It's widely appreciated that liquid–liquid phase separation (LLPS) underlies the formation of membraneless organelles, which function to concentrate proteins and nucleic acids. In the past few decades, major efforts have been devoted to identify the phase separation associated proteins and elucidate their functions. To better utilize the knowledge dispersed in published literature, we developed PhaSepDB (http://db.phasep.pro/), a manually curated database of phase separation associated proteins. Currently, PhaSepDB includes 2914 non-redundant proteins localized in different organelles curated from published literature and database. PhaSepDB provides protein summary, publication reference and sequence features of phase separation associated proteins. The sequence features which reflect the LLPS behavior are also available for other human protein candidates. The online database provides a convenient interface for the research community to easily browse, search and download phase separation associated proteins. As a centralized resource, we believe PhaSepDB will facilitate the future study of phase separation.

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Background: The recent change of terminology from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) has raised heated discussion. We aim to investigate the association of MAFLD or NAFLD with all-cause and cause-specific mortality to compare the outcomes of the two diagnostic criteria in population-based study.Methods: We recruited 12,480 participants from the Third National Health and Nutrition Examination Survey (NHANES III) with matched mortality data in 2015. Participants were divided into four groups for survival analysis: without NAFLD or MAFLD, with only NAFLD, only MAFLD. Cox proportional hazard regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality. Subgroup analysis were applied in MAFLD patients.Results: The weighted prevalence of MAFLD and NAFLD was relatively 27.4 and 27.9%. Participants with NAFLD or MAFLD were largely overlapped (weighted Cohen's kappa coefficient 0.76). MAFLD increased the overall risk for total mortality in a greater magnitude than NAFLD [HR 2.07 (95% CI 1.86, 2.29) vs. 1.47 (1.20, 1.79)], However, the difference was non-significant after metabolic parameters were adjusted. Risks for cardiovascular, neoplasm, and diabetes-related mortality were similar between MAFLD and NAFLD. Referring to individuals without both NAFLD and MAFLD, individuals with only NAFLD showed reduced total mortality [HR 0.48 (0.34, 0.68)] and neoplasm mortality [HR 0.46 (0.24, 0.89)] in crude. Nevertheless, individuals with only MAFLD independently increased the risk for total mortality [adjusted HR 1.47 (1.22, 1.77)] and neoplasm mortality [aHR 1.58 (1.09, 2.28)]. The risk for overall mortality in MAFLD was consistent between subgroups except for race-ethnicity and whether secondary to viral hepatitis.Conclusions: Participants with MAFLD or NAFLD were highly concordant. MAFLD showed greater risk for all-cause mortality and equal risk for cause-specific mortality referring to NAFLD. The new terminology excluded participants with lower mortality risk and included participants with higher risk. Drug development for MAFLD should consider ethnic differences.

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Liver fatty acid-binding protein (L-FABP, FABP1) is a highly conserved key factor in lipid metabolism. This study was undertaken to verify whether the T94A mutation in the L-FABP gene affects fatty acid uptake and intracellular esterification into specific lipid pools. Candidate SNPs were recreated using site-directed mutagenesis and tested for physical function in stably transfected Chang liver cell lines. We found that the T94A mutant of L-FABP lowered FFA uptake but had no effect on FFA efflux. L-FABP T94A-expressing cells showed decreased triglyceride content and increased cholesterol accumulation compared to the wild-type control for cells incubated with an FFA mixture (oleate: palmitate, 2:1 ratio). In conclusion, our study provided additional indications of the functional relevance of the L-FABP T94A SNP in hepatic fatty acid and lipid metabolism in humans.

Participant-level meta-analyses assessed the age-specific relevance of office blood pressure to cardiovascular complications, but this information is lacking for out-of-office blood pressure. At baseline, daytime ambulatory (n=12 624) or home (n=5297) blood pressure were measured in 17 921 participants (51.3% women; mean age, 54.2 years) from 17 population cohorts. Subsequently, mortality and cardiovascular events were recorded. Using multivariable Cox regression, floating absolute risk was computed across 4 age bands (≤60, 61–70, 71–80, and >80 years). Over 236 491 person-years, 3855 people died and 2942 cardiovascular events occurred. From levels as low as 110/65 mm Hg, risk log-linearly increased with higher out-of-office systolic/diastolic blood pressure. From the youngest to the oldest age group, rates expressed per 1000 person-years increased ( P <0.001) from 4.4 (95% CI, 4.0–4.7) to 86.3 (76.1–96.5) for all-cause mortality and from 4.1 (3.9–4.6) to 59.8 (51.0–68.7) for cardiovascular events, whereas hazard ratios per 20-mm Hg increment in systolic out-of-office blood pressure decreased ( P ≤0.0033) from 1.42 (1.19–1.69) to 1.09 (1.05–1.12) and from 1.70 (1.51–1.92) to 1.12 (1.07–1.17), respectively. These age-related trends were similar for out-of-office diastolic pressure and were generally consistent in both sexes and across ethnicities. In conclusion, adverse outcomes were directly associated with out-of-office blood pressure in adults. At young age, the absolute risk associated with out-of-office blood pressure was low, but relative risk high, whereas with advancing age relative risk decreased and absolute risk increased. These observations highlight the need of a lifecourse approach for the management of hypertension.

Background: There is evidence that vitamin B12 and associated metabolite levels are changed in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, their association has been in dispute. Methods: We included 8397 individuals without previous liver condition or excess alcohol intake from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. NAFLD was diagnosed with Fatty Liver Index (FLI) ≥ 60 or USFLI ≥ 30, and participants with advanced fibrosis risks were identified with elevated non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis 4 index (FIB-4), or aspartate aminotransferase (AST)/platelet ratio index (APRI). Step-wide logistic regression adjusting for confounders was used to detect the association between NAFLD or advanced fibrosis with serum vitamin B12, folate, red blood cell folate (RBC folate), homocysteine (HCY), and methylmalonic acid (MMA). Results: The weighted prevalence of NAFLD was 44.2%. Compared with non-NAFLD participants, patients with NAFLD showed significantly increased RBC folate level and RBC counts, decreased serum vitamin B12 and folate, and similar HCY and MMA levels. NAFLD with advanced fibrosis risk had higher MMA and HCY, reduced serum vitamin B12, and similar serum folate and RBC folate levels than NAFLD with low fibrosis risk. Only RBC folate was independently associated with an increased risk of NAFLD (OR (95% CI): 2.24 (1.58, 3.18)). In all participants, MMA (OR: 1.41 (1.10, 1.80)) and HCY (OR: 2.76 (1.49, 5.11)) were independently associated with increased risk for advanced fibrosis. In participants with NAFLD, this independent association still existed (OR: 1.39 (1.04, 1.85) for MMA and 1.95 (1.09, 3.46) for HCY). In all patients, the area under the receiver operating characteristic curve (ROC AUC) on fibrosis was 0.6829 (0.6828, 0.6831) for MMA and 0.7319 (0.7318, 0.7320) for HCY; in participants with NAFLD, the corresponding ROC AUC was 0.6819 (0.6817, 0.6821) for MMA and 0.6926 (0.6925, 0.6928) for HCY. Conclusion: Among vitamin B12-associated biomarkers, RBC folate was independently associated with elevated NAFLD risk, whereas MMA and HCY were associated with increased risk for advanced fibrosis in the total population and NAFLD participants. Our study highlighted the clinical diagnostic value of vitamin B12 metabolites and the possibility that vitamin B12 metabolism could be a therapeutic target for NASH. Further studies using recent perspective data with biopsy proven NASH could be conducted to validate our results.

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