Inducing Homochirality Through Intermediary Catalytic Species: A Stochastic Approach.

A new chiral amplification mechanism based on a stochastic approach is proposed. The mechanism includes five different chemical species, an achiral substrate (A), two chiral forms (L, D), and two intermediary species (LA, DA). The process occurs within a small, semipermeable compartment that can be diffusively coupled with the outside environment. The study considers two alternative primary sources for chiral species within the compartment, one chemical and the other diffusive. As a remarkable fact, the chiral amplification process occurs due to stochastic fluctuations of an intermediary catalytic species (LA, DA) produced in situ, given the interaction of the chiral species with the achiral substrate. The net process includes two different steps: the synthesis of the catalyst (LA and DA) and the catalytic production of new chiral species from the substrate. Stochastic simulations show that proper parameterization can induce a robust chiral state within the compartment regardless of whether the system is open or closed. We also show how an increase in the non-catalytic production of chiral species tends to negatively impact the homochirality degree of the system. By its conception, the proposed mechanism suggests a deeper connection with how most biochemical processes occur in living beings, a fact that could open new avenues for studying this fascinating phenomenon.

From a coenzyme-like mechanism to homochirality.

Inspired in a coenzyme-like behavior, an alternative mechanism to induce homochirality within a small vesicle is proposed. The system includes six different chemical species: an achiral substrate A, the enantiomeric forms L and D, a coenzyme E and two intermediate catalytic forms LE and DE. Whereas the coenzyme and the intermediate catalytic forms are trapped within the vesicle, the substrate and the two enantiomeric forms are able to diffuse selectively across the vesicle boundary. Instead of using autocatalysis, the production of new enantiomers includes two different steps, the production of intermediate catalytic species (LE, DE) and the catalytic production of new enantiomers from the substrate. Using a suitable parameterization, we found that the chiral evolution of the system is highly dependent on the total amount of coenzyme within the vesicle, regardless of whether the surrounding membrane is permeable or not. However, the existence of large flows from the outside can destabilize the homochiral state inside the vesicle. In general, homochiral states tend to arise when the amount of coenzyme is quite low, a value that can vary according to the parametrization. On the other hand, the system tends to decrease the enantiomeric excess when the coenzyme levels are high enough. In general, the appearance of homochirality is conditioned by stochastic fluctuations in coenzyme levels within the vesicle, an effect that is gradually amplified throughout the entire process of enantiomer synthesis.

Distributed and multicore QuBiLS-MIDAS software v2.0: Computing chiral, fuzzy, weighted and truncated geometrical molecular descriptors based on tensor algebra.

Advances to the distributed, multi-core and fully cross-platform QuBiLS-MIDAS software v2.0 (http://tomocomd.com/qubils-midas) are reported in this article since the v1.0 release. The QuBiLS-MIDAS software is the only one that computes atom-pair and alignment-free geometrical MDs (3D-MDs) from several distance metrics other than the Euclidean distance, as well as alignment-free 3D-MDs that codify structural information regarding the relations among three and four atoms of a molecule. The most recent features added to the QuBiLS-MIDAS software v2.0 are related (a) to the calculation of atomic weightings from indices based on the vertex-degree invariant (e.g., Alikhanidi index); (b) to consider central chirality during the molecular encoding; (c) to use measures based on clustering methods and statistical functions to codify structural information among more than two atoms; (d) to the use of a novel method based on fuzzy membership functions to spherically truncate inter-atomic relations; and (e) to the use of weighted and fuzzy aggregation operators to compute global 3D-MDs according to the importance and/or interrelation of the atoms of a molecule during the molecular encoding. Moreover, a novel module to compute QuBiLS-MIDAS 3D-MDs from their headings was also developed. This module can be used either by the graphical user interface or by means of the software library. By using the library, both the predictive models built with the QuBiLS-MIDAS 3D-MDs and the QuBiLS-MIDAS 3D-MDs calculation can be embedded in other tools. A set of predefined QuBiLS-MIDAS 3D-MDs with high information content and low redundancy on a set comprised of 20,469 compounds is also provided to be employed in further cheminformatics tasks. This set of predefined 3D-MDs evidenced better performance than all the universe of Dragon (v5.5) and PaDEL 0D-to-3D MDs in variability studies, whereas a linear independence study proved that these QuBiLS-MIDAS 3D-MDs codify chemical information orthogonal to the Dragon 0D-to-3D MDs. This set of predefined 3D-MDs would be periodically updated as long as new results be achieved. In general, this report highlights our continued efforts to provide a better tool for a most suitable characterization of compounds, and in this way, to contribute to obtaining better outcomes in future applications.

Smoothed Spherical Truncation based on Fuzzy Membership Functions: Application to the Molecular Encoding.

A novel spherical truncation method, based on fuzzy membership functions, is introduced to truncate interatomic (or interaminoacid) relations according to smoothing values computed from fuzzy membership degrees. In this method, the molecules are circumscribed into a sphere, so that the geometric centers of the molecules are the centers of the spheres. The fuzzy membership degree of each atom (or aminoacid) is computed from its distance with respect to the geometric center of the molecule, by using a fuzzy membership function. So, the smoothing value to be applied in the truncation of a relation (or interaction) is computed by averaging the fuzzy membership degrees of the atoms (or aminoacids) involved in the relation. This truncation method is rather different from the existing ones, at considering the geometric center for the whole molecule and not only for atom-groups, as well as for using fuzzy membership functions to compute the smoothing values. A variability study on a set comprised of 20,469 compounds (15,050 drug-like compounds, 2994 drugs approved, 880 natural products from African sources, and 1545 plant-derived natural compounds exhibiting anti-cancerous activity) demonstrated that the truncation method proposed allows to determine molecular encodings with better ability for discriminating among structurally different molecules than the encodings obtained without applying truncation or applying non-fuzzy truncation functions. Moreover, a principal component analysis revealed that orthogonal chemical information of the molecules is encoded by using the method proposed. Lastly, a modeling study proved that the truncation method improves the modeling ability of existing geometric molecular descriptors, at allowing to develop more robust models than the ones built only using non-truncated descriptors. In this sense, a comparison and statistical assessment were performed on eight chemical datasets. As a result, the models based on the truncated molecular encodings yielded statistically better results than 12 procedures considered from the literature. It can thus be stated that the proposed truncation method is a relevant strategy for obtaining better molecular encodings, which will be ultimately useful in enhancing the modeling ability of existing encodings both on small-to-medium size molecules and biomacromolecules. © 2019 Wiley Periodicals, Inc.

Enhancing Acute Oral Toxicity Predictions by using Consensus Modeling and Algebraic Form-Based 0D-to-2D Molecular Encodes.

Quantitative structure-activity relationships (QSAR) are introduced to predict acute oral toxicity (AOT), by using the QuBiLS-MAS (acronym for quadratic, bilinear and N-Linear maps based on graph-theoretic electronic-density matrices and atomic weightings) framework for the molecular encoding. Three training sets were employed to build the models: EPA training set (5931 compounds), EPA-full training set (7413 compounds), and Zhu training set (10 152 compounds). Additionally, the EPA test set (1482 compounds) was used for the validation of the QSAR models built on the EPA training set, while the ProTox (425 compounds) and T3DB (284 compounds) external sets were employed for the assessment of all the models. The k-nearest neighbor, multilayer perceptron, random forest, and support vector machine procedures were employed to build several base (individual) models. The base models with REPA-training ≥ 0.75 ( R = correlation coefficient) and MAEEPA-training ≤ 0.5 (MAE = mean absolute error) were retained to build consensus models. As a result, two consensus models based on the minimum operator and denoted as M19 and M22, as well as a consensus model based on the weighted average operator and denoted as M24, were selected as the best ones for each training set considered. According to the applicability domain (AD) analysis performed, model M19 (built on the EPA training set) has MAEtest-AD = 0.4044, MAEProTox-AD = 0.4067 and MAET3DB-AD = 0.2586 on the EPA test set, ProTox external set, and T3DB external set, respectively; whereas model M22 (built on the EPA-full set) and model M24 (built on the Zhu set) present MAEProTox-AD = 0.3992 and MAET3DB-AD = 0.2286, and MAEProTox-AD = 0.3773 and MAET3DB-AD = 0.2471 on the two external sets accounted for, respectively. These outcomes were compared and statistically validated with respect to 14 QSAR methods (e.g., admetSAR, ProTox-II) from the literature. As a result, model M22 presents the best overall performance. In addition, a retrospective study on 261 withdrawn drugs due to their toxic/side effects was performed, to assess the usefulness of prospectively using the QSAR models proposed in the labeling of chemicals. A comparison with regard to the methods from the literature was also made. As a result, model M22 has the best ability of labeling a compound as toxic according to the globally harmonized system of classification and labeling of chemicals. Therefore, it can be concluded that the models proposed, especially model M22, constitute prominent tools for studying AOT, at providing the best results among all the methods examined. A freely available software was also developed to be used in virtual screening tasks ( http://tomocomd.com/apps/ptoxra ).

The optimal size of protocells from simple entropic considerations.

Potential constraints on protocell size are developed from simple entropic considerations. To do that, two new different indexes as measures of their structural and dynamic order were developed and applied to an elemental model of the heterotrophic protocell. According to our results, cell size should be a key factor determining the potential of these primitive systems to evolve and consequently to support life. Our analyses also suggest that the size of the optimal vesicles could be constrained to have radii in the interval [Formula: see text], where the two extreme limits [Formula: see text] and [Formula: see text] represent the states of maximum structural order (largest accumulation of substrate inside the vesicle) and the maximum flux of entropy production, respectively. According to the above criteria, the size of the optimum vesicles falls, approximately, in the same spatial range estimated for biological living cells assuming plausible values for the second-order rate constant involved in the catabolic process. Furthermore, the existence of very small vesicles could be seriously affected by the limited efficiency, far from the theoretical limits, with which these catabolic processes may proceed in a prebiotic system.

Choquet integral-based fuzzy molecular characterizations: when global definitions are computed from the dependency among atom/bond contributions (LOVIs/LOEIs).

BACKGROUND: Several topological (2D) and geometric (3D) molecular descriptors (MDs) are calculated from local vertex/edge invariants (LOVIs/LOEIs) by performing an aggregation process. To this end, norm-, mean- and statistic-based (non-fuzzy) operators are used, under the assumption that LOVIs/LOEIs are independent (orthogonal) values of one another. These operators are based on additive and/or linear measures and, consequently, they cannot be used to encode information from interrelated criteria. Thus, as LOVIs/LOEIs are not orthogonal values, then non-additive (fuzzy) measures can be used to encode the interrelation among them. RESULTS: General approaches to compute fuzzy 2D/3D-MDs from the contribution of each atom (LOVIs) or covalent bond (LOEIs) within a molecule are proposed, by using the Choquet integral as fuzzy aggregation operator. The Choquet integral-based operator is rather different from the other operators often used for the 2D/3D-MDs calculation. It performs a reordering step to fuse the LOVIs/LOEIs according to their magnitudes and, in addition, it considers the interrelation among them through a fuzzy measure. With this operator, fuzzy definitions can be derived from traditional or recent MDs; for instance, fuzzy Randic-like connectivity indices, fuzzy Balaban-like indices, fuzzy Kier-Hall connectivity indices, among others. To demonstrate the feasibility of using this operator, the QuBiLS-MIDAS 3D-MDs were used as study case and, as a result, a module was built into the corresponding software to compute them ( http://tomocomd.com/qubils-midas ). Thus, it is the only software reported in the literature that can be employed to determine Choquet integral-based fuzzy MDs. Moreover, regression models were created on eight chemical datasets. In this way, a comparison between the results achieved by the models based on the non-fuzzy QuBiLS-MIDAS 3D-MDs with regard to the ones achieved by the models based on the fuzzy QuBiLS-MIDAS 3D-MDs was made. As a result, the models built with the fuzzy QuBiLS-MIDAS 3D-MDs achieved the best performance, which was statistically corroborated through the Wilcoxon signed-rank test. CONCLUSIONS: All in all, it can be concluded that the Choquet integral constitutes a prominent alternative to compute fuzzy 2D/3D-MDs from LOVIs/LOEIs. In this way, better characterizations of the compounds can be obtained, which will be ultimately useful in enhancing the modelling ability of existing traditional 2D/3D-MDs.

GOWAWA Aggregation Operator-based Global Molecular Characterizations: Weighting Atom/bond Contributions (LOVIs/LOEIs) According to their Influence in the Molecular Encoding.

A different perspective to compute global weighted definitions of molecular descriptors from the contributions of each atom (LOVIs) or covalent bond (LOEIs) within a molecule is presented, using the generalized ordered weighted averaging - weighted averaging (GOWAWA) aggregation operator. This operator is rather different from the other norm-, mean- and statistic-based operators used up to date for the descriptors calculation from LOVIs/LOEIs. GOWAWA unifies the generalized ordered weighted averaging (GOWA) and the weighted generalized mean (WGM) functions and, in addition, it uses a smoothing parameter to assign different importance values to both functions depending on the problem under study. With the GOWAWA operator, diversity of novel global aggregations of molecular descriptors can be determined, where the influence that each atom (or covalent bond) has on the molecular characterization is taken into account. Therefore, this approach is completely different from the ones reported in the literature, where the values of LOVIs/LOEIs are considered equally important. To demonstrate the feasibility of using this operator, the QuBiLS-MIDAS descriptors (http://tomocomd.com/qubils-midas) were used and, as a result, a module was built into the corresponding software to compute them, being thus the only software reported in the literature that can be employed to determine weighted descriptors. Moreover, several modeling studies were performed on eight chemical datasets, which demonstrated that, with the GOWAWA aggregation operator, weighted QuBiLS-MIDAS descriptors that contribute to develop models with greater predictive power can be computed, if compared to the models based on the non-weighted descriptors calculated from the other operators used up to date. A non-parametric statistical assessment confirmed that the GOWAWA-based predictions are significantly superior to the others obtained. Therefore, all in all, it can be concluded that, from the results achieved, the GOWAWA operator constitutes a prominent alternative to codify relevant chemical information of the molecules, ultimately useful in improving the modeling ability of several old and recent descriptors whose definition is based on the LOVIs/LOEIs calculation.

Sistema de tareas para la enseñanza combinada de la gramática comunicativa y la gramática tradicional de lengua inglesa / A system of tasks for the combined teaching of communicative and traditional grammar in English

Se realizó el diseño de un sistema de tareas para la enseñanza combinada de la gramática comunicativa y la gramática tradicional de lengua inglesa, con metodología cuali-cuantitativa, en la Facultad de Ciencias Médicas Zoilo Marinello Vidaurreta de la Universidad de Ciencias Médicas de Las Tunas, durante el período comprendido entre septiembre de 2011 y julio de 2014. El objetivo estuvo direccionado a perfeccionar la corrección lingüística en el proceso de enseñanza-aprendizaje del idioma Inglés. La realización del diseño contó con: una revisión bibliográfica de los principales enfoques utilizados en la enseñanza-aprendizaje del Inglés; la revisión documental, que permitió determinar las insuficiencias lingüísticas y la necesidad de combinar la gramática comunicativa con la gramática tradicional, en los estudiantes del cuarto año de la carrera de Estomatología; el intercambio con profesionales con más de quince años de experiencia, para obtener información acerca del proceso de enseñanza-aprendizaje de la gramática;y la aplicación de una valoración equivalente al juicio de expertos, método de agregados individuales, para valorar la propuesta. Los principales resultados fueron: la caracterización de las insuficiencias provocadas por la absolutización del enfoque comunicativo en la enseñanza de la gramática de la lengua inglesa y el diseño de un sistema de tareas para el proceso de enseñanza-aprendizaje de la gramática inglesa en estos estudiantes (AU)

The design of a system of tasks was carried out for the combined teaching of communicative and traditional grammar in English by using a qualitative and quantitative methodology at Zoilo Marinello Vidaurreta Faculty from the Medical University of Las Tunas, since September, 2011 to July, 2014. The objective was aimed at improving linguistic correction in the learning-teaching process of English. The execution of the design included; a bibliographicreview of the main approaches used in the teaching-learning of English; the documentary review which allowed determining the linguistic insufficiencies and the need of combining both, communicative and traditional grammar in 4thyear students from the degree course of Stomatology; the interchange with fifteen-year-experience professionals to gather information on the learning-teaching process of grammar, and the application of an assessment equivalent to experts judgment, method of individual senior teachers to value the proposal. The main results were: the characterization of the insufficiencies provoked by the absolute use of the communicative approach of English grammar teaching, and the design of a system of tasks for the learning-teaching process of English grammar for those students(AU)

Intervención didáctica para la enseñanza de la farmacología en las clases de inglés con fines específicos / A Didactic Intervention for the Teaching of Pharmacology in the Lessons of English for Specific Purposes

Se realizó un estudio cualitativo de intervención, con el objetivo de determinar el vocabulario relacionado con la farmacología, necesario para desarrollar las clases de inglés médico en la carrera de Medicina de la Universidad de Ciencias Médicas de Las Tunas. El grupo de estudio estuvo constituido por los estudiantes y profesores del 5to año de la carrera de Medicina del curso 2011-2012. Las variables fueron la preparación del colectivo de profesores, las afecciones clínicas incluidas en el programa, los grupos farmacológicos implicados y el nombre en inglés de medicamentos específicos. La información se obtuvo de los libros de textos y los trabajos independientes realizados por los estudiantes. Se constató que la preparación profesional de los docentes en el área de la farmacología depende de la disponibilidad de diccionarios actualizados y de los conocimientos que estos han ido adquiriendo de forma empírica. Se observó una tendencia en los estudiantes a relacionar nombres de medicamentos, cuyas pronunciaciones se desconocen, lo cual entorpece la adquisición correcta del contenido lingüístico en inglés. Se evidenció que cuando se trabajan los grupos farmacológicos con un limitado número de medicamentos específicos y reconocidos, se logra un mejor desempeño lingüístico en los estudiantes (AU)

An intervention qualitative study was carried out in order to determine the vocabulary related to pharmacology, needed to develop the lessons of medical English in the specialty of Medicine at the University of Medical Sciences of Las Tunas. The study group was made by the 5th-year-Mecicine students and teachers of the academic year 2011-2012. The variables were the professional preparation of the teachers, the clinical conditions included in the syllabus, the pharmacological groups intended to be worked with and the English names of specific medications. The information was gathered from the textbooks and the project works developed by the students. It was demonstrated that the professional preparation of the teachers about pharmacology depended on the availability of updated dictionaries and on the knowledge they have acquired empirically. There was a tendency in the students to relate drug names with a pronunciation unknown by them. This fact interfered negatively in the proper language acquisition. It became evident that when working with the pharmacological groups with a limited set of well-known specific drugs, the linguistic performance of the students is higher (AU)

Estrategia didáctica para preparar a los profesores de Inglés para impartir la medicina natural y tradicional / A Didactic Strategy to Train the Teachers of English to Teach Natural and Traditional Medicine

Se diseñó un modelo teórico contextualizado para la elaboración de una estrategia didáctica, dirigida a la preparación integral de los profesores de inglés en la enseñanza de la medicina natural y tradicional en la carrera de Medicina. Para ello se realizó un diagnóstico inicial, que permitió sintetizar las limitaciones e insuficiencias que poseen los profesores de inglés para la impartición de contenidos de medicina natural y tradicional, como estrategia curricular del Viceministerio de Docencia e Investigaciones del MINSAP. En la estrategia se incluyeron acciones para ser trabajadas dentro de la superación profesoral, el componente metodológico y el componente investigativo de los docentes de forma tal, que se revierta en un enriquecimiento de la competencia académica que deben poseer para su desempeño profesional, y de este modo enfrentar con éxito la tarea. La estrategia está destinada a todos los profesores de inglés del departamento, ya que estos rotan por los años de inglés general e inglés con fines específicos, respectivamente, y en dependencia de las necesidades de la institución (AU)

A contextualized theoretical model was designed in order to elaborate a didactic strategy intended for the comprehensive preparation of the teachers of English for the teaching of natural and traditional medicine in the specialty of Medicine. To fulfill this purpose an initial diagnosis was carried out which permitted to synthesize the limitations and insufficiencies of the teachers to teach the contents of natural and traditional medicine as a curricular strategy of the Ministry of Public Health. The strategy included actions to be performed within the professional upgrading, as well as the methodological and research component of the teachers. As a consequence, the strategy would lead to an enhancement of the academic competence needed for their professional performance in order to deal with the task successfully. The strategy is destined to all the teachers of the Department of English since they alternate through all the years included in the cycles of General English and English for Specific Purposes, depending on the needs of the college (AU)

Los Cinco Héroes como ejemplo de altruismo para estudiantes y trabajadores de la Universidad de Médica actual / The Cuban Fives as an example of altruism for the students and staff of the current Medical University

La batalla por la libertad de los Héroes cubanos, prisioneros en Estados Unidos por luchar contra el terrorismo, en la Universidad de Ciencias Médicas de Las Tunas se concreta a partir de la creación de la cátedra de Honor y Firmeza, integrada por estudiantes y trabajadores, que inspirados en su ejemplo realizan diferentes acciones, que contribuyen al reforzamiento del valor altruismo (AU)

The battle for the freedom of the Five Cuban Heroes imprisoned in the United States for fighting terrorism materializes at the University of Medical sciences of Las Tunas from the creation of the chair of Honor and Strength formed by the students and staff. Inspired by the heroes´ example, the members of the chair carry out different actions that contribute to the strengthening of values like altruism(AU)