Modulation of cytochrome P450 enzyme activity and PAH -induced skin carcinogenesis by naturally occurring coumarins

The present study was designed to determine the potential anticarcinogenic activity of naturally occurring coumarins and their mechanism of action. The results indicated that several naturally occurring coumarins including bergamottin, coriandrin, imperatorin, isopimpinellin, and ostruthin, to which humans are routinely exposed in the diet, were effective inhibitors and/or inactivators of CYP1A1-mediated ethoxyresorufin-O-dealkylase (EROD) or CYP2B1-mediated pentoxyresorufin-O-dealkylase (PROD) in mouse liver microsomes. In addition, bergamottin and corandrin were also found to be inhibitors of purified human P450 1A1 in vitro. Further studies with coriandrin revealed that this compound was a mechanism-based inactivator of P450 1A1 and covalently bound to the P450 1A1 apoprotein. In cultured mouse keratinocytes, bergamottin and coriandrin effectively inhibited the B(a) P metabolism and significantly decreased covalent binding of B(a) P and DMBA to keratinocyte DNA and anti-diol-epoxide-DNA adducts derived from both B(a) P and DMBA in keratinocytes. The data from in vivo experiments showed that bergamottin and coriandrin were potent inhibitors of covalent binding of B (a) P to epidermal DNA and the formation of (+) anti BPDE-DNA adduct, whereas imperatorin and isopimpinellin were more potent inhibitors of covalent binding of DMBA to epidermal DNA. The ability of coumarins to inhibit covalent binding of B (a) P to DNA in mouse epidermis was positively correlated with their inhibitory effect P450 1A1 in vitro, while the inhibitory effect of coumarins on covalent binding of DMBA to epidermal DNA was positively correlated with their inhibitory effects on P450 2B1 and negatively to their inhibitory activity toward P450 1A1. The data from tumor experiments indicated that bergamottin, ostruthin, and coriandrin inhibited tumor initiation by B (a) P in a two-stage carcinogenesis protocol. Bergamottin was most effective in this regard and produced a dose dependent inhibition of papilloma formation in these experiments. In addition, imperatorin was an effective inhibitor of skin tumorigenesis induced by DMBA in SENCAR mouse skin using both a two-stage and a complete carcinogenesis protocol. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B (a) P. The results to date demonstrate that several naturally occurring coumarins possess the ability to block tumor initiation and tumorigenesis by PAHs such as B (a) P and DMBA through inhibition of the P450s involved in the metabolic activation of these hydrocarbons. A working model for the involvement of specific P450s in the metabolic activation of these two PAHs was proposed. ^

Desarrollo de software sobre entornos PaaS: revisión general, nuevas perspectivas y desafíos para la ingeniería de software

El uso de la computación en la nube ofrece un nuevo paradigma que procura proporcionar servicios informáticos para los cuales no es necesario contar con grandes infraestructuras y sobre todo, con las complejidades de costos, seguridad y mantenimiento implícitas. Si bien se ha posicionado en los últimos años como una plataforma innovadora en el ámbito de la tecnología de consumo masivo y organizacional, también puede ser tópico de investigación importante en ciertas áreas de interés como el desarrollo de Software, presentando en ese campo, una serie de ventajas y retos estimulantes que pueden ser explorados. Este trabajo de investigación, sigue con dicho sentido, el objetivo de exponer la situación actual sobre el empleo de la computación en la nube como entorno de desarrollo de Software, sectorizando a través de su capa PaaS, el modelo conceptual de trabajo, las perspectivas recientes, problemas e implicaciones generales del uso de ésta como herramienta plausible en proyectos de desarrollo de Software. El análisis de los diferentes temas abordados, tiene la intención en general, de proporcionar información objetiva, crítica y cuantitativa sobre la concentración de la investigación relacionada a PaaS, así como un marco de interpretación reciente que aporte una perspectiva referencial para futuras investigaciones asociadas.---ABSTRACT---The use of cloud computing offers a new paradigm to provide computer services for which it is not necessary to have large infrastructure and especially with the complexities of cost, safety and maintenance implied. While it has positioned itself in recent years as an innovative platform in the field of technology and massive organizational consumption, can also be an important research topic in certain areas of interest including, the development of Software, presenting in this field, a series of advantages, disadvantages and stimulating challenges that can be explored. This research, following with that sense, try to present the current situation related to the use of cloud computing as a software development environment, through its sectorized PaaS layer, showing the conceptual working model, actual perspectives, problems and general implications of using this as a possible tool in Software development projects. The analysis of the different topics covered, intends in a general form, provide objective, critical and quantitative information about the concentration of research related to PaaS, and a recent interpretation framework to provide a referential perspective for future related researches.

The C terminus of β-tubulin regulates vinblastine-induced tubulin polymerization

Oligoanions such as sodium triphosphate or GTP prevent and/or reverse vinblastine-induced polymerization of tubulin. We now show that the anions of glutamate-rich extreme C termini of tubulin are similarly involved in the regulation of the vinblastine effect. Cleavage of the C termini by limited proteolysis with subtilisin enhances vinblastine-induced tubulin polymerization and abolishes the anion effect. Only the β-tubulin C terminus needs to be removed to achieve these changes and the later cleavage of the α-tubulin C terminus has little additional effect. In fact, vinblastine concentrations >20 μM block cleavage of the α-tubulin C terminus in the polymer, whereas cleavage of the β-tubulin C terminus proceeds unimpeded over the time used. The vinblastine effect on tubulin polymerization is also highly pH-dependent between pH 6.5 and 7.5; this is less marked, but not absent, after subtilisin treatment. A working model is proposed wherein an anionic domain proximal to the extreme C terminus must interact with a cationic domain to permit vinblastine to promote polymerization. Both exogenous and extreme C-terminal anions compete for the cationic domain with the proximal anionic domain to prevent vinblastine-induced polymerization. We conclude that the electrostatic regulation of tubulin polymerization induced by vinblastine resides primarily in the β-tubulin C terminus but that additional regulation proximal in the tubulin molecule also plays a role.

Copper binding to the prion protein: Structural implications of four identical cooperative binding sites

Evidence is growing to support a functional role for the prion protein (PrP) in copper metabolism. Copper ions appear to bind to the protein in a highly conserved octapeptide repeat region (sequence PHGGGWGQ) near the N terminus. To delineate the site and mode of binding of Cu(II) to the PrP, the copper-binding properties of peptides of varying lengths corresponding to 2-, 3-, and 4-octarepeat sequences have been probed by using various spectroscopic techniques. A two-octarepeat peptide binds a single Cu(II) ion with Kd ≈ 6 μM whereas a four-octarepeat peptide cooperatively binds four Cu(II) ions. Circular dichroism spectra indicate a distinctive structuring of the octarepeat region on Cu(II) binding. Visible absorption, visible circular dichroism, and electron spin resonance spectra suggest that the coordination sphere of the copper is identical for 2, 3, or 4 octarepeats, consisting of a square-planar geometry with three nitrogen ligands and one oxygen ligand. Consistent with the pH dependence of Cu(II) binding, proton NMR spectroscopy indicates that the histidine residues in each octarepeat are coordinated to the Cu(II) ion. Our working model for the structure of the complex shows the histidine residues in successive octarepeats bridged between two copper ions, with both the Nɛ2 and Nδ1 imidazole nitrogen of each histidine residue coordinated and the remaining coordination sites occupied by a backbone amide nitrogen and a water molecule. This arrangement accounts for the cooperative nature of complex formation and for the apparent evolutionary requirement for four octarepeats in the PrP.

Alfabetização no ensino fundamental: novas bases curriculares

Esta dissertação apresenta dados e discussões oriundos de uma experiência coletiva de pesquisa cujo objetivo maior consistiu em articular as bases curriculares da alfabetização no ensino fundamental de nove anos. A partir da transição histórica e política ocorrida pela Lei 11.274/1996, na qual o ensino fundamental passou a ter um ano a mais de duração e a receber as crianças que anteriormente eram atendidas na educação infantil, uma nova configuração se fez necessária. Demonstramos ao longo do trabalho a necessidade de: 1. Um plano que considere as transições (seja entre anos ou entre ciclos) e que sustente as continuidades; 2. Assumir, a partir do ano de ingresso no ensino fundamental, a perspectiva do regime de ciclo, definindo responsabilidades, objetivos e estratégias articuladas a partir de um trabalho em equipe; 3. Aprofundar conhecimentos que permitam considerar os aspectos mais subjetivos da relação educativa, considerando sempre a infância em seu encantamento lúdico; 4. Estabelecer uma relação dinâmica e produtiva entre oralidade e escrita, entre língua e literatura; 5. Dar maior precisão ao manejo da heterogeneidade desde a série de ingresso enfatizando o acompanhamento de singularidades e diferenças como forma de resolver o problema dos desníveis em alfabetização. A perspectiva teórica parte da articulação de várias áreas e temas do conhecimento: a história da escrita; pesquisa sobre oralidade ou cultura oral em tensão com a escrita; a psicanálise e a educação. Pretendemos, a partir das experiências e reflexões apresentadas nesse trabalho, contribuir para as políticas públicas enfatizando a grande relevância do ensino da escrita e da leitura nas séries iniciais do ensino fundamental. Ao longo dessas experiências, constatamos que, para formar leitores e escritores de bom nível na escola pública brasileira, precisamos de um modelo de trabalho coletivo mais complexo, capaz de exercer um manejo pedagógico detalhado, e ampliamos nossa consciência de que nossas buscas metodológicas, nossas experiências e nossos esforços coletivos em torno da heterogeneidade, apesar de consistentes e relevantes, só poderão ser sustentados a partir de uma reorganização do trabalho escolar que insista em fazer da alfabetização e da leitura uma verdadeira prioridade.

Expression of biomineralization-related ion transport genes in Emiliania huxleyi

Biomineralization in the marine phytoplankton Emiliania huxleyi is a stringently controlled intracellular process. The molecular basis of coccolith production is still relatively unknown although its importance in global biogeochemical cycles and varying sensitivity to increased pCO2 levels has been well documented. This study looks into the role of several candidate Ca2+, H+ and inorganic carbon transport genes in E. huxleyi, using quantitative reverse transcriptase PCR. Differential gene expression analysis was investigated in two isogenic pairs of calcifying and non-calcifying strains of E. huxleyi and cultures grown at various Ca2+ concentrations to alter calcite production. We show that calcification correlated to the consistent upregulation of a putative HCO3- transporter belonging to the solute carrier 4 (SLC4) family, a Ca2+/H+ exchanger belonging to the CAX family of exchangers and a vacuolar H+-ATPase. We also show that the coccolith-associated protein, GPA is downregulated in calcifying cells. The data provide strong evidence that these genes play key roles in E. huxleyi biomineralization. Based on the gene expression data and the current literature a working model for biomineralization-related ion transport in coccolithophores is presented.

Modeling hydrogen separation in high temperature silica membrane systems

In this work, a working model is proposed of molecular sieve silica (MSS) multistage membrane systems for CO cleanup at high temperatures (up to 500 degrees C) in a simulated fuel cell fuel processing system. Gases are described as having little interactions with each other relative to the pore walls due to low isosteric heat of adsorption on silica surfaces and high temperatures. The Arrhenius function for activated transport of pure gases was used to predict mixture concentration in the permeate and retentate streams. Simulation predicted CO could be reduced to levels below the required 50 ppmv for polymer electrolyte membrane fuel cell anodes at a stage H-2/CO selectivity of higher than 40 in 4 series membrane units. Experimental validation showed predicting mixture concentrations required only pure gas permeation data. This model has significant application for setting industrial stretch targets and as a robust basis for complex membrane model configurations. (c) 2006 American Institute of Chemical Engineers.

Entrepreneurship and innovation through experience:student and employer perspectives of the value of work-based learning in promoting entrepreneurialism

The 'internationalisation' of Business and Management education, reflective of EU enlargement and the unprecedented globalisation of education, has resulted in growing numbers of overseas students adding a diversity and richness to the learning environment within many contemporary European Higher Educational Institutions (Green, 2006, Sliwa & Grandy, 2006). However, cross-national studies analyzing the impact that the internationalisation of business education has on the employability of business and management graduates are rare. Furthermore, there exists a notable gap in research aimed at identifying and conceptualising the generic business skills and competencies required by European employers of business and management graduates. By proposing a conceptual framework based upon a working model of business graduate employability, this goes some way to addressing this gap.

Parent emotional functioning, parent responsiveness, and child adjustment

Over the past two decades, interest in the psychological development of children has steadily increased (Beg, Casey, & Saunders, 2007), presumably because statistics describing childhood psychological illness are alarming. Certain parent interaction styles or behaviors are known to influence child adjustment. According to attachment theory, the reason for these findings is that interaction with a caregiver informs an individual’s construction of an internal working model (IWM) of the self in relation to others in the environment. The purpose of this study was to gain a greater understanding of the factors contributing to child adjustment by examining the influence of parents’ emotional functioning and parent responsiveness to children’s bids for interaction. This dissertation tested a multivariate model of attachment-related processes and outcomes with an ethnically diverse sample. Results partially supported the model, in that parent emotional intelligence predicted some aspects of child adjustment. Overall, the study adds to knowledge about how parent characteristics influence child adjustment and provides support for conceptualizing emotional intelligence as a concrete and observable manifestation of the nonconscious attachment IWM.

The Relationship of Diet Quality and Blood Serum Lipid Levels in a Population at High Risk for Diabetes: The Strong Heart Family Study

Thesis (Master's)--University of Washington, 2016-08

Memória de longo prazo nos retornos acionistas dos índices de referência da euronext, implicações para a hipótese de mercados eficientes e contributo fractal para aperfeiçoamento do capital asset pricing model

Não existe uma definição única de processo de memória de longo prazo. Esse processo é geralmente definido como uma série que possui um correlograma decaindo lentamente ou um espectro infinito de frequência zero. Também se refere que uma série com tal propriedade é caracterizada pela dependência a longo prazo e por não periódicos ciclos longos, ou que essa característica descreve a estrutura de correlação de uma série de longos desfasamentos ou que é convencionalmente expressa em termos do declínio da lei-potência da função auto-covariância. O interesse crescente da investigação internacional no aprofundamento do tema é justificado pela procura de um melhor entendimento da natureza dinâmica das séries temporais dos preços dos ativos financeiros. Em primeiro lugar, a falta de consistência entre os resultados reclama novos estudos e a utilização de várias metodologias complementares. Em segundo lugar, a confirmação de processos de memória longa tem implicações relevantes ao nível da (1) modelação teórica e econométrica (i.e., dos modelos martingale de preços e das regras técnicas de negociação), (2) dos testes estatísticos aos modelos de equilíbrio e avaliação, (3) das decisões ótimas de consumo / poupança e de portefólio e (4) da medição de eficiência e racionalidade. Em terceiro lugar, ainda permanecem questões científicas empíricas sobre a identificação do modelo geral teórico de mercado mais adequado para modelar a difusão das séries. Em quarto lugar, aos reguladores e gestores de risco importa saber se existem mercados persistentes e, por isso, ineficientes, que, portanto, possam produzir retornos anormais. O objetivo do trabalho de investigação da dissertação é duplo. Por um lado, pretende proporcionar conhecimento adicional para o debate da memória de longo prazo, debruçando-se sobre o comportamento das séries diárias de retornos dos principais índices acionistas da EURONEXT. Por outro lado, pretende contribuir para o aperfeiçoamento do capital asset pricing model CAPM, considerando uma medida de risco alternativa capaz de ultrapassar os constrangimentos da hipótese de mercado eficiente EMH na presença de séries financeiras com processos sem incrementos independentes e identicamente distribuídos (i.i.d.). O estudo empírico indica a possibilidade de utilização alternativa das obrigações do tesouro (OT’s) com maturidade de longo prazo no cálculo dos retornos do mercado, dado que o seu comportamento nos mercados de dívida soberana reflete a confiança dos investidores nas condições financeiras dos Estados e mede a forma como avaliam as respetiva economias com base no desempenho da generalidade dos seus ativos. Embora o modelo de difusão de preços definido pelo movimento Browniano geométrico gBm alegue proporcionar um bom ajustamento das séries temporais financeiras, os seus pressupostos de normalidade, estacionariedade e independência das inovações residuais são adulterados pelos dados empíricos analisados. Por isso, na procura de evidências sobre a propriedade de memória longa nos mercados recorre-se à rescaled-range analysis R/S e à detrended fluctuation analysis DFA, sob abordagem do movimento Browniano fracionário fBm, para estimar o expoente Hurst H em relação às séries de dados completas e para calcular o expoente Hurst “local” H t em janelas móveis. Complementarmente, são realizados testes estatísticos de hipóteses através do rescaled-range tests R/S , do modified rescaled-range test M - R/S e do fractional differencing test GPH. Em termos de uma conclusão única a partir de todos os métodos sobre a natureza da dependência para o mercado acionista em geral, os resultados empíricos são inconclusivos. Isso quer dizer que o grau de memória de longo prazo e, assim, qualquer classificação, depende de cada mercado particular. No entanto, os resultados gerais maioritariamente positivos suportam a presença de memória longa, sob a forma de persistência, nos retornos acionistas da Bélgica, Holanda e Portugal. Isto sugere que estes mercados estão mais sujeitos a maior previsibilidade (“efeito José”), mas também a tendências que podem ser inesperadamente interrompidas por descontinuidades (“efeito Noé”), e, por isso, tendem a ser mais arriscados para negociar. Apesar da evidência de dinâmica fractal ter suporte estatístico fraco, em sintonia com a maior parte dos estudos internacionais, refuta a hipótese de passeio aleatório com incrementos i.i.d., que é a base da EMH na sua forma fraca. Atendendo a isso, propõem-se contributos para aperfeiçoamento do CAPM, através da proposta de uma nova fractal capital market line FCML e de uma nova fractal security market line FSML. A nova proposta sugere que o elemento de risco (para o mercado e para um ativo) seja dado pelo expoente H de Hurst para desfasamentos de longo prazo dos retornos acionistas. O expoente H mede o grau de memória de longo prazo nos índices acionistas, quer quando as séries de retornos seguem um processo i.i.d. não correlacionado, descrito pelo gBm(em que H = 0,5 , confirmando- se a EMH e adequando-se o CAPM), quer quando seguem um processo com dependência estatística, descrito pelo fBm(em que H é diferente de 0,5, rejeitando-se a EMH e desadequando-se o CAPM). A vantagem da FCML e da FSML é que a medida de memória de longo prazo, definida por H, é a referência adequada para traduzir o risco em modelos que possam ser aplicados a séries de dados que sigam processos i.i.d. e processos com dependência não linear. Então, estas formulações contemplam a EMH como um caso particular possível.

Political autonomy and independence: theory and experimental evidence

We study the process by which subordinated regions of a country can obtain a more favourable political status. In our theoretical model a dominant and a dominated region first interact through a voting process that can lead to different degrees of autonomy. If this process fails then both regions engage in a costly political conflict which can only lead to the maintenance of the initial subordination of the region in question or to its complete independence. In the subgame-perfect equilibrium the voting process always leads to an intermediate arrangement acceptable for both parts. Hence, the costly political struggle never occurs. In contrast, in our experiments we observe a large amount of fighting involving high material losses, even in a case in which the possibilities for an arrangement without conflict are very salient. In our experimental environment intermediate solutions are feasible and stable, but purely emotional elements prevent them from being reached.

Allostatic working memory processing in schizophrenia: Human and animal model coherence

The most evident symptoms of schizophrenia are severe impairment of cognitive functions like attention, abstract reasoning and working memory. The latter has been defined as the ability to maintain and manipulate on-line a limited amount of information. Whereas several studies show that working memory processes are impaired in schizophrenia, the specificity of this deficit is still unclear. Results obtained with a new paradigm, involving visuospatial, dynamic and static working memory processing, suggest that schizophrenic patients rely on a specific compensatory strategy. An animal model of schizophrenia with a transient deficit in glutathione during the development reveals similar substitutive processing, masking the impairment in working memory functions in specific test conditions only. Taken together, these results show coherence between working memory deficits in schizophrenic patients and in animal models. More generally, it is possible to consider that the pathological state may be interpreted as a reduced homeostatic reserve. However, this may be balanced in specific situations by efficient allostatic strategies. Thus, the pathological condition would remain latent in several situations, due to such allostatic regulations. However, to maintain a performance based on highly specific strategies requires in turn specific conditions, limitating adaptative resources in humans and in animals. In summary, we suggest that the psychological and physical load to maintain this rigid allostatic state is very high in patients and animal subjects.