Apoptose, stress du réticulum endoplasmique et autophagie induits par les LDL oxydées dans les cellules vasculaires. Rôle protecteur des HDL et de chaperones du RE

L'athérosclérose est une pathologie multi-factorielle complexe à évolution lente caractérisée par la formation de lésions dans la paroi des artères. Le remodelage de la paroi vasculaire est associé à des réactions inflammatoires, des processus de prolifération et de mort cellulaire. Parmi les facteurs pro-athérogènes associés au développement des lésions, les lipoprotéines de basse densité (LDL) jouent un rôle prépondérant, de par leur oxydation dans l'intima. Les LDL oxydées (LDLox) sont impliquées dans la formation des lésions primaires (stries lipidiques) et possèdent des propriétés inflammatoires et apoptotiques qui pourraient participer aux phénomènes d'érosion et de rupture de plaque à l'origine des événements thrombotiques de la maladie. A l'inverse, les lipoprotéines de haute densité (HDL), ont des propriétés anti-athérogènes qui pourraient ralentir la progression des lésions. Les LDLox induisent une apoptose des cellules vasculaires, impliquant une dérégulation de l'homéostasie calcique et l'induction du stress du réticulum endoplasmique (RE). Les travaux actuels montrent que le stress du RE et l'apoptose s'accompagnent d'une réponse autophagique qui jouerait un rôle dans la survie cellulaire. Notre travail de thèse a été focalisé sur le rôle du stress du RE et de l'autophagie dans l'apoptose des cellules vasculaires induite par les LDLox, et l'effet protecteur des HDL. Dans une première partie, nous avons montré que le stress du RE est impliqué dans l'apoptose des cellules endothéliales microvasculaires HMEC-1, via l'induction du facteur proapoptotique CHOP (C/EBP homologous protein) et l'activation de la voie IRE1 (Inositol requiring kinase 1)/c-Jun N-terminal kinase (JNK), qui sont spécifiques du stress du RE. De façon concomitante au stress du RE, nous montrons que les LDLox induisent une réponse autophagique caractérisée par l'augmentation de la forme LC3-II et l'induction de la Beclin-1. L'autophagie pourrait participer à la phagocytose des cellules apoptotiques, en favorisant l'exposition des phosphatidylsérines (PS) à la surface cellulaire. Les HDL inhibent l'induction du stress du RE par les LDLox, en bloquant l'activation des senseurs IRE1a, ATF6 et du substrat de PERK eiF2a, de même que l'activation de JNK et l'induction de CHOP. Les HDL bloquent aussi la réponse autophagique et l'exposition des PS induite par les LDLox. L'activation du stress du RE et de l'autophagie par les LDLox dépend d'une dérégulation de l'homéostasie calcique intracellulaire qui est inhibée par les HDL. Dans une deuxième partie, nous avons étudié l'implication d'une chaperone du RE, la Protéine Disulfide Isomérase (PDI), dans l'apoptose induite par les LDLox. Les LDLox induisent une inhibition progressive de l'activité PDI dans les HMEC-1 et les monocytes/macrophages U937, qui pourrait jouer un rôle dans l'apoptose. L'inhibition de PDI par les LDLox dépend en partie de sa modification par les produits de la peroxydation lipidique, présents dans les LDLox comme le 4-hydroxynonénal (4-HNE) qui forment des adduits sur PDI et modifient son activité. Des adduits de 4-HNE sur PDI sont aussi détectés dans des plaques athérosclérotiques humaines suggérant une perte de fonction de PDI dans les lésions.Atherosclerosis is a multifactorial disease characterized by slowly progressive lesion formation in the arteries. The remodeling of the vascular wall is associated with inflammatory reactions, processes of proliferation and cell death. Among pro-atherogenic factors associated with lesion development, low density lipoprotein (LDL) play a key role, by their oxidation in the intima. Oxidized LDL (oxLDL) are involved in the formation of primary lesions (fatty streaks) and inflammatory and apoptotic properties that could contribute to erosion and plaque rupture at the origin of severe thrombotic disease. Conversely, high density lipoprotein (HDL), have anti-atherogenic properties that could slow the progression of lesions. The oxLDL induce apoptosis of vascular cells, involving deregulation of calcium homeostasis and induction of endoplasmic reticulum stress (ER). The current work shows that ER stress and apoptosis are accompanied by an autophagic response that may play a role in cell survival. This work was focused on the role of ER stress and autophagy in apoptosis of vascular cells induced by oxLDL, and the protective effect of HDL. In the first part, we showed that ER stress is involved in apoptosis of microvascular endothelial cells HMEC-1, via induction of ER stress specific proapoptotic factor CHOP (C / EBP homologous protein). Indeed, HMEC-1 treated with siRNA specific for CHOP, as well as fibroblasts derived from CHOP-KO mice are resistant to apoptosis induced by oxLDL. Moreover, the apoptotic role of ER stress is characterized by the activation of the IRE1a (inositol requiring kinase 1) / c-Jun N-terminal kinase (JNK) pathway. Concomitantly with ER stress, we show that oxLDL induce an autophagic response characterized by increased LC3-II form and the induction of Beclin-1. Autophagy may be involved in phagocytosis of apoptotic cells, promoting the exposure of phosphatidylserine (PS) to the cell surface. HDLs inhibit the induction of ER stress by oxLDL, blocking the activation of sensors IRE1 and ATF6 (activating transcription factor), as well as the activation of JNK and induction of CHOP. Similarly, HDL block the autophagic response and the PS exposure induced by oxLDL. Activation of ER stress and autophagy by oxLDL depends on a deregulation of intracellular calcium homeostasis which is inhibited by HDL. HDL inhibit the oxLDL propapoptotique signaling, probably via inhibition of intracellular oxidative stress. In a second part, we investigated the involvement of a chaperone of the ER, the protein disulfide isomerase (PDI) in apoptosis induced by oxLDL. The oxLDL induced a progressive inhibition of PDI activity in HMEC-1 and monocytes / macrophages, U937, which could play a role in apoptosis. Indeed, inhibition of PDI by bacitracin or by transfection of a vector encoding a PDI mutated at the site enzyme potentiates the induction of CHOPmRNA and apoptosis induced by oxLDL. The inhibition of PDI by oxLDL depends in part on its modification by lipid peroxidation products present in oxLDL such as 4-hydroxynonenal (4-HNE) that form adducts on PDI and modify its activity. An antioxidant, N-acetylcysteine (NAC) reverse the inhibitory effect of oxLDL on the enzymatic activity of PDI and prevents apoptosis. Adducts of 4-HNE on PDI were detected in human atherosclerotic plaques suggesting a loss of function of PDI in the lesions

Onomastique de l'art culinaire en France

La gastronomie et l'onomastique n'ont encore jamais fait l'objet d'étude, de manière conjointe, d'un point de vue linguistique. L objectif de cette thèse est de proposer un point de départ à une réflexion sur la structure, la nature et la place du nom propre dans la gastronomie française. Pour ce faire, après avoir exposé les différentes problématiques liées à la définition des concepts de gastronomie et de nom propre, nous avons réalisé une synthèse des principaux éléments théoriques qui servent de base à la recherche sur les noms de plats, tant sous un angle linguistique, historique qu artistique ou législatif. La nécessité d effectuer une distinction entre appellation culinaire et dénomination gastronomique selon la place qu occupe le nom de plat sur un axe nom propre / nom commun s est vite imposée et pour vérifier dans quelle mesure les types de noms propres dans les noms de plats sont conditionnés par le contexte, deux sortes de corpus ont été constitués. Sera d abord traitée l évolution du nom propre dans la gastronomie à travers le prisme de la norme dictionnairique au cours des 70 dernières années, au moyen d'une comparaison lexicographique des deux éditions du Larousse Gastronomique (1938 et 2007). Pour ce faire, une catégorisation des noms propres relevés dans le corpus a été établie. Dans un deuxième temps, la place des noms propres dans un corpus témoignant de l usage a été examinée, en rassemblant des menus de restaurants parisiens ainsi que des dépliants publicitaires de la restauration livrée.Gastronomy and onomastics have never previously been the subject of a joint study from a linguistic point of view. The objective of this thesis is to provide a starting point for research on the structure, nature and place of proper names in French gastronomy. After considering the various problems related to the definition of such concepts as gastronomy and proper name, we achieved a synthesis of the main theoretical elements that form the basis for research on the names of dishes from a linguistic, artistic, historic or legislative perspective. Then, a distinction was made between culinary denomination and gastronomic designation in relation to the place of a dish name on a proper name / common name axis, although the separation between the two poles is sometimes blurred and cannot be considered to be strict. Two kinds of corpus are established in order to verify that the types of proper names in gastronomy depend on the context where dish names originate. First, the evolution of the proper name in gastronomy over the past 70 years is studied from a normative perspective through the lexical comparison of the first and the latest editions of the Larousse Gastronomique (1938 and 2007) and the establishment of a categorization of proper names. Second, proper names in a corpus reflecting the use was examined using Parisian restaurant menus and flyers advertising for food delivery. The comparison of the results for the two types of corpus will shed light on the differences, both quantitative and classificatory, in the use of proper names in a normative or in a creative context.NANTERRE-PARIS10-Bib. élec. (920509901) / SudocSudocFranceF

A note on connected greedy edge colouring

Following a given ordering of the edges of a graph $G$, the greedy edge colouring procedure assigns to each edge the smallest available colour. The minimum number of colours thus involved is the chromatic index $\chi'(G)$, and the maximum is the so-called Grundy chromatic index. Here, we are interested in the restricted case where the ordering of the edges builds the graph in a connected fashion. Let $\chi_c'(G)$ be the minimum number of colours involved following such an ordering. We show that it is NP-hard to determine whether $\chi_c'(G)>\chi'(G)$. We prove that $\chi'(G)=\chi_c'(G)$ if $G$ is bipartite, and that $\chi_c'(G)\leq 4$ if $G$ is subcubic.Comment: Comments welcome, 12 page

Impacts multi-échelles d'un échange (Mg, Ca)-Pb et ses conséquences sur l'augmentation de la perméabilité d'une bentonite.

The article addresses the structural effects of solutions of lead nitrate on a suspended or compacted bentonite. A permeability increase is observed on compacted clay. Investigating the composition of output solution, using X-Rays Diffusion at Small Angles and Scanning Electron Microscopy, this permeability increase is explained from structural variations at nanometric (reduction of particle size) and micrometric scales (microfissuration of aggregates)

Packing and covering balls in graphs excluding a minor

We prove that for every integer $t\ge 1$ there exists a constant $c_t$ such that for every $K_t$-minor-free graph $G$, and every set $S$ of balls in $G$, the minimum size of a set of vertices of $G$ intersecting all the balls of $S$ is at most $c_t$ times the maximum number of vertex-disjoint balls in $S$. This was conjectured by Chepoi, Estellon, and Vax\`es in 2007 in the special case of planar graphs and of balls having the same radius.Comment: v3: final versio

Community Introduction of Practice Parameters for Autistic Spectrum Disorders: Advancing Early Recognition

Objectives: Within a strong interdisciplinary framework, improvement in the quality of care for children with autistic spectrum disorders through a 2year implementation program of Practice Parameters, aimed principally at improving early detection and intervention. Method: We developed Practice Parameters (PPs) for Pervasive Developmental Disorders and circulated the PPs to all child and adolescent psychiatrists practicing in the region. Results: PP development and parallel information strategies resulted in a significant decrease of 1.5years in the mean-age-at-diagnosis. However, further analysis indicated that improvement was only transient. Conclusion: Despite the encouraging improvement in mean-age-at-diagnosis 2years after PP implementation, other indicators showed a failure to maintain the improvements. A systematic screening program would be the most reliable method to reinforce the PP

Effect of high temperatures on sex ratio and differential expression analysis (RNA-seq) of sex-determining genes in <i>Oreochromis niloticus</i> from different river basins in Benin

peer reviewedAbstract The high temperature sex reversal process leading to functional phenotypic masculinization during development has been widely described in Nile tilapia (Oreochromis niloticus) under laboratory or aquaculture conditions and in the wild. In this study, we selected five wild populations of O. niloticus from different river basins in Benin and produced twenty full-sib families of mixed-sex (XY and XX) by natural reproduction. Progenies were exposed to room temperature or high (36.5°C) temperatures between 10 and 30 days post-fertilization (dpf). In control groups, we observed sex ratios from 40 to 60% males as expected, except for 3 families from the Gobé region which showed a bias towards males. High temperature treatment significantly increased male rates in each family up to 88%. Transcriptome analysis was performed by RNA-sequencing (RNA-seq) on brains and gonads from control and treated batches of six families at 15 dpf and 40 dpf. Analysis of differentially expressed genes, differentially spliced genes, and correlations with sex reversal was performed. In 40 dpf gonads, genes involved in sex determination such as dmrt1, cyp11c1, amh, cyp19a1b, ara, and dax1 were upregulated. In 15 dpf brains, a negative correlation was found between the expression of cyp19a1b and the reversal rate, while at 40 dpf a negative correlation was found between the expression of foxl2, cyp11c1, and sf1 and positive correlation was found between dmrt1 expression and reversal rate. Ontology analysis of the genes affected by high temperatures revealed that male sex differentiation processes, primary male sexual characteristics, autophagy, and cilium organization were affected. Based on these results, we conclude that sex reversal by high temperature treatment leads to similar modifications of the transcriptomes in the gonads and brains in offspring of different natural populations of Nile tilapia, which thus may activate a common cascade of reactions inducing sex reversal in progenies

Smoking cessation and depression after acute coronary syndrome.

Smoking and depression are risk factors for acute coronary syndrome (ACS) that often co-exist. We investigated the evolution of depression according to smoking cessation one-year after ACS. Data from 1822 ACS patients of the Swiss multicenter SPUM-ACS cohort study were analyzed over a one-year follow-up. Participants were classified in three groups based on smoking status one-year post-ACS - continuous smokers, smokers who quit within the year, and non-smokers. Depression status at baseline and one-year was assessed with the Center for Epidemiologic Studies Depression scale (CES-D) and antidepressant drug use. A CES-D score ≥ 16 defined depression. A multivariate-adjusted logistic regression model was used to calculate odds ratios (OR) between groups. The study sample mean age was 62.4 years and females represented 20.8%. At baseline, 22.6% were depressed, 40.9% were smokers, and 47.5% of these quit smoking over the year post-ACS. In comparison to depressed continuous smokers, depressed smokers who quit had an adjusted OR 2.59 (95% confidence interval (CI) 1.27-5.25) of going below a CES-D score of 16 or not using antidepressants. New depression at one-year was found in 24.4% of non-depressed smokers who quit, and in 27.1% of non-depressed continuous smokers, with an adjusted OR 0.85 (95% CI 0.55-1.29) of moving to a CES-D score of ≥16 or using antidepressants. In conclusion, smokers with depression at time of ACS who quit smoking improved their depression more frequently compared to continuous smokers. The incidence of new depression among smokers who quit after ACS was similar compared to continuous smokers

Elucidating tumour-associated microglia/macrophage diversity along glioblastoma progression and under ACOD1 deficiency

In glioblastoma (GBM), tumour-associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical features for the design of effective TAM-targeted therapies. Here, we comprehensively study the cellular and molecular changes of TAMs in the GL261 GBM mouse model, combining single-cell RNA-sequencing with flow cytometry and immunohistological analyses along GBM progression and in the absence of Acod1 (also known as Irg1), a key gene involved in the metabolic reprogramming of macrophages towards an anti-inflammatory phenotype. Similarly to patients, we identify distinct TAM profiles, mainly based on their ontogeny, that reiterate the idea that microglia- and macrophage-like cells show key transcriptional differences and dynamically adapt along GBM stages. Notably, we uncover decreased antigen-presenting cell features and immune reactivity in TAMs along tumour progression that are instead enhanced in Acod1-deficient mice. Overall, our results provide insight into TAM heterogeneity and highlight a novel role for Acod1 in TAM adaptation during GBM progression.publishedVersio