MT-HESS: an efficient Bayesian approach for simultaneous association detection in OMICS datasets, with application to eQTL mapping in multiple tissues.

MOTIVATION: Analysing the joint association between a large set of responses and predictors is a fundamental statistical task in integrative genomics, exemplified by numerous expression Quantitative Trait Loci (eQTL) studies. Of particular interest are the so-called ': hotspots ': , important genetic variants that regulate the expression of many genes. Recently, attention has focussed on whether eQTLs are common to several tissues, cell-types or, more generally, conditions or whether they are specific to a particular condition. RESULTS: We have implemented MT-HESS, a Bayesian hierarchical model that analyses the association between a large set of predictors, e.g. SNPs, and many responses, e.g. gene expression, in multiple tissues, cells or conditions. Our Bayesian sparse regression algorithm goes beyond ': one-at-a-time ': association tests between SNPs and responses and uses a fully multivariate model search across all linear combinations of SNPs, coupled with a model of the correlation between condition/tissue-specific responses. In addition, we use a hierarchical structure to leverage shared information across different genes, thus improving the detection of hotspots. We show the increase of power resulting from our new approach in an extensive simulation study. Our analysis of two case studies highlights new hotspots that would remain undetected by standard approaches and shows how greater prediction power can be achieved when several tissues are jointly considered. AVAILABILITY AND IMPLEMENTATION: C[Formula: see text] source code and documentation including compilation instructions are available under GNU licence at http://www.mrc-bsu.cam.ac.uk/software/

Thromboxane biosynthesis and future events in diabetes: the ASCEND trial

Background and Aims Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by ∼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes. Methods The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made. Results Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00–1.18), 1.16 (1.01–1.34), and 1.06 (0.98–1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed. Conclusions The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis

Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis

Background and Aims Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. Approach and Results To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL(-/-)) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2(-/-)) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL(-/-) mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and beta-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2(-/-) mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E-2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation. Conclusions Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis

Impact of simulated reduced injected dose on the assessment of amyloid PET scans

PURPOSE: To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [18F]flutemetamol and [18F]florbetaben. METHODS: Cognitively impaired and unimpaired individuals (N = 250, 36% Aβ-positive) were included and injected with [18F]flutemetamol (N = 175) or [18F]florbetaben (N = 75). PET scans were acquired in list-mode (90-110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aβ-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aβ- and Aβ + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated. RESULTS: At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [18F]flutemetamol and [18F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were  80% for both tracers. CONCLUSION: This proof-of-concept study showed that for both [18F]flutemetamol and [18F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances

Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration

Background & Aims: Liver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration. Methods: Hepatocyte proliferation was studied in vitro in hepatoma cell lines and ex vivo in precision-cut human liver slices. Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL-/-) and specifically invalidated in hepatocytes (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGLMye-/- mice. Results: Precision-cut human liver slices from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice. Conclusions: Our data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming. Impact and Implications: By using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.The authors thank V. Fauveau, Institut Cochin, for help in surgery experiments; Olivier Thibaudeau of the Plateau de Morphologie Facility (INSERM UMR 1152, France) and Nicolas Sorhaindo of the Plateforme de Biochimie (CRI, INSERM UMR1149) for their help in the histology and liver function tests; and K. Bailly from the cytometry platform of Cochin Institute and H. Fohrer-Ting from the Centre de Recherche des Cordeliers, Paris University, for cell sorting analyses.Scopu

Event shapes and azimuthal correlations in Z plus jets events in pp collisions at root √s=7TeV^{√s=7 TeV}

is produced in association with jets in proton–proton collisions. The data collected with the CMS detector at the CERN LHC at $^{√s=7 TeV}$ correspond to an integrated luminosity of 5.0 fb$^{-1}$. The analysis provides a test of predictions from perturbative QCD for a process that represents a substantial background to many physics channels. Results are presented as a function of jet multiplicity, for inclusive Z boson production and for Z bosons with transverse momenta greater than 150 GeV, and compared to predictions from Monte Carlo event generators that include leading-order multiparton matrix-element (with up to four hard partons in the final state) and next-to-leading-order simulations of Z+1-jet events. The experimental results are corrected for detector effects, and can be compared directly with other QCD model

Health-economical comparison between health care dialysis modalities : hemodialysis versus peritoneal dialysis

Les objectifs sont d’évaluer l’efficience (survie, qualité de vie et le coût) des deux techniques de dialyse de rechercher les déterminants qui orientent le choix vers l’une ou l’autre des techniques de dialyse et d’évaluer le parcours de soins des patients en dialyse. La première partie de ce travail de thèse à analyser les données de la région PACA issues du registre REIN. Cette analyse est descriptive et porte sur le profil des patients démarrent un traitement en dialyse (HD et DP). Une analyse de survie a été réalisée selon la technique de dialyse initiale et selon le parcours de soins. Dans une seconde partie, le coût et sur la qualité de vie ont été évalués selon les différentes techniques de dialyse afin d’évaluer l’efficience de ces modalités à partir des données recueillies dans un PHRC régional. Dans une troisième partie, les facteurs liés au choix initial de la technique de dialyse, DP ou HD ont été recherchés. Ce travail a fait l’objet d’une étude ciblée auprès de patients et de néphrologues au sein de 4 structures de dialyse. La survie et la qualité de vie des patients sont similaires entre HD et DP. Le changement de technique, de la DP vers l'HD, a un impact positif sur la survie. La DP est moins coûteuse que l’HD. Les contre-indications médicales à la DP ne concernaient que 26,7% des patients inclus. En absence de contre-indications, la préférence du patient et les pratiques des professionnelles (information et pratiques de centre) sont les deux principaux facteurs liés au choix initial de la technique de dialyse, notamment par la DP. Une meilleure information pourrait contribuer à augmenter le choix de la DP.The objectives of this work were to assess and compare the efficiency (survival, quality of life and cost) of patients initially treated with peritoneal dialysis (PD) or hemodialysis (HD), to search determinants that guide the initial choice towards either dialysis techniques and to assess the trajectory between dialysis modalities. The first part of this thesis was to analyze the database, from the PACA region (2004 – 2014), issue from the French REIN registry. This analysis was descriptive and focused to analyze main characteristics and outcome (survival) of dialysis patients (initial dialysis and switching) and to identify risk factors. The second part of this thesis was to measure and compare dialysis patient quality of life and health’s care costs between dialysis modalities (HD and PD). Database was issued from PHRC. The third part was to search the factors related to the initial choice of dialysis technique, PD or HD. This work was the subject of a targeted survey of patients and neurologists in a dialysis structure. The survival and the quality of life were similar between hemodialysis and peritoneal dialysis. Switching to HD may improve positively the survival compared to those who remained on PD, whereas, switching to PD was not. The DP is less expensive than HD. Medical contraindications to the PD were for 26.7%. In the absence of contraindications, patient preference and professional practices (information and practical center) are the two main factors related to the initial choice of dialysis technique, in particular to choice of PD. Better information could help to increase the choice of D

Effets pleiotropiques des statines (un rôle anti-inflammatoire impliquant la HO-1 et antifibrogénique impliquant la COX-2)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF