unidades terminológicas permitiu a realização de uma hierarquização através de suas relações coordenadas e subordinadas em três grandes categorias: o grafema, o uso e o processo de ensino. A hierarquização das unidades terminológicas permitiu obter um sistema de conceitos que estrutura o ensino da escrita japonesa. Essa estrutura apresenta as características do ensino da escrita japonesa, que são o conhecimento acerca do grafema semântico (ideograma) e o grafema fonético (fonograma); do uso dos grafemas segundo as normas vigentes de ortografia japonesa e de como desenvolver o ensino da escrita japonesa. O sistema de conceitos permite visualizar todo conhecimento necessário para se desenvolver um bom trabalho de transferência de conhecimento e uma seleção adequada de recursos didáticos. ______________________________________________________________________________ ABSTRACTThis research project aims to investigate the features of the teaching of Japanese writing by means of the analysis of the specialized language of that area found in specialized texts. The corpus used for the collection of terminological units relevant to the research was selected among texts specialized in the teaching of Japanese writing. The categorization of such terminological units has allowed us to place them in a hierarchy drawn up from their relations of coordination and subordination. Three major categories were found: the grapheme, the use and the teaching process. The hierarchical ordering of the terminological units has allowed us to obtain a system of concepts that structures the knowledge about the teaching of Japanese writing. Such a structure reflects the features of the teaching of Japanese writing, which are knowledge about the semantic grapheme (ideogram) and the phonetic grapheme (phonogram); about the use of such graphemes according to the Japanese ortographic rules in effect, and about how to carry out the teaching of Japanese writing. The system of concepts allows one to visualize all the knowledge which is necessary for doing a good job of passing on knowledge and for making an appropriate selection of teaching materials