Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of ​interferon-λ4 (​IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.

Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms

Learnings of 30 years of R & D on molten core concrete interaction and remaining perspectives

International audienceThe Nuclear Energy Agency (NEA) of the Organization for Economic Co-operation and Development (OECD) has, since 2002, sponsored Melt Coolability and Concrete Interactions (MCCI) co-operative project in two phases to investigate ex-vessel melt coolability and concrete interaction by means of separate-effects tests and large scale integral tests carried out at the Argonne National Laboratory (ANL). A working group was established in April 2012 within the frame of the Working Group on Accident Management and Analysis (WGAMA) to address the preparation of a state-of-the-art report on melt coolability and core concrete interactions that captures the last thirty years of international research results. This paper synthesizes this new state of the art report on molten core concrete interaction

Learnings of 30 years of R & D on molten core concrete interaction and remaining perspectives

International audienceThe Nuclear Energy Agency (NEA) of the Organization for Economic Co-operation and Development (OECD) has, since 2002, sponsored Melt Coolability and Concrete Interactions (MCCI) co-operative project in two phases to investigate ex-vessel melt coolability and concrete interaction by means of separate-effects tests and large scale integral tests carried out at the Argonne National Laboratory (ANL). A working group was established in April 2012 within the frame of the Working Group on Accident Management and Analysis (WGAMA) to address the preparation of a state-of-the-art report on melt coolability and core concrete interactions that captures the last thirty years of international research results. This paper synthesizes this new state of the art report on molten core concrete interaction

Learnings of 30 years of R & D on molten core concrete interaction and remaining perspectives

International audienceThe Nuclear Energy Agency (NEA) of the Organization for Economic Co-operation and Development (OECD) has, since 2002, sponsored Melt Coolability and Concrete Interactions (MCCI) co-operative project in two phases to investigate ex-vessel melt coolability and concrete interaction by means of separate-effects tests and large scale integral tests carried out at the Argonne National Laboratory (ANL). A working group was established in April 2012 within the frame of the Working Group on Accident Management and Analysis (WGAMA) to address the preparation of a state-of-the-art report on melt coolability and core concrete interactions that captures the last thirty years of international research results. This paper synthesizes this new state of the art report on molten core concrete interaction

Active DNA demethylation at enhancers during the vertebrate phylotypic period

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