Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical d Show more
Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
The Lipoprotein(a) (LPA) rs3798220 and rs10455872 polymorphisms have been indicated to be involved with the coronary heart disease (CHD) susceptibility. However, there are still differences between th Show more
The Lipoprotein(a) (LPA) rs3798220 and rs10455872 polymorphisms have been indicated to be involved with the coronary heart disease (CHD) susceptibility. However, there are still differences between the individual studies. To explore the correlation of LPA gene rs3798220 and rs10455872 polymorphisms and CHD, the current meta-analysis was performed. The random or fixed effect genetic models were used to calculate the pooled odds ratios (ORs) and their corresponding 95 % confidence intervals (CI). A significant association was found between LPA rs3798220 polymorphism and CHD under allelic (OR: 1.488), recessive (OR: 1.543), dominant (OR: 1.534), homozygous (OR: 1.544), heterozygous (OR: 1.498) and additive genetic models (OR: 1.531). There was also a significant association between LPA rs10455872 polymorphism and CHD under allelic (OR: 1.607), dominant (OR: 1.751), heterozygous (OR: 1.723) and additive genetic models (OR: 1.686). LPA rs3798220 and rs10455872 polymorphisms were significantly associated with increased CAD risk. The persons carrying C allele of LPA rs3798220 and G allele of LPA rs10455872 polymorphisms might have higher CHD risk than the T allele of rs3798220 or A allele of rs10455872 carriers. Show less
The paraventricular hypothalamus (PVH) controls behavioral and physiologic processes, including appetite, social behavior, autonomic outflow, and pituitary hormone secretion. However, molecular marker Show more
The paraventricular hypothalamus (PVH) controls behavioral and physiologic processes, including appetite, social behavior, autonomic outflow, and pituitary hormone secretion. However, molecular markers for centrally projecting PVH neuron populations remain largely undefined, and a complete census of PVH cell types has not been established. Therefore, we performed extensive single-cell/nucleus RNA sequencing to catalog PVH neuron subtypes and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to map them spatially. Our spatial transcriptomic atlas resolves 26 Sim1 Show less
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress respons Show more
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress response. Accumulating evidence highlights its context-dependent regulatory roles in hepatocellular carcinoma (HCC)-the most prevalent primary liver malignancy with high mortality and limited therapeutic efficacy. This review systematically summarizes the core mechanisms by which TRIM21 orchestrates HCC progression: ① Autophagy regulation: TRIM21 modulates HCC autophagy via multiple axes, including CCR4-NOT complex (TNKS1BP1/CNOT4)-mediated substrate ubiquitination, ATG14-dependent autophagosome initiation, and RETREG1-driven reticulophagy, with context-dependent effects on tumor proliferation. ② Drug resistance: TRIM21 enhances oxaliplatin sensitivity by ubiquitinating and degrading G6PD (the rate-limiting enzyme of the pentose phosphate pathway), while its role in sorafenib resistance involves dual pathways-the MST1/YAP axis and the ApoE/cholesterol/PI3K-AKT cascade. ③ Metastasis suppression: TRIM21 restricts HCC invasion and metastasis by ubiquitinating key oncoproteins, preserving epithelial integrity and inhibiting mesenchymal transition. ④ Reactive oxygen species (ROS) balance: TRIM21 regulates oxidative stress in HCC via the SQSTM1/p62-Keap1-NRF2 axis, coordinating with HIF1α to modulate antioxidant responses and tumor cell survival. Additionally, we discuss the regulatory significance of TRIM21 in HCC associated with hepatitis B virus (HBV) infection (via HBx/DNA polymerase ubiquitination) and nonalcoholic steatohepatitis (NASH) (via suppressing lipogenic enzymes to reduce steatosis-driven carcinogenesis). This review provides a theoretical basis for TRIM21 as a potential diagnostic marker and therapeutic target for HCC. Show less
This study investigated the synergistic effects of combining ferulic acid esterase (FAE)-producing lactobacillus with homofermentative and heterofermentative lactic acid bacteria (LAB) on the fermenta Show more
This study investigated the synergistic effects of combining ferulic acid esterase (FAE)-producing lactobacillus with homofermentative and heterofermentative lactic acid bacteria (LAB) on the fermentation quality, nutrient composition, and aerobic stability of corn stover silage. In this study, five LAB strains were isolated and identified from various silages. Among them, strain AR1 was identified as The results showed that the co-fermentation of homofermentative and heterofermentative strains improved silage fermentation quality. The addition of AR1 to the combination of homofermentative and heterofermentative LAB further enhanced lactic acid and acetic acid production, decreased neutral and acid detergent fiber contents, and improved aerobic stability. Principal component analysis and membership function analysis identified the LPLR group (an equal mixture of AR1, R10, JF2, and R3 at 1 × 10 Show less
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson' Show more
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson's disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520-7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population. Show less
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, w Show more
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, we identify a regulatory axis wherein the transcription factor ZBED6 activates the expression of the autophagy-initiating kinase PIK3C3 via the repression of IGF2, thereby driving pro-tumorigenic autophagy. Spatial analysis confirms the co-localization of ZBED6 and PIK3C3 in tumor tissues. Using genes associated with this axis, we develop a six-gene prognostic signature that stratifies patients with distinct survival outcomes and differential responses to immunotherapy and targeted therapy. Functional assays show that ZBED6 promotes ccRCC cell proliferation, migration, and invasion. This work elucidates a pathway governing autophagy in ccRCC and provides a framework for prognostic assessment and precision therapy. Show less
Probiotics such as The intestinal colonization ability of CIQ249 was assessed using cFDA-SE labeling and flow cytometry. Growth performance and intestinal morphology were evaluated in mice. Antimicrob Show more
Probiotics such as The intestinal colonization ability of CIQ249 was assessed using cFDA-SE labeling and flow cytometry. Growth performance and intestinal morphology were evaluated in mice. Antimicrobial activity of CIQ249 cell-free supernatant was tested against various pathogens, and pathogen damage was visualized by scanning electron microscopy. Protective effects against CIQ249 demonstrated strong intestinal colonization and increased villus height and the villus-to-crypt ratio, contributing to improved growth performance. Its cell-free supernatant selectively inhibited enteropathogens and induced structural damage in CIQ249 enhances mucosal defense against enteropathogenic bacteria through a dual mechanism-strengthening the epithelial barrier and activating a coordinated DC-Tfh-IgA immune axis. These findings provide a multi-level mechanistic basis for its application as a microecological agent against intestinal infections. Show less
The global aging crisis has increased the risk of atherosclerosis (AS), positioning vascular senescence as a critical therapeutic target. Procyanidin C1 (PCC1), a bioactive polyphenol from hawthorn, d Show more
The global aging crisis has increased the risk of atherosclerosis (AS), positioning vascular senescence as a critical therapeutic target. Procyanidin C1 (PCC1), a bioactive polyphenol from hawthorn, demonstrates dual senolytic and longevity-enhancing effects. This study explored the regulatory role and mechanisms of PCC1 in AS using an ApoE Show less
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited treatment options and frequent drug resistance. Novel therapeutic targets are urgently needed. We performed a druggabl Show more
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited treatment options and frequent drug resistance. Novel therapeutic targets are urgently needed. We performed a druggable genome-wide Mendelian randomization (MR) analysis using blood cis-expression quantitative trait locus (eQTL) and HS genome-wide association study (GWAS) data. Colocalization, transcriptomic validation, single-cell RNA sequencing, and cell-cell communication analyses were integrated to explore gene function and cell-type specificity. We identified eight genes that showed significant associations with HS through MR analysis. Colocalization analysis further prioritized PSMA4 and MAST3 as the most promising druggable targets for HS. Specifically, PSMA4 (single nucleotide polymorphisms [SNPs] = 10; inverse-variance weighted [IVW] OR = 1.912, 95% CI: 1.492-2.450, Show less
Hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) are characterized by left ventricular hypertrophy and diastolic dysfunction. Despite overlapping remodeling features, their disti Show more
Hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) are characterized by left ventricular hypertrophy and diastolic dysfunction. Despite overlapping remodeling features, their distinct mechanisms and therapeutic responses remain unclear. This study integrated genetic, imaging, and proteomic data to identify key mediators underlying β1-adrenergic receptor blockers (β1-blockers)-related therapeutic heterogeneity between HHD and HCM. Genetic instruments for β1-blockers were derived from two genome-wide association studies and integrated with cardiac magnetic resonance radiomic traits and plasma proteomic data from the UK Biobank, along with disease outcomes from FinnGen. A refined two-stage network Mendelian randomization framework with pleiotropy-robust estimators identified mediators of treatment response. To further elucidate their biological and clinical significance, additional analyses were performed, including drug-target profiling, molecular docking, adverse events (AEs) assessment, and drug prediction. We identified three types of imaging features and ten mediator proteins that contributed to therapeutic responses in HHD and HCM. These mediators were categorized as either mediating (aligned with therapeutic outcomes) or suppressing (opposing therapeutic outcomes). Left ventricular regional radial strain acted as a suppressing factor in HHD but a mediating factor in HCM, whereas end-diastolic and end-systolic volumes consistently showed suppressing effects in both. Regional myocardial wall thickness also exerted a suppressing role in HCM. Among protein mediators, APOE, CGREF1, ITGA5, LSP1, NOS3, and NPPB were linked to HHD, whereas DUSP13, ITGA11, NID1, and SERPINA4 were related to HCM. Specifically, APOE, ITGA5, NOS3, NPPB, DUSP13, and ITGA11 acted as mediating factors, while CGREF1, LSP1, NID1, and SERPINA4 served as suppressing ones. These findings remained robust after pleiotropy adjustment and other genetic analyses. Molecular docking revealed interactions between ADRB1, the β1-blockers target, and downstream proteins, while drug prediction identified eight potential compounds linked to these mediators. Additionally, AE analyses indicated that some targets, such as DUSP13, could both mitigate and aggravate common AEs while contributing to cardiac therapy. This integrative multi-omics analysis revealed distinct imaging and proteomic mechanisms of genetically proxied β1-blockers in HHD and HCM, providing genetic evidence for differential therapeutic responses and highlighting molecular targets for precision cardiovascular therapy. Show less
Tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC); however, acquired resistance remains a major clinical challenge. While lysosomes hav Show more
Tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC); however, acquired resistance remains a major clinical challenge. While lysosomes have been implicated in drug resistance, their precise role in EGFR-TKI resistance remains unclear. In this study, we found that EGFR-TKI, including gefitinib and osimertinib, impaired WWP2-mediated proteasomal degradation of LAPTM4B. Through analysis of clinical tumor samples, genetic manipulation, and functional assays, we identify the lysosomal protein LAPTM4B as a key driver of EGFR-TKI resistance by enhancing EGFR phosphorylation and downstream signaling. Mechanistically, LAPTM4B interacts with ATP1A1 and facilitates its endocytosis, while simultaneously preventing its degradation by suppressing TRIM8-mediated K63-linked ubiquitination and proteasomal turnover. This stabilization of ATP1A1 enhances lysosomal acidification, ultimately promoting EGFR-TKI resistance. To identify potential therapeutic strategies, we conducted an unbiased high-content drug screen and identified compounds that suppress LAPTM4B expression. These compounds synergistically enhance the efficacy of EGFR-TKIs in NSCLC models Show less
Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer's disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association b Show more
Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer's disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association between DM and AD risk while others have not. Therefore, this meta-analysis aimed to systematically evaluate the association between DM and AD risk. Comprehensive searches were conducted in PubMed, Web of Science, and Embase databases to identify cohort or case-control studies investigating the association between DM and AD risk. All eligible studies published before October 2025 were included. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. Hazard ratio (HR) and 95% confidence interval (CI) were pooled as the effect size for meta-analysis. Heterogeneity among studies was evaluated using Cochran's A total of 11 studies involving 3,393,545 participants were included. A meta-analysis revealed that DM was significantly associated with an increased risk of AD (HR = 1.36, 95% CI (1.19, 1.55), This meta-analysis provides compelling evidence that DM is an independent risk factor for AD, offering important implications for clinical practice and future research. However, due to the methodological limitations of this study, the results should be interpreted with caution. Large-scale, high-quality prospective cohort studies are needed to fully investigate the relationship between DM and AD risk. https://www.crd.york.ac.uk/prospero/, identifier CRD420251159844. Show less
Major depressive disorder (MDD) in adolescents is a critical public health concern, yet objective diagnostic biomarkers remain lacking. We conducted an integrative lipidomics study across human cohort Show more
Major depressive disorder (MDD) in adolescents is a critical public health concern, yet objective diagnostic biomarkers remain lacking. We conducted an integrative lipidomics study across human cohorts and a chronic unpredictable mild stress (CUMS) rat model. Targeted UPLC-MS/MS profiling was applied to a training cohort (95 MDD, 40 controls), and untargeted UPLC-HRMS profiling to an independent cohort (56 MDD, 37 controls). Candidate biomarkers were identified using univariate tests, partial least squares discriminant analysis, and three feature-selection methods (Boruta, LASSO, RFE), with predictive performance evaluated by cross-validation and external replication. Translational relevance was examined in CUMS rats through behavioral assays and lipidomic profiling of serum and brain tissues. Pathway enrichment and regression models explored metabolic context and clinical associations. In the training cohort, we found that 244 lipids were significantly altered, highlighting altered glycerophospholipid, glycerolipid, and sphingolipid metabolism. A 29-lipid panel achieved 90.4% cross-validation accuracy, while a reduced 7-lipid subset reached 94.8%. In the validation cohort, an 8-lipid panel achieved 71.2% accuracy, and a minimal 2-lipid set-LPA(18:2) and SPH(d16:1)-reached 72.1%. Cross-species analysis confirmed consistent downregulation of SPH(d16:1) in serum of both humans and rats, and of LPC(0:0/16:0) specifically in the rat prefrontal cortex. Regression analyses linked sex, age, and anxiety severity to lipid alterations. This cross-platform, cross-species study identifies reproducible lipid signatures of adolescent MDD, highlights SPH(d16:1) and LPC(0:0/16:0) as translational biomarkers, and implicates glycerophospholipid metabolism in MDD pathophysiology, providing a foundation for biomarker-guided diagnostics and therapeutics. Show less
Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of ph Show more
Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of phenylacetylglutamine (PAGln), a novel gut microbiota metabolite, in Dox-induced cardiotoxicity (DIC). DIC models were established in vivo and in vitro, and a series of experiments were performed to verify the cardioprotective effect of PAGln. RNA sequencing (RNA-seq) was employed to explore the mechanism of PAGln in DIC. Subsequently, the differentially expressed genes (DEGs) were subjected to comprehensive analysis using diverse public databases, and RT-PCR was used to confirm the expression levels of the candidate genes. Finally, molecular docking techniques were used for validation. PAGln effectively prevented both in vivo and in vitro Dox-induced myocardial injury and cell apoptosis. RNA-seq results showed that 40 genes were up-regulated and 54 down-regulated in the Dox group compared to the Con group, displaying opposite changes in the Dox + PAGln group. Enrichment analysis highlighted several mechanisms by which PAGln alleviated Dox-induced cardiotoxicity, including the lipid metabolic process, calcium-mediated signaling, positive regulation of store-operated calcium channel activity, and hypertrophic cardiomyopathy. In vitro and in vivo experiments confirmed that PAGln treatment could reverse the changes in the expression levels of Klb, Ece2, Nmnat2, Casq1, Pak1, and Apob in Dox. Molecular docking results showed that these genes had good binding activity with PAGln. PAGln shows potential in alleviating Dox-induced cardiotoxicity, with Ece2 identified as key regulatory molecules related to endothelial dysfunction. Show less
To ascertain the level of psychological resilience, examine the latent profiles of individuals within infertile couples who experience recurrent implantation failure (RIF), identify the relevant influ Show more
To ascertain the level of psychological resilience, examine the latent profiles of individuals within infertile couples who experience recurrent implantation failure (RIF), identify the relevant influencing factors, and lay a foundation for developing customized intervention strategies. Convenience sampling was adopted in this study. Participants were selected from individuals in infertile couples with RIF who attended the Second West China Hospital of Sichuan University between November 2024 and July 2025. Data were collected via a general information questionnaire and validated scales assessing psychological resilience, social support, sleep quality, family adaptability and cohesion, anxiety, and depression. Latent profile analysis (LPA) was performed to explore the psychological resilience profiles of individuals with RIF, while univariate analysis and multivariate Logistic regression analyses were employed to identify the influencing factors associated with different profile categories. A total of 303 valid questionnaires were collected, including 194 from females and 109 from males. The overall psychological resilience score was (26.66 ± 6.319). Latent profile analysis categorized psychological resilience into three subgroups: the low tenacity-low strength subgroup (31.4%), the moderate tenacity-moderate strength subgroup (53.1%), and the high tenacity-high strength subgroup (15.5%); Multivariate Logistic regression analysis indicated that gender, family adaptability and depression severity (all Marked interindividual heterogeneity exists in the psychological resilience of individuals with RIF. Gender, family adaptability and depression severity serve as the core influencing factors. In clinical practice, stratified and targeted interventions should be delivered according to distinct psychological resilience subgroups. It yields clinical implications for an association between improved psychological resilience among individuals from couples with RIF and enhanced treatment adherence. Show less
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less
Diabetic kidney disease (DKD) is a major diabetic complication that often progresses to end-stage renal disease and causes high mortality. Early diagnosis is essential for effective prevention and tre Show more
Diabetic kidney disease (DKD) is a major diabetic complication that often progresses to end-stage renal disease and causes high mortality. Early diagnosis is essential for effective prevention and treatment. To explore the underlying mechanisms of DKD and identify plasma biomarkers for early diagnosis. In this study, healthy adults and individuals with diabetes mellitus (classified into normal albuminuria (NA), microalbuminuria (MI), and macroalbuminuria (MA) groups) were recruited. Plasma samples were collected from all participants, and 12 subjects per group were then randomly selected as a discovery cohort for proteomic analysis. Proteomics identified 95 differentially expressed proteins (DEPs) among the groups. These DEPs associated pathways evolved in a stage-specific manner in which inflammation dominated the early NA/Ctrl stage, complement and coagulation cascades became the main drivers during MI/NA, and MA/MI exhibited newly emerged disturbances in oxidative detoxification, lysosomal function, and nitrogen metabolism alongside sustained complement and coagulation changes. Among them, the complement and coagulation cascades were closely related to DKD progression. Through hub protein analysis, five proteins (FGG, ITIH4, A2M, C3, and APOE) that showed consistent trends across disease stages were identified as potential diagnostic biomarkers for DKD. Our research provides new insights into the mechanisms and early diagnosis of DKD. Show less
Liver metastasis is the predominant cause of mortality among individuals diagnosed with colorectal cancer (CRC). However, the mechanisms underlying the tumor-microenvironment interactions that promote Show more
Liver metastasis is the predominant cause of mortality among individuals diagnosed with colorectal cancer (CRC). However, the mechanisms underlying the tumor-microenvironment interactions that promote this process remain poorly defined. Here, we developed an integrative multiomics framework to dissect the cellular and molecular determinants of colorectal cancer liver metastasis (CRLM). By analyzing 1,156 metastasis-associated genes, we identified three molecular subtypes with distinct prognostic and immunometabolic features: C1 with mixed phenotypes and favorable survival, C2 with metabolic activation and immune suppression, and C3 with immune activation and signaling dysregulation, which had the poorest outcomes. Mechanistically, we discovered that SPP1⁺ macrophages secrete PDGFB, which activates PDGFRB signaling in FADS1⁺ tumor cells to trigger epithelial-mesenchymal transition (EMT) and promote liver metastasis. This macrophage-tumor crosstalk was validated by single-cell transcriptomics, genetic perturbation, and coculture experiments. Collectively, our findings define a macrophage-derived PDGFB-PDGFRB axis that drives CRC liver metastasis and highlight a potential therapeutic target for overcoming metastatic progression and immune resistance. Show less
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the ef Show more
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less
Frailty is associated with increased risks of falls, disability, hospitalization, and mortality. The 24-h movement behaviors (24HMB) framework conceptualizes sleep, sedentary behavior (SB), light-inte Show more
Frailty is associated with increased risks of falls, disability, hospitalization, and mortality. The 24-h movement behaviors (24HMB) framework conceptualizes sleep, sedentary behavior (SB), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) as mutually constrained components of daily time use and may inform frailty prevention and management. This scoping review maps evidence on associations between 24HMB and frailty and identifies methodological gaps to inform future research and nursing practice. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and follows Joanna Briggs Institute (JBI) guidance. We searched PubMed, Embase, CINAHL, and Web of Science. We included observational studies of adults aged ≥18 years. Exposures were objectively measured or validated self-reported sleep, SB, LPA, and MVPA, including step counts, breaks in SB, isotemporal substitution models (ISM), and compositional data analysis (CoDA). Outcomes were frailty or prefrailty assessed using validated instruments. Quality was appraised with JBI tools. Thirty-three studies showed good methodological quality. Longer SB, particularly prolonged, uninterrupted bouts, was associated with higher frailty. Greater MVPA was consistently associated with lower frailty. Light-intensity physical activity was generally beneficial but often attenuated when MVPA or total activity volume was modeled. Sleep fragmentation and poor sleep quality were associated with frailty. Isotemporal substitution models and compositional data analysis indicated that reallocating sedentary time to MVPA would yield the largest theoretical benefit, followed by reallocating to LPA. Higher daily step counts and more frequent or higher-intensity breaks in SB were associated with lower frailty. Evidence supports a 24-h integrated movement-behavior approach centered on MVPA, combined with reducing prolonged SB and improving sleep quality, for the prevention and nursing management of frailty. The study design and analytical protocol were prospectively registered on the Open Science Framework (OSF). The unique identifier is S39Y4, and the publicly accessible URL is https://doi.org/10.17605/OSF.IO/S39Y4. Show less
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gek Show more
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression. Show less
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Show more
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective coho Show more
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective cohort study. Two large multi-center cohorts (UK Biobank [UKB] and Whitehall II [WHII] study) across the UK and an Eastern multi-center cohort ONE-IBD Study from China. UK Biobank discovery cohort (n=10,229) for signature derivation, internal validation cohort (n=91,306), external validation cohort Whitehall-II (n=7,893), and three additional cohorts (two Western and ONE-IBD) for validation of key metabolic drivers. Primary outcomes were UPF-related circulating metabolic signatures and their associations with CD risk; secondary outcomes included evidence supporting causal roles of candidate metabolites and genetic pathways assessed by Mendelian randomization, colocalization, and gene-environment analysis. A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HR The adverse effects of UPF on CD risk may be driven by a relative deficiency of protective metabolites such as DHA, apart from additive harm to metabolic depletion. This reframes UPF-related risk and highlighting potential targets for precision nutrition in CD prevention. Show less
Neonatal regulatory T (Treg) cells in secondary lymphoid organs have greater proliferative capacity and more potent suppressive functions than adult Treg cells. However, the phenotypic and functional Show more
Neonatal regulatory T (Treg) cells in secondary lymphoid organs have greater proliferative capacity and more potent suppressive functions than adult Treg cells. However, the phenotypic and functional features of Tregs in neonatal nonlymphoid organs are not well understood. Our prior work demonstrated that thymus-derived Treg cells entering the neonatal mouse liver enhance immune tolerance and periportal liver maturation. Compared to splenic Treg cells, these hepatic Tregs have faster turnover and superior suppression of naïve T-cell proliferation. To further define this population, we conducted single-cell transcriptomic and immunophenotypic analyses of liver- and spleen-derived Tregs from neonatal and adult mice. Our analysis revealed a distinct T-box transcription factor Tbx21 (T-bet) Show less
Cutaneous squamous cell carcinoma (cSCC) involves complex immune interactions. This study aimed to identify a T cell-related gene signature to characterize the immune landscape and aid in molecular di Show more
Cutaneous squamous cell carcinoma (cSCC) involves complex immune interactions. This study aimed to identify a T cell-related gene signature to characterize the immune landscape and aid in molecular diagnosis. We integrated single-cell RNA sequencing (scRNA-seq) and five bulk microarray datasets, utilizing an independent RNA-seq cohort for external validation. Feature genes were identified from the intersection of scRNA-seq-defined T cell-related genes (TRGs) and bulk differentially expressed genes using machine learning. A diagnostic nomogram was constructed, and its performance was assessed via ROC curves. In addition, immune infiltration, immunofluorescence staining, drug interactions, and clinical expression (qRT-PCR) were evaluated. Screening yielded 28 T cell-related DEGs enriched in extracellular matrix functions. machine learning selected a core signature: APOE, CYBA, and S100A2. The diagnostic model demonstrated high diagnostic performance in the studied cohorts (AUC > 0.9) across training and external validation cohorts. Clinically, qRT-PCR supported significant upregulation of CYBA and S100A2. APOE exhibited distinct immunomodulatory connectivity, correlating positively with Th17 cells and negatively with Tregs, whereas CYBA and S100A2 were associated with Treg infiltration. Immunofluorescence results revealed significantly elevated levels of S100A2 and Foxp3 in cSCC tissues compared to the control group. Pharmacogenetic analysis highlights the association of these genes, particularly the APOE gene, with drug response. This T cell-associated signature highlights the potential link between molecular diagnosis and immune characterization. Specifically, CYBA and S100A2 are identified as promising diagnostic candidate signatures, while APOE may reflect immunomodulatory heterogeneity. These findings offer insights for developing diagnostic strategies and targeted immunotherapies in cSCC. Show less
The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Pa Show more
The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Participants (n = 376,533) of white-British ancestry from the UK biobank with cognitive, neuroimaging, and whole-exome sequencing data were included. Six cognitive outcomes were assessed: fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), trail making (TRAIL1 and TRAIL2), and prospective memory (PMEM). Seven brain regions of interest were assessed: total brain (TBV), grey matter (GMV), left and right white matter (LWM/RWM), left and right hippocampi (LHC/RHC), and white matter hyperintensities (WMH) volumes. A total of 3487 genetic variants across 39 DNA repair genes were tested. SNP and gene/gene-set level associations were tested using regression models adjusted for age, sex, APOE ε4, ancestry, and outcome-specific covariates. Genetic interactions with a multidimensional cardiometabolic risk index (CMRI), encompassing established risk factors, were assessed. We detected 107 genetic variants (mostly extremely rare) across 36 DNA repair genes associated at Bonferroni-significance (p ≤ 1.4 × 10 Show less
Zhongxiao Lin, Jianyu Xiong, Fuyuan Zhang+15 more · 2026 · Molecular therapy : the journal of the American Society of Gene Therapy · Elsevier · added 2026-04-24
Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role an Show more
Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role and underlying mechanisms of lysine acetyltransferase 8 (KAT8), a key histone acetyltransferase, in maintaining endothelial cell homeostasis and preventing vascular senescence. We found that KAT8 expression is consistently downregulated in human aged vessels, senescent rats and mice, and cellular models of aging. Using CRISPR-Cas9-based loss-of-function and gain-of-function approaches in endothelial cells, C57BL/6J mice, and ApoE Show less