Mapping the Distribution of Invasive Staphylococcus aureus across Europe

Franklin Lowy discusses a new study in PLoS Medicine in which the investigators developed an interactive tool for analyzing the spatial distribution of invasive Staphylococcus aureus

A combinatorial TIR1/AFB–Aux/IAA co-receptor system for differential sensing of auxin

The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires assembly of an auxin co-receptor complex consisting of TIR1 and an Aux/IAA protein. Heterologous experiments in yeast and quantitative IAA binding assays using purified proteins showed that different combinations of TIR1 and Aux/IAA proteins form co-receptor complexes with a wide range of auxin-binding affinities. Auxin affinity seems to be largely determined by the Aux/IAA. As there are 6 TIR1/AUXIN SIGNALING F-BOX proteins (AFBs) and 29 Aux/IAA proteins in Arabidopsis thaliana, combinatorial interactions may result in many co-receptors with distinct auxin-sensing properties. We also demonstrate that the AFB5–Aux/IAA co-receptor selectively binds the auxinic herbicide picloram. This co-receptor system broadens the effective concentration range of the hormone and may contribute to the complexity of auxin response

E-Cadherin Destabilization Accounts for the Pathogenicity of Missense Mutations in Hereditary Diffuse Gastric Cancer

E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo

Blood neutrophil counts are associated with exacerbation frequency and mortality in COPD

BACKGROUND: Identifying patients with COPD at increased risk of poor outcomes is challenging due to disease heterogeneity. Potential biomarkers need to be readily available in real-life clinical practice. Blood eosinophil counts are widely studied but few studies have examined the prognostic value of blood neutrophil counts (BNC). METHODS: In a large population-based COPD registry in the East of Scotland (TARDIS: Tayside Allergic and Respiratory Disease Information System), BNC were compared to measures of disease severity and mortality for up to 15 years follow-up. Potential mechanisms of disease modification by BNC were explored in a nested microbiome substudy. RESULTS: 178,120 neutrophil counts were obtained from 7220 people (mean follow up 9 years) during stable disease periods. Median BNC was 5200cells/μL (IQR 4000-7000cells/μL). Mortality rates among the 34% of patients with elevated BNCs (defined as 6000-15000cells/μL) at the study start were 80% higher (14.0/100 person years v 7.8/100py, P < 0.001) than those with BNC in the normal range (2000-6000cells/μL). People with elevated BNC were more likely to be classified as GOLD D (46% v 33% P < 0.001), have more exacerbations (mean 2.3 v 1.3/year, P < 0.001), and were more likely to have severe exacerbations (13% vs. 5%, P < 0.001) in the following year. Eosinophil counts were much less predictive of these outcomes. In a sub-cohort (N = 276), patients with elevated BNC had increased relative abundance of Proteobacteria and reduced microbiome diversity. CONCLUSIONS: High BNC may provide a useful indicator of risk of exacerbations and mortality in COPD patients

Relacao entre o nivel de atividade fisica estimado pelo Baltimore Activity Scale for Intermittent Claudication e a pedometria em pacientes com claudicacao intermitente

CONTEXTO: Os pacientes com claudicação intermitente apresentam níveis reduzidos de atividade física. A Baltimore Activity Scale for Intermittent Claudication (BASIC) foi validada para quantificar o nível de atividade física destes pacientes. No entanto, esta validação se baseou em apenas dois dias de monitoramento com acelerômetros, de modo que ainda permanece incerto se a BASIC fornece informações sobre os níveis de atividade física semanal. OBJETIVO: Analisar a correlação entre o nível de atividade física estimada pela BASIC e o nível obtido pelo pedômetro em uma semana, em pacientes com claudicação intermitente. MÉTODOS: Foram estudados 150 pacientes com claudicação intermitente, com idade entre 30 e 80 anos. Foram obtidos os dados sociodemográficos e verificada a presença de comorbidades e de fatores de risco cardiovascular, e a BASIC. O pedômetro foi utilizado por sete dias consecutivos, sendo a análise feita em três diferentes períodos de monitorização (todos os dias, dias da semana e do fim de semana). RESULTADOS: Foi observada correlação entre a BASIC e a média de passos de todos os dias (rho=0,343; p<0,001), dos dias de semana (rho=0,336; p<0,001) e dos dias do final de semana (rho=0,317; p<0,001). CONCLUSÃO: Em pacientes com claudicação intermitente, o nível de atividade física estimado pela BASIC se correlaciona com o nível de atividade física semanal