New insights into the role of endosomal proteins for African swine fever virus infection.

African swine fever virus (ASFV) infectious cycle starts with the viral adsorption and entry into the host cell. Then, the virus is internalized via clathrin/dynamin mediated endocytosis and macropinocytosis. Similar to other viruses, ASF virion is then internalized and incorporated into the endocytic pathway. While the endosomal maturation entails luminal acidification, the decrease in pH acts on the multilayer structure of the virion dissolving the outer capsid. Upon decapsidation, the inner viral membrane is exposed to interact with the limiting membrane of the late endosome for fusion. Viral fusion is then necessary for the egress of incoming virions from endosomes into the cytoplasm, however this remains an intriguing and yet essential process for infection, specifically for the egress of viral nucleic acid into the cytoplasm for replication. ASFV proteins E248R and E199L, located at the exposed inner viral membrane, might be implicated in the fusion step. An interaction between these viral proteins and cellular endosomal proteins such as the Niemann-Pick C type 1 (NPC1) and lysosomal membrane proteins (Lamp-1 and -2) was shown. Furthermore, the silencing of these proteins impaired ASFV infection. It was also observed that NPC1 knock-out cells using CRISPR jeopardized ASFV infection and that the progression and endosomal exit of viral cores was arrested within endosomes at viral entry. These results suggest that the interactions of ASFV proteins with some endosomal proteins might be important for the membrane fusion step. In addition to this, reductions on ASFV infectivity and replication in NPC1 KO cells were accompanied by fewer and smaller viral factories. Our findings pave the way to understanding the role of proteins of the endosomal membrane in ASFV infection.

Association between long work hours and poor self-reported general health among Latin American immigrant and native workers in the United States and Spain.

BACKGROUND: The relationship between hours worked per week and self-reported general health (SRGH) has not been assessed in Latin American immigrant and native workers across host countries. METHODS: Cross-sectional study of the association between long work hours (LWH) (i.e., >51 hr per week) and poor SRGH using data from 2,626 workers in the United States (immigrants = 10.4%) and 8,306 workers in Spain (immigrants = 4.1%). RESULTS: Both countries' natives working >51 hr per week had increased odds of reporting poor SRGH compared to those working fewer hours (U.S.: OR = 1.59; 95%CI = 1.01-2.49; Spain: OR = 2.17; 95%CI = 1.71-2.75); when stratified by sex, increased odds also were observed among immigrant female workers in Spain (OR = 3.47; 95%CI = 1.15-10.5). CONCLUSIONS: LWH were associated with differential health outcomes in populations of native and Latin American immigrant workers in the United States and Spain, which may reflect social or occupational inequalities in general or resulting from the 2008 financial crisis. Am. J. Ind. Med. 59:1105-1111, 2016. © 2016 Wiley Periodicals, Inc.

A common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice.

Objective: Genome wide association studies have identified an exon 6 CTRB2 deletion variant that associates with increased risk of pancreatic cancer. To acquire evidence on its causal role, we developed a new mouse strain carrying an equivalent variant in Ctrb1 , the mouse orthologue of CTRB2 . Design: We used CRISPR/Cas9 to introduce a 707bp deletion in Ctrb1 encompassing exon 6 ( Ctrb1 Δexon6 ). This mutation closely mimics the human deletion variant. Mice carrying the mutant allele were extensively profiled at 3 months to assess their phenotype. Results: Ctrb1 Δexon6 mutant mice express a truncated CTRB1 that accumulates in the ER. The pancreas of homozygous mutant mice displays reduced chymotrypsin activity and total protein synthesis. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic analyses of the pancreas of mutant mice reveals acinar program down-regulation and increased activity of ER stress-related and inflammatory pathways. Heterozygous mice have an intermediate phenotype. Agr2 is one of the most up-regulated genes in mutant pancreata. Ctrb1 Δexon6 mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of TUDCA or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort. Conclusions: This mouse strain provides formal evidence that the Ctrb1 Δexon6 variant causes ER stress and inflammation in vivo , providing an excellent model to understand its contribution to pancreatic ductal adenocarcinoma development and to identify preventive strategies. SUMMARY BOX: What is already known about this subject?: - CTRB2 is one of the most abundant proteins produced by human pancreatic acinar cells. - A common exon 6 deletion variant in CTRB2 has been associated with an increased risk of pancreatic ductal adenocarcinoma. - Misfolding of digestive enzymes is associated with pancreatic pathology.What are the new findings?: - We developed a novel genetic model that recapitulates the human CTRB2 deletion variant in the mouse orthologue, Ctrb1 . - Truncated CTRB1 misfolds and accumulates in the ER; yet, mutant mice display a histologically normal pancreas at 3 months age.- CTRB1 and associated chaperones colocalize in the ER, the cytoplasm, and the nucleus of acinar cells.- Transcriptomics analysis reveals reduced activity of the acinar program and increased activity of pathways involved in ER stress, unfolded protein response, and inflammation.- Mutant mice are sensitized to pancreatic damage and do not recover properly from a mild caerulein-induced pancreatitis.- TUDCA administration partially relieves the ER stress in mutant mice.How might it impact on clinical practice in the foreseeable future?: - The new mouse model provides a tool to identify the mechanisms leading to increased pancreatic cancer risk in CTRB2 exon 6 carriers. - The findings suggest that drugs that cause ER stress relief and/or reduce inflammation might provide preventive opportunities.

Growth hormone remodels the 3D-structure of the mitochondria of inflammatory macrophages and promotes metabolic reprogramming.

Introduction: Macrophages are a heterogeneous population of innate immune cells that support tissue homeostasis through their involvement in tissue development and repair, and pathogen defense. Emerging data reveal that metabolism may control macrophage polarization and function and, conversely, phenotypic polarization may drive metabolic reprogramming. Methods: Here we use biochemical analysis, correlative cryogenic fluorescence microscopy and cryo-focused ion-beam scanning electron microscopy. Results: We demonstrate that growth hormone (GH) reprograms inflammatory GM-CSF-primed monocyte-derived macrophages (GM-MØ) by functioning as a metabolic modulator. We found that exogenous treatment of GM-MØ with recombinant human GH reduced glycolysis and lactate production to levels similar to those found in anti-inflammatory M-MØ. Moreover, GH treatment of GM-MØ augmented mitochondrial volume and altered mitochondrial dynamics, including the remodeling of the inner membrane to increase the density of cristae. Conclusions: Our data demonstrate that GH likely serves a modulatory role in the metabolism of inflammatory macrophages and suggest that metabolic reprogramming of macrophages should be considered as a new target to intervene in inflammatory diseases.

[Health status among immigrant in Catalonia from a gender perspective: PELFI project]. / Estado de salud de personas inmigrantes en Cataluña desde una perspectiva de género: Proyecto PELFI.

OBJECTIVE: The objective of the study is to assess the health status of immigrant men and women from non-EU countries living in the Metropolitan Area of Barcelona (Catalonia, Spain) and to identify the social determinants of health from a gender perspective. METHOD: Cross-sectional analysis from a cohort of immigrant families recruited in Badalona and Santa Coloma de Gramenet, in Spain (PELFI cohort). In 2015-2016, 167 immigrants answered the baseline epidemiological questionnaire and the 5-level EuroQol instrument (EQ-5D) which measures health status. To identify health determinants, Tobit models were constructed to the EQ-5D index. RESULTS: Women rated poorer self-perceived health (p=0.005). To be diagnosed with and illness was only associated with poor self-perceived health among men (p<0.05). Length of residence, domestic work, and especially double workload deteriorated women's health. After adjusting models by demographics and social determinants, permanent administrative status (-0.136; p=0.015) and social support (0.182; p=0.02) were associated with health status in both sexes. To have a job was associated with better health only in men. CONCLUSIONS: Non-EU immigrants living in the Metropolitan Area of Barcelona are a socially vulnerable group of population and present inequalities in health by sex. Social support and occupation are key factors of their health status. Interventions to reduce immigrant vulnerabilities and inequalities in health should promote their social inclusion and cohesion from a gender perspective.

Estado de salud de personas inmigrantes en Cataluña desde una perspectiva de género: proyecto PELFI / Health status among immigrant in Catalonia from a gender perspective: PELFI project

Objetivo: Evaluar el estado de salud de hombres y mujeres inmigrantes extracomunitarios residentes en el Área Metropolitana de Barcelona (Cataluña, España) e identificar determinantes sociales de la salud desde una perspectiva de género. Método: Análisis transversal de una cohorte de familias inmigrantes reclutadas en Badalona y Santa Coloma de Gramenet (cohorte PELFI). En 2015-2016, 167 inmigrantes respondieron al cuestionario epidemiológico basal y al instrumento EuroQol de cinco dimensiones (EQ-5D) que mide el estado de salud. Para identificar determinantes de la salud se construyeron modelos Tobit con el índice EQ-5D. Resultados: Las mujeres declararon una peor salud percibida (p=0,005). Tener una enfermedad diagnosticada se asoció con una peor percepción de la salud en los hombres (p<0,05). El tiempo de estancia y las cargas familiares, en especial la doble jornada de trabajo, empeoraron la salud percibida de las mujeres. En el modelo ajustado por variables demográficas y determinantes sociales, la situación administrativa estable (−0.136; p=0,015) y el apoyo social (0,182; p=0,02) se asociaron con el índice EQ-5D en ambos sexos. Estar ocupado se asoció a mejor salud en los hombres. Conclusiones: Las personas inmigrantes extracomunitarias residentes en el Área Metropolitana de Barcelona son una población vulnerable y presentan desigualdades en salud por sexo. El apoyo social y la ocupación son factores clave de su estado de salud. Las intervenciones para reducir las vulnerabilidades y desigualdades en salud de las personas inmigrantes deberían promover su inclusión y cohesión social, e incorporar la perspectiva de género. (AU)

Objective: The objective of the study is to assess the health status of immigrant men and women from non-EU countries living in the Metropolitan Area of Barcelona (Catalonia, Spain) and to identify the social determinants of health from a gender perspective. Method: Cross-sectional analysis from a cohort of immigrant families recruited in Badalona and Santa Coloma de Gramenet, in Spain (PELFI cohort). In 2015-2016, 167 immigrants answered the baseline epidemiological questionnaire and the 5-level EuroQol instrument (EQ-5D) which measures health status. To identify health determinants, Tobit models were constructed to the EQ-5D index. Results: Women rated poorer self-perceived health (p=0.005). To be diagnosed with and illness was only associated with poor self-perceived health among men (p<0.05). Length of residence, domestic work, and especially double workload deteriorated women's health. After adjusting models by demographics and social determinants, permanent administrative status (−0.136; p=0.015) and social support (0.182; p=0.02) were associated with health status in both sexes. To have a job was associated with better health only in men. Conclusions: Non-EU immigrants living in the Metropolitan Area of Barcelona are a socially vulnerable group of population and present inequalities in health by sex. Social support and occupation are key factors of their health status. Interventions to reduce immigrant vulnerabilities and inequalities in health should promote their social inclusion and cohesion from a gender perspective. (AU)

The Impact of Education and Socioeconomic and Occupational Conditions on Self-Perceived and Mental Health Inequalities Among Immigrants and Native Workers in Spain.

There is limited evidence on the influence of social determinants on the self-perceived and mental health of immigrants settled at least 8 years in Spain. The aim of this study was to examine differences between workers related to migrant-status, self-perceived and mental health, and to assess their relationship to occupational conditions, educational level and occupational social class, stratified by sex. Using data from the Spanish National Health Survey of 2011/12, we computed prevalence, odds ratios and explicative fractions. Mental (OR 2.02; CI 1.39-2.93) and self-perceived health (OR 2.64; CI 1.77-3.93) were poorer for immigrant women compared to natives. Occupational social class variable contributes 25% to self-perceived health OR in immigrant women. Settled immigrant women workers are a vulnerable group in Spain.