Protein codes promote selective subcellular compartmentalization.

Cells have evolved mechanisms to distribute ~10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must efficiently assemble. Here, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. A protein language model, ProtGPS, was developed that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in targeted subcellular compartments. ProtGPS also identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code, but also a previously unrecognized code governing their distribution in specific cellular compartments.

Distinct chemical environments in biomolecular condensates.

Diverse mechanisms have been described for selective enrichment of biomolecules in membrane-bound organelles, but less is known about mechanisms by which molecules are selectively incorporated into biomolecular assemblies such as condensates that lack surrounding membranes. The chemical environments within condensates may differ from those outside these bodies, and if these differed among various types of condensate, then the different solvation environments would provide a mechanism for selective distribution among these intracellular bodies. Here we use small molecule probes to show that different condensates have distinct chemical solvating properties and that selective partitioning of probes in condensates can be predicted with deep learning approaches. Our results demonstrate that different condensates harbor distinct chemical environments that influence the distribution of molecules, show that clues to condensate chemical grammar can be ascertained by machine learning and suggest approaches to facilitate development of small molecule therapeutics with optimal subcellular distribution and therapeutic benefit.

The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.

BACKGROUND AND AIMS: NAFLD is a leading cause of liver-related morbidity and mortality. We assessed the global and regional prevalence, incidence, and mortality of NAFLD using an in-depth meta-analytic approach. APPROACH AND RESULTS: PubMed and Ovid MEDLINE were searched for NAFLD population-based studies from 1990 to 2019 survey year (last published 2022) per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Meta-analysis was conducted using random-effects models. Bias risk assessment was per Joanna Briggs Institute. Of 2585 studies reviewed, 92 studies (N=9,361,716) met eligibility criteria. Across the study period (1990-2019), meta-analytic pooling of NAFLD prevalence estimates and ultrasound-defined NAFLD yielded an overall global prevalence of 30.05% (95% CI: 27.88%-32.32%) and 30.69% (28.4-33.09), respectively. Global NAFLD prevalence increased by +50.4% from 25.26% (21.59-29.33) in 1990-2006 to 38.00% (33.71-42.49) in 2016-2019 ( p <0.001); ultrasound-defined NAFLD prevalence increased by +38.7% from 25.16% (19.46-31.87) in 1990-2006 to 34.59% (29.05-40.57) ( p =0.029). The highest NAFLD prevalence was in Latin America 44.37% (30.66%-59.00%), then Middle East and North Africa (MENA) (36.53%, 28.63%-45.22%), South Asia (33.83%, 22.91%-46.79%), South-East Asia (33.07%, 18.99%-51.03%), North America (31.20%, 25.86%-37.08%), East Asia (29.71%, 25.96%-33.76%), Asia Pacific 28.02% (24.69%-31.60%), Western Europe 25.10% (20.55%-30.28%). Among the NAFLD cohort diagnosed without a liver biopsy, pooled mortality rate per 1000 PY was 12.60 (6.68-23.67) for all-cause mortality; 4.20 (1.34-7.05) for cardiac-specific mortality; 2.83 (0.78-4.88) for extrahepatic cancer-specific mortality; and 0.92 (0.00-2.21) for liver-specific mortality. CONCLUSIONS: NAFLD global prevalence is 30% and increasing which requires urgent and comprehensive strategies to raise awareness and address all aspects of NAFLD on local, regional, and global levels.

Sarcopenia, healthy living, and mortality in patients with chronic liver diseases.

Chronic liver diseases (CLDs) are associated with increased morbidity and mortality. Sarcopenia is an important complication of CLD that can be impacted by several modifiable risk factors. Our aim was to assess the associations between healthy living, sarcopenia, and long-term outcomes among patients with CLD. We used the Third National Health and Nutrition Examination Survey data with National Death Index-linked mortality files. We used the American Heart Association's Life's Simple 7 (LS7) metrics as surrogates of healthy living. The study included 12,032 subjects (34.9% CLDs [0.5% hepatitis B virus (HBV), 1.8% hepatitis C virus (HCV), 5.7% alcohol-associated liver disease (ALD), 26.9% nonalcoholic fatty liver disease (NAFLD)] and 65.1% controls). Prevalence of sarcopenia was higher among NAFLD than other CLDs and the controls (40.7% in NAFLD, 27.2% in ALD, 22.4% in HCV, 16.8% in HBV, and 18.5% in controls; p < 0.001). Among NAFLD and ALD, patients with sarcopenia were less likely to meet ideal LS7 metrics than those without sarcopenia. During 27 years of follow-up, among 4 patients with CLDs and the controls, all-cause cumulative mortality was highest among patients with HCV (35.2%), followed by ALD (34.7%) and NAFLD (29.6%). The presence of sarcopenia was associated with higher risk of all-cause mortality only among subjects with NAFLD (hazard ratio [HR] 1.24; 95% confidence interval [CI] 1.01-1.54; p = 0.04). Among subjects with NAFLD, presence of sarcopenia was associated with higher risk of cardiovascular-specific (HR 2.28 [1.71-3.05; p < 0.01]), cancer-specific (HR 1.90 [1.37-2.65]; p < 0.01), diabetes-specific (HR 6.42 [2.87-14.36]; p < 0.01), and liver-specific mortality (HR 2.49 [1.08-5.76]; p = 0.04). The multivariable model showed that component of LS7 metrics that provided the strongest protection against sarcopenia were ideal body mass index, ideal blood pressure, ideal physical activity, and ideal glycemic control among subjects with NAFLD subjects. Conclusions: Among subjects with NAFLD, sarcopenia is associated with a higher risk of all-cause mortality and liver mortality. Attainment of ideal LS7 metrics provides protection against sarcopenia in NAFLD.