BACKGROUND:Target organ damage is crucial for hypertension risk stratification. However, the lack of sensitive assessment tools for early target organ damage in the presence of elevated blood pressure limits timely intervention. This study used the retina to investigate subclinical neurovascular damage and identify early imaging biomarkers. METHODS:We monitored male spontaneously hypertensive rats and Wistar-Kyoto controls weekly from 4 to 9 weeks of age. Weekly assessments included noninvasive blood pressure and multimodal fundus imaging, including optical coherence tomography, optical coherence tomography angiography and electroretinography. Histological analyses and fluorescein fundus angiography validated structural microvascular changes and blood-retinal barrier integrity. RESULTS:The blood pressure of spontaneously hypertensive rats increased significantly from 5 weeks of age (P<0.05). At the prehypertensive stage (6 weeks), spontaneously hypertensive rats exhibited decreased superficial vascular plexus density and reduced scotopic electroretinography b-wave amplitude. Fluorescein fundus angiography demonstrated that the blood-retinal barrier remained functionally intact without leakage at this stage. These microvascular and functional deficits preceded structural changes on optical coherence tomography. Subsequently, vascular damage progressed to deeper plexuses, accompanied by inner retinal thinning, apoptosis, and continued functional decline. Linear mixed-effects modeling confirmed a negative correlation between the prehypertensive stage and decreased superficial vascular density (P<0.001). CONCLUSIONS:In spontaneously hypertensive rats, superficial microvascular rarefaction and inner retinal dysfunction represent the initiating pathological events, preceding blood-retinal barrier breakdown and macrovascular remodeling. Optical coherence tomography angiography-quantified superficial vascular plexus density is a sensitive and objective imaging biomarker for assessing retinal damage during the prehypertensive stage, which significantly precedes macrovascular signs.

Background:Sleep duration is associated with various health outcomes like metabolic disturbances and mortality, but the underlying mechanisms remain unclear. Objectives:To investigate the link between sleep duration, metabolic markers, and mortality using data from the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). Methods:Sleep duration was self-reported, and metabolic markers were quantified using nuclear magnetic resonance spectroscopy. The outcomes of interest were all-cause and cause-specific mortality. Linear regression was conducted to assess the association between sleep duration and metabolic markers, which were further compared with the association between metabolic markers and all-cause and cause-specific mortality using Cox models. Results:In both cohorts, sleep duration showed positive associations with all-cause and cause-specific mortality after adjustment. A total of 17 metabolic markers-encompassing lipoprotein subclasses in high-density lipoprotein cholesterol, relative lipoprotein lipid concentrations in very-low-density lipoproteins, cholesterol, and ketone bodies-were significantly associated with sleep duration and mortality. In general, the associations of sleep duration with metabolic markers and of these markers with mortality showed similar patterns for lipoprotein subclasses and relative lipoprotein lipid concentrations, whereas contrary patterns were observed for cholesterol and ketone bodies in the CKB. Furthermore, significant associations were also observed in the UKB cohort, with metabolic markers presenting generally consistent association patterns with sleep duration and mortality. Gender-specific analyses revealed significant links in females in the CKB and in both genders in the UKB. Sensitivity analyses confirmed the stability of these associations. Conclusions:Our findings suggest that lipid metabolism may partially explain the effect of sleep duration on mortality. These insights highlight the potential of targeted metabolic interventions to mitigate the risks associated with abnormal sleep patterns, especially when modifying sleep duration itself is challenging, and the projected health burden associated with sleep disorders could be reduced through metabolic-focused strategies. Lay Summary:What question did this study address, and why does it matter? This study examined whether sleep duration is associated with metabolic markers and whether these markers, in turn, are associated with mortality risk, using data from two large population-based cohorts in China and the UK. Sleep problems are becoming increasingly common worldwide, and identifying metabolic pathways that may link sleep to health outcomes could inform future prevention strategies. Where was the study done and what were the main results? The study used data from the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). In both cohorts, sleep duration was associated with changes in specific metabolic markers, including lipoprotein subclasses, cholesterol, and ketone bodies. These metabolic changes were further associated with all-cause and cause-specific mortality. While lipoprotein subclasses showed broadly consistent patterns across the two cohorts, cholesterol and ketone bodies exhibited contrary associations with mortality in the CKB compared to the UKB. Sex-specific differences were also observed, particularly in the CKB cohort, where significant associations were found only in women. What do these findings mean in practice? These findings suggest that lipid metabolism may play a role in the relationship between sleep duration and mortality. This raises the possibility that metabolic monitoring or targeted interventions-such as lifestyle or dietary modifications-could potentially help reduce the health risks associated with abnormal sleep duration, particularly in settings where sleep modification itself is challenging. However, further research is needed to determine whether these associations are causal and to explore their underlying mechanisms.

Background Age-related molecular trajectories of metabolic dysfunction-associated steatotic liver disease (MASLD) remain insufficiently characterized, limiting age-stratified risk assessment and intervention. Objective To test whether MASLD-related molecular changes with age merely reflect accelerated physiological aging or represent a disease-specific divergence. Methods We utilized public transcriptomic data from normal liver and MASLD samples to identify differential transcriptomic signals. We employed Spearman correlation analysis and generalized additive models (GAM) for nonlinear age-related trajectory modeling, and functional enrichment analysis for signaling pathway characterization. Results We integrated 1,354 public liver transcriptome samples from GEO and GTEx databases to construct a cross-age cohort. Differential expression and age-correlation analyses showed minimal overlap (only 22 genes) between age-associated genes in MASLD and controls, with some genes displaying opposite age-related trends. GAM identified four major expression patterns in MASLD—stable, early-life change, late-life acceleration, and mid-life fluctuation—with trajectory inflection time points around ages ~35 and ~75. Functional enrichment indicated that control age-associated genes mainly involved classical cell cycle processes, whereas MASLD changes were enriched for protein deubiquitination, proteostasis imbalance, and p53-related stress and apoptotic signaling. Many MASLD age-associated genes were also associated with fibrosis stage or NAS, largely in concordant directions. Conclusion MASLD exhibits disease-specific age-related transcriptional remodeling characterized by dysregulation of proteostasis and deubiquitination pathways, activation of cellular stress-response programs, and enrichment of p53-associated apoptotic signaling, rather than a simple acceleration of physiological aging.

Advanced hepatocellular carcinoma (HCC) with extensive metastases is associated with a poor prognosis, highlighting the need for individualized, multimodal treatment strategies. We present the case of a 54-year-old male with advanced HCC (cT3NxM1, Child-Pugh B) and spinal as well as bilateral pulmonary metastases who experienced disease progression after multiple lines of therapy. A dynamically adjusted, multidisciplinary regimen was implemented, incorporating transarterial chemoembolization (TACE), surgery, immunotherapy, and targeted therapy. The final regimen - combining nivolumab plus ipilimumab (O+Y) with TACE and lenvatinib - achieved a partial response in lung metastases, with a progression-free survival exceeding one year and overall survival of over 24 months. This case underscores the therapeutic potential of O+Y in later-line settings and demonstrates the clinical value of an integrated, personalized treatment paradigm for advanced HCC.

Background:Transarterial chemoembolisation (TACE) is the standard treatment for unresectable, non-metastatic hepatocellular carcinoma (UR/NM HCC). The addition of PD-1/PD-L1 inhibitors (PIs) plus anti-VEGF drugs (AVDs) after TACE (TPA group) has been proposed as a strategy to enhance antitumor efficacy; however, evidence regarding its survival benefit is still uncertain. To address this issue, we performed a pooled analysis of randomized controlled trials (RCTs) to determine whether this combination strategy confers additional clinical benefit over TACE alone. Methods:Six databases were systematically searched to identify eligible RCTs comparing TPA with TACE alone among individuals diagnosed with UR/NM HCC. Key endpoints consisted of overall survival (OS) and progression-free survival (PFS), whereas additional endpoints covered tumor responses, adverse events (AEs), and patient status at the data cutoff. PFS and tumor responses were assessed according to both RECIST version 1.1 and mRECIST criteria. Results:A total of 4 RCTs (CARES-005, EMERALD-1, LEAP-012, and TALENTACE) involving 1,431 patients were included. Compared with TACE alone, TPA significantly improved PFS (HR: 0.62 [0.47, 0.81], p = 0.0006) and objective response rate (ORR, RR: 1.44 [1.25, 1.66], p < 0.00001), whereas no statistically significant improvement in OS was observed (HR: 0.87 [0.71, 1.07], p = 0.20). Subgroup analyses demonstrated that the PFS benefit of the TPA group was consistent across nearly all predefined subgroups. However, TPA also showed an increased occurrence of grade 3-4/serious treatment-emergent AEs (TEAEs), grade 3-4/serious treatment-related AEs (TRAEs), and total/grade 3-4 immune-related AEs (irAEs). At the cutoff, more patients in the TPA group discontinued treatment due to AEs, whereas fewer discontinued due to disease progression. Conclusion:In patients with UR/NM HCC, TPA significantly improves PFS and ORR but does not yet demonstrate a significant OS benefit, and it is associated with increased grade 3-4 AEs. Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/view/CRD420261290301, CRD420261290301.

Hepatic stellate cell (HSC) activation can lead to liver fibrosis, for which there are no effective treatments. Aberrant cytoskeletal reorganization is a central driver of HSC activation. Non-muscle myosin II (NM II) is known to regulate cytoskeleton remodeling via its actin cross-linking and contractile properties. However, the molecular players controlling actomyosin assembly and contractility in HSCs during liver fibrosis remain poorly defined. Here, we identified integrin β-like 1 (ITGBL1) as a gatekeeper of HSC quiescence by negatively regulating actomyosin contractility-driven mechanotransduction in HSCs. ITGBL1 expression was markedly elevated in activated HSCs found in patient and mouse fibrotic livers. Unexpectedly, HSC-specific Itgbl1 deficiency worsened liver fibrosis, whereas ITGBL1 overexpression in HSCs limited it, suggesting a protective role for ITGBL1 against a pathogenic HSC activation. Multi-omics and functional analyses revealed that ITGBL1 impaired F-actin filament organization in HSCs by disrupting myosin heavy chain 9 (MYH9, also named NM II heavy chain A)-dependent actomyosin assembly. In line, HSC-specific Myh9 deficiency or silencing of Myh9 in HSCs alleviated liver fibrosis. Taken together, our findings unveil the ITGBL1-MYH9 interaction acts as a critical mechano-regulatory brake that maintains cytoskeletal equilibrium and mechanical homeostasis in HSCs, providing a promising therapeutic strategy to combat liver fibrosis.

BACKGROUND:Acute liver failure due to Drug-induced liver injury (DILI-ALF) is a life-threatening syndrome with rapid progression and high mortality. Although oxidative stress and lipid peroxidation are implicated, the molecular mechanisms underlying DILI-ALF remain incompletely understood. This study aimed to explored the molecular mechanisms of DILI-ALF. METHODS:We performed an integrated analysis combining proteomic profiling of liver tissues from patients with DILI-ALF, reanalysis of public single-cell transcriptomic data, and experimental validation in human liver tissues and an acetaminophen (APAP)-induced liver failure model. Lipid peroxidation, ultrastructural changes, and ACSL4 expression were assessed using biochemical assays, transmission electron microscopy, western blotting, immunohistochemistry. RESULTS:Proteomic analysis revealed significant enrichment of lipid peroxidation and ferroptosis-related pathways in DILI-ALF, with ACSL4 identified as a prominently dysregulated molecule. Single-cell transcriptomic analysis further showed increased ACSL4 expression in specific hepatocytes populations during DILI-ALF. In liver tissues from patients with DILI-ALF, increased ACSL4 expression was accompanied by elevated malondialdehyde and lipid peroxide levels, as well as mitochondrial abnormalities consistent with ferroptosis-associated injury. Similar findings were observed in APAP-induced mouse livers, whereas inhibition of ACSL4 could significantly attenuated levels of lipid peroxidation and liver injury. CONCLUSION:These study identifies and validates an ACSL4-associated ferroptotic lipid peroxidation signature and support the involvement of ferroptosis-related lipid remodeling in the pathogenesis of in DILI-ALF. ACSL4 may represent a potential biomarker and therapeutic target for this severe condition.

OBJECTIVE:Depression poses major global health challenges and accelerates chronic disease development, yet remains undertreated due to reliance on subjective diagnostics. The retina, as an embryological extension of the central nervous system and the organ allowing direct visualization of neurovascular structures, has been demonstrated to serve as an accessible window for systemic health assessment. This study aimed to prospectively examine associations of retinal vascular features with incident depression in healthy individuals and subsequent chronic disease development in those with depression. METHODS:This UK Biobank cohort study included 43,445 participants with acceptable-quality fundus photographs, divided into healthy (n = 40,905) and baseline depression (n = 2540) cohorts. After excluding 1033 participants with pre-existing chronic diseases, 1507 were eligible for chronic disease outcome analysis. Retinal vascular features were quantified using AutoMorph and Cox models examined associations with outcomes. RESULTS:Over a median 11.3-year follow-up, wider retinal veins were associated with increased incident depression risk (central retinal vein equivalent: HR 1.25, 95% CI 1.06-1.48; vein average width: HR 1.31, 95% CI 1.12-1.54). Among those with baseline depression, lower arterial vessel density was associated with overall chronic disease risk (HR 0.71, 95% CI 0.54-0.95), while increased retinal tortuosity was associated with cardiovascular disease risk (vein tortuosity density: HR 2.24, 95% CI 1.25-4.01; artery tortuosity density: HR 1.90, 95% CI 1.17-3.07). CONCLUSIONS:Retinal venous caliber and arterial tortuosity were robustly associated with incident depression and cardiovascular disease risk, respectively, supporting retinal vascular imaging as a promising biomarker candidate warranting further validation.

Diabetic retinopathy (DR) is a leading cause of visual impairment among patients with type 2 diabetes mellitus (T2DM). Evidence regarding the association between lower extremity physical performance and DR remains limited; therefore, this study aimed to investigate this relationship among patients with T2DM in China. A cross-sectional study was conducted among adult patients with diagnosed T2DM attending community health centers in Shaoguan. Lower extremity physical performance was assessed using the balance status, chair stand time, and gait speed. DR was determined through retinal photography. Multivariable logistic regression models were used to assess the association between lower extremity physical performance and the presence of DR. Among 3079 participants with type 2 diabetes, 999 (32.3

Colorectal cancer (CRC) screening remains limited by invasiveness and suboptimal sensitivity of current methods. Retinal microvasculature, a noninvasive window into systemic vascular health, may reflect CRC-associated angiogenesis and inflammation. We investigated whether artificial intelligence (AI)-derived retinal vascular features (RVFs) are associated with CRC risk and prognosis. This analysis included UK Biobank participants with baseline fundus imaging. Multidimensional RVFs, including tortuosity, branching angle, caliber, density, and complexity, were quantified using the Retina-based Microvascular Health Assessment System (RMHAS). Associations of RVFs with incident CRC and mortality among patients with CRC were evaluated using univariable and multivariable Cox regression models. Among 55,798 participants (mean age 55.47 ± 8.09 years; 55.07

Laser capture microdissection (LCM) provides spatial access to specific cell populations within complex tissues through in situ visualization and isolation. To enable transcriptomic analysis of histologically defined regions in fixed tissue, a detailed LCM protocol is presented for RNA extraction from paraformaldehyde (PFA)-fixed, Optimal Cutting Temperature (OCT) compound-embedded mouse liver sections. The protocol details the identification and collection of microscale samples (approximately 1,000 cells) through a workflow encompassing tissue fixation, sucrose dehydration, OCT embedding, cryosectioning, hematoxylin staining, and laser-capture of targeted histological areas. Using this method, a high-purity RNA (A260/A280: 1.9-2.1) was obtained. The RNA integrity number (RIN) was 6.7 ± 0.9, reflecting the expected fragmentation associated with PFA fixation. However, quantitative PCR for β-actin yielded Ct values of 17-19, and RNA sequencing performed using fragmentation-optimized library preparation generated high-quality reads, with >90% of bases meeting Q20 and Q30 thresholds, confirming that the RNA is suitable for sensitive downstream analyses. Therefore, this protocol enables spatially resolved, targeted gene expression analysis by providing RNA of defined purity and integrity from specific histological regions of PFA-fixed liver tissue.

Rationale: In the reconstruction of diabetic bone defects, 3D-printed scaffolds often encounter the challenge of limited and delayed tissue ingrowth in their central regions, which is critical for successful osseointegration and prognostic outcomes. Hyperglycemia induces endothelial apoptosis and impedes angiogenesis, thus inhibiting osteogenic differentiation of bone marrow stem cells (BMSCs). Methods: Drawing inspiration from the growth pattern of vines, we developed a Zn@BP/Si coating on the 3D-printed titanium scaffold to promote the coupling of angiogenesis and osteogenesis. This coating was achieved by Zn2+-modified black phosphorus (BP), which not only enhances the stability and photothermal properties of BP, but also prevents endothelial apoptosis. The effectiveness of Zn@BP/Si in the reconstruction of diabetic bone defects was investigated in rat model of diabetic femoral defect. Its effect on osteogenesis-angiogenesis coupling has also been explored in BMSCs and HUVECs. Results: Zn@BP/Si regulated mitochondrial dynamics and provided motivation for cell adhesion and migration, just like the climbing of vines. Notably, the regulation of enzymatic activity plays a crucial role in its inhibition of excessive mitochondrial fission. The results demonstrate that the Zn@BP/Si promotes the growth of "vascular vines" and ameliorates the angiogenic and osteogenic inhibition in diabetes. Conclusions: The study reveals the potential of bio-inspired Zn@BP/Si coating in angiogenesis-osteogenesis coupling and the treatment of diabetic bone defects.

BACKGROUND:Colorectal cancer (CRC), the third most prevalent malignancy globally, urgently requires novel screening approaches. Although retinal structural abnormalities have emerged as biomarkers for systemic disorders, their association with CRC remains largely unexplored. METHODS:A total of 38 370 participants from UK Biobank, who were free of CRC at baseline, were included in the current study. Retinal structure measurements were obtained using optical coherence tomography (OCT), including ganglion cell-inner plexiform layer (GCIPL). Cox proportional hazards regression models were used to examine longitudinal associations between OCT-quantified retinal layer thicknesses and incident CRC. To elucidate potential biological mechanisms, we performed comprehensive phenotypic and genetic analyses. The phenotypic analyses incorporated multivariable linear regression and mediation analysis to quantify CRC-related factor contributions. Genetic analyses included linkage disequilibrium score regression, MiXeR analysis, conditional/conjunctional false discovery rate (condFDR/conjFDR), and Mendelian randomization (MR) to explore the shared genetic architecture. RESULTS:Over a median follow-up period of 11.27 years, 461 (1.2%) participants developed CRC. In the fully adjusted model, each standard deviation increase in baseline GCIPL thickness was associated with a 10% decrease in incident CRC risk (hazard ratio = 0.90, 95% confidence interval: 0.81-0.99, P = 0.025). CRC-related factors including physical activity, non-communicable chronic diseases, and body mass index were associated with GCIPL thickness variations and BMI mediated 1.62% of the GCIPL-CRC association. Genetic analyses for the GCIPL-CRC association demonstrated significant common genetic variants. MiXeR identified 40 shared causal variants. The condFDR/conjFDR discovered 196 SNPs linked to 32 protein-coding genes. Gene Ontology analysis highlighted enrichment in chromatin remodeling pathways. MR analysis showed no evidence of causal associations. CONCLUSIONS:GCIPL thinning is independently associated with increased CRC risk. Mechanistic analyses suggest this association is driven by shared risk factors and common genetic variants, rather than direct causation. These findings suggest retinal imaging may serve as an indicator of systemic processes influencing CRC.

BackgroundIn recent years, the incidence of alcoholic liver disease (ALD) has rapidly increased worldwide, becoming a significant health issue. Silibinin capsules have shown potential in treating ALD, but clinical evidence is still insufficient. This meta-analysis aimed to evaluate the efficacy and safety of Silibinin capsules in the treatment of ALD.MethodsThe study was registered with PROSPERO (CRD42024509676). Randomized controlled trials (RCTs) were included from six databases, covering the period from database inception to 30 December 2023. Primary outcomes included liver function indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TBIL), lipid indicators including triglycerides (TG) and total cholesterol (TC), coagulation indicators including prothrombin time (PT), liver fibrosis indicator (PC-III), and Effective Rate. Analysis was performed using Review Manager 5.4.1 and STATA 14.0.ResultsIn 15 RCTs involving 1,221 patients, compared to the non-Silibinin group, Silibinin capsules showed significant efficacy in terms of liver function, lipid levels, and effective rate in patients with ALD. Detailed parameters were as follows: ALT [SMD = −1.16, 95% CI (−1.84, −0.47)], AST [SMD = −1.56, 95% CI (−2.18, −0.95)], GGT [SMD = −1.48, 95% CI (−2.09, −0.87)], TBIL [SMD = −1.14, 95% CI (−2.16, −0.13)], TG [SMD = −1.29, 95% CI (−1.93, −0.66)], TC [SMD = −1.11, 95% CI (−1.61, −0.61)], PT [SMD = −0.01, 95% CI (−0.29, 0.26)], PC-III [SMD = −1.94, 95% CI (−3.04, −0.84)], and Effective Rate [OR = 3.60, 95% CI (2.28, 5.70)]. Importantly, Silibinin capsules exhibited a favorable safety profile, with only mild gastrointestinal reactions and reports of insomnia as adverse events.ConclusionThis review reveals the clinical efficacy and safety of Silibinin capsules in the treatment of ALD, and confirms that the drug is an effective adjuvant therapy to alleviate ALD. At present, the mechanism of action of this drug for ALD is still unclear, and we expect more experimental studies to prove the clinical value of Silibinin capsules.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=509676.

OBJECTIVES:Aortic aneurysm (AA) is a life-threatening disease with high mortality. Up-to-date, information on AA burden in China is limited, which is required for health-care planning, resource allocation, and disease prevention. This study investigated the burden of AA in China from 1990 to 2021, and then compared it with other G20 countries. STUDY DESIGN:A comprehensive analysis of the Global Burden of Disease Study 2021 data. METHODS:Estimates of mortality and years of life lost (YLLs) for AA were generated from the Global Burden of Diseases Study (GBD) 2021. Mortality was estimated from vital registration data with the cause of death ensemble model, and YLLs were calculated with the use of standard GBD lifetables. The age-specific and sex-specific patterns, attributable risk factors, and trends regarding the burden of AA in China as well as other G20 nations were summarized. RESULTS:In 2021, there were an estimated 9.04 thousand (95 % uncertainty interval 7.04 to 11.58) deaths due to AA in China, representing a 241.29 % increase since 1990. The age-standardised death rate was 0.46 per 100,000 (0.36-0.59), with a 37.27 % increase from 1990 to 2021. The 2021 YLLs count was 242.11 thousand (185.41-315.41) in China, an increase of 180.74 %, with an age-standardised YLLs rate of 12.4 per 100,000 (9.54-16.09), an increase of 38.89 % since 1990. Both mortality and YLLs were higher in males than in females within all age groups. An upward trend with age in mortality and YLLs was observed. In 2021, smoking remained a major attributable risk factor for AA burden in Chinese males, but high systolic blood pressure was the major factor in females. Furthermore, high body-mass index has risen to the top three risk factors both in males and females. Compared with G20 countries, China was ranked 10th in deaths number in 1990 and then increased to 6th in 2021, and YLLs also increased from 5th to 4th. From 1990 to 2021, unlike China, most G20 countries presented decreased age-standardised rates of death and YLLs, with the largest decrease in Australia, Canada, United Kingdom, and United States of America. CONCLUSIONS:AA remains a serious threat to public health in China, especially for the male and elderly population. Smoking, high systolic blood pressure, and high body-mass index were major attributable risk factors for AA in China. Targeted and cost-effective interventions are urgently needed in China to reduce this burden.

Cardiorespiratory fitness (CRF) is a modifiable risk factor for chronic diseases, but its association with depressive symptoms remains unclear, particularly across different populations. We aimed to investigate the link between estimated CRF (eCRF) and incident depressive symptoms among individuals over 50 years old, and to explore potential cross-country variations in this association. Data were retrieved from three national cohorts: the Health and Retirement Study (HRS, United States), the English Longitudinal Study of Ageing (ELSA, England), and the China Health and Retirement Longitudinal Study (CHARLS, China). eCRF was estimated using sex-specific algorithms and categorized into low (quintiles 1), moderate (quintiles 2–3), and high (quintiles 4–5) levels. Depressive symptoms were measured using the 8-item Center for Epidemiological Studies Depression Scale (CESD-8) (cutoff ≥ 3) in HRS and ELSA, and the 10-item version (CESD-10) (cutoff ≥ 10) in CHARLS. Cox proportional hazard models estimated hazard ratios (HRs) and 95

Glia maturation factor-β (Gmfb), an actin filament debrancher, was initially identified in brain and recently linked to liver diseases. To investigate the role of hepatocyte Gmfb (hep-Gmfb) in liver reparative regeneration, hepatocyte-specific gmfb knockout (HepGKO) and overexpression (HepGOE) zebrafish strains were constructed. Both transgenic and wild-type (WT) zebrafish underwent partial hepatectomy (PHX) or were fed high-fat, high-cholesterol diets to model metabolism-associated steatotic liver disease (MASLD). Under physiological conditions, the HepGKO, HepGOE, and WT fish displayed similar survival, gross appearance, and liver histology. Following PHX, WT liver gmfb levels positively correlated with cell proliferation and proinflammatory cytokine levels. HepGOE showed enhanced regeneration and reduced liver steatosis compared with WT, whereas HepGKO exhibited opposite effects. In MASLD, WT liver gmfb increased with disease progression. HepGKO experienced worsening liver enlargement, steatosis, ballooning, inflammation, and endoplasmic reticulum stress, whereas HepGOE showed improvements. HepGOE liver had the highest cell proliferation, but all three groups showed similar levels of cell apoptosis. Moreover, elevated proinflammatory cytokines were observed across MASLD groups, being the highest in HepGKO and lowest in HepGOE. However, signal transducer and activator of transcription 3 (stat3) activation was the lowest in HepGKO and highest in HepGOE, whereas jnk and mapk/extracellularly regulated kinase (erk) activation was consistent across the MASLD groups. In il6-treated primary hepatocytes, gmfb abundance influenced stat3 activation, and hep-gmfb abundance significantly affected actin filaments distribution in hepatocytes both in vivo and vitro. Hep-Gmfb boosts regenerative processes by enhancing hepatocyte proliferation, alleviating fatty liver histological abnormalities, and modulating the Il6/Stat3 signaling, potentially through remodeling of actin-filament network within hepatocytes.NEW & NOTEWORTHY Glia maturation factor-β (Gmfb) has shown important implications in liver disease. Using transgenic zebrafish models, our research demonstrates that Gmfb in hepatocytes confers protective benefits for liver regeneration and repair. It promotes hepatocyte proliferation, alleviates steatosis and ballooning, and modulates Il6/Stat3 signaling in response to liver injuries, potentially through remodeling of actin-filament network. This submission represents the first in vivo observation of the phenotypic effects of Gmfb in hepatocytes during liver injury.

Background:Coronary heart disease (CHD) and depression are highly comorbid and increase mortality risk. Although age-related eye diseases (AREDs) are independently associated with CHD and depression, their link to comorbidity remains unknown. Therefore, we aim to investigate the association between AREDs and the comorbidity of CHD and depression. Methods:Using UK Biobank data, we conducted a prospective cohort analysis with baseline assessments from March 2006 to December 2010 and follow-up until July 2021. AREDs include age-related macular degeneration, glaucoma, cataract, and diabetes-related eye diseases (DRED). Incident cases were identified via self-reports and hospital records. Multivariable Cox proportional hazard regression models were applied to investigate the association between AREDs and comorbidity risk. Results:Among 116,501 participants free of CHD and depression at baseline, 7,750 (6.65%), 3,682 (3.16%), and 741 (0.64%) developed CHD, depression, and their comorbidity over a mean of 11.82 years (inter-quartile range: 11.51-13.11) of follow-up. After adjusting for confounders, individuals with AREDs had a higher risk of developing CHD (hazard ratio [HR] 1.10, 95% confidence interval [CI]: 1.03-1.17), depression (HR 1.28, 95% CI: 1.16-1.42), and comorbidity (HR 1.37, 95% CI: 1.12-1.67). Compared to those without AREDs, individuals with cataract were associated with increased risks of comorbidity (HR 1.57, 95% CI: 1.23-2.03) and depression (HR 1.26, 95% CI: 1.10-1.43), while those with DRED had an increased risk of incident CHD (HR 1.33, 95% CI: 1.13-1.56). Conclusion:The study found that individuals with AREDs had a higher risk of comorbid CHD and depression than of either condition independently. Our findings highlighted the importance of screening for the comorbidity of CHD and depression in the longitudinal management of AREDs.

Depression, which is increasingly prevalent among older adults, has traditionally been diagnosed through symptom-based questionnaires. However, emerging evidence suggests that retinal changes could serve as objective biomarkers for depression. In this study, we investigated the optic disc signature of depression by leveraging automated fundus morphometrics (deep learning segmentation) and Olink-based plasma proteome profiling to explore potential mechanistic pathways. A total of 412 participants from two independent cohorts, the UK Biobank and the Guangdong Ophthalmic-Psychological Health Study (GD-OPHS), were included in the analysis. Our findings indicate that individuals with depression exhibited increased roundness of the optic disc (UK Biobank: OR = 1.12, 95