Protein constraints in genome-scale metabolic models: Data integration, parameter estimation, and prediction of metabolic phenotypes.

Genome-scale metabolic models provide a valuable resource to study metabolism and cell physiology. These models are employed with approaches from the constraint-based modeling framework to predict metabolic and physiological phenotypes. The prediction performance of genome-scale metabolic models can be improved by including protein constraints. The resulting protein-constrained models consider data on turnover numbers (kcat ) and facilitate the integration of protein abundances. In this systematic review, we present and discuss the current state-of-the-art regarding the estimation of kinetic parameters used in protein-constrained models. We also highlight how data-driven and constraint-based approaches can aid the estimation of turnover numbers and their usage in improving predictions of cellular phenotypes. Finally, we identify standing challenges in protein-constrained metabolic models and provide a perspective regarding future approaches to improve the predictive performance.

Theoretical models of staurosporine and analogs uncover detailed structural information in biological solution.

Staurosporine and its analogs (STA-analogs) are indolocarbazoles (ICZs) compounds able to inhibit kinase proteins in a non-specific way, while present antimicrobial and cytostatic properties. The knowledge of molecular features associated to the complexation, including the ligand shape in solution and thermodynamics of complexation, is substantial to the development of new bioactive ICZs with improved therapeutic properties. In this context, the empirical approach of GROMOS force field is able to accurately reproduce condensed phase physicochemical properties of molecular systems after parameterization. Hence, through parameterization under GROMOS force field and molecular simulations, we assessed STA-analogs dynamics in aqueous solution, as well as its interaction with water to probe conformational and structural features involved in complexation to therapeutic targets. The coexistence of multiple conformers observed in simulations, and confirmed by metadynamics calculations, expanding the conformational space knowledge of these ligands with potential implications in understanding the ligand conformational selection during complexation. Also, changes in availability to H-bonding concerning the different substituents and water can reflect on effects at complexation free energy due to variation at the desolvation energetic costs. Based on these results, we expect the obtained structural data provide systemic framework for rational chemical modification of STA-analogs.

Solvatochromism and solution π-stacking of N-(4-pyridyl)-1,8-naphthalimide and its corresponding triruthenium coordination complex.

Due to the scarcity of spectroscopic studies on metal-coordinated naphthalimides, and aiming to investigate fundamental spectroscopic aspects, we have described here the aggregates of N-(4-pyridyl)-1,8-naphthalimide (NI-py) in solution as well as solvatochromism displayed by it and by the coordination compounds [Ru3O(CH3COO)6(NI-py)3]n, n = +1 or 0. Based both on theoretical calculations and luminescence spectra, we demonstrated that in aqueous media, the NI-py π-stacking is thermodynamically favored, suggesting a preferable conformation where the pyridine and naphthalene moieties of two NI-py molecules are parallel to each other, but are not co-planar within an individual molecule, due to steric hindrance. The NI-py ππ* band displayed positive solvatochromism, to which the major contribution was the Catalan's SP parameter (solvent polarizability). This observation is fully consistent with the extended π-electron cloud of the NI-py naphthalene ring. However, a secondary contribution of the SA (solvent acidity) was also observed, owing to the electron pairs available at the N-heteroatom of the pyridine rings and at the carbonyl-group oxygen atoms. Finally, the multiparametric solvent effect analysis indicated that the electronic coupling between coordinated NI-py and the metallic core is modulated by the charge of the [Ru3O(CH3COO)6] core, being higher for the reduced species [Ru3O(CH3COO)6(NI-py)]0. In addition, in this reduced species, there is no overlap between NI-py ππ* and the [Ru3O(CH3COO)6] charge transfer (CT) transitions, leading to the observation of the dependence of the CT energy with the SdP parameter (solvent dipolarity) since the CT transition implies in a charge-separation state.

Improving 1-propanol force field: a new methodology.

A new force field for 1-propanol, in the united and all atom models, has been obtained by combining two different empirical methodologies. The first was developed by scaling atom charges and Lennard-Jones parameters to fit the dielectric constant, surface tension, and density; this methodology is named three steps systematic parameterization procedure (3SSPP), as reported by Pérez de la Luz et al. (J Chem Theory Comput 14:5949-5958, 2018). The second methodology consists of moving these parameters and together with the bond distance to obtain the liquid-vapor phase diagram of the CO2 molecule as discussed by Harris and Yung (J Phys Chem 99:12021-12024, 1995). The last methodology is used to obtain the self-diffusion coefficient, which was not consider in the 3SSPP. The 3SSPP/bond methodology is the 3SSPP plus the bond distance scaling. With this new methodology, the experimental density, dielectric constant, surface tension, and self-diffusion coefficient at ambient temperature could be achieved. Furthermore, we show the temperature dependence of the aforementioned properties. The static structure factors are in accordance with the experimental spectrum. Solubility is increased to the experimental value for the united atom (UA) model after applying this methodology and for all atom (AA) scheme, the experimental solubility value is maintained. Graphical abstract The reduction in bond distance of the 1-propanol molecule does not modify the structure factor.

Employing Spectral Analysis to Obtain Dispersion Parameters in an Atmospheric Environment Driven by a Mesoscale Downslope Windstorm.

Considering the influence of the downslope windstorm called "Vento Norte" (VNOR; Portuguese for "North Wind") in planetary boundary layer turbulent features, a new set of turbulent parameterizations, which are to be used in atmospheric dispersion models, has been derived. Taylor's statistical diffusion theory, velocity spectra obtained at four levels (3, 6, 14, and 30 m) in a micrometeorological tower, and the energy-containing eddy scales are used to calculate neutral planetary boundary layer turbulent parameters. Vertical profile formulations of the wind velocity variances and Lagrangian decorrelation time scales are proposed, and to validate this new parameterization, it is applied in a Lagrangian Stochastic Particle Dispersion Model to simulate the Prairie Grass concentration experiments. The simulated concentration results were shown to agree with those observed.

Competencias Informacionales en los profesores en la Universidad de Ciencias Médicas de La Habana / Information skills among teachers of the University of Medical Sciences of Havana

RESUMEN Introducción: Competencias Informacionales permiten a los profesores, dominar el contenido y ampliar investigaciones, para asumir su aprendizaje. Objetivo: Diagnosticar los problemas que dificultan el desarrollo de las Competencias Informacionales en los profesores. Material y métodos: Se realizó una investigación pedagógica con enfoque cualitativo, se trabajó con una muestra no probabilística, de 60 profesores. Resultados: Se realizó el procedimiento para el diagnóstico con la parametrización del objeto de estudio, estableciéndose como variable el desempeño docente de los profesores. En el campo de estudio se establecen tres dimensiones: función docente en la Educación Médica, la superación profesional y el comportamiento profesional y humano, con sus indicadores y los instrumentos aplicados que dan salida a cada indicador. Conclusiones: Se expone la metodología utilizada. La relación entre las competencias informacionales y desempeño docente permitió realizar la parametrización de la variable. Se identificaron dimensiones e indicadores, los instrumentos caracterizaron el estado del desarrollo de las competencias informacionales. Las indagaciones teóricas identificaron insuficiencias y potencialidades de la variable. El inventario de problemas y las potencialidades, permiten modelar una alternativa de superación, que el desarrollo de competencias informacionales en los profesores.

ABSTRACT Introduction: Information skills allow teachers to master the contents and to expand research to undertake learning. Objective: To diagnose the problems that affect the development of information skills among teachers of the University of Medical Sciences of Havana. Material and methods: A pedagogical qualitative research was conducted; the probabilistic sample was composed of 60 teachers. Results: The diagnostic procedure was carried out with parameterization of the object of study, establishing teacher performance as variable. Three dimensions were established in the field of study: teaching performance in Medical Education, professional improvement and professional and human behavior; they included their indicators and the instruments applied that meet every indicator. Conclusions: The methodology used is presented. The relationship between information skills and teaching performance allowed us to carry out the parameterization of the variable. Dimensions and indicators were identified; the instruments characterized the level of development of information skills. Theoretical investigations identified the weaknesses and strengths of the variable. The list of problems and potentialities allowed us to develop an improvement alternative for the development of information skills among teachers.

AMBER parameters and topology data of 2-pentylpyrrole adduct of arginine with 4-hydroxy-2-nonenal.

The data described here supports a part of the research article "Effect of 4­HNE Modification on ZU5-ANK Domain and the Formation of Their Complex with ß­Spectrin: A Molecular Dynamics Simulation Study" [1]. Dataset on Gaff force field parameters of AMBER is provided for the non-standard arginine resulting of reaction with 4-hydroxy-2-nonenal (4-HNE), the major secondary product of lipids peroxidation. Arg-HNE 2-pentilpyrrole adduct is part of the 4-hydroxyalkenals described in various physiopathological disorders related to increased oxidative stress. Data include a framework for derivation of missing bonds, angles and dihedral parameters for modified arginine, alongside optimized partial charges derived with Restrained Electrostatic Potential (RESP) method and the new force field parameters obtained by quantum mechanicals methods (QM) using Hartree-Fock (HF)/6 - 31G** level of theory. Benchmark as a graphics tutorial summary steps to obtained new parameters and the validation of non-standard amino acids is presented. The new residue constructed is put available to the scientific community to perform molecular dynamics simulations of modified 4-HNE proteins on arginine residue and complete the set of data parameters for nucleophilic residues with this reactive aldehyde ADDIN EN.CITE ADDIN EN.CITE.DATA [2]. Data that could be used for the researchers interested in the role of protein oxidation as mediator in cellular pathophysiological.

Density functional theory study of π-aromatic interaction of benzene, phenol, catechol, dopamine isolated dimers and adsorbed on graphene surface.

We analyze the influence of different groups on the intermolecular energy of aromatic homodimers and on the interaction between a single aromatic molecule and a graphene surface. The analysis is performed for benzene, phenol, catechol, and dopamine. For calculating the energies, we employ density functional theory within the local density approximation (LDA-DFT). Our results show that the lowest intermolecular energies between the aromatic molecules are related to the T-shaped configurations. This lower energy results from the quadrupole interaction. In the case of the interaction between the graphene sheet and the aromatic molecules, the lowest energy configuration is the face to face. The adsorption energy of a molecule on a graphene surface involves π - π interactions that explain the face to face arrangement. These results provide insight into the manner by which substituents can be utilized in crystal engineering, supramolecular chemistry, bioinspired materials, formation of various molecular clusters, parameterization of force fields suitable for classical simulations, and design of novel sensing, drug delivery, and filters based on graphene.

Two approaches to calculate TVDI in humid subtropical climate of southern Brazil

Soybean crops occupy most areas in Rio Grande do Sul State and are highly dependent on rainfall since most of them are non-irrigated. Rainfall during the harvest period is often insufficient to meet the water demand, making water indicators an important tool for the crops. This study compared two approaches in the parameterization process of TVDI (Temperature-Vegetation Dryness Index) in a subtropical climate region of Brazil. The process used Moderate Resolution Imaging Spectroradiometer (MODIS) images of the surface temperature (TS) and Normalized Difference Vegetation Index (NDVI), with spatial resolutions of 1,000 m and periods of 8-16 d, respectively. The evaporative triangles for the TS/NDVI scatter plots were built either for each image (scene-specific parameterization) or for all images at once (crop-type parameterization). The rainfall data were obtained from meteorological stations located in the study site and the analysis period comprised two contrasting harvests regarding soybean yield (most important crop in the region). The scene-specific parameterization allowed to analyze water status in the study site by inspecting the wet and dry edge of each image and identifying the areas of stress in each one. TVDI crop parameterization showed that the model was able to determine the time and frequency of water stress events during the crop-seasons. TVDI crop-parameterization, therefore, is more consistent for crop monitoring and forecasting purposes.(AU)

Two approaches to calculate TVDI in humid subtropical climate of southern Brazil

Soybean crops occupy most areas in Rio Grande do Sul State and are highly dependent on rainfall since most of them are non-irrigated. Rainfall during the harvest period is often insufficient to meet the water demand, making water indicators an important tool for the crops. This study compared two approaches in the parameterization process of TVDI (Temperature-Vegetation Dryness Index) in a subtropical climate region of Brazil. The process used Moderate Resolution Imaging Spectroradiometer (MODIS) images of the surface temperature (TS) and Normalized Difference Vegetation Index (NDVI), with spatial resolutions of 1,000 m and periods of 8-16 d, respectively. The evaporative triangles for the TS/NDVI scatter plots were built either for each image (scene-specific parameterization) or for all images at once (crop-type parameterization). The rainfall data were obtained from meteorological stations located in the study site and the analysis period comprised two contrasting harvests regarding soybean yield (most important crop in the region). The scene-specific parameterization allowed to analyze water status in the study site by inspecting the wet and dry edge of each image and identifying the areas of stress in each one. TVDI crop parameterization showed that the model was able to determine the time and frequency of water stress events during the crop-seasons. TVDI crop-parameterization, therefore, is more consistent for crop monitoring and forecasting purposes.

Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations.

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC50 = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.

Development and benchmark to obtain AMBER parameters dataset for non-standard amino acids modified with 4-hydroxy-2-nonenal.

The data described here support the research article "4-HNE carbonylation induces local conformational changes on bovine serum albumin and thioredoxin. A molecular dynamics study" (Alviz-Amador et al., 2018) . Dataset on Gaff force field parameters of AMBER is provided for assembled three non-standard amino acids resulting of the 4-HNE Michael addition, the main end product of lipids peroxidation. Data include a framework for derivation of missing bonds, angles and dihedral parameters for Cys, His, and Lys modified amino acids, alongside optimized partial charges derived with Restrained Electrostatic Potential (RESP) method and the new force field parameters obtained by quantic mechanical (QM) using HF/6-31G** level of theory. Benchmark as a graphics tutorial summary steps to obtained new parameters and the validation of non-standard amino acids is presented. The new residues constructed are put available to the scientific community to perform molecular dynamics simulations of modified 4-HNE proteins.

Aumento gradual da variabilidade de prática: efeito na aprendizagem da estrutura e na parametrização da habilidade / Gradual increment on practice variability: effects on structure learning and skill parametrization

Resumo Tradicionalmente, na aprendizagem de habilidades motoras a prática tem sido estruturada de forma constante, em blocos, seriada ou aleatória. Tem sido proposta a superioridade da prática variada sobre a prática constante bem como da prática aleatória e seriada sobre a prática em blocos. Atualmente tem sido observada uma especificidade do tipo de prática: a prática constante auxilia na formação de uma estrutura de movimento, especialmente no inicio da aprendizagem e a prática variada na melhora da parametrização. O presente estudo investigou diferentes regimes de prática e a sua combinaçao numa sequência que fornece um aumento gradual de variabilidade (constante, blocos e aleatório) na aquisição de habilidades motoras. A amostra foi distribuida em quatro grupos (n = 10): CCC (constante), BBB (blocos), AAA (aleatório) e CBA (constante-blocos-aleatório). O experimenta foi dividido em fase de aquisição e teste de transferência. Na fase de aquisição a tarefa foi pressionar teclas numéricas do teclado de um computador em uma sequência (2, 8, 6, 4) com o dedo indicador, com tempo relativo entre os componentes especificado (22,2%, 44,4% e 33,3%) e com os seguintes tempos totais (700, 900 e 1100 ms) estabelecidos conforme o delineamento experimental. Os resultados do teste demonstraram superioridade dos grupos CBA e AAA na medida de erro absoluta, dos grupos CCC e BBB na medida de erro relativo e dos grupos CCC, BBB e CBA na medida de variabilidade de erro relativo. Tais resultados demonstram que os regimes de prática que forneceram menor variabilidade conduziram ao aprendizado de uma estrutura de movimento, enquanto que as que forneceram maior variabilidade resultaram na melhora da capacidade de parametrização.(AU)

Abstract Traditionally, on the learning of motor skill practice has been scheduled in constant, blocked, serial or random fashion. A superiority of variable over constant practice has been suggested as well as random and serial practices over blocked practice. Recently a specificity of the type of practice has been observed: constant practice helps the formation of a movement structure, especially in the early learning, and the variable practice improves parameterization. This study investigated different practice schedules and their combinations in a sequence that provides a gradual increment of variability (constant, blocked, and random) in the acquisition of motor skills. Participants were divided into four groups (n = 10): CCC [constant), BBB (blocked), RRR (random) and CBR (constant-blocked-random). The experiment consisted of an acquisition phase and a transfer test. In the acquisition phase the task comprised pressing a numeric keyboard in a given sequence (2, 8, 6, 4) with the index finger, with fixed relative timing among presses (22.2%, 44.4% and 33.3%) and specific total times (700, 900 and 1100 ms) determined by the experimental design. The test results showed a superiority of CBR and RRR groups in the absolute error measure, of CCC and BBB groups in the relative error measure, and CCC, BBB and CBR groups in the variability of relative error measure. These results evidence the practice schedules that provided smaller variability led to the learning of a movement structure, whereas the ones that provided greater variability culminated in the improvement in parameterization.(AU)

Propiedades matemáticas del modelo de Gompertz y su aplicación al crecimiento de los cerdos / Mathematical properties of the Gompertz model and its application to the growing pig / Propriedades matemáticas do modelo de Gompertz e sua aplicação ao crescimento de suínos

En esta investigación se utiliza el modelo de crecimiento de Gompertz para describir el crecimiento corporal, de la canal y de los componentes químicos (proteína, lípido, ceniza y agua) de cerdos en condiciones comerciales de producción. La descripción del crecimiento y los cambios en la deposición de macromoléculas se realizó en 10 edades (1, 21, 63, 99, 126, 154, 175, 210, 239 y 273 días de edad), sacrificando 39 cerdos. Se colectaron muestras de canal, vísceras rojas y vísceras blancas y se analizaron los componentes químicos. Se verificó que los parámetros del modelo tienen un significado y sensibilidad biológica, que pueden ser interpretados por la madurez al 50% y el peso adulto, los cuales sirven para estimar la influencia de factores ambientales que modifican los parámetros de crecimiento. Los hallazgos de este estudio sitúan las tasas de retención de proteína en 129 g/día, es decir un 17.3% inferior a los hallazgos con genotipos altamente seleccionados y soportan la teoría que establece que las tasas de retención de proteína están estrechamente relacionadas con los patrones de ganancia diaria de peso corporal. El grupo experimental presentó comportamientos en la deposición de los componentes químicos corporales similares a las de animales no mejorados.

In this study, the Gompertz model is used to describe the changes in chemical components (protein, lipids, ash and water) in growing pigs, as body weigh increases. Growth and changes in deposition of several molecules was evaluated at 10 different ages (1, 21, 63, 99,126,154,175, 210, 239 and 273 days of age) in 39 pigs. Carcass samples, red and white viscera were collected and submitted for chemical analysis. Our study demonstrated that the model parameters have significance and biological sensitivity, which can be interpreted through maturity at 50% and at adult weight. These traits can be used to estimate the effect of environmental factors on growth and adult weight. The 129 g/day protein retention rate found in the present study was 17.3% lower than the rate observed for highly selected genotypes, and it supports the theory that protein retention rates are highly related to daily body weight gain patterns. The studied genotype presented a similar pattern for the dynamics of chemical components as non-selected animals.

Nesta pesquisa é utilizado o modelo de crescimento de Gompertz para descrever as relações entre o peso corporal, o peso da canal e os componentes químicos (proteína, lipídeos, cinzas e água) do suíno. A descrição do crescimento e das mudanças na acumulação de macromoléculas foi realizada em 10 diferentes períodos (1, 21, 63, 99, 126, 154, 175, 210, 239 y 273 dias de idade), por meio do sacrifício de 39 suínos. Foram coletadas amostras de canal, vísceras vermelhas e brancas para analise dos componentes químicos. Foi demonstrado que os parâmetros do modelo têm um significado e uma sensibilidade biológica que pode ser interpretada pela maturidade ao 50% e o peso adulto que são úteis para estimar a influencia dos fatores ambientais que modificam o crescimento e o peso adulto. Os resultados desta pesquisa mostraram taxas de retenção de proteína de 129 g/dia, quer dizer 17.3% inferior aos encontrados com genótipos altamente escolhidos e sustenta a teoria que estabelece que as taxas de retenção de proteína estejam intimamente relacionadas com os padrões de ganho diário de peso corporal. O genótipo avaliado apresentou comportamentos na dinâmica dos componentes químicos corporais similares aos dos animais não melhorados.