An Integrative Genomic and Transcriptomic Analysis Reveals Potential Targets Associated with Cell Proliferation in Uterine Leiomyomas

Background: Uterine Leiomyomas (ULs) are the most common benign tumours affecting women of reproductive age. ULs represent a major problem in public health, as they are the main indication for hysterectomy. Approximately 40-50% of ULs have non-random cytogenetic abnormalities, and half of ULs may have copy number alterations (CNAs). Gene expression microarrays studies have demonstrated that cell proliferation genes act in response to growth factors and steroids. However, only a few genes mapping to CNAs regions were found to be associated with ULs. Methodology: We applied an integrative analysis using genomic and transcriptomic data to identify the pathways and molecular markers associated with ULs. Fifty-one fresh frozen specimens were evaluated by array CGH (JISTIC) and gene expression microarrays (SAM). The CONEXIC algorithm was applied to integrate the data. Principal Findings: The integrated analysis identified the top 30 significant genes (P<0.01), which comprised genes associated with cancer, whereas the protein-protein interaction analysis indicated a strong association between FANCA and BRCA1. Functional in silico analysis revealed target molecules for drugs involved in cell proliferation, including FGFR1 and IGFBP5. Transcriptional and protein analyses showed that FGFR1 (P = 0.006 and P<0.01, respectively) and IGFBP5 (P = 0.0002 and P = 0.006, respectively) were up-regulated in the tumours when compared with the adjacent normal myometrium. Conclusions: The integrative genomic and transcriptomic approach indicated that FGFR1 and IGFBP5 amplification, as well as the consequent up-regulation of the protein products, plays an important role in the aetiology of ULs and thus provides data for potential drug therapies development to target genes associated with cellular proliferation in ULs. © 2013 Cirilo et al.

Anti-Candida targets and cytotoxicity of casuarinin isolated from Plinia cauliflora leaves in a bioactivity-guided study

In addition to the bio-guided investigation of the antifungal activity of Plinia cauliflora leaves against different Candida species, the major aim of the present study was the search for targets on the fungal cell. The most active antifungal fraction was purified by chromatography and characterized by NMR and mass spectrometry. The antifungal activity was evaluated against five Candida strains according to referenced guidelines. Cytotoxicity against fibroblast cells was determined. The likely targets of Candida albicans cells were assessed through interactions with ergosterol and cell wall composition, porosity and architecture. The chemical major component within the most active antifungal fraction of P. cauliflora leaves identified was the hydrolysable tannin casuarinin. The cytotoxic concentration was higher than the antifungal one. The first indication of plant target on cellular integrity was suggested by the antifungal activity ameliorated when using an osmotic support. The most important target for the tannin fraction studied was suggested by ultrastructural analysis of yeast cell walls revealing a denser mannan outer layer and wall porosity reduced. It is possible to imply that P. cauliflora targeted the C. albicans cell wall inducing some changes in the architecture, notably the outer glycoprotein layer, affecting the cell wall porosity without alteration of the polysaccharide or protein level. © 2013 by the authors.

Estudo de métodos para classificação e localização precisa de padrões usando um sistema de luz estruturada

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

An assessment of the economic impact of climate change on the Agriculture, Energy and Health sectors in Trinidad and Tobago

This report analyses the agriculture, energy, and health sectors in Trinidad and Tobago to assess the potential economic impacts of climate change on the sectors. The fundamental aim of this report is to assist with the development of strategies to deal with the potential impact of climate change on Trinidad and Tobago. It also has the potential to provide essential input for identifying and preparing policies and strategies to help advance the Caribbean subregion closer to solving problems associated with climate change and attaining individual and regional sustainable development goals. Some of the key anticipated impacts of climate change for the Caribbean include elevated air and sea-surface temperatures, sea-level rise, possible changes in extreme events and a reduction in freshwater resources. The economic impact of climate change on the three sectors was estimated for the A2 and B2 IPCC scenarios until 2050. An exploration of various adaptation strategies was also undertaken for each sector using standard evaluation techniques. The study of the impact of climate change on the agriculture sector focused on root crops, green vegetables and fisheries. For these sectors combined, the cumulative loss under the A2 scenario is calculated as approximately B$2.24 and approximately B$1.72 under the B2 scenario by 2050. This is equivalent to 1.37% and 1.05% of the 2008 GDP under the A2 and B2 scenarios, respectively. Given the potential for significant damage to the agriculture sector a large number of potential adaptation measures were considered. Out of these a short-list of 10 potential options were selected by applying 10 evaluation criteria. All of the adaptation strategies showed positive benefits. The analysis indicate that the options with the highest net benefits are: (1) Building on-farm water storage, (2) Mainstreaming climate change issues into agricultural management and (3) Using drip irrigation. Other attractive options include water harvesting. The policy decisions by governments should include these assessments, the omitted intangible benefits, as well as the provision of other social goals such as employment. The analysis of the energy sector has shown that the economic impact of climate change during 2011-2050 is similar under the A2 (US$142.88 million) and B2 (US$134.83 million) scenarios with A2 scenario having a slightly higher cost (0.737% of 2009 GDP) than the B2 scenario (0.695% of 2009 GDP) for the period. On the supply side, analyses indicate that Trinidad and Tobago’s energy sector will be susceptible to the climate change policies of major energy-importing countries (the United States of America and China), and especially to their renewable energy strategies. Implementation of foreign oil substitution policy by the United States of America will result in a decline in Trinidad and Tobago’s Liquefied Natural Gas (LNG) export (equivalent to 2.2% reduction in 2009 GDP) unless an alternative market is secured for the lost United States of America market. China, with its rapid economic growth and the highest population in the world, offers a potential replacement market for Trinidad and Tobago’s LNG export. In this context the A2 scenario will offer the best option for Trinidad and Tobago’s energy sector. The cost-benefit analysis undertaken on selected adaptation strategies reveal that the benefit-cost ratio of replacing electric water heaters with solar water heaters is the most cost-effective. It was also found that the introduction of Compact Fluorescent Light (CFL) and Variable Refrigerant Volume (VRV) air conditioners surpasses the projected cost of increased electricity consumption due to climate change, and provides an economic rationale for the adoption of these adaptation options even in a situation of increased electricity consumption occasioned by climate change. Finally, the conversion of motor fleets to Compressed Natural Gas (CNG) is a cost-effective adaptation option for the transport sector, although it has a high initial cost of implementation and the highest per capita among the four adaptation options evaluated. To investigate the effect of climate change on the health sector dengue fever, leptospirosis, food borne illnesses, and gastroenteritis were examined. The total number of new dengue cases for the period 2008 to 2050 was 204,786 for BAU, 153,725 for A2 and 131,890 for the B2 scenario. With regard to the results for leptospirosis, A2 and B2 seem to be following a similar path with total number of new cases in the A2 scenario being 9,727 and 9,218 cases under the B2 scenario. Although incidence levels in the BAU scenario coincided with those of A2 and B2 prior to 2020, they are somewhat lower post 2020. A similar picture emerges for the scenarios as they relate to food-borne illnesses and to gastroenteritis. Specifically for food-borne illnesses, the BAU scenario recorded 27,537 cases, the A2 recorded 28,568 cases and the B2 recorded 28,679 cases. The focus on the selected sources of morbidity in the health sector has highlighted the fact that the vulnerability of the country’s health sector to climate change does not depend solely on exogenously derived impacts, but also on the behaviour and practices among the population. It is clear that the vulnerability which became evident in the analysis of the impacts on dengue fever, leptospirosis and food-borne illnesses is not restricted solely to climate or other external factors. The most important adaptation strategy being recommended targets lifestyle, behaviour and attitude changes. The population needs to be encouraged to alter their behaviours and practices so as to minimise their exposure to harmful outcomes as it relates to the incidence of these diseases.

Exchange rate pass-through and inflation targets in Chile

Using quarterly data on the Chilean economy from 1986 to 2009, this article looks at the effect of gradual implementation of an inflation-targeting regime on exchange rate pass-through to prices. Initially, the introduction of inflation-targeting contributes to substantial reductions in the pass-through coefficient. However, in the second phase of implementation, once the monetary authority extends the policy horizon and introduces greater flexibility into the exchange rate system, the pass-through coefficient rises sharply. The findings of this study show that exchange rate pass-through to prices, in addition to being sensitive to the inflationary environment, is closely tied to the rules of the game that shape the monetary policy framework.

Ciclo de política curricular do estado do Pará (2008-2012): a enunciação discursiva sobre relações “raciais”

O presente estudo analisa os enunciados discursivos do ciclo de Política curricular do Estado do Pará sobre as relações “raciais” no período de 2008 a 2012, a partir da abordagem do ciclo de políticas, proposto por Stephen Ball. Nesta análise, é focalizada a produção das políticas no contexto de influência, contexto de produção de textos políticos e contexto da prática. O referencial teórico-metodológico que subsidia a análise parte da Teoria sócio-histórica e dialógica da linguagem com base em Bakhtin (2010, 2011), abordagem do ciclo de políticas abalizado pelas teorizações de Ball et al (1992), para os estudos acerca Relações “Raciais” partimos dos conceitos de Guimarães (1999, 2002, 2008) e Coelho (2009) sobre raça. E, sobre as relações sociais estabelecidas no campo educacional, utilizamos as noções conceituais de campo e de habitus em Bourdieu (2008, 2009, 2010). O estudo é de abordagem qualitativa (FLICK, 2004). Utilizamos como fontes de coleta de dados documentos orais e escritos, dentre os quais destacamos: Artigos, Teses e Dissertações sobre Relações “Raciais” e Política Curricular realizado em duas bases de dados nacionais e uma internacional: a) ANPED (GT-21); b) site da CAPES/PPGE; c) Fundação Ford. Publicações: a) Política de Educação Básica do Estado do Pará, especialmente o eixo da Política Curricular; b) I Conferência Estadual de Educação: Diagnósticos, diretrizes, objetivos e metas aprovadas; c) Educação Básica no Pará: elementos para uma política educacional democrática e de qualidade Pará todos (vol I e II) e entrevista semiestruturada com quatorze agentes sociais que atuavam na SEDUC, USE e escolas da Rede Pública Estadual, os quais participaram da Política Curricular do Estado do Pará. Os dados foram analisados por meio da análise do processo enunciativo-discursivo com base em Bakhtin (2010, 2011). A partir da análise da enunciação discursiva do ciclo de política curricular do Estado do Pará sobre as relações “raciais” e da interpenetração dos discursos entre os contextos de influência, contexto de definição de textos políticos e contexto da prática os resultados do estudo revelam que os diferentes enunciados produzidos nos variados contextos são marcados pela hibridização de discursos, resultado de processos de recontextualização. Infere-se que a política curricular do Estado do Pará se apresenta em inter-relações entre múltiplos contextos no ciclo de políticas (BALL, et al, 1992). A despeito do caráter contínuo e não hierarquizado das políticas, da articulação macro e micropolíticas avançarem em relação às abordagens estadocêntricas e do processo de recontextualização política que ocorre no contexto da prática, o estudo conclui que a política curricular do Estado do Pará existe como uma política de Estado, existe como uma política educacional. No entanto, na exequibilidade dessa política de Estado e educacional na escola no tocante as relações “raciais”, ela não ocorre por conta da fragilização da competência cultural e teórica desse agente social que deve executá-la. A fragilização está na concretização dessa política no contexto da prática. Há um problema entre o que se projeta e o que se prática, o que ajuda a atribuir a realidade social a disseminação e ratificação do racismo e discriminação nos diferentes contextos que compõe a política de currículo.

GALANT: a Cytoscape plugin for visualizing data as functional landscapes projected onto biological networks

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Recombinant disintegrin targets alpha(v) beta(3) integrin and leads to mediator production

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Glycosomal Targets for Anti-Trypanosomatid Drug Discovery

Glycosomes are peroxisome-related organelles found in all kinetoplastid protists, including the human pathogenic species of the family Trypanosomatidae: Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Glycosomes are unique in containing the majority of the glycolytic/gluconeogenic enzymes, but they also possess enzymes of several other important catabolic and anabolic pathways. The different metabolic processes are connected by shared co-factors and some metabolic intermediates, and their relative importance differs between the parasites or their distinct life-cycle stages, dependent on the environmental conditions encountered. By genetic or chemical means, a variety of glycosomal enzymes participating in different processes have been validated as drug targets. For several of these enzymes, as well as others that are likely crucial for proliferation, viability or virulence of the parasites, inhibitors have been obtained by different approaches such as compound libraries screening or design and synthesis. The efficacy and selectivity of some initially obtained inhibitors of parasite enzymes were further optimized by structure-activity relationship analysis, using available protein crystal structures. Several of the inhibitors cause growth inhibition of the clinically relevant stages of one or more parasitic trypanosomatid species and in some cases exert therapeutic effects in infected animals. The integrity of glycosomes and proper compartmentalization of at least several matrix enzymes is also crucial for the viability of the parasites. Therefore, proteins involved in the assembly of the organelles and transmembrane passage of substrates and products of glycosomal metabolism offer also promise as drug targets. Natural products with trypanocidal activity by affecting glycosomal integrity have been reported.

THE RETINAL TARGETS OF CENTRIFUGAL NEURONS AND THE RETINAL NEURONS PROJECTING TO THE ACCESSORY OPTIC-SYSTEM

In birds, neurons of the isthmo-optic nucleus (ION), as well as ''ectopic'' neurons, send axons to the retina, where they synapse on cells in the inner nuclear layer (INL). Previous work has shown that centrifugal axons can be divided into two anatomically distinct types depending on their mode of termination: either ''convergent'' or ''divergent'' (Ramon y Cajal, 1889; Maturana and Frenk, 1965). We show that cytochrome-oxidase histochemistry specifically labels ''convergent'' centrifugal axons and target neurons which appear to be amacrine cells, as well as three ''types'' of ganglion cells: two types found in the INL (displaced ganglion cells) and one in the ganglion cell layer. Labeled target amacrine cells have distinct darkly labeled ''nests'' of boutons enveloping the somas, are associated with labeled centrifugal fibers, and are confined to central retina. Lesions of the isthmo-optic tract abolish the cytochrome-oxidase labeling in the centrifugal axons and in the target amacrine cells but not in the ganglion cells. Cytochromeoxidase-labeled ganglion cells in the INL are large; one type is oval and similar to the classical displaced ganglion cells of Dogiel, which have been reported to receive centrifugal input; the other type is rounder. Rhodamine beads injected into the accessory optic system results in retrograde label in both types of cells, showing that two distinct types of displaced ganglion cells project to the accessory optic system in chickens. The ganglion cells in the ganglion cell layer that label for cytochrome oxidase also project to the accessory optic system. These have proximal dendrites that ramify in the outer inner plexiform layer. Neither the target amacrine cells nor either of the displaced ganglion cells are immunoreactive for the inhibitory transmitter gamma aminobutyric acid. At least some of the target amacrine cells may, however, be cholinoceptive: we found that the antibody to the alpha-7 subunit of the nicotinic ACh receptor labels a population of cells in the INL that are similar in location, size, and the presence of labeled bouton-like structures to those we find labeled with cytochrome oxidase. This antibody also labels neurons in the ION proper but not ectopic cells. In conclusion, it appears that cytochrome oxidase may be a marker for ''convergent'' centrifugal axons and at least one of their target cells in the INL.

The perspective of the teaching of arts projected by H. Gardner and the National Syllabus Parameters - (arts) of elementary school

In a concise way, the article reports part of the Master of Arts dissertation in Music entitled The meaning of the teaching of Arts in H. Gardner's perspective, presented in the IAUNESP [Arts Institute-State of Sao Paulo University] in 2008. Some considerations on the Statutory Law n. 11.769/08 were added to the original text. The produced research had an exploratory nature and a theoretical mark. Some texts by Howard Gardner, by the psychologist Eliane Leao, as well as the text of the National Syllabus Parameters-Art, from the Department of Elementary Education, served as a foundation for this article. The intended aim was to demonstrate to what extent the pedagogical proposition of the Arts Education projected by H. Gardner is similar to the one proposed by the National Syllabus Parameters, and which would the benefits be in this age group of an artistic sensitizing work for the development of the individual's personality.

Stem cell factor: a hemopoietic cytokine with important targets in asthma

We review evidence that Stem Cell Factor (SCF) plays an important role in the pathophysiology of asthma. SCF is produced by a wide variety of cells present in asthmatic lung, including mast cells and eosinophils. Its receptor, c-kit, is broadly expressed on mature mast cells and eosinophils. SCF promotes recruitment of mast cell progenitors into tissues, as well as their local maturation and activation. It also promotes eosinophil survival, maturation and functional activation. SCF enhances IgE-dependent release of mediators from mast cells, including histamine, leukotrienes, cytokines (TNF-alpha, IL-5, GM-CSF) and chemokines (RANTES/CCL5, MCP-1/CCL2, TARC/CCL17 e MDC/CCL22); it is required for IL-4 production in mast cells. SCF, acting in concert with IgE, also upregulates the expression and function of CC chemokine receptors in mast cells. Structural and resident airway cells express increased levels of SCF in the bronchus of asthmatic patients. In a murine model of asthma, allergen exposure increased production of SCF by epithelial cells and alveolar macrophages, which was transient and paralleled by histamine release. SCF induced long-lived airway hyperreactivity, which was prevented by local neutralization of SCF, as well as by inhibitors of the production or activity of cysteinyl-leukotrienes. Together, these observations suggest that SCF has an important role in asthma.

Molecular expression profile reveals potential biomarkers and therapeutic targets in canine endometrial lesions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)