Identification and functional characterization of Rca1, a transcription factor involved in both antifungal susceptibility and host response in Candida albicans.

The identification of novel transcription factors associated with antifungal response may allow the discovery of fungus-specific targets for new therapeutic strategies. A collection of 241 Candida albicans transcriptional regulator mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in terms of their role in antifungal response were further investigated, and the function of one of them, a mutant of orf19.6102 (RCA1), was characterized by transcriptome analysis. Strand-specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from RCA1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutant collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this transcription factor and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response.

Controlo Interno como factor de melhoria empresarial - estudo de caso prático Centro de Emprego e Formação Profissonal Santa Cruz

A problemática do controlo interno como factor de melhoria empresarial, foi a que orientou esta pesquisa realizada no CEFPSC (Centro de Emprego e Formação Profissional de Santa Cruz). É que, segundo Morais & Martins (2007, pág. 27) existe controlo adequado quando a gestão planeou e organizou, isto é, concebeu, de tal modo que foi assegurado uma garantia razoável que os riscos da organização foram adequadamente geridos e de que os objectivos e metas da organização serão alcançados de forma eficiente e económica. Sendo assim, é de notar a importância desta ferramenta em traçar estratégias de gestão no processo decisório, servindo assim de uma mais-valia à entidade com vista a permitir responder à questão: Em que medida o controlo interno tem sido utilizado como método de apoio à gestão do Centro de Emprego e Formação Profissional de Santa Cruz? Este trabalho tem como objectivo compreender a actuação e a contribuição do Controlo Interno na gestão eficiente do CEFPSC. As informações foram recolhidas mediante a aplicação de um questionário de controlo interno e entrevistas ao Responsável do CEFPSC, bem como ao Presidente do IEFP, enquanto órgão central. O tratamento dos dados foi realizado com auxílio informático, utilizando, para tal, o programa Excel.

Responsiveness of astrocytes in serum-free aggregate cultures to epidermal growth factor: dependence on the cell cycle and the epidermal growth factor concentration.

Serum-free aggregating cell cultures of fetal rat telencephalon treated with low doses (0.5 nM) of epidermal growth factor (EGF) showed a small, transient increase in DNA synthesis but no significant changes in total DNA and protein content. By contrast, treatment with high doses (13 nM) of EGF caused a marked stimulation of DNA synthesis as well as a net increase in DNA and protein content. The expression of the astrocyte-specific enzyme, glutamine synthetase, was greatly enhanced both at low and at high EGF concentrations. These results suggest that at low concentration EGF stimulates exclusively the differentiation of astrocytes, whereas at high concentration, EGF has also a mitogenic effect. Nonproliferating astrocytes in cultures treated with 0.4 microM 1-beta-D-arabinofuranosyl-cytosine were refractory to EGF treatment, indicating that their responsiveness to EGF is cell cycle-dependent. Binding studies using a crude membrane fraction of 5-day cultures showed a homogeneous population of EGF binding sites (Kd approximately equal to 2.6 nM). Specific EGF binding sites were found also in non-proliferating (and nonresponsive) cultures, although they showed slightly reduced affinity and binding capacity. This finding suggests that the cell cycle-dependent control of astroglial responsiveness to EGF does not occur at the receptor level. However, it was found that the specific EGF binding sites disappear with progressive cellular differentiation.

Hypotensive effect of the active fragment derived from factor XII is mediated by an activation of the plasma kallikrein-kinin system.

Plasma protein fraction (PPF) contaminated by factor XII active fragment (XIIf) may cause hypotensive reactions when infused to patients. This study was planned to assess in conscious normotensive rats whether the blood pressure response to the factor XIIf is mediated by an activation of the plasma kallikrein-kinin system or by stimulation of prostaglandin synthesis. To test whether the factor XIIf-induced blood pressure fall is due partially to an enhanced generation of vasodilating prostaglandins, the blood pressure effect of XIIf (1 microgram i.v.) was investigated 15 min after treatment with indomethacin (5 mg i.v.), an inhibitor of cyclo-oxygenase. Factor XIIf reduced mean blood pressure similarly in indomethacin- and vehicle-treated rats (-23 +/- 4 mmHg, n = 5, and -23 +/- 5 mmHg, n = 4, respectively). Other rats received factor XIIf 15 min after depletion of circulating prekallikrein by the administration of dextran sulfate. Thirty minutes after a 0.25 mg i.v. dose of this agent, plasma prekallikrein activity averaged 0.12 +/- 0.015 mumol/min/ml (n = 6) as compared to 2.48 +/- 0.31 mumol/min/ml in control rats (n = 4, P less than .001). Factor XIIf decreased mean blood pressure by only 4 +/- 2 mm Hg in rats pretreated with dextran sulfate. Thus, it was possible to blunt the acute hypotensive effect of factor XIIf by depleting circulating prekallikrein, but not by inhibiting prostaglandin production. This strongly suggests that the blood pressure effects of factor XIIf is mediated by a stimulation of the plasma kallikrein-kinin system.

Factor structure of the SOCRATES questionnaire in hospitalized medical patients.

The Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES), a 19-item instrument developed to assess readiness to change alcohol use among individuals presenting for specialized alcohol treatment, has been used in various populations and settings. Its factor structure and concurrent validity has been described for specialized alcohol treatment settings and primary care. The purpose of this study was to determine the factor structure and concurrent validity of the SOCRATES among medical inpatients with unhealthy alcohol use not seeking help for specialized alcohol treatment. The subjects were 337 medical inpatients with unhealthy alcohol use, identified during their hospital stay. Most of them had alcohol dependence (76%). We performed an Alpha Factor Analysis (AFA) and Principal Component Analysis (PCA) of the 19 SOCRATES items, and forced 3 factors and 2 components, in order to replicate findings from Miller and Tonigan (Miller, W. R., & Tonigan, J. S., (1996). Assessing drinkers' motivations for change: The Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Psychology of Addictive Behavior, 10, 81-89.) and Maisto et al. (Maisto, S. A., Conigliaro, J., McNeil, M., Kraemer, K., O'Connor, M., & Kelley, M. E., (1999). Factor structure of the SOCRATES in a sample of primary care patients. Addictive Behavior, 24(6), 879-892.). Our analysis supported the view that the 2 component solution proposed by Maisto et al. (Maisto, S.A., Conigliaro, J., McNeil, M., Kraemer, K., O'Connor, M., & Kelley, M.E., (1999). Factor structure of the SOCRATES in a sample of primary care patients. Addictive Behavior, 24(6), 879-892.) is more appropriate for our data than the 3 factor solution proposed by Miller and Tonigan (Miller, W. R., & Tonigan, J. S., (1996). Assessing drinkers' motivations for change: The Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Psychology of Addictive Behavior, 10, 81-89.). The first component measured Perception of Problems and was more strongly correlated with severity of alcohol-related consequences, presence of alcohol dependence, and alcohol consumption levels (average number of drinks per day and total number of binge drinking days over the past 30 days) compared to the second component measuring Taking Action. Our findings support the view that the SOCRATES is comprised of two important readiness constructs in general medical patients identified by screening.

Inundações urbanas: desafios ao ordenamento do território. O caso da Cidade da Praia (Cabo Verde)

Pela sua posição geográfica e particulares condições climáticas, devidas à sua inserção na faixa saheliana com caraterísticas de marcada aridez, Cabo Verde é um arquipélago com condições naturais adversas, pautado principalmente pela seca prolongada. Muitas vezes esta conjuntura é interpolada por curtos períodos de fortes chuvadas que podem originar cheias e inundações nos principais centros urbanos. Os eventos ocorridos revelam consequências graves, desde prejuízos na agricultura, perda de animais, destruição de infra-estruturas, perda de bens materiais e, mesmo, vítimas humanas mortais. Este estudo tem como objetivos principais: (i) perceber os problemas e desafios que se colocam à cidade da Praia (maior centro urbano do país, com forte crescimento e expansão urbana) perante situações de inundação; (ii) contribuir para o maior conhecimento das causas e consequências dessas inundações; (iii) definir quais as áreas de maior suscetibilidade às cheias e quais as que possuem um maior risco potencial. Optou-se por uma metodologia integrada, através do levantamento bibliográfico, cartográfico, numérico e percetivo (com base em entrevistas e inquéritos). Para o estudo das bacias hidrográficas foram calculados índices morfométricos, definidas classes de permeabilidade do substrato geológico e aplicado o método multicritério de Reis (2011) para a definição das áreas suscetíveis às cheias. Analisaram-se as precipitações máximas diárias anuais e respetivos períodos de retorno, com a aplicação do método de Gumbel. A análise de notícias de jornais, referentes ao período compreendido entre 1980 e 2011, foi fundamental para o conhecimento da distribuição espácio-temporal dos eventos perigosos de inundação em Cabo Verde e na cidade da Praia. Os resultados obtidos revelam um significativo grau de suscetibilidade às cheias na cidade da Praia. As áreas de maior risco potencial às inundações encontram-se no setor central da cidade, resultante da conjugação da convergência do escoamento das três ribeiras principais, da elevada densidade populacional e de construção desordenada nos leitos de cheia e nas áreas deprimidas, onde se acumulam as águas.

Drug use and suicide attempts: the role of personality factors.

This study on suicide attempts is part of a large research project on dependent behavior in adolescents and young adults. 228 subjects aged 14-25 (107 "drug abusers," 121 controls) from the French speaking part of Switzerland were evaluated on the basis of a semi-structured interview (Mini International Neuropsychiatric Interview), enabling a DSM-IV diagnosis, and self-reports (SSS by Zuckermann, MMPI-2, IDI by Hirschfeld). 31.5% of "drug abuser" males and 41.2% of "drug abuser" females committed one or more suicide attempts. The results of a logistic regression show that the significant factor explaining suicide attempts in drug users is emotional reliance for males and experience-seeking for females.

Risk management under a two-factor model of the term structure of interest rates

This paper presents several applications to interest rate risk managementbased on a two-factor continuous-time model of the term structure of interestrates previously presented in Moreno (1996). This model assumes that defaultfree discount bond prices are determined by the time to maturity and twofactors, the long-term interest rate and the spread (difference between thelong-term rate and the short-term (instantaneous) riskless rate). Several newmeasures of ``generalized duration" are presented and applied in differentsituations in order to manage market risk and yield curve risk. By means ofthese measures, we are able to compute the hedging ratios that allows us toimmunize a bond portfolio by means of options on bonds. Focusing on thehedging problem, it is shown that these new measures allow us to immunize abond portfolio against changes (parallel and/or in the slope) in the yieldcurve. Finally, a proposal of solution of the limitations of conventionalduration by means of these new measures is presented and illustratednumerically.

Asset pricing implications of benchmarking: A two-factor CAPM

In this paper we consider the equilibrium effects of an institutionalinvestor whose performance is benchmarked to an index. In a partialequilibrium setting, the objective of the institutional investor is modeledas the maximization of expected utility (an increasing and concave function,in order to accommodate risk aversion) of final wealth minus a benchmark.In equilibrium this optimal strategy gives rise to the two-beta CAPM inBrennan (1993): together with the market beta a new risk-factor (that wecall active management risk) is brought into the analysis. This new betais deffined as the normalized (to the benchmark's variance) covariancebetween the asset excess return and the excess return of the market overthe benchmark index. Different to Brennan, the empirical test supports themodel's predictions. The cross-section return on the active management riskis positive and signifficant especially after 1990, when institutionalinvestors have become the representative agent of the market.

Glutamine Stimulates Biosynthesis and Secretion of Insulin-like Growth Factor 2 (IGF2), an Autocrine Regulator of Beta Cell Mass and Function.

IGF2 is an autocrine ligand for the beta cell IGF1R receptor and GLP-1 increases the activity of this autocrine loop by enhancing IGF1R expression, a mechanism that mediates the trophic effects of GLP-1 on beta cell mass and function. Here, we investigated the regulation of IGF2 biosynthesis and secretion. We showed that glutamine rapidly and strongly induced IGF2 mRNA translation using reporter constructs transduced in MIN6 cells and primary islet cells. This was followed by rapid secretion of IGF2 via the regulated pathway, as revealed by the presence of mature IGF2 in insulin granule fractions and by inhibition of secretion by nimodipine and diazoxide. When maximally stimulated by glutamine, the amount of secreted IGF2 rapidly exceeded its initial intracellular pool and tolbutamide, and high K(+) increased IGF2 secretion only marginally. This indicates that the intracellular pool of IGF2 is small and that sustained secretion requires de novo synthesis. The stimulatory effect of glutamine necessitates its metabolism but not mTOR activation. Finally, exposure of insulinomas or beta cells to glutamine induced Akt phosphorylation, an effect that was dependent on IGF2 secretion, and reduced cytokine-induced apoptosis. Thus, glutamine controls the activity of the beta cell IGF2/IGF1R autocrine loop by increasing the biosynthesis and secretion of IGF2. This autocrine loop can thus integrate changes in feeding and metabolic state to adapt beta cell mass and function.

Inundações Urbanas - Desafios ao Ordenamento do Território - O

Pela sua posição geográfica e particulares condições climáticas, devidas à sua inserção na faixa saheliana com caraterísticas de marcada aridez, Cabo Verde é um arquipélago com condições naturais adversas, pautado principalmente pela seca prolongada. Muitas vezes esta conjuntura é interpolada por curtos períodos de fortes chuvadas que podem originar cheias e inundações nos principais centros urbanos. Os eventos ocorridos revelam consequências graves, desde prejuízos na agricultura, perda de animais, destruição de infra-estruturas, perda de bens materiais e, mesmo, vítimas humanas mortais. Este estudo tem como objetivos principais: (i) perceber os problemas e desafios que se colocam à cidade da Praia (maior centro urbano do país, com forte crescimento e expansão urbana) perante situações de inundação; (ii) contribuir para o maior conhecimento das causas e consequências dessas inundações; (iii) definir quais as áreas de maior suscetibilidade às cheias e quais as que possuem um maior risco potencial. Optou-se por uma metodologia integrada, através do levantamento bibliográfico, cartográfico, numérico e percetivo (com base em entrevistas e inquéritos). Para o estudo das bacias hidrográficas foram calculados índices morfométricos, definidas classes de permeabilidade do substrato geológico e aplicado o método multicritério de Reis (2011) para a definição das áreas suscetíveis às cheias. Analisaram-se as precipitações máximas diárias anuais e respetivos períodos de retorno, com a aplicação do método de Gumbel. A análise de notícias de jornais, referentes ao período compreendido entre 1980 e 2011, foi fundamental para o conhecimento da distribuição espácio-temporal dos eventos perigosos de inundação em Cabo Verde e na cidade da Praia. Os resultados obtidos revelam um significativo grau de suscetibilidade às cheias na cidade da Praia. As áreas de maior risco potencial às inundações encontram-se no setor central da cidade, resultante da conjugação da convergência do escoamento das três ribeiras principais, da elevada densidade populacional e de construção desordenada nos leitos de cheia e nas áreas deprimidas, onde se acumulam as águas.

Unique and conserved functions of B cell-activating factor of the TNF family (BAFF) in the chicken.

The chicken represents the best-characterized animal model for B cell development in the so-called gut-associated lymphoid tissue (GALT) and the molecular processes leading to B cell receptor diversification in this species are well investigated. However, the mechanisms regulating B cell development and homeostasis in GALT species are largely unknown. Here we investigate the role played by the avian homologue of B cell-activating factor of the tumor necrosis factor family (BAFF). Flow cytometric analysis showed that the receptor for chicken B cell-activating factor of the tumor necrosis factor family (chBAFF) is expressed by mature and immature B cells. Unlike murine and human BAFF, chBAFF is primarily produced by B cells both in peripheral lymphoid organs and in the bursa of Fabricius, the chicken's unique primary lymphoid organ. In vitro and in vivo studies revealed that chBAFF is required for mature B cell survival. In addition, in vivo neutralization with a decoy receptor led to a reduction of the size and number of B cell follicles in the bursa, demonstrating that, in contrast to humans and mice, in chickens BAFF is also required for the development of immature B cells. Collectively, we show that chBAFF has phylogenetically conserved functions in mature B cell homeostasis but displays unique and thus far unknown properties in the regulation of B cell development in birds.