MKS1 regulates ciliary INPP5E levels in Joubert syndrome

Background Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation \u27the molar tooth sign\u27. Mutations in \u3e 27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1- related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. Methods We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of diseaserelated MKS1 mutations. Results We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1- related JS carry \u3e1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. Conclusions MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B

Consumers' Willingness to Pay for Quality and Safety in Clams

The aim of the research is to estimate the potential demand for certified clams in Italy and to investigate the determinants of maximum amount that respondents are willing to pay for this product. Quantitative analysis was used based on 1,067 face-to-face interviews collected in 3 Italian regions in the north bordering the Adriatic Sea (Friuli-Venezia Giulia, Veneto, and Emilia-Romagna) carried out during 2008. The consumers' willingness to pay (WTP) is measured using a contingent valuation method. In order to estimate separately the determinants of the probability that respondents are willing to pay and the maximum that they are willing to pay, a generalization of Tobit model was adopted. The results indicate that consumers are willing to pay a premium price mainly to purchase better quality products. The research provides some initial insight into consumers' WTP that can be useful for certified fish farming. © 2014 Taylor & Francis Group, LLC

JINGLE V: Dust properties of nearby galaxies derived from hierarchical Bayesian SED fitting

We study the dust properties of 192 nearby galaxies from the JINGLE survey using photometric data in the 22-850μm range. We derive the total dust mass, temperature T and emissivity index β of the galaxies through the fitting of their spectral energy distribution (SED) using a single modified black-body model (SMBB). We apply a hierarchical Bayesian approach that reduces the known degeneracy between T and β. Applying the hierarchical approach, the strength of the T-β anti-correlation is reduced from a Pearson correlation coefficient R = -0.79 to R = -0.52. For the JINGLE galaxies we measure dust temperatures in the range 17 - 30 K and dust emissivity indices β in the range 0.6 - 2.2. We compare the SMBB model with the broken emissivity modified black-body (BMBB) and the two modified black-bodies (TMBB) models. The results derived with the SMBB and TMBB are in good agreement, thus applying the SMBB, which comes with fewer free parameters, does not penalize the measurement of the cold dust properties in the JINGLE sample. We investigate the relation between T and β and other global galaxy properties in the JINGLE and Herschel Reference Survey (HRS) sample. We find that β correlates with the stellar mass surface density (R = 0.62) and anti-correlates with the HI mass fraction (MHI/M*, R = -0.65), whereas the dust temperature correlates strongly with the SFR normalized by the dust mass (R = 0.73). These relations can be used to estimate T and β in galaxies with insufficient photometric data available to measure them directly through SED fitting

Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years.

BACKGROUND Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection. FUNDING Swiss HIV Cohort Study, Swiss National Science Foundation, and Gilead Sciences

Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years

BACKGROUND: Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS: In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS: Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION: In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection

JINGLE, a JCMT legacy survey of dust and gas for galaxy evolution studies: II. SCUBA-2 850 μm data reduction and dust flux density catalogues

We present the SCUBA-2 850μm component of JINGLE, the new JCMT large survey for dust and gas in nearby galaxies, which with 193 galaxies is the largest targeted survey of nearby galaxies at 850 μm. We provide details of our SCUBA-2 data reduction pipeline, optimized for slightly extended sources, and including a calibration model adjusted to match conventions used in other far-infrared (FIR) data. We measure total integrated fluxes for the entire JINGLE sample in 10 infrared/submillimetre bands, including all WISE, Herschel-PACS, Herschel-SPIRE, and SCUBA-2 850 μm maps, statistically accounting for the contamination by CO(J = 3-2) in the 850 μm band. Of our initial sample of 193 galaxies, 191 are detected at 250 μm with a ≥5σ significance. In the SCUBA-2 850 μm band we detect 126 galaxies with ≥3σ significance. The distribution of the JINGLE galaxies in FIR/sub-millimetre colour-colour plots reveals that the sample is not well fit by single modified-blackbody models that assume a single dust-emissivity index (β). Instead, our new 850 μm data suggest either that a large fraction of our objects require β < 1.5, or that a model allowing for an excess of sub-mm emission (e.g. a broken dust emissivity law, or a very cold dust component ≲10 K) is required. We provide relations to convert FIR colours to dust temperature and β for JINGLE-like galaxies. For JINGLE the FIR colours correlate more strongly with star-formation rate surface-density rather than the stellar surface-density, suggesting heating of dust is greater due to younger rather than older stellar-populations, consistent with the low proportion of early-type galaxies in the sample

PAK6 phosphorylates 14-3-3γ to regulate steady state phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain

Prevalence and association of asthma and allergic sensitization with dietary factors in schoolchildren: data from the french six cities study

International audienceBackground: The prevalence of asthma and allergy has recently risen among children. This increase in prevalence might be related to various factors, particularly diet. The aim of this study is to assess the prevalence and association of asthma and allergic sensitization with dietary factors in the French Six Cities Study. Methods: Cross-sectional studies were performed among 7432 schoolchildren aged 9-11 years in Bordeaux, Clermont-Ferrand, Creteil, Marseille, Reims, and Strasbourg. Parental questionnaires, based on the International Study on Asthma and Allergies in Childhood (ISAAC), were used to collect information on allergic diseases and potential exposure factors including a food frequency questionnaire to evaluate dietary habits. Skin prick testing to common allergens for allergic sensitization and bronchial hyper-responsiveness (BHR) testing to exercise were performed. Confounders control was performed with multiple logistic regressions. Results: Asthma symptoms, asthma and allergic sensitization were more prevalent in boys than in girls and were more prevalent in the South than in the North of France. After adjustment for confounders, fruit juice intake was associated with a low prevalence of lifetime asthma (ORa [95 % CI]; 0.73 [0.56-0.97]), butter intake was positively associated with atopic wheeze (1.48 [1.07-2.05]) and having lunch at the canteen 1-2 times/week compared to never or occasionally was associated with a lower prevalence of past year wheeze (0.71 [0.52-0.96]), lifetime asthma (0.76 [0.60-0.96]) and allergic sensitization (0.80 [0.67-0.95]). Meat intake was inversely related to past year wheeze among atopic children (0.68 [0.50-0.98]) while fast food consumption and butter intake were associated with an increase prevalence of asthma (2.39 [1.47-3.93] and 1.51 [1.17-2.00] respectively). Fish intake was associated with a lower prevalence of asthma among non-atopic children (0.61 [0.43-0.87]. None of the dietary factors was associated with BHR. Conclusions: Diet is associated with wheeze, asthma and allergic sensitization but not with BHR in children. These results provide further evidence that adherence to a healthy diet including fruits, meat and fish seems to have a protective effect on asthma and allergy in childhood. However, prospective and experimental studies are needed to provide causal evidence concerning the effect of diet on asthma and atopy

Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum

OBJECTIVE: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes. METHODS: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS. RESULTS: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31/114 gene-disease relationships curated (27%); moderate for 38 (33%); limited for 43 (38%); and 2 as disputed (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 autosomal dominant, and 3 X-linked. INTERPRETATION: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multi-system organ surveillance, recurrence risk counselling, reproductive choice, natural history studies and eligibility for interventional clinical trials. This article is protected by copyright. All rights reserved

Maternal exposure to air pollution before and during pregnancy related to changes in newborn's cord blood lymphocyte subpopulations. The EDEN study cohort

<p>Abstract</p> <p>Background</p> <p>Toxicants can cross the placenta and expose the developing fetus to chemical contamination leading to possible adverse health effects, by potentially inducing alterations in immune competence. Our aim was to investigate the impacts of maternal exposure to air pollution before and during pregnancy on newborn's immune system.</p> <p>Methods</p> <p>Exposure to background particulate matter less than 10 μm in diameter (PM₁₀) and nitrogen dioxide (NO₂) was assessed in 370 women three months before and during pregnancy using monitoring stations. Personal exposure to four volatile organic compounds (VOCs) was measured in a subsample of 56 non-smoking women with a diffusive air sampler during the second trimester of pregnancy. Cord blood was analyzed at birth by multi-parameter flow cytometry to determine lymphocyte subsets.</p> <p>Results</p> <p>Among other immunophenotypic changes in cord blood, decreases in the CD4+CD25+ T-cell percentage of 0.82% (p = 0.01), 0.71% (p = 0.04), 0.88% (p = 0.02), and 0.59% (p = 0.04) for a 10 μg/m³increase in PM₁₀levels three months before and during the first, second and third trimester of pregnancy, respectively, were observed after adjusting for confounders. A similar decrease in CD4+CD25+ T-cell percentage was observed in association with personal exposure to benzene. A similar trend was observed between NO₂exposure and CD4+CD25+ T-cell percentage; however the association was stronger between NO₂exposure and an increased percentage of CD8+ T-cells.</p> <p>Conclusions</p> <p>These data suggest that maternal exposure to air pollution before and during pregnancy may alter the immune competence in offspring thus increasing the child's risk of developing health conditions later in life, including asthma and allergies.</p