ER stress activates the NLRP3 inflammasome via an UPR-independent pathway.

Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1β. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.

The role of the Fanconi anemia network in the response to DNA replication stress.

Fanconi anemia is a genetically heterogeneous disorder associated with chromosome instability and a highly elevated risk for developing cancer. The mutated genes encode proteins involved in the cellular response to DNA replication stress. Fanconi anemia proteins are extensively connected with DNA caretaker proteins, and appear to function as a hub for the coordination of DNA repair with DNA replication and cell cycle progression. At a molecular level, however, the raison d'être of Fanconi anemia proteins still remains largely elusive. The thirteen Fanconi anemia proteins identified to date have not been embraced into a single and defined biological process. To help put the Fanconi anemia puzzle into perspective, we begin this review with a summary of the strategies employed by prokaryotes and eukaryotes to tolerate obstacles to the progression of replication forks. We then summarize what we know about Fanconi anemia with an emphasis on biochemical aspects, and discuss how the Fanconi anemia network, a late acquisition in evolution, may function to permit the faithful and complete duplication of our very large vertebrate chromosomes.

Apprendre dans l'urgence

Nous avons effectué une étude dans le but d'investiger les stratégies utilisées par les ambulanciers pour préserver leur santé. Parmi les stratégies que nous avons identifiées, celles contribuant au maintien et au développement des compétences nous ont semblé particulièrement intéressantes car elles permettent de réduire le stress lié à la peur de l'erreur. Elles permettent aussi aux ambulanciers "d'apprivoiser l'urgence" en leur donnant la possibilité de jouer un rôle actif face aux difficultés rencontrées. Nous présentons quelques-unes de ces stratégies dans cet article.

Fecundity and survival in relation to resistance to oxidative stress in a free-living bird.

Major life history traits, such as fecundity and survival, have been consistently demonstrated to covary positively in nature, some individuals having more resources than others to allocate to all aspects of their life history. Yet, little is known about which resources (or state variables) may account for such covariation. Reactive oxygen species (ROS) are natural by-products of metabolism and, when ROS production exceeds antioxidant defenses, organisms are exposed to oxidative stress that can have deleterious effects on their fecundity and survival. Using a wild, long-lived bird, the Alpine Swift (Apus melba), we examined whether individual red cell resistance to oxidative stress covaried with fecundity and survival. We found that males that survived to the next breeding season tended to be more resistant to oxidative stress, and females with higher resistance to oxidative stress laid larger clutches. Furthermore, the eggs of females with low resistance to oxidative stress were less likely to hatch than those of females with high resistance to oxidative stress. By swapping entire clutches at clutch completion, we then demonstrated that hatching failure was related to the production of low-quality eggs by females with low resistance to oxidative stress, rather than to inadequate parental care during incubation. Although male and female resistance to oxidative stress covaried with age, the relationships among oxidative stress, survival, and fecundity occurred independently of chronological age. Overall, our study suggests that oxidative stress may play a significant role in shaping fecundity and survival in the wild. It further suggests that the nature of the covariation between resistance to oxidative stress and life history traits is sex specific, high resistance to oxidative stress covarying primarily with fecundity in females and with survival in males.

Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that can be activated by fatty acids and peroxisome proliferators. The PPAR alpha subtype mediates the pleiotropic effects of these activators in liver and regulates several target genes involved in fatty acid catabolism. In primary hepatocytes cultured in vitro, the PPAR alpha gene is regulated at the transcriptional level by glucocorticoids. We investigated if this hormonal regulation also occurs in the whole animal in physiological situations leading to increased plasma corticosterone levels in rats. We show here that an immobilization stress is a potent and rapid stimulator of PPAR alpha expression in liver but not in hippocampus. The injection of the synthetic glucocorticoid dexamethasone into adult rats produces a similar increase in PPAR alpha expression in liver, whereas the administration of the antiglucocorticoid RU 486 inhibits the stress-dependent stimulation. We conclude that glucocorticoids are major mediators of the stress response. Consistent with this hormonal regulation, hepatic PPAR alpha mRNA and protein levels follow a diurnal rhythm, which parallels that of circulating corticosterone. To test the effects of variations in PPAR alpha expression on PPAR alpha target gene activity, high glucocorticoid-dependent PPAR alpha expression was mimicked in cultured primary hepatocytes. Under these conditions, hormonal stimulation of receptor expression synergizes with receptor activation by WY-14,643 to induce the expression of the PPAR alpha target gene acyl-CoA oxidase. Together, these results show that regulation of the PPAR alpha expression levels efficiently modulates PPAR activator signaling and thus may affect downstream metabolic pathways involved in lipid homeostasis.

Biomarkers of oxidative stress and its association with the urinary reducing capacity in bus maintenance workers.

BACKGROUND: Exposure to particles (PM) induces adverse health effects (cancer, cardiovascular and pulmonary diseases). A key-role in these adverse effects seems to be played by oxidative stress, which is an excess of reactive oxygen species relative to the amount of reducing species (including antioxidants), the first line of defense against reactive oxygen species. The aim of this study was to document the oxidative stress caused by exposure to respirable particles in vivo, and to test whether exposed workers presented changes in their urinary levels for reducing species.METHODS: Bus depot workers (n = 32) exposed to particles and pollutants (respirable PM4, organic and elemental carbon, particulate metal content, polycyclic aromatic hydrocarbons, NOx, O3) were surveyed over two consecutive days. We collected urine samples before and after each shift, and quantified an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine), the reducing capacity and a biomarker of PAH exposure (1-hydroxypyrene). We used a linear mixed model to test for associations between the oxidative stress status of the workers and their particle exposure as well as with their urinary level of reducing species.RESULTS: Workers were exposed to low levels of respirable PM4 (range 25-71 μg/m3). However, urinary levels of 8-hydroxy-2'-deoxyguanosine increased significantly within each shift and between both days for non-smokers. The between-day increase was significantly correlated (p < 0.001) with the concentrations of organic carbon, NOx, and the particulate copper content. The within-shift increase in 8OHdG was highly correlated to an increase of the urinary reducing capacity (Spearman ρ = 0.59, p < 0.0001).CONCLUSIONS: These findings confirm that exposure to components associated to respirable particulate matter causes a systemic oxidative stress, as measured with the urinary 8OHdG. The strong association observed between urinary 8OHdG with the reducing capacity is suggestive of protective or other mechanisms, including circadian effects. Additional investigations should be performed to understand these observations.

Jevons et Walras : entre philosophie morale et économie sociale, un jalon dans la compréhension de la décision publique

This PhD dissertation deals with the question of evaluating social welfare and public policy making through the works of William Stanley Jevons (1835-1882) and Léon Walras (1834-1910), two economists who lived in the 19th century. These authors, well-known for their analyses on pure economics, were also deeply interested in the social problems of their time and proposed solutions to remedy them. In accordance with utilitarianism, Jevons was convinced that the reforms implemented by public authorities should improve social welfare (viewed as dependant on individual utilities). As for Walras, he defined a justice criterion based on a particular definition of natural law, and the reforms he proposed had the objective of restoring the rights following from this definition. We have drawn two principal conclusions from our work. First, the analyses of Jevons and Walras, who are often considered marginalise, are different not only in pure economics (as suggested by Jaffé in the seventies), but also from the point of view of welfare economics (defined as a science dealing with the evaluation of different social states). Secondly, these authors propose two different ways of justifying social reforms which have similarities with modern theory even though neither Jevons nor Walras are considered pioneers of welfare economics or public economics. Based on these two conclusions, we claim that studying these authors' theories might be of interest for the evaluation of public projects by the economists of today. Not only were their problems similar to ours, but also the original ideas present in their analyses may lead to the refinement of modern methods.Résumé en françaisCette these de doctorat porte sur les manières dont deux économistes du XIXe siècle, William Stanley Jevons (1835-1882) et Léon Walras (1834-1910), abordent la question du bien- etre collectif et la prise de décision publique. Connus principalement pour leurs travaux en économie pure, ces auteurs s'intéressent également à la question sociale et proposent des solutions pour y remédier. Jevons, conformément à son adhésion à la tradition utilitariste, estime que les interventions des autorités publiques doivent avoir pour objectif l'amélioration du bien- être collectif. Quant à Walras, il adopte un critère de justice qui relève du « droit naturel » et les propositions sociales qu'il préconise sont justifiées sur la base de leur conformité avec ce dernier. A l'issue du travail effectué dans le cadre de cette thèse, nous avons abouti à deux résultats principaux : (1) Les analyses de Jevons et Walras, deux économistes qui sont souvent considérés comme des « marginalistes » diffèrent fondamentalement non seulement dans leur analyse de l'économie pure, comme Jaffé le soulignait (1976), mais également en termes d'économie du bien-être (comprise comme une science ayant pour objectif l'évaluation des différents états sociaux). (2) Il existe deux voies originales pour justifier les réformes sociales dans les oeuvres de Jevons et Walras qui partagent des similarités importantes avec les théories modernes bien que ces auteurs ne fassent pas partie des jalons généralement retenus de l'histoire de l'économie du bien-être et de l'économie publique. Ces deux résultats nous conduisent à avancer que l'étude des approches de Jevons et de Walras peut contribuer à la formulation de nouvelles solutions à des problèmes rencontrés dans l'évaluation des différentes politiques publiques, car non seulement les préoccupations de ces auteurs était similaires aux nôtres, mais vu les éléments originaux que leurs propositions comportent, elles peuvent permettre de nuancer certaines aspects des méthodes modernes.

Inhibition of the renin-angiotensin system does not reduce platelet activity at rest or during stress in hypertension.

OBJECTIVES: We investigated the influence of angiotensin receptor blockade and angiotensin-converting enzyme inhibition on stress-induced platelet activation in hypertensive patients. Secondary aims were effects on inflammation, coagulation, and endothelial function. METHODS: Following a 4-week placebo period, 25 hypertensive patients entered a double-blind, crossover study comparing enalapril (20 mg once daily) and losartan (100 mg once daily) treatment (each for 8 weeks). Patients were studied at rest and after a standardized exercise test. RESULTS: Mean arterial pressure was reduced from 119 ± 2 to 104 ± 2 (enalapril) and 106 ± 2 (losartan) mmHg (both P <0.001). Plasma angiotensin II decreased from 2.4 ± 0.4 to 0.5 ± 0.1 pmol/l with enalapril, and increased to 7.2 ± 1.3 pmol/l with losartan (both P <0.001). Exercise-evoked platelet activation, as evidenced by increased numbers of P-selectin-positive platelets (P <0.01), elevated circulating platelet-platelet aggregates (P <0.01) and soluble P-selectin levels (P <0.001), and increased platelet responsiveness to adenosine diphosphate and thrombin (both P <0.05). Neither drug influenced these markers of platelet activation at rest or following exercise. Markers of inflammation (high-sensitivity C reactive protein, interleukin-6, tissue necrosis factor-α), coagulation (tissue plasminogen activator antigen, prothrombin fragment F1+2), and endothelial function (von Willebrand factor, soluble vascular cellular adhesion molecule-1, and intercellular adhesion molecule-1) were also uninfluenced by treatment. CONCLUSION: Enalapril and losartan failed to reduce platelet activity both at rest and during exercise in hypertensive patients. Markers of inflammation, coagulation, and endothelial function were similarly unaffected. Inhibition of the renin-angiotensin system promotes its beneficial effects in hypertension through mechanisms other than platelet inhibition.