A structural and dynamic model for the assembly of Replication Protein A on single-stranded DNA

Replication Protein A (RPA), the major eukaryotic single stranded DNA-binding protein, binds to exposed ssDNA to protect it from nucleases, participates in a myriad of nucleic acid transactions and coordinates the recruitment of other important players. RPA is a heterotrimer and coats long stretches of single-stranded DNA (ssDNA). The precise molecular architecture of the RPA subunits and its DNA binding domains (DBDs) during assembly is poorly understood. Using cryo electron microscopy we obtained a 3D reconstruction of the RPA trimerisation core bound with ssDNA (∼55 kDa) at ∼4.7 Å resolution and a dimeric RPA assembly on ssDNA. FRET-based solution studies reveal dynamic rearrangements of DBDs during coordinated RPA binding and this activity is regulated by phosphorylation at S178 in RPA70. We present a structural model on how dynamic DBDs promote the cooperative assembly of multiple RPAs on long ssDNA

Air Pollution and Lymphocyte Phenotype Proportions in Cord Blood

Effects of air pollution on morbidity and mortality may be mediated by alterations in immune competence. In this study we examined short-term associations of air pollution exposures with lymphocyte immunophenotypes in cord blood among 1,397 deliveries in two districts of the Czech Republic. We measured fine particulate matter < 2.5 μm in diameter (PM(2.5)) and 12 polycyclic aromatic hydrocarbons (PAHs) in 24-hr samples collected by versatile air pollution samplers. Cord blood samples were analyzed using a FACSort flow cytometer to determine phenotypes of CD3(+) T-lymphocytes and their subsets CD4(+) and CD8(+), CD19(+) B-lymphocytes, and natural killer cells. The mothers were interviewed regarding sociodemographic and lifestyle factors, and medical records were abstracted for obstetric, labor and delivery characteristics. During the period 1994 to 1998, the mean daily ambient concentration of PM(2.5) was 24.8 μg/m(3) and that of PAHs was 63.5 ng/m(3). In multiple linear regression models adjusted for temperature, season, and other covariates, average PAH or PM(2.5) levels during the 14 days before birth were associated with decreases in T-lymphocyte phenotype fractions (i.e., CD3(+) CD4(+), and CD8(+)), and a clear increase in the B-lymphocyte (CD19(+)) fraction. For a 100-ng/m(3) increase in PAHs, which represented approximately two standard deviations, the percentage decrease was −3.3% [95% confidence interval (CI), −5.6 to −1.0%] for CD3(+), −3.1% (95% CI, −4.9 to −1.3%) for CD4(+), and −1.0% (95% CI, −1.8 to −0.2%) for CD8(+) cells. The corresponding increase in the CD19(+) cell proportion was 1.7% (95% CI, 0.4 to 3.0%). Associations were similar but slightly weaker for PM(2.5). Ambient air pollution may influence the relative distribution of lymphocyte immunophenotypes of the fetus

Guía de autocuidados para el manejo de la nutrición enteral domiciliaria

Introducción: La nutrición enteral domiciliaria (NED) consiste en la administración de nutrientes al tubo digestivo en aquellos pacientes que no pueden satisfacer sus necesidades nutricionales por vía oral, pero mantienen la funcionalidad del tubo digestivo, en el hogar del paciente. Se indica con mayor frecuencia en pacientes con patologías neurológicas que cursan con afagia o disfagia. Se evidenció que es fundamental una buena formación de pacientes y cuidadores por parte de enfermería para mejorar la calidad de vida, aumentar la adherencia y disminuir el índice de complicaciones. Objetivo: Difundir los cuidados que requieren los pacientes portadores de NED para mejorar así, su calidad de vida. Metodología: Elaborar una guía de autocuidados siguiendo la propuesta por Hernández Zambrano et al. en Cómo elaborar Guías de Recomendaciones de Autocuidado para Pacientes y Cuidadores. Se trata aquellos temas que generaban más inquietud entre pacientes y cuidadores, recogidos en la bibliografía. Conclusiones: Una guía dirigida a los pacientes usuarios de NED y a sus cuidadores, empleando un lenguaje de fácil comprensión, difunde los cuidados de enfermería que requieren estos pacientes. Además, se ha conseguido mejorar la calidad de vida de los pacientes y disminuir su ansiedad por déficit de conocimientos. <br /

FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP

Protein folding homeostasis in the endoplasmic reticulum (ER) is defended by an unfolded protein response that matches ER chaperone capacity to the burden of unfolded proteins. As levels of unfolded proteins decline, a metazoan-specific FIC-domain-containing ER-localized enzyme (FICD) rapidly inactivates the major ER chaperone BiP by AMPylating T518. Here we show that the single catalytic domain of FICD can also release the attached AMP, restoring functionality to BiP. Consistent with a role for endogenous FICD in de-AMPylating BiP, FICD$_{-/-}$ hamster cells are hypersensitive to introduction of a constitutively AMPylating, de-AMPylation-defective mutant FICD. These opposing activities hinge on a regulatory residue, E234, whose default state renders FICD a constitutive de-AMPylase $\textit{in vitro}$. The location of E234 on a conserved regulatory helix and the mutually antagonistic activities of FICD $\textit{in vivo}$, suggest a mechanism whereby fluctuating unfolded protein load actively switches FICD from a de-AMPylase to an AMPylase.Supported by Wellcome Trust Principal Research Fellowship to D.R. (Wellcome 200848/Z/16/Z), a UK Medical Research Council PhD studentship to L.A.P. and a Wellcome Trust Strategic Award to the Cambridge Institute for Medical Research (Wellcome 100140)

Training simulated patients: evaluation of a training approach using self-assessment and peer/tutor feedback to improve performance

<p>Abstract</p> <p>Background</p> <p>Most medical schools use simulated patients (SPs) for teaching. In this context the authenticity of role play and quality of feedback provided by SPs is of paramount importance. The available literature on SP training mostly addresses instructor led training where the SPs are given direction on their roles. This study focuses on the use of peer and self evaluation as a tool to train SPs.</p> <p>Methods</p> <p>SPs at the medical school participated in a staff development and training programme which included a) self-assessment of their performance while observing video-tapes of their role play using a structured guide and b) peer group assessment of their performance under tutor guidance. The pre and post training performance in relation to authenticity of role play and quality of feedback was blindly assessed by students and tutors using a validated instrument and the scores were compared. A focus group discussion and a questionnaire assessed acceptability of the training programme by the SPs.</p> <p>Results</p> <p>The post-training performance assessment scores were significantly higher (p < 0.05) than the pre-training scores. The degree of improvement in the quality of feedback provided to students was more when compared to the improvement of role play. The acceptability of the training by the SPs was very satisfactory scoring an average of 7.6 out of 10. The majority of the SPs requested the new method of training to be included in their current training programme as a regular feature.</p> <p>Conclusion</p> <p>Use of structured self-reflective and peer-interactive, practice based methods of SP training is recommended to improve SP performance. More studies on these methods of training may further refine SP training and lead to improvement of SP performance which in turn may positively impact medical education.</p

Equilibration times in numerical simulation of structural glasses: Comparing parallel tempering and conventional molecular dynamics

Generation of equilibrium configurations is the major obstacle for numerical investigation of the slow dynamics in supercooled liquid states. The parallel tempering (PT) technique, originally proposed for the numerical equilibration of discrete spin-glass model configurations, has recently been applied in the study of supercooled structural glasses. We present an investigation of the ability of parallel tempering to properly sample the liquid configuration space at different temperatures, by mapping the PT dynamics into the dynamics of the closest local potential energy minima (inherent structures). Comparing the PT equilibration process with the standard molecular dynamics equilibration process we find that the PT does not increase the speed of equilibration of the (slow) configurational degrees of freedom.Comment: 5 pages, 3 figure

A transient tribodynamic approach for the calculation of internal combustion engine piston slap noise

An analytical/numerical methodology is presented to calculate the radiated noise due to internal combustion engine piston impacts on the cylinder liner through a film of lubricant. Both quasi-static and transient dynamic analyses coupled with impact elasto-hydrodynamics are reported. The local impact impedance is calculated, as well as the transferred energy onto the cylinder liner. The simulations are verified against experimental results for different engine operating conditions and for noise levels calculated in the vicinity of the engine block. Continuous wavelet signal processing is performed to identify the occurrence of piston slap noise events and their spectral content, showing good conformance between the predictions and experimentally acquired signals

Multiclasificadores basados en aprendizaje automático como herramienta para la evaluación del perfil neurotóxico de líquidos iónicos

Los líquidos iónicos poseen un perfil fisicoquímico único, el cual los provee de un amplio rango de aplicaciones. Su variabilidad estructural casi ilimitada permite su diseño para tareas específicas. Sin embargo, su sustentabilidad, específicamente su seguridad desde el punto de vista toxicológico, ha sido frecuentemente cuestionada. Este último aspecto limita significativamente el cumplimiento de las regulaciones establecidas por la Unión Europea para el registro, evaluación, autorización y restricción de compuestosquímicos (REACH), así como su aplicación final. Debido a que la mayoría de los líquidos iónicos no han sido sintetizados, se hace evidente la importancia del desarrollo de herramientas quimioinformáticas que, de forma eficiente, permitan evaluar el potencial toxicológico de estos compuestos. En este sentido, el uso combinado de múltiples clasificadores ha demostrado superar las limitaciones de desempeño asociadas al uso de clasificadores individuales. En el presente trabajo fueron evaluadas varias estrategias alternativas de multiclasificadores basados en técnicas de aprendizaje automático supervisado, como herramientas para la evaluación del perfil neurotóxico de líquidos iónicos basado en la inhibición de la enzima acetilcolinesterasa, como indicador de neurotoxicidad. Se obtuvieron dos multiclasificadores con una alta capacidad predictiva sobre un conjunto de validación externa (no utilizado en el proceso de aprendizaje de los modelos). De acuerdo a los resultados obtenidos el 96% de un conjunto de nuevos líquidos iónicos podrá ser correctamente clasificado con la utilizaciónde estos multiclasificadores, los cuales constituyen herramientas de toma de decisión útiles en el campo del diseño y desarrollo de nuevos líquidos iónicos sustentables

Interdisciplinariedad científica en la gestión de la información científica-tecnológica

The current Cuban organizational system assumes the importance of incorporating science in the fulfillment of its social mission. To achieve this, investigative work is vital, directed towards the development of an elementary scientific culture that guides towards the success of that objective. An effective way to do this is the management of scientific-technological information based on the establishment of interdisciplinary relationships. Theoretical methods such as bibliographic and documentary analysis were used, in addition to conducting interviews with specialists from the different actors. From this knowledge, the creation of events that implement a holistic, comprehensive and interdisciplinary vision to solve current problems, which can only be achieved with work and collective knowledge, is provided. The main objective of this article is to emphasize the importance of interdisciplinarity in the construction of knowledge and its contribution to the design and implementation of events. Those that can constitute a network from the responsible management of the same in an organization like the Idict. It reflects on the importance of knowledge management as a dynamic unit of these concepts. It is concluded that sustainable human development can be approached from different disciplines, but none by itself will be able to respond to its main problems, with very little contribution from multidisciplinary teams if the organizations that create them offer only a technical vision of their respective specialties, without articulating knowledge and without managing it.El sistema organizacional cubano actual asume la importancia de la incorporación de la ciencia en el cumplimiento de su misión social. Para lograrlo resulta vital el quehacer investigativo, direccionado hacia el desarrollo de una cultura científica elemental que guíe hacia el éxito de ese objetivo. Un camino eficaz para ello lo constituye la gestión de la información científica-tecnológica a partir del establecimiento de relaciones interdisciplinarias. Se emplearon métodos teóricos como el análisis bibliográfico y documental, además de la realización de entrevistas a especialistas de los diferentes actores. Desde estos saberes se proporcionan la creación de eventos que implementen una visión holística, integral e interdisciplinaria para resolver los problemas actuales, que sólo se logra con el trabajo y el conocimiento colectivo. El principal objetivo del presente artículo es recalcar la importancia de la interdisciplinariedad en la construcción del conocimiento y su aporte al diseño y realización de eventos. Esos que pueden constituir una red a partir de la gestión responsable de los mismos en una organización como el Idict. Se reflexiona acerca de la importancia de la Gestión del conocimiento como unidad dinamizadora de estos conceptos. Se concluye que el desarrollo humano sostenible puede abordarse desde diferentes disciplinas, pero ninguna por sí sola podrá responder a sus principales problemas, siendo muy poco lo que aportan los equipos multidisciplinarios si las organizaciones que los crean ofrecen sólo una visión técnica de sus respectivas especialidades, sin articular el conocimiento y sin gestionarlo