Mathematical model of brain tumour with glia-neuron interactions and chemotherapy treatment

Acknowledgements This study was possible by partial financial support from the following Brazilian government agencies: Fundação Araucária, EPSRC-EP/I032606/1 and CNPq, CAPES and Science Without Borders Program Process nos. 17656125, 99999.010583/2013-00 and 245377/2012-3.Peer reviewedPreprin

New directions in antimalarial target validation

Introduction: Malaria is one of the most prevalent human infections worldwide with over 40% of the world's population living in malaria-endemic areas. In the absence of an effective vaccine, emergence of drug-resistant strains requires urgent drug development. Current methods applied to drug target validation, a crucial step in drug discovery, possess limitations in malaria. These constraints require the development of techniques capable of simplifying the validation of Plasmodial targets. Areas covered: The authors review the current state of the art in techniques used to validate drug targets in malaria, including our contribution - the protein interference assay (PIA) - as an additional tool in rapid in vivo target validation. Expert opinion: Each technique in this review has advantages and disadvantages, implying that future validation efforts should not focus on a single approach, but integrate multiple approaches. PIA is a significant addition to the current toolset of antimalarial validation. Validation of aspartate metabolism as a druggable pathway provided proof of concept of how oligomeric interfaces can be exploited to control specific activity in vivo. PIA has the potential to be applied not only to other enzymes/pathways of the malaria parasite but could, in principle, be extrapolated to other infectious diseases

Podridão-do-caule e podridão-dos-ramos da mamoneira causada por Botryodiplodia theobromae Pat.

For several years, the occurrence of stem and branch rot of the Castor-oil plant has been detected in the fields of castor bean of the state of Bahia, Brazil. It was observed that the fungus Botryodiplodia sp. was frequently associated to the symptoms of this disease. It was afterward identified as Lasiodiplodia theobromae (Pat.) Griff & Maubl. (= Botryodiplodia theobromae (Pat.). Pathogenicity studies showed that the fungus B. theobromae was the etiological agent of the "rot of Botryodiplodia". This disease is characterized by the rot, dry and death of the stem and branches of Castor-oil plants with pycnidium formation of the pathogen on the infected tissue.Há vários anos tem-se constatado em municípios produtores de mamona do Estado da Bahia a ocorrência de podridão-do-caule e podridão-dos-ramos da mamoneira. Observou-se que o fungo Botryodiplodia sp. encontrava-se constantemente associado aos sintomas desta doença, sendo posteriormente identificado como Lasiodiplodia theobromae (Pat.) Griff & Maubl. (= Botryodiplodia theobromae Pat.). Estudos de patogenicidade evidenciaram que este fungo era o agente etiológico da podridão-de-botryodiplodia, doença caracterizada pela podridão, seca e morte do caule e dos ramos da mamoneira, com formação de picnídios do patógeno sobre o tecido infectado

Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase

Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis

Las comunidades vegetales de la sabana del Parque Nacional del Palmar (Argentina)

El Parque Nacional El Palmar, Entre Ríos, preserva desde 1965 el mayor remanente de la sabana de Butia yatay, un ecosistema rico en especies amenazado por la actividad humana. Para estudiar el funcionamiento de este ecosistema y gestionar su preservación, es necesario contar con una adecuada caracterización de la heterogeneidad de su vegetación. En este trabajo presentamos una clasificación fitosociológica de las comunidades vegetales de la sabana del Parque, describimos su estructura, composición y diversidad florística y detallamos su distribución en el paisaje. Con el fin de estratificar la obtención de datos, delimitamos primero las principales unidades geomorfológicas del paisaje. En la primavera de 1999 y en el verano siguiente, realizamos censos florísticos completos en 73 "stands" de sabana con diferentes historias de incendio, distribuidos en las diferentes unidades geomorfológicas. Utilizamos técnicas de análisis multivariado y clasificación numérica para agrupar los censos en comunidades y las especies en grupos florísticos. Finalmente, resumimos las diferencias entre las comunidades en un escalamiento multidimensional métrico. Obtuvimos 7 comunidades, descriptas por 20 grupos florísticos. El patrón de similitudes entre estas comunidades sugiere que la heterogeneidad florística se ordena según dos componentes, uno asociado con diferencias en la textura del suelo y el otro con diferencias en el régimen de humedad del suelo. Tres de las comunidades, afines entre sí, se distribuyen en las terrazas altas e interfluvios que conforman la matriz del paisaje, en correspondencia con diferencias graduales de topografía y suelos. Estas comunidades cambian sucesionalmente por el avance de la lignificación desencadenada por la exclusión del ganado y mantenida por la escasez de incendios naturales. Las restantes cuatro comunidades aparecen estrictamente asociadas con afloramientos rocosos, depósitos arenosos o vías de escurrimiento que interrumpen la matriz del paisaje; en ellas no es evidente la lignificación.Fil: Batista, William B.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Rolhauser, Andrés Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Biganzoli, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Burkart, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Goveto, Liliana. Administración de Parques Nacionales; ArgentinaFil: Maranta, Aristobulo. Administración de Parques Nacionales; ArgentinaFil: Pignataro, Ana Genoveva. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Morandeira, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Rabadan, Mirta Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentin

Silanol-Assisted Carbinolamine Formation in an Amine-Functionalized Mesoporous Silica Surface: Theoretical Investigation by Fragmentation Methods

The aldol reaction catalyzed by an amine-substituted mesoporous silica nanoparticle (amine-MSN) surface was investigated using a large molecular cluster model (Si392O958C6NH361) combined with the surface integrated molecular orbital/molecular mechanics (SIMOMM) and fragment molecular orbital (FMO) methods. Three distinct pathways for the carbinolamine formation, the first step of the amine-catalyzed aldol reaction, are proposed and investigated in order to elucidate the role of the silanol environment on the catalytic capability of the amine-MSN material. The computational study reveals that the most likely mechanism involves the silanol groups actively participating in the reaction, forming and breaking covalent bonds in the carbinolamine step. Therefore, the active participation of MSN silanol groups in the reaction mechanism leads to a significant reduction in the overall energy barrier for the carbinolamine formation. In addition, a comparison between the findings using a minimal cluster model and the Si392O958C6NH361 cluster suggests that the use of larger models is important when heterogeneous catalysis problems are the target

Corncob as carbon source in the production of xanthan gum in different strains Xanthomonas sp.

Xanthan gum (XG) is a biopolymer obtained in fermentation and used as a rheology control agent in aqueous systems and in stabilizing emulsions and suspensions. XG, together with other polysaccharides, can form soft, cohesive composite gels. The carbon source in the fermentative process is responsible for one-third of the production costs, and the search for less expensive and sustainable alternatives is ongoing. The use of agricultural residues such as the corncob is highly suggestive due to their abundance. This study aims to evaluate the use of derived hemicellulose fractions from the alkaline extraction of corncob as a carbon source in the production of XG in trials using four strains of Xanthomonas sp. (629, 1078, 254, and S6). The results indicate that strain 629 provides the higher yield (8.37 ± 5.75 g L−1) while using a fermentation medium containing a carbon source of saccharose (1.25%), hemicellulose fractions (3.75%), and salts. In this same medium, the strain 629 produces gum in 3% aqueous solution, showing the higher apparent viscosity (9298 ± 31 mPa s−1) at a shear rate of 10 s−1 at 25 °C. In conclusion, corncob is proven to be a promising sustainable alternative carbon source in the obtention of XG, improving the economic viability of the process within a biorefinery context. Saccharose must, however, also be included in the fermentation medium.0F1A-358B-43B5 | Fernando Jorge Ribeiro da MataN/

Identification and Characterization of a Small Molecule that Activates Thiosulfate Sulfurtransferase and Stimulates Mitochondrial Respiration

The enzyme Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), is a positive genetic predictor of diabetes type 2 and obesity. As increased TST activity protects against the development of diabetic symptoms in mice, an activating compound for TST may provide therapeutic benefits in diabetes and obesity. We identified a small molecule activator of human TST through screening of an inhouse small molecule library. Kinetic studies in vitro suggest that two distinct isomers of the compound are required for full activation as well as an allosteric mode of activation. Additionally, we studied the effect of TST protein and the activator on TST activity through mitochondrial respiration. Molecular docking and molecular dynamics (MD) approaches supports an allosteric site for the binding of the activator, which is supported by the lack of activation in the E. coli. mercaptopyruvate sulfurtransferase. Finally, we show that increasing TST activity in isolated mitochondria increases mitochondrial oxygen consumption. This article is protected by copyright. All rights reserved.</p

Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

The appearance of multi-drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross-reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging-particularly in the most dangerous malaria parasite, Plasmodium falciparum. Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials

O sistema PBL, problem-based learning, no ensino de medicina no Brasil : análise bibliográfica sobre a sua execução

Introdução: Entre as estratégias de ensino e aprendizagem utilizadas nas práticas pedagógicas, a Problem Based Learning (PBL) (Aprendizagem Baseada em Problemas) é utilizada desde 1960, em especial nos cursos de Medicina. Mesmo sendo uma estratégia valiosa, um dos seus obstáculos é a pouca prática dos alunos em atividades autodirigidas, pesquisa e construção coletiva do conhecimento. Objetivo: Rastrear elementos constitutivos da PBL através de dados colhidos em artigos pesquisados em sítios de divulgação científica; Avaliar, nos estudos selecionados, os aspectos positivos e negativos que estejam relacionados com a metodologia do Sistema PBL aplicada ao ensino médico no Brasil. Metodologia: Estudo bibliográfico de 13 textos utilizando um modelo de desconstrução, denominada Análise Textual Discursiva (ATD) que consiste em: transformação dos artigos em pedaços menores; análise textual; identificação de padrões convergentes e divergentes em relação a PBL; organização e síntese dos dados, culminando com a elaboração de estratégia adaptativa da PBL para o curso de Medicina. Resultados: Foram encontradas 116 citações que convergiam para referências positivos acerca da metodologia PBL e 40 citações que divergiam acerca dos pontos positivos. Os aspectos positivos como o desenvolvimento de atitudes e habilidades; desenvolvimento de competências anteriores ao curso; efeitos positivos depois de terminada a graduação, como autonomia de estudo e a articulação entre currículo e realidade profissional, representam pontos a serem reforçados na aula. Em contraponto, foi observado que dentre os negativos a não compreensão do papel do professor como tutor; necessidade de conteúdo formal tradicional pelos alunos e a expectativa que o professor retire as suas dúvidas são pontos a serem evitados. Conclusões: A metodologia PBL deverá servir como metodologia ativa para aproveitar ao máximo as habilidades que os alunos já apresentam, potencializando o aprendizado na educação médica em sala de aula. Palavras-Chave: PBL; curso de medicina; metodologia ativa; educação médica.ABSTRACT Introduction: Among the teaching and learning strategies used in teaching practices, the Problem Based Learning (PBL) (Problem Based Learning) has been used since 1960, especially in medical courses. Although a valuable strategy, one of its obstacles is the lack of practice of students in self-directed activities, research and collective construction of knowledge. Objective: Tracking constitutive elements of PBL through data collected on items surveyed in science communication sites and arrange them in order to develop a student's adaptation strategy to this methodological way. Evaluate the selected studies, the positive and negative aspects that are related to the methodology of PBL system applied to medical education in Brazil. Methodology: bibliographic study of 13 texts using a deconstruction model, called Discursive Textual Analysis (DTA) consisting of: transforming items into smaller pieces; textual analysis; identifying convergent and divergent patterns in relation to PBL; organization and synthesis of data, culminating with in the development of adaptive strategy of PBL to Medical Course. Results: It has been found 116 quotes that converged into positive notes about the PBL methodology and 40 quotes that differed about the positive ones. These quotations are placed in lines of analysis, based on a model of adaptation of the PBL student body. The positive aspects represent points to be reinforced in the classroom and the negative ones to be avoided. Conclusions: The PBL methodology should serve as active methodology to make the most of the skills that students already have, enhancing learning in medical education in the classroom Keywords: PBL; medical schools; active methodology; medical education