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Primary biliary cholangitis (PBC) is a chronic immuneassociated cholestatic liver disease with unclear complex/multifactorial etiopathogenesis affecting mostly middle-aged women. Patients with PBC exhibit reduced expression of the AE2/SLC4A2 gene. Herein, we found that AE2 promoter regions are hypermethylated in the liver and peripheral blood mononuclear cells of patients with PBC. This increased methylation is associated with downregulated AE2-gene expression, which might contribute to the pathogenesis of PBC. Therefore, novel epigenetic targets may improve treatment in patients with PBC who respond poorly to current pharmacological therapies.

This study provides a contrastive analysis of the film cultures in Francoist Spain and the German Democratic Republic in the late 1950s and early 1960s. In the context of this period of classic cinephilia, the article focuses on the institutional position of film clubs and on their function as ‘places of negotiation’ in which different forces and interests collided: more or less independent film activists acted within, against, or parallel to state organizations trying to implement certain cultural activities and discourses. The arguments are based on broad archival material from Spain and Germany (Archivo General de la Administración, Bundesarchiv Berlin etc.) and, specifically, on the analysis of two of these institutions in Barcelona and Leipzig. The initial hypothesis holds that in their reactions to these institutions, the Spanish and East German states present two different conceptions of state cultural policies (authoritarian and totalitarian). At the same time, the activities of the clubs (screenings, discussions, edition of magazines) can also be read as part of a broader attempt to redefine the film-cultural field along three axes (time, place and status), connecting them to other European film cultures of the time and enabling us to widen and differentiate the analysis of classical cinephilia within a broader international context.

Primary biliary cirrhosis (PBC) is a cholestatic disease associated with autoimmune phenomena and alterations in both biliary bicarbonate excretion and expression of the bicarbonate carrier AE2. The bile acid ursodeoxycholic acid (UCDA) is currently used in treatment of cholestatic liver diseases and is the treatment of choice in PBC; however, a subset of PBC patients respond poorly to UDCA monotherapy. In these patients, a combination of UDCA and glucocorticoid therapy appears to be beneficial. To address the mechanism of this benefit, we analyzed the effects of UDCA and dexamethasone on AE2 gene expression in human liver cells from hepatocyte and cholangiocyte lineages. The combination of UDCA and dexamethasone, but not UDCA or dexamethasone alone, increased the expression of liver-enriched alternative mRNA isoforms AE2b1 and AE2b2 and enhanced AE2 activity. Similar effects were obtained after replacing UDCA with UDCA conjugates. In in vitro and in vivo reporter assays, we found that a UDCA/dexamethasone combination upregulated human AE2 alternate overlapping promoter sequences from which AE2b1 and AE2b2 are expressed. In chromatin immunoprecipitation assays, we demonstrated that combination UCDA/dexamethasone treatment induced p300-related interactions between HNF1 and glucocorticoid receptor on the AE2 alternate promoter. Our data provide a potential molecular explanation for the beneficial effects of the combination of UDCA and glucocorticoids in PBC patients with inadequate response to UDCA monotherapy.