Bayesian uncertainty management in temporal dependence of extremes

Both marginal and dependence features must be described when modelling the extremes of a stationary time series. There are standard approaches to marginal modelling, but long- and short-range dependence of extremes may both appear. In applications, an assumption of long-range independence often seems reasonable, but short-range dependence, i.e., the clustering of extremes, needs attention. The extremal index 0 < ≤ 1 is a natural limiting measure of clustering, but for wide classes of dependent processes, including all stationary Gaussian processes, it cannot distinguish dependent processes from independent processes with = 1. Eastoe and Tawn (Biometrika 99, 43–55 2012) exploit methods from multivariate extremes to treat the subasymptotic extremal dependence structure of stationary time series, covering both 0 < <1 and = 1, through the introduction of a threshold-based extremal index. Inference for their dependence models uses an inefficient stepwise procedure that has various weaknesses and has no reliable assessment of uncertainty. We overcome these issues using a Bayesian semiparametric approach. Simulations and the analysis of a UK daily river flow time series show that the new approach provides improved efficiency for estimating properties of functionals of clusters

Sirtuin 3 deficiency does not alter host defenses against bacterial and fungal infections.

Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase. SIRT3 regulates cell metabolism and redox homeostasis, and protects from aging and age-associated pathologies. SIRT3 may drive both oncogenic and tumor-suppressive effects. SIRT3 deficiency has been reported to promote chronic inflammation-related disorders, but whether SIRT3 impacts on innate immune responses and host defenses against infections remains essentially unknown. This aspect is of primary importance considering the great interest in developing SIRT3-targeted therapies. Using SIRT3 knockout mice, we show that SIRT3 deficiency does not affect immune cell development and microbial ligand-induced proliferation and cytokine production by splenocytes, macrophages and dendritic cells. Going well along with these observations, SIRT3 deficiency has no major impact on cytokine production, bacterial burden and survival of mice subjected to endotoxemia, Escherichia coli peritonitis, Klebsiella pneumoniae pneumonia, listeriosis and candidiasis of diverse severity. These data suggest that SIRT3 is not critical to fight infections and support the safety of SIRT3-directed therapies based on SIRT3 activators or inhibitors for treating metabolic, oncologic and neurodegenerative diseases without putting patients at risk of infection

The systemic deletion of interleukin-1α reduces myocardial inflammation and attenuates ventricular remodeling in murine myocardial infarction.

Myocardial inflammation following myocardial infarction (MI) is crucial for proper myocardial healing, yet, dysregulated inflammation may promote adverse ventricular remodeling and heart failure. IL-1 signaling contributes to these processes, as shown by dampened inflammation by inhibition of IL-1β or the IL-1 receptor. In contrast, the potential role of IL-1α in these mechanisms has received much less attention. Previously described as a myocardial-derived alarmin, IL-1α may also act as a systemically released inflammatory cytokine. We therefore investigated the effect of IL-1α deficiency on post-MI inflammation and ventricular remodeling in a murine model of permanent coronary occlusion. In the first week post-MI, global IL-1α deficiency (IL-1α KO mice) led to decreased myocardial expression of IL-6, MCP-1, VCAM-1, hypertrophic and pro-fibrotic genes, and reduced infiltration with inflammatory monocytes. These early changes were associated with an attenuation of delayed left ventricle (LV) remodeling and systolic dysfunction after extensive MI. In contrast to systemic Il1a-KO, conditional cardiomyocyte deletion of Il1a (CmIl1a-KO) did not reduce delayed LV remodeling and systolic dysfunction. In conclusion, systemic Il1a-KO, but not Cml1a-KO, protects against adverse cardiac remodeling after MI due to permanent coronary occlusion. Hence, anti-IL-1α therapies could be useful to attenuate the detrimental consequences of post-MI myocardial inflammation

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.

Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity

La hiérarchie des rubriques: un outil de description de la presse.

Aux prises avec des informations de toute nature, venant de tous les coins du monde, les journaux, après avoir sélectionné les informations qui feront l'objet d'un article, ont comme outil de classement et de hiérarchisation la rubrique. Le lecteur ne se rend pas toujours compte de l'importance de la rubrique dans l'image que le quotidien se donne et de son rôle en tant qu'indice d'un positionnement sur le marché. La taille respective des rubriques est l'indice révélateur d'une identité. En accentuant une rubrique au détriment d'une autre, le journal propose un profil original dans le champ médiatique. Sur une même région linguistique, à l'exemple ici de la Suisse romande, les différents journaux visent des segments de marché différents et/ou concurrents. Leur positionnement dans ce marché est lisible à travers l'examen de leurs rubriques. Inversement, l'examen des rubriques permet de vérifier si le segment de marché occupé est effectivement celui qui est visé.Herman Thierry, Lugrin Gilles. La hiérarchie des rubriques : un outil de description de la presse. In: Communication et langages, n°122, 4ème trimestre 1999. Dossier : Revue de la presse. pp. 72-85

Expression pattern of sirtuins in innate immune cells and influence of Sirtuin 1/2 inhibition on innate immune responses to Toll-like receptor ligands and to infection

Purpose/Objective: The family of histone deacetylases comprises 18 members in mammals, among which seven sirtuins (SIRT1-7). Sirtuins are NADP-dependent enzymes that have been involved in the control of cell metabolism, proliferation and survival. The expression pattern of sirtuins and their influence on host response to microbial infection remain largely unknown. The aim of the study was to analyze the expression of SIRT1-7 and to address the effects of SIRT1/2 inhibition on innate immune responses in vitro and in vivo.. Materials and methods: in vitro: Bone marrow (BM), BM-derived macrophages (BMDMs) and dendritic cells (BMDCs) and RAW 264.7 and J774.1 macrophage cell lines were stimulated for 0, 2, 6 and 18 h with LPS, Pam3CSK4 and CpG ODN. SIRT1-7 mRNA was quantified by real time-PCR. TNF was measured by ELISA. In vivo: BALB/c mice were challenged with LPS (350 lg i.p.) with or without a SIRT1/2 inhibitor. Blood and organs were collected after 0, 1, 4, 8 and 24 h to quantify SIRT1-7 and TNF. Mortality was assessed daily. Results: Bone marrow, macrophages and DCs express, in order of abundance, SIRT2 &gt; &gt; SIRT1, SIRT3 and SIRT6 &gt; SIRT4, SIRT5 and SIRT7. Microbial products decrease the expression of all sirtuins except SIRT6 in a time dependent manner in BMDMs (0_24 h). SIRT2 is the most expressed sirtuin also in the liver, kidney (together with SIRT3) and spleen. Upon LPS challenge, SIRT1, SIRT3, SIRT4 and SIRT7 mRNA levels decrease in the liver (from 4 h to 24 h), whereas SIRT1-7 mRNA levels decrease within 1 h in both kidney and spleen. Pharmacological inhibition of SIRT1/2 decreases TNF production by macrophages stimulated with LPS, Pam3CSK4 and CpG ODN (n = 6; P &lt; 0.001). In agreement, prophylactic treatment with a SIRT1/2 inhibitor decreases TNF production (n = 8; P = 0.04) and increases survival (n = 13, P = 0.03) of mice challenged with LPS. Conclusions: Sirtuins are expressed in innate immune cells. Inhibition of SIRT1/2 activity decreases cytokine production by macrophages and protects from endotoxemia, suggesting that sirtuin inhibitors may represent novel adjunctive therapy for treating inflammatory disorders such as sepsis