Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Changes in the Brain Microstructure of Children with Primary Monosymptomatic Nocturnal Enuresis: A Diffusion Tensor Imaging Study

Background: Primary monosymptomatic nocturnal enuresis (PMNE) is a common disorder in school-aged children. Previous studies have suggested that a developmental delay might play a role in the pathology of children with PMNE. However, microstructural abnormalities in the brains of these children have not been thoroughly investigated. Methodology/Principal Findings: In this work, we evaluated structural changes in the brains of children with PMNE using diffusion tensor imaging (DTI). Two groups consisting of 26 children with PMNE and 26 healthy controls were scanned using magnetic resonance DTI. The diffusion parameters of fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain, voxel-wise group comparisons using statistical parametric mapping (SPM). When compared to healthy subjects, children with PMNE showed both a decrease in FA and an increase in MD in the thalamus. MD also increased in the frontal lobe, the anterior cingulate cortex and the insula; these areas are all involved in controlling micturition. The significant changes seen in the thalamus could affect both urine storage and arousal from sleep. Conclusions/Significance: The microstructure abnormalities were observed in the thalamus, the medial frontal gyrus, the anterior cingulate cortex and the insula, which are involved in micturition control network. This indicates developmenta

Structural Modifications of the Brain in Acclimatization to High-Altitude

Adaptive changes in respiratory and cardiovascular responses at high altitude (HA) have been well clarified. However, the central mechanisms underlying HA acclimatization remain unclear. Using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) with fractional anisotropy (FA) calculation, we investigated 28 Han immigrant residents (17–22 yr) born and raised at HA of 2616–4200 m in Qinghai-Tibetan Plateau for at least 17 years and who currently attended college at sea-level (SL). Their family migrated from SL to HA 2–3 generations ago and has resided at HA ever since. Control subjects were matched SL residents. HA residents (vs. SL) showed decreased grey matter volume in the bilateral anterior insula, right anterior cingulate cortex, bilateral prefrontal cortex, left precentral cortex, and right lingual cortex. HA residents (vs. SL) had significantly higher FA mainly in the bilateral anterior limb of internal capsule, bilateral superior and inferior longitudinal fasciculus, corpus callosum, bilateral superior corona radiata, bilateral anterior external capsule, right posterior cingulum, and right corticospinal tract. Higher FA values in those regions were associated with decreased or unchanged radial diffusivity coinciding with no change of longitudinal diffusivity in HA vs. SL group. Conversely, HA residents had lower FA in the left optic radiation and left superior longitudinal fasciculus. Our data demonstrates that HA acclimatization is associated with brain structural modifications, including the loss of regional cortical grey matter accompanied by changes in the white matter, which may underlie the physiological adaptation of residents at HA

Gravidez na adolescência e características socioeconômicas dos municípios do Estado de São Paulo, Brasil: análise espacial Teenage pregnancy rates and socioeconomic characteristics of municipalities in São Paulo State, Southeast Brazil: a spatial analysis

A gravidez na adolescência é um problema de saúde pública comum em todo o mundo. O objetivo deste estudo ecológico é estudar o padrão espacial da associação entre os percentuais de gravidez na adolescência e características socioeconômicas dos municípios do Estado de São Paulo, Brasil. Para isso, foi utilizado um modelo bayesiano com uma distribuição espacial que segue uma estrutura condicional autorregressiva (CAR), baseado em algoritmos Monte Carlo em cadeias de Markov (MCMC). Foram usados dados do Sistema de Informações sobre Nascidos Vivos (SINASC) e do Instituto Brasileiro de Geografia e Estatística (IBGE). Verificou-se que a ocorrência de gravidezes precoces apresentou-se maior nos municípios de menor produto interno bruto (PIB) per capita, com maior incidência de pobreza, de menor tamanho populacional, menor índice de desenvolvimento humano (IDH) e maior percentual de indivíduos com índice paulista de vulnerabilidade social (IPVS) igual a 5 ou 6, ou seja, mais vulneráveis. O estudo demonstra uma estreita associação entre gravidez na adolescência e indicadores econômicos e sociais.<br>Teenage pregnancy is a common public health problem worldwide. The objective of this ecological study was to investigate the spatial association between teenage pregnancy rates and socioeconomic characteristics of municipalities in São Paulo State, Southeast Brazil. We used a Bayesian model with a spatial distribution following a conditional autoregressive (CAR) form based on Markov Chain Monte Carlo algorithm. We used data from the Live Birth Information System (SINASC) and the Brazilian Institute of Geography and Statistics (IBGE). Early pregnancy was more frequent in municipalities with lower per capital gross domestic product (GDP), higher poverty rate, smaller population, lower human development index (HDI), and a higher percentage of individuals with State social vulnerability index of 5 or 6 (more vulnerable). The study demonstrates a significant association between teenage pregnancy and socioeconomic indicators