Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.

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Intracellular microtubule motor proteins may direct the motile properties and/or morphogenesis of the mitotic spindle (reviewed in ref. 3). The recent identification of kinesin-like proteins important for mitosis or meiosis indicates that kinesin-related proteins may play a universal role in eukaryotic cell division, but the precise function of such proteins in mitosis remains unknown. Here we use an in vitro assay for spindle assembly, derived from Xenopus egg extracts, to investigate the role of Eg5, a kinesin-like protein in Xenopus eggs. Eg5 is localized along spindle microtubules, and particularly enriched near spindle poles. Immunodepletion of Eg5 from egg extracts markedly reduces the extent of spindle formation in extracts, as does direct addition of anti-Eg5 antibodies. We also demonstrate that Eg5 is a plus-end-directed microtubule motor in vitro. Our results suggest a novel mechanism for the dynamic self-organization of spindle poles in mitosis.

Chronic liver disease due to alcohol use disorder contributes markedly to the global burden of disease and mortality 1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-Duan et al.

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297), text (3634), references (29) + 1 supplementary material Ratio (HR)=2•77 (95% CI 2•07-3•71) and (HR=3•83 (2•29-6•42)), respectively. On adjusted multivariable analysis, exposure to DAA was associated with a decrease in all cause-mortality (HR=0•48 (95% CI 0•33-0•70)) and HCC (HR=0•66 (0•46-0•93)), and was no longer associated with decompensated cirrhosis (HR=1•14 (0•57-2•27)). InterpretationDAA treatment is associated with a reduced risk of mortality and HCC and should be considered in all patients with chronic HCV infection.

Termination of translation in higher organisms is a GTP‐dependent process. However, in the structure of the single polypeptide chain release factor known so far (eRF1) there are no GTP binding motifs. Moreover, in prokaryotes, a GTP binding protein, RF3, stimulates translation termination. From these observations we proposed that a second eRF should exist, conferring GTP dependence for translation termination. Here, we have shown that the newly sequenced GTP binding Sup35‐like protein from Xenopus laevis, termed eRF3, exhibits in vitro three important functional properties: (i) although being inactive as an eRF on its own, it greatly stimulates eRF1 activity in the presence of GTP and low concentrations of stop codons, resembling the properties of prokaryotic RF3; (ii) it binds and probably hydrolyses GTP; and (iii) it binds to eRF1. The structure of the C‐domain of the X.laevis eRF3 protein is highly conserved with other Sup35‐like proteins, as was also shown earlier for the eRF1 protein family. From these and our previous data, we propose that yeast Sup45 and Sup35 proteins belonging to eRF1 and eRF3 protein families respectively are also yeast termination factors. The absence of structural resemblance of eRF1 and eRF3 to prokaryotic RF1/2 and RF3 respectively, may point to the different evolutionary origin of the translation termination machinery in eukaryotes and prokaryotes. It is proposed that a quaternary complex composed of eRF1, eRF3, GTP and a stop codon of the mRNA is involved in termination of polypeptide synthesis in ribosomes.