In Silico Study to Identify New Antituberculosis Molecules from Natural Sources by Hierarchical Virtual Screening and Molecular Dynamics Simulations

The authors acknowledge the Graduate Program in Biotechnology/UEFS for academic support.Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, responsible for 1.5 million documented deaths in 2016. The increase in reported cases of M. tuberculosis resistance to the main drugs show the need for the development of new and efficient drugs for better TB control. Based on these facts, this work aimed to use combined in silico techniques for the discovery of potential inhibitors to β-ketoacyl-ACP synthase (MtKasA). Initially compounds from natural sources present in the ZINC database were selected, then filters were sequentially applied by virtual screening, initially with pharmacophoric modeling, and later the selected compounds (based on QFIT scores) were submitted to the DOCK 6.5 program. After recategorization of the variables (QFIT score and GRID score), compounds ZINC35465970 and ZINC31170017 were selected. These compounds showed great hydrophobic contributions and for each established system 100 ns of molecular dynamics simulations were performed and the binding free energy was calculated. ZINC35465970 demonstrated a greater capacity for the KasA enzyme inhibition, with a ΔGbind = −30.90 kcal/mol and ZINC31170017 presented a ΔGbind = −27.49 kcal/mol. These data can be used in other studies that aim at the inhibition of the same biological targets through drugs with a dual action

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

Hierarchical Virtual Screening and Binding Free Energy Prediction of Potential Modulators of Aedes Aegypti Odorant-Binding Protein 1

The Aedes aegypti mosquito is the main hematophagous vector responsible for arbovirus transmission in Brazil. The disruption of A. aegypti hematophagy remains one of the most efficient and least toxic methods against these diseases and, therefore, efforts in the research of new chemical entities with repellent activity have advanced due to the elucidation of the functionality of the olfactory receptors and the behavior of mosquitoes. With the growing interest of the pharmaceutical and cosmetic industries in the development of chemical entities with repellent activity, computational studies (e.g., virtual screening and molecular modeling) are a way to prioritize potential modulators with stereoelectronic characteristics (e.g., pharmacophore models) and binding affinity to the AaegOBP1 binding site (e.g., molecular docking) at a lower computational cost. Thus, pharmacophore- and docking-based virtual screening was employed to prioritize compounds from Sigma-Aldrich® (n = 126,851) and biogenic databases (n = 8766). In addition, molecular dynamics (MD) was performed to prioritize the most potential potent compounds compared to DEET according to free binding energy calculations. Two compounds showed adequate stereoelectronic requirements (QFIT > 81.53), AaegOBP1 binding site score (Score > 42.0), volatility and non-toxic properties and better binding free energy value (∆G < −24.13 kcal/mol) compared to DEET ((N,N-diethyl-meta-toluamide)) (∆G = −24.13 kcal/mol)

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

Aedes aegypti is the main vector that transmits viral diseases such as dengue, hemorrhagic dengue, urban yellow fever, zika, and chikungunya. Worldwide, many cases of dengue have been reported in recent years, showing significant growth. The best way to manage diseases transmitted by Aedes aegypti is to control the vector with insecticides, which have already been shown to be toxic to humans; moreover, insects have developed resistance. Thus, the development of new insecticides is considered an emergency. One way to achieve this goal is to apply computational methods based on ligands and target information. In this study, sixteen compounds with acceptable insecticidal activities, with 100% larvicidal activity at low concentrations (2.0 to 0.001 mg·L−1), were selected from the literature. These compounds were used to build up and validate pharmacophore models. Pharmacophore model 6 (AUC = 0.78; BEDROC = 0.6) was used to filter 4793 compounds from the subset of lead-like compounds from the ZINC database; 4142 compounds (dG < 0 kcal/mol) were then aligned to the active site of the juvenile hormone receptor Aedes aegypti (PDB: 5V13), 2240 compounds (LE < −0.40 kcal/mol) were prioritized for molecular docking from the construction of a chitin deacetylase model of Aedes aegypti by the homology modeling of the Bombyx mori species (PDB: 5ZNT), which aligned 1959 compounds (dG < 0 kcal/mol), and 20 compounds (LE < −0.4 kcal/mol) were predicted for pharmacokinetic and toxicological prediction in silico (Preadmet, SwissADMET, and eMolTox programs). Finally, the theoretical routes of compounds M01, M02, M03, M04, and M05 were proposed. Compounds M01–M05 were selected, showing significant differences in pharmacokinetic and toxicological parameters in relation to positive controls and interaction with catalytic residues among key protein sites reported in the literature. For this reason, the molecules investigated here are dual inhibitors of the enzymes chitin synthase and juvenile hormonal protein from insects and humans, characterizing them as potential insecticides against the Aedes aegypti mosquito

Exploring integument transcriptomes, cuticle ultrastructure, and cuticular hydrocarbons profiles in eusocial and solitary bee species displaying heterochronic adult cuticle maturation.

Differences in the timing of exoskeleton melanization and sclerotization are evident when comparing eusocial and solitary bees. This cuticular maturation heterochrony may be associated with life style, considering that eusocial bees remain protected inside the nest for many days after emergence, while the solitary bees immediately start outside activities. To address this issue, we characterized gene expression using large-scale RNA sequencing (RNA-seq), and quantified cuticular hydrocarbon (CHC) through gas chromatography-mass spectrometry in comparative studies of the integument (cuticle plus its underlying epidermis) of two eusocial and a solitary bee species. In addition, we used transmission electron microscopy (TEM) for studying the developing cuticle of these and other three bee species also differing in life style. We found 13,200, 55,209 and 30,161 transcript types in the integument of the eusocial Apis mellifera and Frieseomelitta varia, and the solitary Centris analis, respectively. In general, structural cuticle proteins and chitin-related genes were upregulated in pharate-adults and newly-emerged bees whereas transcripts for odorant binding proteins, cytochrome P450 and antioxidant proteins were overrepresented in foragers. Consistent with our hypothesis, a distance correlation analysis based on the differentially expressed genes suggested delayed cuticle maturation in A. mellifera in comparison to the solitary bee. However, this was not confirmed in the comparison with F. varia. The expression profiles of 27 of 119 genes displaying functional attributes related to cuticle formation/differentiation were positively correlated between A. mellifera and F. varia, and negatively or non-correlated with C. analis, suggesting roles in cuticular maturation heterochrony. However, we also found transcript profiles positively correlated between each one of the eusocial species and C. analis. Gene co-expression networks greatly differed between the bee species, but we identified common gene interactions exclusively between the eusocial species. Except for F. varia, the TEM analysis is consistent with cuticle development timing adapted to the social or solitary life style. In support to our hypothesis, the absolute quantities of n-alkanes and unsaturated CHCs were significantly higher in foragers than in the earlier developmental phases of the eusocial bees, but did not discriminate newly-emerged from foragers in C. analis. By highlighting differences in integument gene expression, cuticle ultrastructure, and CHC profiles between eusocial and solitary bees, our data provided insights into the process of heterochronic cuticle maturation associated to the way of life

Qualidade de vida, ponto de partida ou resultado final? Quality of life, starting point or final result?

O que é qualidade de vida e o quanto podemos medir dela? Pensa-se em qualidade de vida como resultado das políticas públicas e desenvolvimento de uma sociedade, onde os determinantes socioambientais se manifestam como atributo de seus atores. Ao mesmo tempo, pode-se entender esta idéia no outro extremo da análise, a partir da percepção de uma população protagonista de sua realidade, do que vem a ser qualidade de vida segundo ela mesma. Partindo-se dos aspectos conceituais de qualidade de vida, passou-se a adotar os conceitos de diferenciais intra-urbanos como a melhor maneira de caracterizar os desajustes e as desigualdades urbanas, para assim entender os componentes da iniqüidade desse meio. A primeira iniciativa marcou a utilização do método genebrino ou distancial. Hoje, já na segunda versão desse método, incorporou-se a esse contexto outras metodologias que possibilitam maior consistência de análise para ampliar a validade dessas medições. Soma-se a esse contexto, a análise de cluster e o Sistema de Informações Geográficas, tanto no cenário intra-urbano, quanto intermunicipal.<br>What is quality of life and how much of it can be measured? Quality of life is thought of as the result of public policies and the development of a given society, where social-environmental determinants present themselves as attributes of its stakeholders. At the same time, this idea can be understood from the other end of the analyses, from the standpoint of a given population acting out its own reality, what it considers as being quality of life. Starting from the conceptual aspects of the scenarios that express quality of life, concepts about intra-urban differential aspects were adopted as the best way to characterise urban inadequacies and inequalities for a better understanding of the components of the inequities existing in this environment. Initially, the genebrino or distance method was adopted. At present, in the second version of this method, the context has been enriched by other methodologies that provide more consistency to the analysis, thus increase the validity of the measurements. Cluster Analysis and Geographic Information System were also added to this process, both in the intra-urban and multi-centric contexts

Mineração de dados e características da mortalidade infantil Data mining and characteristics of infant mortality

O estudo busca identificar padrões de características materno-fetais na predição da mortalidade infantil, por meio da incorporação de técnicas inovadoras, como a Mineração de Dados, que se mostram relevantes em Saúde Pública. Foi elaborada uma base de dados, com óbitos infantis analisados pelos Comitês de Prevenção da Mortalidade Infantil de 2000 a 2004, a partir da integração dos Sistemas de Informações de Nascidos Vivos, da Mortalidade e da Investigação da Mortalidade Infantil no Estado do Paraná. O programa da mineração foi o WEKA, de uso livre. A mineração faz busca em banco de dados e fornece regras que devem ser analisadas para transformação em informação útil. Após a mineração, selecionaram-se 4.230 regras, por exemplo: mãe adolescente e peso ao nascer < 2.500g, ou parto pós-termo e mãe adolescente com outro filho, ou com afecções maternas, aumentam o risco para óbito neonatal. Vê-se a necessidade de estabelecer maior atenção às adolescentes, às crianças com peso ao nascer < 2.500g, pós-termo e filhas de mães com afecções maternas, confirmando resultados de outros estudos.<br>This study aims to identify patterns in maternal and fetal characteristics in the prediction of infant mortality by incorporating innovative techniques like data mining, with proven relevance for public health. A database was developed with infant deaths from 2000 to 2004 analyzed by the Committees for the Prevention of Infant Mortality, based on integration of the Information System on Live Births (SINASC), Mortality Information System, and Investigation of Infant Mortality in the State of Paraná. The data mining software was WEKA (open source). The data mining conducts a database search and provides rules to be analyzed to transform the data into useful information. After mining, 4,230 rules were selected: teenage pregnancy plus birth weight < 2,500g, or post-term birth plus teenage mother with a previous child or intercurrent conditions increase the risk of neonatal death. The results highlight the need for greater attention to teenage mothers, newborns with birth weight < 2,500g, post-term neonates, and infants of mothers with intercurrent conditions, thus corroborating other studies