Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

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The budding yeast Saccharomyces cerevisiae is a eukaryotic microorganism that is able to choose between different unicellular and multicellular lifestyles. The potential of individual yeast cells to switch between different growth modes is advantageous for optimal dissemination, protection and substrate colonization at the population level. A crucial step in lifestyle adaptation is the control of self- and foreign adhesion. For this purpose, S. cerevisiae contains a set of cell wall-associated proteins, which confer adhesion to diverse biotic and abiotic surfaces. Here, we provide an overview of different aspects of S. cerevisiae adhesion, including a detailed description of known lifestyles, recent insights into adhesin structure and function and an outline of the complex regulatory network for adhesin gene regulation. Our review shows that S. cerevisiae is a model system suitable for studying not only the mechanisms and regulation of cell adhesion, but also the role of this process in microbial development, ecology and evolution.

In the budding yeast Saccharomyces cerevisiae, self-recognition and the thereby promoted aggregation of thousands of cells into protective flocs is mediated by a family of cell-surface adhesins, the flocculins (Flo). Based on this social behavior FLO genes fulfill the definition of "greenbeard" genes, which direct cooperation toward other carriers of the same gene. The process of flocculation plays an eminent role in the food industry for the production of beer and wine. However, the precise mode of flocculin-mediated surface recognition and the exact structure of cognate ligands have remained elusive. Here, we present structures of the adhesion domain of a flocculin complexed to its cognate ligands derived from yeast high-mannose oligosaccharides at resolutions up to 0.95 Å. Besides a PA14-like architecture, the Flo5A domain reveals a previously undescribed lectin fold that utilizes a unique DcisD calcium-binding motif for carbohydrate binding and that is widely spread among pro-and eukaryotes. Given the high abundance of high-mannose oligosaccharides in yeast cell walls, the Flo5A structure suggests a model for recognition, where social non-selfinstead of unsocial self-interactions are favored.altruism | molecular recognition | fungal development | atomic resolution S elf-recognition is key to both microbial growth and tissue formation. The molecular basis of this phenomenon is well understood only for a few cases-e.g., during neural differentiation and immune recognition. In the microbial world, the formation of multicellular structures by self-recognition is mediated by specific, surface-exposed adhesins and provides protection and promotes long-term survival, substrate exploration, or host invasion (1, 2). In the budding yeast Saccharomyces cerevisiae, aggregation of vegetative cells is a paradigm for biofilm formation (3, 4) and the evolution of social behavior (5, 6). Self-recognition in this organism is mediated by flocculin proteins, which belong to a family of fungal adhesins that are present in pathogenic yeasts as well (7). The general architecture of flocculins includes an N-terminal A domain corresponding to a lectin-like adhesin domain, a stalk-like, repetitive and highly glycosylated B domain, and a C domain that carries a GPI anchoring site (8). The genome of S. cerevisiae contains at least four functional FLO genes (FLO1, FLO5, FLO9, and FLO10) whose N-terminal A domains are predicted to belong to the PA14-like protein family (9) first described in the anthrax-protective antigen (10). This protein family has been found to be widely distributed among all domains of life including human galactosyltransferases and fibrocystin (9, 11).Flocculins confer dominant, calcium-dependent cell-cell adhesion that can be inhibited by hexoses like mannose (12, 13). This process is known as flocculation and has been exploited for centuries by the brewing industry (14). Flocculin genes also mediate social behavior of S. cerevisiae and have here been found to fulfill the definition of "greenbeard" genes (5, 6). E...

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given offlabel. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n ¼ 59) or placebo (n ¼ 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity 2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label Gastroenterology 2019;157:74-86 CLINICAL AT treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

In baker's yeast Saccharomyces cerevisiae, cell-cell and cell-surface adhesion are required for haploid invasive growth and diploid pseudohyphal development. These morphogenetic events are induced by starvation for glucose or nitrogen and require the cell surface protein Flo11p. We show that amino acid starvation is a nutritional signal that activates adhesive growth and expression of FLO11 in both haploid and diploid strains in the presence of glucose and ammonium, known suppressors of adhesion. Starvation-induced adhesive growth requires Flo11p and is under control of Gcn2p and Gcn4p, elements of the general amino acid control system. Tpk2p and Flo8p, elements of the cAMP pathway, are also required for activation but not Ste12p and Tec1p, known targets of the mitogen-activated protein kinase cascade. Promoter analysis of FLO11 identifies one upstream activation sequence (UAS R ) and one repression site (URS) that confer regulation by amino acid starvation. Gcn4p is not required for regulation of the UAS R by amino acid starvation, but seems to be indirectly required to overcome the negative effects of the URS on FLO11 transcription. In addition, Gcn4p controls expression of FLO11 by affecting two basal upstream activation sequences (UAS B ). In summary, our study suggests that amino acid starvation is a nutritional signal that triggers a Gcn4p-controlled signaling pathway, which relieves repression of FLO11 gene expression and induces adhesive growth.

Comparative models of the extracellular and transmembrane domains of GABA A receptors in the agonist-free state were generated based on the recently published structures of the nicotinic acetylcholine receptor. The models were validated by computational methods, and their reliability was estimated by analyzing conserved and variable elements of the cys-loop receptor topology. In addition, the methodological limits in the interpretation of such anion channel receptor models are discussed. Alignment ambiguities in the helical domain were resolved for helix 3 by placing two gaps into the linker connecting helices 2 and 3. The resulting models were shown to be consistent with a wide range of pharmacological and mutagenesis data from GABA A and glycine receptors. The loose packing of the models results in a large amount of solvent-accessible space and offers a natural explanation for the rich pharmacology and the great flexibility of these receptors that are known to exist in numerous drug-induced conformational states. Putative drug binding pockets found within and between subunits are described, and amino acid residues important for the action and subtype selectivity of volatile and intravenous anesthetics, barbiturates, and furosemide are shown to be part of these pockets. The entire helical domain, however, seems to be crucial not only for binding of drugs but also for transduction of binding to gating or of allosteric modulation. These models can now be used to design new experiments for clarification of pharmacological and structural questions as well as for investigating and visualizing drug induced conformational changes.GABA A receptors mediate a large part of the fast inhibitory transmission in the central nervous system and are the targets for many clinically important drugs, such as sedatives, hypnotics, anxiolytics, anticonvulsives, muscle relaxants, and anesthetics (Sieghart, 1995). They are composed of five subunits that can belong to different homologous subunit classes and form a chloride channel that can be opened by GABA. Individual neurons can express many different subunits, resulting in the formation of a large variety of functionally different receptor subtypes (Sieghart and Sperk, 2002). Depending on the subunit composition, these receptors exhibit a distinct pharmacology (Sieghart, 1995).The subunit organization with the extracellular ligand binding domain containing the "signature" disulfide, four transmembrane segments, and a large variable cytoplasmic domain (termed the "cytoplasmic loop") of unknown structure, as well as the receptor organization as a pentamer, are hallmarks of the superfamily of cys-loop receptors (pentameric ligand-gated ion channels) comprising the cation-conducting nicotinic acetylcholine (nACh) and serotonin type 3 (5HT 3 -) receptors and the anion-conducting GABA A and glycine receptors.In 2001, the X-ray crystallographic structure of acetylcholine binding protein (AChBP) has revealed the fold in which the ␤-strand rich "extracellular domain" of the superfam...

The human pathogenic yeast Candida glabrata harbors more than 20 surface-exposed, epithelial adhesins (Epas) for host cell adhesion. The Epa family recognizes host glycans and discriminates between target tissues by their adhesin (A) domains, but a detailed structural basis for ligand-binding specificity of Epa proteins has been lacking so far. In this study, we provide high-resolution crystal structures of the Epa1A domain in complex with different carbohydrate ligands that reveal how host cell mucin-type O-glycans are recognized and allow a structure-guided classification of the Epa family into specific subtypes. Further detailed structural and functional characterization of subtype-switched Epa1 variants shows that specificity is governed by two inner loops, CBL1 and CBL2, involved in calcium binding as well as by three outer loops, L1, L2, and L3. In summary, our study provides the structural basis for promiscuity and specificity of Epa adhesins, which might further contribute to developing anti-adhesive antimycotics and combating Candida colonization. molecular recognition | T-antigen | lectin | fungal pathogen