Machine Learning Toxicity Prediction: Latest Advances by Toxicity End Point

Machine learning (ML) models to predict the toxicity of small molecules have garnered great attention and have become widely used in recent years. Computational toxicity prediction is particularly advantageous in the early stages of drug discovery in order to filter out molecules with high probability of failing in clinical trials. This has been helped by the increase in the number of large toxicology databases available. However, being an area of recent application, a greater understanding of the scope and applicability of ML methods is still necessary. There are various kinds of toxic end points that have been predicted in silico. Acute oral toxicity, hepatotoxicity, cardiotoxicity, mutagenicity, and the 12 Tox21 data end points are among the most commonly investigated. Machine learning methods exhibit different performances on different data sets due to dissimilar complexity, class distributions, or chemical space covered, which makes it hard to compare the performance of algorithms over different toxic end points. The general pipeline to predict toxicity using ML has already been analyzed in various reviews. In this contribution, we focus on the recent progress in the area and the outstanding challenges, making a detailed description of the state-of-the-art models implemented for each toxic end point. The type of molecular representation, the algorithm, and the evaluation metric used in each research work are explained and analyzed. A detailed description of end points that are usually predicted, their clinical relevance, the available databases, and the challenges they bring to the field are also highlighted.Fil: Cavasotto, Claudio Norberto. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Scardino, Valeria. Universidad Austral; Argentin

The canonical equilibrium of constrained molecular models

In order to increase the efficiency of the computer simulation of biological molecules, it is very common to impose holonomic constraints on the fastest degrees of freedom; normally bond lengths, but also possibly bond angles. Since the maximum time step required for the stability of the dynamics is proportional to the shortest period associated with the motions of the system, constraining the fastest vibrations allows to increase it and, assuming that the added numerical cost is not too high, also increase the overall efficiency of the simulation. However, as any other element that affects the physical model, the imposition of constraints must be assessed from the point of view of accuracy: both the dynamics and the equilibrium statistical mechanics are model-dependent, and they will be changed if constraints are used. In this review, we investigate the accuracy of constrained models at the level of the equilibrium statistical mechanics distributions produced by the different dynamics. We carefully derive the canonical equilibrium distributions of both the constrained and unconstrained dynamics, comparing the two of them by means of a “stiff” approximation to the latter. We do so both in the case of flexible and hard constraints, i.e., when the value of the constrained coordinates depends on the conformation and when it is a constant number. We obtain the different correcting terms associated with the kinetic energy mass-metric tensor determinants, but also with the details of the potential energy in the vicinity of the constrained subspace (encoded in its first and second derivatives). This allows us to directly compare, at the conformational level, how the imposition of constraints changes the thermal equilibrium of molecular systems with respect to the unconstrained case. We also provide an extensive review of the relevant literature, and we show that all models previously reported can be considered special cases of the most general treatments presented in this work. Finally, we numerically analyze a simple methanol molecule in order to illustrate the theoretical concepts in a practical case.This work has been supported by the research projects E24/3 (DGA, Spain), FIS2009- 13364-C02-01 (MICINN, Spain), 200980I064 (CSIC, Spain) and ARAID and Ibercaja grant for young researchers (Spain). P. G.-R. is supported by a JAE PREDOC grant (CSIC, Spain)

In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, almost 1,5 million people have been infected, with more than 85,000 casualties. Today, no vaccine nor antiviral drug is available. While the development of a vaccine might take at least a year, and for a novel drug, even longer; finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a docking-based screening using a quantum mechanical scoring of a library built from approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the anaylysis of our structure-based compound screening, we propose several structurally diverse compounds (either FDA-approved or in clinical trials) that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.Fil: Cavasotto, Claudio Norberto. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Di Filippo, Juan Ignacio. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentin

Evaluation of Silicone Fluids and Resins as CO2Thickeners for Enhanced Oil Recovery Using a Computational and Experimental Approach

CO2thickeners have the potential to be a game changer for enhanced oil recovery, carbon capture utilization and storage, and hydraulic fracturing. Thickener design is challenging due to polymers’ low solubility in supercritical CO2(scCO2) and the difficulty of substantially increasing the viscosity of CO2. In this contribution, we present a framework to design CO2soluble thickeners, combining calculations using a quantum mechanical solvation model with direct laboratory viscosity testing. The conductor-like polarizable continuum model for solvation free-energy calculations was used to determine functional silicone and silsesquioxane solubilities in scCO2. This method allowed for a fast and efficient identification of CO2-soluble compounds, revealing silsesquioxanes as more CO2-philic than linear polydimethylsiloxane (PDMS), the most efficient non-fluorinated thickener know to date. The rolling ball apparatus was used to measure the viscosity of scCO2with both PDMS and silicone resins with added silica nanoparticles. Methyl silicone resins were found to be stable and fast to disperse in scCO2while having a significant thickening effect. They have a larger effect on the solution viscosity than higher-molecular-weight PDMS and are able to thicken CO2even at high temperatures. Silicone resins are thus shown to be promising scCO2thickeners, exhibiting enhanced solubility and good rheological properties, while also having a moderate cost and being easily commercially attainable.Fil: Gallo, Gonzalo. Instituto Tecnológico de Buenos Aires; ArgentinaFil: Erdmann, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Investigaciones para la Industria Química. Universidad Nacional de Salta. Facultad de Ingeniería. Instituto de Investigaciones para la Industria Química; ArgentinaFil: Cavasotto, Claudio Norberto. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentin

Obtenção e caracterização de óxido de cério, obtido a partir da decomposição térmica do tris(8-hidroxiquinolinato)cério(III)

In the present work, it was investigated the influence of the final pH of precipitation, agitation time and mode of agitation, which assessed the mechanical agitation mode and ultrasound to obtain the cerium dioxide. For process optimization, it was used a tool called Planning Factor, which provides an estimative of better conditions, considering a response variable from the experimental data. The responsible variable adopted in this work was Decomposition Final Temperature and Particle Average Size. The cerium dioxide was obtained from the thermal decomposition of the complex tris (8-hydroxyquinolinate) cerium (III), synthesized by chemical precipitation using 8-hydroxyquinolinechelator and characterized by infrared spectroscopy (FTIR) and scanning electronic microscopy (SEM). In addition, it was performed the study of the complex thermal behavior with assistance of thermogravimetry (TG), derivative thermogravimetry (DTG) and differential thermal analysis (DTA); The cerium dioxide was characterized by FTIR and X-ray diffraction (XRD), in which it was based to the determination of the particle average size using Scherrer's formula. The Factorial design pointed out to response variable Decomposition Final temperature that, for both modes of agitation, the best synthesis conditions are for higher values of final pH's precipitation. Also, the stirring time had no significant influence when used the 95% significance studied range. For response variable Average Size, the test pointed out to both ways of stirring, when none of the variables had significant influence at 95% significance within the studied range, assigning the average particle size only to the method of synthesis. Thereby, there was no significant difference between the stirring modes.CAPESNo presente trabalho foi estudado a influência do pH final de precipitação, tempo e modo de agitação, onde foi avaliado o modo de agitação mecânico e por ultrassom na obtenção do dióxido de cério. Para a otimização do processo, fez-se o uso de uma ferramenta chamada Planejamento Fatorial, na qual, a partir dos dados experimentais fornece uma estimativa para melhores condições levando em consideração uma variável resposta. As variáveis resposta adotadas no trabalho foram Temperatura Final de Decomposição e Tamanho médio de Partícula. O dióxido de cério foi obtido a partir da decomposição térmica do complexo tris(8-hidroxiquinolinato)cério(III), que foi sintetizado por meio da técnica de precipitação química, empregando o quelante 8-hidroxiquinolina e caracterizado por meio de espectroscopia na região do infravermelho (FTIR) e microscopia eletrônica de varredura (MEV), foi também realizado o estudo do comportamento térmico do complexo, com auxílio da térmogravimetria (TG), térmogravimetria derivada (DTG) e análise térmica diferencial (DTA); o dióxido de cério foi caracterizado por meio de FTIR e difratometria de raios X (DRX), a partir dos dados de DRX foi calculado o tamanho médio de partículas com o auxílio da fórmula de Scherrer. O Planejamento Fatorial indicou para variável resposta Temperatura Final de Decomposição, que para ambos modos de agitação as melhores condições de síntese são para maiores valores de pH´s finais de precipitação, o tempo de agitação não teve influência significativa a 95% de significância, dentro da faixa estudada. Para variável resposta Tamanho Médio de Partícula, o teste mostrou para os dois modos de agitação, que nenhuma das variáveis teve influência significativa a 95% de significância, dentro da faixa estudada, atribuindo então o tamanho médio de partículas somente ao método de síntese. Não houve diferença significativa entre os modos de agitação também

Functional and druggability analysis of the SARS-CoV-2 proteome

The infectious coronavirus disease (COVID-19) pandemic, caused by the coronavirus SARS-CoV-2, appeared in December 2019 in Wuhan, China, and has spread worldwide. As of today, more than 22 million people have been infected, with almost 800,000 fatalities. With the purpose of contributing to the development of effective therapeutics, this work provides an overview of the viral machinery and functional role of each SARS-CoV-2 protein, and a thorough analysis of the structure and druggability assessment of the viral proteome. All structural, non-structural, and accessory proteins of SARS-CoV-2 have been studied, and whenever experimental structural data of SARS-CoV-2 proteins were not available, homology models were built based on solved SARS-CoV structures. Several potential allosteric or protein-protein interaction druggable sites on different viral targets were identified, knowledge that could be used to expand current drug discovery endeavors beyond the cysteine proteases and the polymerase complex. It is our hope that this study will support the efforts of the scientific community both in understanding the molecular determinants of this disease and in widening the repertoire of viral targets in the quest for repurposed or novel drugs against COVID-19.Fil: Cavasotto, Claudio Norberto. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; ArgentinaFil: Sánchez Lamas, Maximiliano. Universidad Austral; ArgentinaFil: Maggini, Julián. Universidad Austral; Argentin

O consentimento do cônjuge como condição para realização de laqueadura no Brasil: votação da autonomia sobre o corpo e do direito ao livre planejamento familiar

Trabalho de Conclusão de Curso, apresentado para obtenção do grau de Bacharel no curso de Direito da Universidade do Extremo Sul Catarinense, UNESC.Este trabalho tem por objetivo analisar a limitação que condiciona a escolha pela laqueadura ao consentimento do cônjuge, submetendo a mulher casada que não deseja mais engravidar à vontade do outro. O tema é relevante pois consiste em considerar as desigualdades nas relações de gênero sobretudo no âmbito familiar, diante da importância da autodeterminação da mulher na sociedade e pelo reconhecimento de seus direitos fundamentais como indivíduo livre, capaz e singular, mesmo sendo parte numa relação conjugal. A opção pela laqueadura, uma escolha que diz respeito à vida particular da mulher como ser humano capaz de tomar decisões e de ser responsável por seus próprios atos, na vigência de sociedade conjugal, não interfere na liberdade do outro. Para que o objetivo deste estudo fosse alcançado, foi desenvolvida uma pesquisa teórica e qualitativa com a revisão de material bibliográfico sobre o tema. Primeiramente, examinam-se o tratamento jurídico do planejamento familiar no Brasil e a laqueadura entre os métodos para evitar uma gravidez indesejada. Também, abordam-se os direitos sexuais e reprodutivos das mulheres, a autonomia reprodutiva na sociedade conjugal, bem como a função dos limites do Estado nessa questão. Por fim, estuda-se o capítulo mais recente deste debate na Ação Direta de Inconstitucionalidade pela Lei 9.263/96. Conclui-se, ao final da pesquisa, que essa restrição que condiciona a escolha pela laqueadura ao consentimento do cônjuge é absolutamente indevida e contribui para a perpetuação das relações assimétricas. O Estado deve abster-se de intervir na esfera privada e agir no sentido de promover serviços de saúde que incrementem o acesso à educação sexual e reprodutiva

Solvent effects on the NMR shieldings of stacked DNA base pairs

Stacking effects are among the most important effects in DNA. We have recently studied their influence in fragments of DNA through the analysis of NMR magnetic shieldings, firstly in vacuo. As a continuation of this line of research we show here the influence of solvent effects on the shieldings through the application of both explicit and implicit models. We found that the explicit solvent model is more appropriate for consideration due to the results matching better in general with experiments, as well as providing clear knowledge of the electronic origin of the value of the shieldings. Our study is grounded on a recently developed theoretical model of our own, by which we are able to learn about the magnetic effects of given fragments of DNA molecules on selected base pairs. We use the shieldings of the atoms of a central base pair (guanine-cytosine) of a selected fragment of DNA molecules as descriptors of physical effects, like π-stacking and solvent effects. They can be taken separately and altogether. The effect of π-stacking is introduced through the addition of some pairs above and below of the central base pair, and now, the solvent effect is considered including a network of water molecules that consist of two solvation layers, which were fixed in the calculations performed in all fragments. We show that the solvent effects enhance the stacking effects on the magnetic shieldings of atoms that belong to the external N-H bonds. The net effect is of deshielding on both atoms. There is also a deshielding effect on the carbon atoms that belong to C 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 O bonds, for which the oxygen atom has an explicit hydrogen bond (HB) with a solvent water molecule. Solvent effects are found to be no higher than a few percent of the total value of the shieldings (between 1% and 5%) for most atoms, although there are few for which such an effect can be higher. There is one nitrogen atom, the acceptor of the HB between guanine and cytosine, that is more highly shielded (around 15 ppm or 10%) when the explicit solvent is considered. In a similar manner, the most external nitrogen atom of cytosine and the hydrogen atom that is bonded to it are highly deshielded (around 10 ppm for nitrogen and around 3 ppm for hydrogen).Fil: Martínez, Fernando Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Modelado e Innovación Tecnológica. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Modelado e Innovación Tecnológica; ArgentinaFil: Adler, Natalia Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Modelado e Innovación Tecnológica. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Modelado e Innovación Tecnológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Cavasotto, Claudio Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Modelado e Innovación Tecnológica. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Modelado e Innovación Tecnológica; Argentina. Universidad Austral; ArgentinaFil: Aucar, Gustavo Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Modelado e Innovación Tecnológica. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Modelado e Innovación Tecnológica; Argentina. Universidad Nacional del Nordeste; Argentin

Diálogos possíveis através do Projovem

It was researched Projovem, a formation and inclusion policy for the youth, through observation, qualitative analysis and participatory research, from which it is constructing texts that discuss the different discourses used by the program / context. What kinds of discourses are ingrained from its drafting, through passing teachers and students so that, theoretically, reaffirm the place of exclusion that young people already occupy in society. Due how the curriculum is articulated,  the mode of operation and organization of this program, cooperate for a functional literacy. The initial series of school memories, as well as the living conditions of students, impregnate testimonies collected in this research. The trajectories of these young school failures continuous, in the initial series, made us investigate the construction of this failure at school. The data were collected through interviews, observations at the school where Projovem is held, in the city of Canoas.Key-words: Projovem, exclusion, inclusion, functional illiteracy, school failure.Pesquisou-se o Projovem, uma política de formação e inclusão para os jovens. Pla observação, análise qualitativa e pesquisa participante foi-se construindo textos que abordam os diversos discursos utilizados por este programa: que tipos de discursos se encontram entranhados desde a sua elaboração, passando por professores e alunos, de modo que, em tese, reafirmam o lugar de exclusão que os jovens ocupam na sociedade? Argumenta-se que devido à forma como está articulado o currículo, o modo de funcionamento e organização deste programa colabora para um alfabetismo funcional. As memórias escolares das séries iniciais, assim como as condições de vida dos alunos impregnam relatos colhidos nesta pesquisa. As trajetórias de repetências contínuas desses jovens nos fizeram indagar a construção do fracasso escolar. Os dados foram coletados por entrevistas, observações na escola onde ocorreu o Projovem na cidade de Canoas.Palavras-chave: Projovem, exclusão, inclusão, alfabetismo funcional, fracasso escolar

Ecologia e história natural de Hypsiboas curupi (Anura, Hylidae): um anfíbio endêmico do sul da Mata Atlântica

Data on habitat use and life history are essential for evaluation of the conservation status of species, and may direct policy for preservation of natural environments. Over the course of a year, we investigated populations of Hypsiboas curupi regarding (i) nighttime activity patterns; (ii) associations with climatic variables; (iii) the spatial distribution patterns of males and females with respect to microhabitat use; and (iv) variation in body size. The study was carried out from August 2010 to July 2011 in the Parque Estadual Fritz Plaumann, a seasonal deciduous forest fragment in the western region of Santa Catarina, southern Brazil. Calling activity was highest from August to November. The number of calling males was highest at 23h, and the frequency of occurrence was influenced by the air humidity. Calling males, non-calling males, and females differed in their distance from the bank and substrate type used. Females were significantly larger and heavier than males. Our results indicate that H. curupi is highly dependent on bank vegetation, and that changes in riparian vegetation structure due to human activity can result in the loss of sites for calling and oviposition, and may reduce availability of food and shelter.Keywords: life history, riparian forest, stream-dwelling amphibians, seasonal deciduous forest, microhabitat use.Informações sobre o habitat e história de vida são essenciais para avaliar o status de conservação das espécies e definir ações para a preservação dos ambientes naturais. Ao longo de um ano, investigamos em populações de Hypsiboas curupi (i) o padrão de atividade noturna; (ii) relações com variáveis climáticas; (iii) o padrão de distribuição espacial de machos e fêmeas em termos de uso de microambientes; e (iv) variação no tamanho corporal. Conduzimos o estudo de agosto de 2010 a julho de 2011 no Parque Estadual Fritz Plaumann, um fragmento de Floresta Estacional Decidual na região oeste de Santa Catarina, sul do Brasil. O período de maior atividade foi de agosto a novembro. O maior número de machos vocalizando ocorreu às 23h e a frequência de ocorrência foi influenciada pela umidade do ar. Machos vocalizantes, não-vocalizantes e fêmeas foram discriminados pela distância da margem e tipo de substrato utilizado. Fêmeas foram significativamente maiores e mais pesadas do que machos. Os resultados indicam que H. curupi é altamente dependente da vegetação marginal. Assim, mudanças na estrutura da mata ciliar devido a ações humanas podem resultar na perda de sítios de canto e oviposição e reduzir a disponibilidade de alimento e abrigo.Palavras-chave: história de vida, mata ciliar, anfíbios de riachos, floresta estacional decidual, uso de microambiente