Design of a structure-based model for protein folding from flexible conformations.

The use of coarse-grained models is important in many fields, especially those that use computer simulation to analyze large systems in processes that span long-time scales, as happens in protein folding. Among those approaches, structure-based models have been widely and successfully used for a few decades now. They usually take a single native conformation, experimentally solved, of the protein studied to determine the native contacts, which subsequently define the interaction potential for the simulation. The characteristics of the folding transition can then be analyzed from the computed trajectories. In this paper, we consider the possibility of enriching these models by considering the structural fluctuations present in the native state of a globular protein at room temperature in an aqueous environment. We use the different conformers experimentally provided when the protein structure was determined by nuclear magnetic resonance (NMR) spectroscopy as an approximate ensemble to test our methodology, which includes the definition of a global interaction potential and the analysis of the thermodynamic and structural characteristics of the folding process. The results are compared with traditional, single structure models.

Recessive spinocerebellar ataxia with paroxysmal cough attacks: a report of five cases.

Hereditary ataxias are a heterogeneous group of neurological diseases characterized by progressive cerebellar syndrome and numerous other features, which result in great diversity of ataxia subtypes. Despite the characterization of a number of both autosomal dominant and autosomal recessive ataxias, it is thought that a large group of these conditions remains to be identified. In this study, we report the characterization of five patients (three Mexicans and two Italians) who exhibit a peculiar form of recessive ataxia associated with coughing. The main clinical and neurophysiological features of these patients include cerebellar ataxia, paroxysmal cough, restless legs syndrome (RLS), choreic movements, atrophy of distal muscles, and oculomotor disorders. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy, while video polysomnography (VPSG) studies showed a severe pattern of breathing-related sleep disorder, including sleep apnea, snoring, and significant oxygen saturation in the absence of risk factors. All patients share clinical features in the peripheral nervous system, including reduction of amplitude and prolonged latency of sensory potentials in median and sural nerves. Altogether, clinical criteria as well as molecular genetic testing that was negative for different autosomal dominant and autosomal recessive ataxias suggest the presence of a new form of recessive ataxia. This ataxia, in which cerebellar signs are preceded by paroxysmal cough, affects not only the cerebellum and its fiber connections, but also the sensory peripheral nervous system and extracerebellar central pathways.

Long-term perspective on the relationship between phytoplankton and nutrient concentrations in a southeastern Australian estuary.

Sixteen years (1997-2013) of physicochemical, nutrient and phytoplankton biomass (Chlorophyll-a (Chl-a)) data and a decade (2003-2013) of phytoplankton composition and abundance data were analyzed to assess how the algal community in a temperate southeastern Australian estuary has responded to decreased chronic point source nitrogen loading following effluent treatment upgrade works in 2003. Nitrogen concentrations were significantly lower (P<0.05) following enhanced effluent treatment and Chl-a levels decreased (P<0.05) during the warmer months. Temperature and nutrient concentrations significantly influenced temporal changes of Chl-a (explaining 55% of variability), while salinity, temperature, pH and nutrient concentrations influenced phytoplankton abundance and composition (25% explained). Harmful Algal Bloom (HAB) dynamics differed between sites likely influenced by physical attributes of the estuary. This study demonstrates that enhanced effluent treatment can significantly decrease chronic point source nitrogen loading and that Chl-a concentrations can be lowered during the warmer months when the risk of blooms and HABs is greatest.

Unusual Ventilatory Response to Exercise in Patient with Arnold-Chiari Type 1 Malformation after Posterior Fossa Decompression.

We present a case of a 17-year-old Hispanic male with Arnold-Chiari Type 1 [AC-Type 1] with syringomyelia, status post decompression, who complains of exercise intolerance, headaches, and fatigue with exertion. The patient was found to have diurnal hypercapnia and nocturnal alveolar hypoventilation. Cardiopulmonary testing revealed blunting of the ventilatory response to the rise in carbon dioxide (CO2) resulting in failure of the parallel correlation between increased CO2 levels and ventilation; the expected vertical relationship between PETCO2 and minute ventilation during exercise was replaced with an almost horizontal relationship. No new pathology of the brainstem was discovered by MRI or neurological evaluation to explain this phenomenon. The patient was placed on continuous noninvasive open ventilation (NIOV) during the day and CPAP at night for a period of 6 months. His pCO2 level decreased to normal limits and his symptoms improved; specifically, he experienced less headaches and fatigue during exercise. In this report, we describe the abnormal response to exercise that patients with AC-Type 1 could potentially experience, even after decompression, characterized by the impairment of ventilator response to hypercapnia during exertion, reflecting a complete loss of chemical influence on breathing with no evidence of abnormality in the corticospinal pathway.

Anti-inflammatory effect of prophylactic macrolides on children with chronic lung disease: a protocol for a double-blinded randomised controlled trial.

INTRODUCTION: Recent studies suggest that the high mortality rate of respiratory viral infections is a result of an overactive neutrophilic inflammatory response. Macrolides have anti-inflammatory properties, including the ability to downregulate the inflammatory cascade, attenuate excessive cytokine production in viral infections, and may reduce virus-related exacerbations. In this study, we will test the hypothesis that prophylactic macrolides will reduce the severity of respiratory viral illness in children with chronic lung disease by preventing the full activation of the inflammatory cascade. METHODS AND ANALYSIS: A randomised double-blind placebo-controlled trial that will enrol 92 children to receive either azithromycin or placebo for a period of 3-6 months during two respiratory syncytial virus (RSV) seasons (2015-2016 and 2016-2017). We expect a reduction of at least 20% in the total number of days of unscheduled face-to-face encounters in the treatment group as compared with placebo group. Standard frequentist and Bayesian analyses will be performed using an intent-to-treat approach. DISCUSSION: We predict that the prophylactic use of azithromycin will reduce the morbidity associated with respiratory viral infections during the winter season in patients with chronic lung disease as evidenced by a reduction in the total number of days with unscheduled face-to-face provider encounters. ETHICS AND DISSEMINATION: This research study was approved by the Institutional Review Board of the University of Texas Health Science Center in Houston on 9 October 2014. On completion, the results will be published. TRIAL REGISTRATION NUMBER: NCT02544984.

Monte Carlo calculations for the intrinsic viscosity of several dendrimer molecules.

We have performed Monte Carlo simulations to reproduce the intrinsic viscosity corresponding to different generation of several types of dendrite molecules: polyamidoamine dendrimers with an ethylendiamine core, polypropylene-imine with a diaminobutane core, and monodendrons and tridendrons of polybenzylether. With this end, we have employed coarse-grained idealizations of the molecules constituted by only two beads in each repeat unit (one in a branching or end unit and one intermediate along the repeat unit) and a simple hard-sphere potential between non-neighboring beads. Our goal is to investigate if this simple model is able to provide a reasonable description of some differences between these systems that have been observed experimentally, in particular, the location of the maximum in the intrinsic viscosity as a function of the generation number. Experimental radii of gyration in a given solvent are reproduced by a fit of the hard-sphere potential diameter. Subsequently, intrinsic viscosities are calculated by the variational approach of Fixman, which yields an accurate lower-bound value with an additional hydrodynamic interaction parameter (the friction radius of the beads). The results show a pronounced variation of the maximum location with the value of the friction radius and the structural details that cannot be mimicked with simpler models. The initial conformations for the Monte Carlo procedure are taken from atomistic configurations thermalized by means of a molecular dynamics.

Evolutionary method for the assembly of rigid protein fragments.

Genetic algorithms constitute a powerful optimization method that has already been used in the study of the protein folding problem. However, they often suffer from a lack of convergence in a reasonably short time for complex fitness functions. Here, we propose an evolutionary strategy that can reproducibly find structures close to the minimum of a potential function for a simplified protein model in an efficient way. The model reduces the number of degrees of freedom of the system by treating the protein structure as composed of rigid fragments. The search incorporates a double encoding procedure and a merging operation from subpopulations that evolve independently of one another, both contributing to the good performance of the full algorithm. We have tested it with protein structures of different degrees of complexity, and present our conclusions related to its possible application as an efficient tool for the analysis of folding potentials.

Evaluación de sistemas de salud y la estrategia de APS / Evaluation of health care systems and primary health care strategy

OBJETIVO: evaluar la calidad de los sistemas de salud y la estrategia de Atención Primaria de la Salud (APS) en distintas áreas geográficas del país. MÉTODO: estudio de corte transversal con abordaje metodológico triangular que involucró:a) encuestas a las personas que demandan la atención, b) entrevistas a referentes claves del equipo de salud y c) grupos focales con los equipos de salud. Los componentes de estructura, proceso y resultados de los sistemas de salud basados en APS se evaluaron por medio de indicadores específicos. RESULTADOS:el análisis de la información muestra un déficit evidente de la integración del equipo profesional, principalmente en la actividad comunitaria y social, la carencia de normativas adecuadas y problemas de accesibilidad estructural para población discapacitada. Se destaca, además, el alto porcentaje de personal que desconoce los programas en ejecución dentro de la institución, así como la falta de un sistema de información adecuado sobre la población del área y de registros de los procesos de gestión en la mayoría de las unidades analizadas. CONCLUSIÓN: a pesar de los esfuerzos para definir y ejecutar la estrategia de APS, los centros de salud continúan realizando sus actividades en base al modelo tradicional de atención exclusiva de la demanda

OBJECTIVE: the aim of this project was to evaluate the quality of health care systems based on the strategy of Primary Health Care in different areas of the country. METHOD: cross-sectional study with a triangular approach, including a) a survey to the population demanding care, b) interviews to key referents of the health team, and c)health team focus groups. The components of structure, process and outcomes of the health system based on PHC were evaluated by specific indicators. RESULTS: the analysis of the information shows an evident deficit of the integration of the professional team, mainly in the activities towards community, the lack of norms and lack of facilities for disable people. It must be noted also the high percentage of the health care team that does not know about current institutional health programs and the lack of an adequate information system for the area population and for the administrative process in most of the sites studied. CONCLUSION: in spite of the efforts to implement the PHC strategy, most of health centers evaluated are still providing care based on the traditional model oriented to the demands of care