Moral education in Kant

En este escrito se indaga sobre la propuesta educativa kantiana como factor que contribuye al desenvolvimiento moral, y la consistencia de esta propuesta, con sus tesis acerca del desarrollo de la moralidad, entendido como el destino último del género humano. Se examina en este sentido, el enfoque pedagógico propuesto por el filósofo de Königsberg, la influencia de la cultura, y algunas condiciones de posibilidad internas y externas, que pueden contribuir a la aproximación de dicho destino.In this paper is studied the educational proposal of Kant as a contributing factor to moral development. It is analyze the consistency of this proposal, with his thesis on the development of morality, understood as the ultimate destiny of mankind. It is examined in this sense, pedagogical approach proponed by the philosopher of königsberg, the influence of culture, and some conditions of internal and external possibility, which may to contribute to the approximation of this destination

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs

Systematic analysis of primary sequence domain segments for the discrimination between class C GPCR subtypes

G-protein-coupled receptors (GPCRs) are a large and diverse super-family of eukaryotic cell membrane proteins that play an important physiological role as transmitters of extracellular signal. In this paper, we investigate Class C, a member of this super-family that has attracted much attention in pharmacology. The limited knowledge about the complete 3D crystal structure of Class C receptors makes necessary the use of their primary amino acid sequences for analytical purposes. Here, we provide a systematic analysis of distinct receptor sequence segments with regard to their ability to differentiate between seven class C GPCR subtypes according to their topological location in the extracellular, transmembrane, or intracellular domains. We build on the results from the previous research that provided preliminary evidence of the potential use of separated domains of complete class C GPCR sequences as the basis for subtype classification. The use of the extracellular N-terminus domain alone was shown to result in a minor decrease in subtype discrimination in comparison with the complete sequence, despite discarding much of the sequence information. In this paper, we describe the use of Support Vector Machine-based classification models to evaluate the subtype-discriminating capacity of the specific topological sequence segments.Peer ReviewedPostprint (author's final draft

Competencia matemática pensar y razonar: el caso de la razón y la proporción

Este es un avance de una investigación en curso, que se adelanta en el marco de la Maestría en Educación con Énfasis en Didáctica de la Matemática, en la línea de investigación: competencias Matemáticas. Esta línea está adscrita al proyecto macro: Formación y Desarrollo de Competencias Matemáticas, perteneciente al grupo de investigación Desarrollo institucional integrado de la Universidad de la Amazonia de Florencia, Caquetá, Colombia. Este reporte presenta un diseño previo de un modelo de competencia con el cual se pretende caracterizar la competencia matemática pensar y razonar, en el estudio de la razón y proporción a partir de tareas propuestas en una secuencia didáctica a los estudiantes del grado séptimo (7°) de la Institución Educativa Siglo XXI de la ciudad de Florencia, Caquetá, y que permitirá establecer el nivel de competencia que alcanzan los estudiantes. Dicho modelo previo toma como base el modelo de competencia de Solar (2009) y se complementa con otros componentes de la competencia como la metacognición y la tendencia a la acción, ya que de esta forma se integran los componentes ser, saber y saber hacer

Inspección y levantamiento de planos de las instalaciones eléctricas de la institución educativa Alfonso Jaramillo Gutiérrez

El presente escrito, tiene como principal propósito identificar el estado actual del sistema eléctrico y de iluminación de la institución educativa Alfonzo Jaramillo Gutiérrez así como señalar falencias en el diseño actual de las instalaciones y las posteriores adecuaciones a implementar para contar con un sistema eléctrico y de iluminación acorde a las normas vigentes establecidas en el RETIE, NTC2050 y RETILAP

Operational models of allosteric modulation : caution is needed

The operational model of allosteric modulation and allosteric agonism [1-5] is being used routinely to assess the functional effects of allosteric modulators. Because the meaning of parameters and concepts often loses precision after extensive use, it may be timely to revise some particularities of the model to preclude possible misinterpretations. To do so, I will use the equation for the model as expressed in [4]:where Em is the maximum effect of the system; n, a parameter related with the slope of the curves; [A] and [B], the concentrations of the agonist A and the allosteric modulator B, respectively; τA and τB, the operational efficacies of A and B, respectively; KA and KB, the dissociation constants of A and B, respectively; and α and β, the cooperativity parameters governing binding and function, respectively

Evaluating Allosteric Perturbations in Cannabinoid Receptor 1 by In Silico Single-Point Mutation

Cannabinoid receptor 1 (CB1) is a promising drug target involved in many physiological processes. Using atomistic molecular dynamics (MD) simulations, we examined the structural effect of F237L mutation on CB1, a mutation that has qualitatively similar effects to allosteric ligand ORG27569 binding. This mutation showed a global effect on CB1 conformations. Among the observed effects, TM6 outward movement and the conformational change of the NPxxY motif upon receptor activation by CB1 agonist CP55940 were hindered compared to wt CB1. Within the orthosteric binding site, CP55940 interactions with CB1 were altered. Our results revealed that allosteric perturbations introduced by the mutation had a global impact on receptor conformations, suggesting that the mutation site is a key region for allosteric modulation in CB1

Structural Assessment of Agonist Efficacy in the μ-Opioid Receptor : Morphine and Fentanyl Elicit Different Activation Patterns

Over the past two decades, the opioid epidemic in the United States and Canada has evidenced the need for a better understanding of the molecular mechanisms of medications used to fight pain. Morphine and fentanyl are widely used in opiate-mediated analgesia for the treatment of chronic pain. These compounds target the μ-opioid receptor (MOR), a class A G protein-coupled receptor (GPCR). In light of described higher efficacy of fentanyl with respect to morphine, we have performed independent μs-length unbiased molecular dynamics (MD) simulations of MOR complexes with each of these ligands, including the MOR antagonist naltrexone as a negative control. Consequently, MD simulations totaling 58 μs have been conducted to elucidate at the atomic level ligand-specific receptor activity and signal transmission in the MOR. In particular, we have identified stable binding poses of morphine and fentanyl, which interact differently with the MOR. Different ligand-receptor interaction landscapes directly induce sidechain conformational changes of orthosteric pocket residues: Asp1493.32, Tyr1503.33, Gln1262.60, and Lys2355.39. The induced conformations determine Asp1493.32-Tyr3287.43 sidechain-sidechain interactions and Trp2956.48-Ala2425.46 sidechain-backbone H-bond formations, as well as Met1533.36 conformational changes. In addition to differences in ligand binding, different intracellular receptor conformational changes are observed as morphine preferentially activates transmembrane (TM) helices: TM3 and TM5, while fentanyl preferentially activates TM6 and TM7. As conformational changes in TM6 and TM7 are widely described as being the most crucial aspect in GPCR activation, this may contribute to the greater efficacy of fentanyl over morphine. These computationally observed functional differences between fentanyl and morphine may provide new avenues for the design of safer but not weaker opioid drugs because it is desirable to increase the safety of medicines without sacrificing their efficacy

Datos acerca de la vegetación briofítica terrícola en Salamanca

Se estudian diversas comunidades briofíticas terrícolas presentes en la provincia de Salamanca, comentándose diversos aspectos sinecológicos, sinfisionómicos, sintaxonómicos y sincorológicos de las mismas.This is a study of the terricolous bryophytic vegetation in the Salamanca province, with some comments on synecologic, symphysionomic, syntaxonomic and synchorologic aspects

Quantifying conformational changes in GPCRs : glimpse of a common functional mechanism

Background: G-protein-coupled receptors (GPCRs) are important drug targets and a better understanding of their molecular mechanisms would be desirable. The crystallization rate of GPCRs has accelerated in recent years as techniques have become more sophisticated, particularly with respect to Class A GPCRs interacting with G-proteins. These developments have made it possible for a quantitative analysis of GPCR geometrical features and binding-site conformations, including a statistical comparison between Class A GPCRs in active (agonist-bound) and inactive (antagonist-bound) states. Results: Here we implement algorithms for the analysis of interhelical angles, distances, interactions and binding-site volumes in the transmembrane domains of 25 Class A GPCRs (7 active and 18 inactive). Two interhelical angles change in a statistically significant way between average inactive and active states: TM3-TM6 (by -9°) and TM6-TM7 (by +12°). A third interhelical angle: TM5-TM6 shows a trend, changing by -9°. In the transition from inactive to active states, average van der Waals interactions between TM3 and TM7 significantly increase as the average distance between them decreases by >2 Å. Average H-bonding between TM3 and TM6 decreases but is seemingly compensated by an increase in H-bonding between TM5 and TM6. In five Class A GPCRs, crystallized in both active and inactive states, increased H-bonding of agonists to TM6 and TM7, relative to antagonists, is observed. These protein-agonist interactions likely favour a change in the TM6-TM7 angle, which creates a narrowing in the binding pocket of activated receptors and an average ~200 Å3 reduction in volume. Conclusions: In terms of similar conformational changes and agonist binding pattern, Class A GPCRs appear to share a common mechanism of activation, which can be exploited in future drug development