Distinct Transcriptome Expression of the Temporal Cortex of the Primate Microcebus murinus during Brain Aging versus Alzheimer's Disease-Like Pathology

Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, “AD-like” animals that presented ß-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and “AD-like” animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and “AD-like” in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in “AD-like” animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the “AD-like” group. Functional categorization showed that most of the genes that were up-regulated in healthy old animals and down-regulated in “AD-like” animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in “AD-like” animals. These results open the way to new exploration of physiological and “AD-like” aging in primates

NGF Causes TrkA to Specifically Attract Microtubules to Lipid Rafts

Membrane protein sorting is mediated by interactions between proteins and lipids. One mechanism that contributes to sorting involves patches of lipids, termed lipid rafts, which are different from their surroundings in lipid and protein composition. Although the nerve growth factor (NGF) receptors, TrkA and p75NTR collaborate with each other at the plasma membrane to bind NGF, these two receptors are endocytosed separately and activate different cellular responses. We hypothesized that receptor localization in membrane rafts may play a role in endocytic sorting. TrkA and p75NTR both reside in detergent-resistant membranes (DRMs), yet they responded differently to a variety of conditions. The ganglioside, GM1, caused increased association of NGF, TrkA, and microtubules with DRMs, but a decrease in p75NTR. When microtubules were induced to polymerize and attach to DRMs by in vitro reactions, TrkA, but not p75NTR, was bound to microtubules in DRMs and in a detergent-resistant endosomal fraction. NGF enhanced the interaction between TrkA and microtubules in DRMs, yet tyrosine phosphorylated TrkA was entirely absent in DRMs under conditions where activated TrkA was detected in detergent-sensitive membranes and endosomes. These data indicate that TrkA and p75NTR partition into membrane rafts by different mechanisms, and that the fraction of TrkA that associates with DRMs is internalized but does not directly form signaling endosomes. Rather, by attracting microtubules to lipid rafts, TrkA may mediate other processes such as axon guidance

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Measurements of prompt charm production cross-sections in pp collisions at s=5 \sqrt{s}=5 TeV

See paper for full list of authors - All figures and tables, along with any supplementary material and additional information, are available at this https URL - Submitted to JHEPInternational audienceProduction cross-sections of prompt charm mesons are measured using data from pp collisions at the LHC at a centre-of-mass energy of 5TeV. The data sample corresponds to an integrated luminosity of 8.60±0.33pb−1 collected by the LHCb experiment. The production cross-sections of D0, D+, D+s, and D∗+ mesons are measured in bins of charm meson transverse momentum, pT, and rapidity, y. They cover the rapidity range 2.0<y<4.5 and transverse momentum ranges 0<pT<10GeV/c for D0 and D+ and 1<pT<10GeV/c for D+s and D∗+ mesons. The inclusive cross-sections for the four mesons, including charge-conjugate states, within the range of 1<pT<8GeV/c are determined to beσ(pp→D0X)=1190±3±64μbσ(pp→D+X)=456±3±34μbσ(pp→D+sX)=195±4±19μbσ(pp→D∗+X)=467±6±40μbwhere the uncertainties are statistical and systematic, respectively

Time and age trends in smoking cessation in Europe

Background Smoking is the main risk factor for most of the leading causes of death. Cessation is the single most important step that smokers can take to improve their health. With the aim of informing policy makers about decisions on future tobacco control strategies, we estimated time and age trends in smoking cessation in Europe between 1980 and 2010. Methods Data on the smoking history of 50,228 lifetime smokers from 17 European countries were obtained from six large population-based studies included in the Ageing Lungs in European Cohorts (ALEC) consortium. Smoking cessation rates were assessed retrospectively, and age trends were estimated for three decades (1980–1989, 1990–1999, 2000–2010). The analyses were stratified by sex and region (North, East, South, West Europe). Results Overall, 21,735 subjects (43.3%) quit smoking over a total time-at-risk of 803,031 years. Cessation rates increased between 1980 and 2010 in young adults (16–40 years), especially females, from all the regions, and in older adults (41–60 years) from North Europe, while they were stable in older adults from East, South and West Europe. In the 2000s, the cessation rates for men and women combined were highest in North Europe (49.9 per 1,000/year) compared to the other regions (range: 26.5–32.7 per 1,000/year). A sharp peak in rates was observed for women around the age of 30, possibly as a consequence of pregnancy-related smoking cessation. In most regions, subjects who started smoking before the age of 16 were less likely to quit than those who started later. Conclusions Our findings suggest an increasing awareness on the detrimental effects of smoking across Europe. However, East, South and West European countries are lagging behind North Europe, suggesting the need to intensify tobacco control strategies in these regions. Additional efforts should be made to keep young adolescents away from taking up smoking, as early initiation could make quitting more challenging during later life

Florilege : a database gathering microbial phenotypes of food interest

Food fermentation and biopreservation processes involve the use of various species and strains of bacteria and yeast. These strains are responsible for the targeted qualities of the food products that are sanitary, organoleptic (aroma and texture) and healthy qualities. The Florilege database project aims at (i) gathering bacterial and yeast phenotypes of food product of interest that are automatically extracted from PubMed-referenced full-text litterature by using a text mining approach (ii) managing the information in a relational database (iii) enabling multi-criteria requests via a Web user-friendly interface. To date 368 phenotypes, 260 synthetised or degraded molecules, 1076 medium or food products, 1181 bacterial taxons have been acquired by a combinaison of automatic and manual annotations of text, used for training the text-mining method.Food products are automatically categorized in Florilege according to the OntoBiotope ontology that we have extended with dairy and bakery products definitions. Taxa are categorized by the NCBI taxonomy. An ontology of microbial characteristics has been specifically enriched by the Florilege project. This ontology defines microbial phenotypes (Ontobiotope-Phenotype), including intracellular characteristics of cells (such as shape, antibiotic resistance...) and microbial uses (Ontobiotope-Use) that express the microbial alteration of the external environment, food or matrix, such as aroma, vitamin or other molecule production, degradation or food coloring.A preliminary Web interface is available for querying taxa, culture medium and food products at http://genome.jouy.inra.fr/Florilege/. The public availability of Florilege database is planned for the end of 2017 with a user-friendly interface for multi-criteria requests and access to various phenotypes.Florilege will be a highly valuable tool to (i) assess phenotypic biodiversity of food microbes (ii) assign biochemical functions to each strain/species from fermented or biopreserved food products (iii) help into the development of innovative food products in particular those that involve fermentation or biopreservation processes