Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA

Indexación: Web of Science; Scopus.Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyano-fluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure-activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations.We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes. © 2015 Mena-Ulecia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.014277

An improved cosmological bound on the thermal axion mass

Relic thermal axions could play the role of an extra hot dark matter component in cosmological structure formation theories. By combining the most recent observational data we improve previous cosmological bounds on the axion mass m_a in the so-called hadronic axion window. We obtain a limit on the axion mass m_a < 0.42eV at the 95% c.l. (m_a < 0.72eV at the 99% c.l.). A novel aspect of the analysis presented here is the inclusion of massive neutrinos and how they may affect the bound on the axion mass. If neutrino masses belong to an inverted hierarchy scheme, for example, the above constraint is improved to m_a < 0.38eV at the 95% c.l. (m_a < 0.67eV at the 99% c.l.). Future data from experiments as CAST will provide a direct test of the cosmological bound.Comment: 5 Pages, 3 Figure

Wormholes as Basis for the Hilbert Space in Lorentzian Gravity

We carry out to completion the quantization of a Friedmann-Robertson-Walker model provided with a conformal scalar field, and of a Kantowski-Sachs spacetime minimally coupled to a massless scalar field. We prove that the Hilbert space determined by the reality conditions that correspond to Lorentzian gravity admits a basis of wormhole wave functions. This result implies that the vector space spanned by the quantum wormholes can be equipped with an unique inner product by demanding an adequate set of Lorentzian reality conditions, and that the Hilbert space of wormholes obtained in this way can be identified with the whole Hilbert space of physical states for Lorentzian gravity. In particular, all the normalizable quantum states can then be interpreted as superpositions of wormholes. For each of the models considered here, we finally show that the physical Hilbert space is separable by constructing a discrete orthonormal basis of wormhole solutions.Comment: 23 pages (Latex), Preprint IMAFF-RC-04-94, CGPG-94/5-

Enhancing students' well-being with a unified approach based on contextual behavioural science: A randomised experimental school-based intervention

A new generation of interventions has begun to move towards principles of acceptance that deal with the context and function of psychological events. The aim of this paper is to analyse the effectiveness of a brief contextual behavioural intervention to improve the psychological well-being of secondary school students. This intervention represents a unified model with key processes based on contextual behavioural science, including Acceptance and Commitment Therapy (ACT) and Functional Analytic Psychotherapy (FAP). We conducted an intervention with 94 students (age range 17–19 years), randomly assigned to an experimental group (n = 50) or control group (n = 44). Participants took a pretest and post-test of distress, life satisfaction, psychological flexibility and mindfulness. The intervention consisted of three sessions of 1 h each. The results showed significant differences between the groups in distress and significant differences for the interaction (group × pre–post) in all the other variables. The intervention had greater benefits for girls than for boys. These results may provide a breakthrough, thus leading to a process of evidence-based therapies, which would be responsible for inducing psychological improvements in brief periods, in a population with an increasing risk of distress.This study was carried out in Marbella (Spain), did not receive funding and was self-financed. Funding for open access charge: Universidad de Málaga / CBUA

An SIS-based sideband-separating heterodyne mixer optimized for the 600 to 720 GHz band

The Atacama Large Millimeter Array (ALMA) is the largest radio astronomical enterprise ever proposed. When completed, each of its 64 constituting radio-telescopes will be able to hold 10 heterodyne receivers covering the spectroscopic windows allowed by the atmospheric transmission at the construction site, the altiplanos of the northern Chilean Andes. In contrast to the sideband-separating (2SB) receivers being developed at low frequencies, double-side-band (DSB) receivers are being developed for the highest two spectroscopic windows (bands 9 and 10). Despite of the well known advantages of 2SB mixers over their DSB counterparts, they have not been implemented at the highest-frequency bands as the involved dimensions for some of the radio frequency components are prohibitory small. However, the current state-of-the-art micromachining technology has proved that the structures necessary for this development are attainable. Here we report the design, modeling, realization, and characterization of a 2SB mixer for band 9 of ALMA (600 to 720 GHz). At the heart of the mixer, two superconductor-insulator-superconductor (SIS) junctions are used as mixing elements. The constructed instrument presents an excellent performance as shown by two important figures of merit: noise temperature of the system and side band ratio, both of them within ALMA specifications

Cosmic no-hair: non-linear asymptotic stability of de Sitter universe

We study the asymptotic stability of de Sitter spacetime with respect to non-linear perturbations, by considering second order perturbations of a flat Robertson-Walker universe with dust and a positive cosmological constant. Using the synchronous comoving gauge we find that, as in the case of linear perturbations, the non-linear perturbations also tend to constants, asymptotically in time. Analysing curvature and other spacetime invariants we show, however, that these quantities asymptotically tend to their de Sitter values, thus demonstrating that the geometry is indeed locally asymptotically de Sitter, despite the fact that matter inhomogeneities tend to constants in time. Our results support the inflationary picture of frozen amplitude matter perturbations that are stretched outside the horizon, and demonstrate the validity of the cosmic no-hair conjecture in the nonlinear inhomogeneous settings considered here.Comment: 8 pages, REVTEX, submitted to Physical Review Lette

On Unitary Time Evolution in Gowdy T3T^3 Cosmologies

A non-perturbative canonical quantization of Gowdy $T^3$ polarized models carried out recently is considered. This approach profits from the equivalence between the symmetry reduced model and 2+1 gravity coupled to a massless real scalar field. The system is partially gauge fixed and a choice of internal time is performed, for which the true degrees of freedom of the model reduce to a massless free scalar field propagating on a 2-dimensional expanding torus. It is shown that the symplectic transformation that determines the classical dynamics cannot be unitarily implemented on the corresponding Hilbert space of quantum states. The implications of this result for both quantization of fields on curved manifolds and physically relevant questions regarding the initial singularity are discussed.Comment: 16 pages, no figures, latex file; references added, a proof included. Final version to appear in IJMP

Harrison-Z'eldovich primordial spectrum is consistent with observations

Inflation predicts primordial scalar perturbations with a nearly scale-invariant spectrum and a spectral index approximately unity (the Harrison--Zel'dovich (HZ) spectrum). The first important step for inflationary cosmology is to check the consistency of the HZ primordial spectrum with current observations. Recent analyses have claimed that a HZ primordial spectrum is excluded at more than 99% c.l.. Here we show that the HZ spectrum is only marginally disfavored if one considers a more general reionization scenario. Data from the Planck mission will settle the issue.Comment: 4 Pages, 2 Figure

Spherically symmetric perfect fluid in area-radial coordinates

We study the spherically symmetric collapse of a perfect fluid using area-radial coordinates. We show that analytic mass functions describe a static regular centre in these coordinates. In this case, a central singularity can not be realized without an infinite discontinuity in the central density. We construct mass functions involving fluid dynamics at the centre and investigate the relationship between those and the nature of the singularities.Comment: Accepted by CQG. LaTex file, 14 pages, no figure