In silico approaches to develop new phenyl-pyrimidines as glycogen synthase kinase 3 (GSK-3) inhibitors with halogen-bonding capabilities: 3D-QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies.

Glycogen synthase kinase 3 (GSK-3) is involved in different diseases, such as manic-depressive illness, Alzheimer's disease and cancer. Studies have shown that insulin inhibits GSK-3 to keep glycogen synthase active. Inhibiting GSK-3 may have an indirect pro-insulin effect by favouring glycogen synthesis. Therefore, the development of GSK-3 inhibitors can be a useful alternative for the treatment of type II diabetes. Aminopyrimidine derivatives already proved to be interesting GSK-3 inhibitors. In the current study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have been performed on a series of 122 aminopyrimidine derivatives in order to generate a robust model for the rational design of new compounds with promising antidiabetic activity. The q2 values obtained for the best CoMFA and CoMSIA models have been 0.563 and 0.598, respectively. In addition, the r2 values have been 0.823 and 0.925 for CoMFA and CoMSIA, respectively. The models were statistically validated, and from the contour maps analysis, a proposal of 10 new compounds has been generated, with predicted pIC50 higher than 9. The final contribution of our work is that: (a) we provide an extensive structure-activity relationship for GSK-3 inhibitory pyrimidines; and (b) these models may speed up the discovery of GSK-3 inhibitors based on the aminopyrimidine scaffold. Finally, we carried out docking and molecular dynamics studies of the two best candidates, which were shown to establish halogen-bond interactions with the enzyme.Communicated by Ramaswamy H. Sarma.

Estudiantes universitarias nuligestas en edad fértil y su postura acerca de posibles vías del parto / Nuligest university students of childbearing age and their position about possible ways of delivery

Resumen Introducción: Tanto a nivel sudamericano como mundial, el incremento de la tasa de cesáreas electivas ha sido abrumante. Esto se considera un problema de salud pública, ya que el parto vaginal es la vía más fisiológica para el nacimiento y trae beneficios de salud para la madre y el recién nacido, tanto inmediatos como a futuro. Objetivo: Evaluar la postura de mujeres nuligestas en edad fértil acerca de las vías del parto a través de sus conocimientos, percepciones y preferencias. Método: Estudio de corte transversal. Se aplicó una encuesta a estudiantes universitarias para la recopilación de datos mediante SPSS, y análisis con prueba de diferencias de proporciones y de χ2. Resultados: 210 mujeres encuestadas. Un 80% de ellas desconoce la menor morbilidad infantil asociada a un parto vaginal, más de la mitad estima una ventaja de la cesárea que evite el dolor y un gran porcentaje desconoce los riesgos médicos asociados a la cesárea. Conclusiones: Existe un alto nivel de desconocimiento respecto a beneficios, riesgos y consecuencias de las diferentes vías del parto.

Abstract Introduction: Both in South America and worldwide, the increase in the rate of elective caesarean sections has been overwhelming. This is considered a public health problem, since vaginal delivery is the most physiological route for birth and brings health benefits for the mother and the newborn, immediately and in the future. Objective: To evaluate the position of nulliparous women of childbearing age regarding the delivery pathways through their knowledge, perceptions, and preferences. Method: Cross-sectional study with an analytical component. A survey was applied to university students for data collection through SPSS, and analysis was made with the difference of proportions and χ2 test. Results: 210 women surveyed; 80% of them are unaware of the lower infant morbidity associated with a vaginal delivery, more than a half estimate an advantage of a cesarean section that it avoids pain, and a large percentage are unaware of the medical risks associated with cesarean sections. Conclusions: There is a high level of ignorance regarding the benefits, risks and consequences of the different delivery routes.

Spider Toxin SNX-482 Gating Modifier Spontaneously Partitions in the Membrane Guided by Electrostatic Interactions.

Spider toxin SNX-482 is a cysteine-rich peptide that interferes with calcium channel activity by binding to voltage-sensing domains of the CaV2.3 subtype. Two mechanisms dominate the binding process of cysteine-rich peptides: direct binding from the aqueous phase or through lateral diffusion from the membrane, the so-called reduction in dimensionality mechanism. In this work, via coarse-grained and atomistic molecular dynamics simulations, we have systematically studied the spontaneous partitioning of SNX-482 with membranes of different anionic compositions and explored via diffusional analysis both binding mechanisms. Our simulations revealed a conserved protein patch that inserts in the membrane, a preference for binding towards partially negatively charged membranes, and that electrostatics guides membrane binding by incrementing and aligning the molecular dipole. Finally, diffusivity calculations showed that the toxin diffusion along the membrane plane is an order of magnitude slower than the aqueous phase suggesting that the critical factor in determining the SNX-482-CaV2.3 binding mechanism is the affinity between the membrane and SNX-482.

Mechanism of voltage sensing in Ca2+- and voltage-activated K+ (BK) channels.

In neurosecretion, allosteric communication between voltage sensors and Ca2+ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.

On the effects of induced polarizability at the water-graphene interface via classical charge-on-spring models.

Molecular models of the water-graphene interaction are essential to describe graphene in condensed phases. Different challenges are associated with the generation of these models, in particular π-π and dispersion interactions; thus quantum and classical models have been developed and due to the numerical efficiency of the latter, they have been extensively employed. In this work, we have systematically studied, via molecular dynamics, two polarizable graphene models, denominated CCCP and CCCPD, employing the charge-on-spring model of the GROMOS forcefield, both being compatible with the polarizable water models COS/G2 and COS/D2, respectively. These models were compared with non-polarizable graphene and SPC water models. We focused the study on the water-graphene interface in two distinct systems and under the influence of an electric field: one composed of graphene immersed in water and the other composed of graphene with a water droplet above it. In the former, the orientation of water close to the graphene layer is affected by polarizable graphene in comparison to non-polarizable graphene. This effect is emphasised when an electric field is applied. In the latter, carbon polarizability reduced water contact angles, but graphene retained its hydrophobicity and the computed angles are within the experimental data. Given the significant extra computational cost, the use of polarizable models instead of the traditional fixed-charged approach for the graphene-water interaction may be justified when polarizability effects are relevant, for example, when applying relatively strong fields or in very anisotropic systems, such as the vacuum-bulk interface, as these models are more responsive to such conditions.

What do users think about Virtual Reality relaxation applications? A mixed methods study of online user reviews using natural language processing.

The advent of affordable Virtual Reality (VR) technology has spurred consumer and commercial interest in VR relaxation applications, which has quickly grown into a popular non-gaming genre on digital marketplaces. While laboratory studies have demonstrated efficacy of VR relaxation for mental health purposes, little is known about how users experience this type of intervention and no study has examined the reception of consumer versions among regular users in everyday life. Studying published user reviews offers a unique window into naturalistic user experiences that complements traditional qualitative methods by circumventing the sampling bias of interview studies, and allowing analyses on full samples, unconstrained by coding resources. Using an innovative, semi-automated Natural Language Processing technique, the current study analyzed 1379 published reviews (including star ratings) of 30 different VR relaxation applications available for the Oculus Go and Gear VR. The uncovered topic structure and sentiment analysis thereof suggests that users have an overall positive view of VR relaxation applications, describing them as successful in inducing immersion and relaxation, and having appreciated gamification elements. However, perceived quality varied substantially between applications that explained more variance in star ratings than specific features. Critical issues raised were both technical (e.g. "overheating") in nature and related to specific design elements and use. Implications for the design of consumer VR applications and future research are discussed.

How to depolarise the ethical debate over human embryonic stem cell research (and other ethical debates too!).

The contention of this paper is that the current ethical debate over embryonic stem cell research is polarised to an extent that is not warranted by the underlying ethical conflict. It is argued that the ethical debate can be rendered more nuanced, and less polarised, by introducing non-binary notions of moral rightness and wrongness. According to the view proposed, embryonic stem cell research--and possibly other controversial activities too--can be considered 'a little bit right and a little bit wrong'. If this idea were to become widely accepted, the ethical debate would, for conceptual reasons, become less polarised.

Risk and mid-level moral principles.

We discuss ethical aspects of risk-taking with special focus on principlism and mid-level moral principles. A new distinction between the strength of an obligation and the degree to which it is valid is proposed. We then use this distinction for arguing that, in cases where mid-level moral principles come into conflict, the moral status of the act under consideration may be indeterminate, in a sense rendered precise in the paper. We apply this thought to issues related to pandemic influenza vaccines. The main conclusion of the paper is that on a principlist approach some acts may be neither right nor wrong (or neither permissible nor impermissible), and we claim that this has important implications for how we ought to make decisions under risk.

Prevalencia de ascaris lumbricoides y otros enteroparásitos en habitantes de 12 comunidades rurales del estado Monagas Venezuela / Prevalence of ascaris lumbricoides and others enteroparasites in inhabitants of 12 rural communities of the state Monagas Venezuela

El objetivo de este estudio fue establecer la prevalencia de A. lumbricoides y otros parásitos intestinales, en habitantes de doce comunidades rurales del Municipio Piar, Estado Monagas, diciembre de 2004 a julio de 2005. Fueron evaluados mediante examen directo de heces, 2.648 individuos, de ambos exos y todas las edades. Los resultados se analizaron mediante frecuencias relativas. La prevalencia de parasitosis intestinal fue de 91,10 por ciento . El patógeno más observado fue A. lumbricoides, con una prevalencia de 40,97 por ciento. Otros patógenos: G. lamblia (39,24 por ciento), E. histolytica/E. dispar (11,52 por ciento), H. nana (6,57 por ciento), B. hominis (2,83 por ciento), T. trichiuria (1,17 por ciento), E. vermicularis (0,98 por ciento), A. duodenale (0,64 por ciento), S. stercoralis (0,38 por ciento), T. solium (0,11 por ciento) y comensales en 12,72 por ciento. La alta prevalencia de parasitosis en las comunidades estudiadas, se ve justificada por inadecuado saneamiento ambiental presente en cada uno de los poblados y obliga a realizar futuras investigaciones tendientes a establecer los factores determinantes de estas infecciones, ya que esas altas tasas, aunado al gran poliparasitismo, reflejan una mayor frecuencia de exposición con heces humanas.