Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were appr Show more
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less
The association between obesity and atrial fibrillation (AF) has garnered increasing attention. Obesity is a significant risk factor for cardiovascular diseases and promotes the occurrence of AF throu Show more
The association between obesity and atrial fibrillation (AF) has garnered increasing attention. Obesity is a significant risk factor for cardiovascular diseases and promotes the occurrence of AF through multiple mechanisms. This study aims to explore the molecular mechanisms of obesity-induced AF using GLP-1R/GIPR dual-target agonist fusion protein (Fc) loaded into adipose-derived mesenchymal stem cell (ADSC) exosome-liposome hybrid nanoparticles (LE@Fc NPs). We successfully constructed and purified the Fc, verifying its purity and functional activity through SDS-PAGE and UV absorption spectroscopy. The fusion protein was then loaded into nanovesicles, and their morphology, size, and stability were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and dynamic light scattering (DLS). In vitro experiments demonstrated that LE@Fc NPs exhibit high fusion efficiency and targeted delivery capability. In vivo experimental results show that LE@Fc NPs significantly inhibit ferroptosis in the epicardial adipose tissue (EAT) of obese mice (iron content: 3.69 ± 0.36 vs. 0.88 ± 0.09), by restoring GSH levels (0.45 ± 0.08 vs. 0.87 ± 0.08) and Gpx4 expression (0.32 ± 0.06 vs. 1.01 ± 0.16), and reducing ROS (12.01 ± 0.95 vs. 2.68 ± 0.17), MDA (3.17 ± 0.29 vs. 0.95 ± 0.09), and 4-HNE (3.74 ± 0.51 vs. 0.91 ± 0.09) levels. Furthermore, LE@Fc NPs treatment significantly improved the inflammatory response (IL-1β: 44.08 ± 3.74 vs. 12.07 ± 0.65, IL-6: 515.59 ± 47.70 vs. 288.43 ± 16.81, MCP-1: 1401.04 ± 194.88 vs. 600.28 ± 45.54, TNF-α: 39.96 ± 2.48 vs. 18.01 ± 0.85). LE@Fc NPs also reduced atrial fibrosis, thereby effectively lowering the incidence of AF. Echocardiography and electrocardiogram monitoring revealed that LE@Fc NPs treatment significantly improved atrial remodeling and reduced the occurrence of AF in obese mice. In addition, LE@Fc NPs significantly improved obesity-induced systemic inflammation and metabolic disorders. In conclusion, LE@Fc NPs show great potential for the treatment of obesity-related AF. Show less
To explore the risk factors of post pancreatectomy diabetes mellitus (PPTDM)in pancreatic ductal carcinoma (PDAC) patients and the value of perioperative fasting blood glucose (FBG) level expression o Show more
To explore the risk factors of post pancreatectomy diabetes mellitus (PPTDM)in pancreatic ductal carcinoma (PDAC) patients and the value of perioperative fasting blood glucose (FBG) level expression on the long-term survival after surgery. Between December 2015 and December 2019, a cohort of 509 patients diagnosed with PDAC and undergoing resection at our hospital was analyzed. They were stratified into two groups, Control group (Control) and study group (PPTDM), depending on the onset of postoperative diabetes mellitus. We analyzed the survival rates at 6 months, 12 months and 24 months post-operation in the two groups. We use univariate and logostic multivariate regressions to analyze the risk factors for PPTDM. ROC curve analysis was conducted to assess the diagnostic significance of perioperative FBG levels regarding patients' long-term survival rates. The Kaplan-Meier method was employed to assess the impact of both preoperative and postoperative FBG levels on the survival rates within 24 months for each patient group. The comparison of general clinical data between the two groups shows marginal differences without statistical significance(P > 0.05); Patients in PPTDM group had significantly higher BMI, preoperative jaundice proportion, larger tumor diameter, higher TNM stage and higher proportion of distal pancreatectomy (DP), with P values of 0.023, 0.010, 0.040, 0.012 and 0.005, respectively. The levels of preoperative FBG and postoperative FBG in PPTDM patients exhibited statistically significant elevation compared to the control group (P < 0.05). There were no significant differences in surgery-related indicators between the two groups in operative time, number of dissected positive lymph nodes, total number of dissected lymph nodes, intraoperative blood loss and other related data (P > 0.05). Hospitalization duration of PPTDM patients was longer than control group (P = 0.047). PPTDM group had significantly higher expression concentrations of BUN, Cr, TG, LDL and Apo-B factors (P = 0.023, 0.024, 0.013, 0.045 and 0.017). 17 patients (5.03%) died in the PPTDM group and 4 patients (2.35%) in control group which had significantly difference (P = 0.020). In univariate and logostic multivariate regression analysis indicated tumor size, jaundice, BUN, Cr, TG, LDL, Apo-B concentrations and DP approach were significantly correlated to the risk for PPTDM (P < 0.05). ROC curve analysis results showed combining of preoperative and postoperation FBG showed the highest diagnostic efficacy, followed by postoperation FBG and preoperative FBG. The AUC areas of the three groups were 0.745, 0.623 and 0.588, respectively, and the critical values of the three groups were 9.81/9.95 mmol/L, 10.18 mmol/L and 10.23 mmol/L, respectively, with statistical significance (P < 0.05). Results were considered statistically significant if the p-value was less than 0.05. PPTDM stands as a significant postoperative complication following pancreatic cancer surgery, characterized by a high incidence and severity. Several risk factors have garnered considerable attention among clinical surgeon. PPTDM may be an influential factor in postoperative prognosis of pancreatic cancer. The expression levels of preoperative and postoperative blood glucose hold diagnostic value for the long-term prognosis of pancreatic cancer patients. Early regulation and intervention by surgeons concerning perioperative FBG could potentially mitigate the risk of PPTDM. Show less
This study identified fibroblast-specific genes to develop a RiskScore model to improve prognostic accuracy and guide personalized treatment in glioblastoma (GBM). We analyzed fibroblast-specific sign Show more
This study identified fibroblast-specific genes to develop a RiskScore model to improve prognostic accuracy and guide personalized treatment in glioblastoma (GBM). We analyzed fibroblast-specific signatures in the GSE273274 cohort using "Seurat" R package for scRNA-seq data processing. Fibroblast-related gene modules were identified via WGCNA, and functional enrichment was assessed with "clusterProfiler" package. A RiskScore model was established using univariate, Lasso Cox regression analysis, and "survival" package, validated by "timeROC" for receiver operator characteristic (ROC) curve. Finally, immune infiltration and drug sensitivity was evaluated applying "ESTIMATE," "TIMER," "MCPcounter," and "pRRophetic" packages. Experimental validation included qPCR for gene expression detection, and CCK-8, wound healing, and Transwell assays for functional measurement. The scRNA-seq analysis identified nine cell types of cells, with fibroblasts elevated in the GBM group. Fibroblast signatures were linked to tumorigenesis, cytoskeleton remodeling, and regulation of neuronal development process that affected GBM invasion. A 6-gene RiskScore divided GBM patients into high- and low-risk groups in training and validation sets, with high-risk patients exhibiting poorer survival, elevated StromalScore, and negative correlations with the infiltration of neutrophils and B_cells. Moreover, high-risk patients demonstrated heightened sensitivity to Cisplatin, MG-132, AZ628, Dasatinib, CGP-60474, A-770041, TGX221, and Bortezomib. Finally, qPCR showed that the VWA1 was upregulated in GBM cells, while knock-down of VWA1 inhibited the cell proliferation, migration, and invasion activity. We constructed a RiskScore model for predicting the survival outcomes based on fibroblasts-related genes. These findings highlighted the role of fibroblasts in GBM development and offered six potential therapeutic targets (VWA1, DUSP6, LOXL1, IGFBP4, CYGB, and ZIC3) for GBM treatment. Additionally, immune infiltration analysis and drug sensitivity prediction further supported the model's utility in guiding personalized treatment of GBM. Show less
Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This stu Show more
Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This study comprehensively identified ASassociated genes by integrating data from the Gene Expression Omnibus (GEO) database and expression quantitative trait locus (eQTL) analyses, complemented by Mendelian randomization (MR) analysis, followed by experimental validation of their functional roles. Results indicated significant upregulation of CLEC5A and ISG20 in patients with AS, with MR analysis revealing positive causal relationships between both genes and AS risk (CLEC5A: OR = 1.001, P = 0.047; ISG20: OR = 1.001, P = 0.030), while HOXA2 showed a negative causal association. Functional enrichment analysis highlighted CLEC5A and ISG20's involvement in immune responses, inflammatory pathways, and lipid metabolism regulation. Experimental validation in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages and apolipoprotein E-deficient (ApoE This study represents the first to elucidate the molecular mechanism by which ISG20 promotes AS progression through macrophage lipid accumulation and inflammatory responses, positioning it as a potential novel therapeutic target for AS. Show less
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and ga Show more
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and gain-of-function assays using shRNA-mediated knockdown and ectopic overexpression of MACF1 and NR2F1 in LUAD cell lines (H1299 and Calu-3). Cell proliferation, adhesion, and migration were assessed by CCK-8, EdU, crystal violet, and Transwell assays. In vivo tumor growth and metastasis were evaluated using subcutaneous and tail vein xenograft models in nude mice. RNA-seq and GSEA were performed to identify MACF1-regulated pathways, followed by nuclear-cytoplasmic fractionation, dual-luciferase reporter assays, and immunofluorescence to assess WNT/β-catenin activity. ChIP-qPCR and ChIP-seq data from ENCODE were used to validate NR2F1 binding to the MACF1 promoter. MACF1 knockdown significantly suppressed LUAD cell proliferation, DNA replication, adhesion, and migration, and reduced tumor burden and lung metastases in vivo. Mechanistically, MACF1 activated WNT/β-catenin signaling by promoting CTNNB1 nuclear translocation, which upregulated focal adhesion genes (Paxillin, FAK, ITGB1). CTNNB1 agonist TWS119 restored focal adhesion in MACF1-deficient cells. Bioinformatic prediction and ChIP validation identified NR2F1 as a transcription factor directly targeting the MACF1 promoter. NR2F1 deficiency reduced MACF1 expression and phenocopied its functional loss, while MACF1 overexpression rescued the impaired phenotype. Our study uncovers a previously unrecognized NR2F1-MACF1-WNT axis that drives focal adhesion formation and LUAD progression. Targeting this regulatory circuit may offer new avenues for anti-metastatic therapy in lung adenocarcinoma. 1. NR2F1 is identified as a direct upstream transcription factor that activates MACF1 expression in LUAD. 2. MACF1 promotes LUAD cell proliferation, adhesion, and migration by enhancing focal adhesion assembly. 3. MACF1 activates the WNT/CTNNB1 signaling cascade, facilitating CTNNB1 nuclear translocation and downstream target expression. 4. Loss of MACF1 impairs focal adhesion formation and metastatic potential both in vitro and in xenograft and tail vein models. 5. The NR2F1-MACF1-WNT axis represents a novel regulatory circuit driving LUAD metastasis and offers potential therapeutic targets. Show less
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C ( Show more
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C (MYBPC3) is the most frequently mutated gene leading to HCM. In this study, peripheral blood mononuclear cells isolated from an HCM patient harboring a heterozygous MYBPC3 missense mutation (c.3072C > A; p.S1024R) were reprogrammed via Sendai virus vectors to generate a patient-specific induced pluripotent stem cell (iPSC) line. The iPSC line exhibits normal morphology and karyotype, alongside definitive hallmarks of pluripotency, including trilineage differentiation potential. Show less
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to dete Show more
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor-promoting tumor growth, cell survival, angiogenesis and metastasis-as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Show less
Rubia cordifolia L. (RCL) is a widely used medicinal with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhauste Show more
Rubia cordifolia L. (RCL) is a widely used medicinal with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhausted exercise (EE) might cause cardiac damage, RCL has been shown to provide cardioprotective effects. The effects and mechanisms of RCL on exercise-induced myocardial injury remain unclear. In this study, we tested the RCL extract using a rat model of exhausted swimming. We evaluated the therapeutic effect of RCL on exercise-induced myocardial damage using PCR, ELISA, hematoxylin-eosin (H&E) staining, DHE staining, and other methods. UPLC-Q-TOF-MS was employed to identify the components of the RCL extract and its blood-entry components, and network pharmacology was constructed. LC-MS was utilized to investigate left ventricular metabolomics. These two approaches were combined to predict the possible metabolic pathways regulated by RCL. Finally, the targets of the metabolic pathway were verified using molecular docking and western blot analysis. The findings suggest that rubioncolin B, 4-hydroxy-2-carbexyanthraquinone, and 9-Oxo-9H-xanthene-4-carboxylic acid may be the primary active compounds of RCL. RCL promotes the degradation pathway of branched-chain amino acids (BCAA), including valine, leucine, and isoleucine, regulates the proteins BCAT2 and BCKDK, reduces pathological injuries, inflammation, oxidative stress, and collagen deposition, and mitigates the effects of exhaustion-induced myocardial injuries by influencing the key target AKR1C1 and the metabolite L-Valine. This study provides a foundation for the development of RCL as a sports supplement to alleviate EE-induced myocardial injury. Show less
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key u Show more
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less
Yuanpeng Zhu, Di Liu, Xiangjie Yin+3 more · 2025 · The spine journal : official journal of the North American Spine Society · Elsevier · added 2026-04-24
Current clinical guidelines lack clear, quantitative recommendations on intensity-specific physical activity (PA) levels for preventing back pain. Moreover, accelerometer-based evidence regarding dose Show more
Current clinical guidelines lack clear, quantitative recommendations on intensity-specific physical activity (PA) levels for preventing back pain. Moreover, accelerometer-based evidence regarding dose-response relationships and interactions between PA and genetic susceptibility remains limited. To determine the relationships between accelerometer-measured total and intensity-specific PA and incident back pain, and to assess potential effect modification by polygenic risk scores (PRS). Prospective, large-scale, population-based study using UK Biobank data. UK Biobank participants who wore wrist accelerometers for 7 days (N=71,601). Incident back pain, defined as the first recorded ICD-10 dorsalgia code (M54). Total PA, light PA (LPA), and moderate-to-vigorous PA (MVPA) were derived using validated machine-learning algorithms from raw accelerometer data. Dose-response relationships were modeled using restricted cubic splines within Cox proportional hazards models, with adjustment for and stratification by a polygenic risk score (PRS). Point estimates for the population attributable fraction (PAF) were then calculated. Body mass index (BMI) mediation was assessed. Over a median follow-up of 7.0 years, total PA and MVPA exhibited nonlinear inverse associations with incident back pain, independent of genetic risk, with thresholds at approximately 35 milli-g (total PA) and 60 min/day (MVPA). The adjusted PAF was 15.9% for low MVPA and 9.9% for low total PA. Associations were strongest for MVPA, followed by total PA; no significant association was observed for LPA. Within both PRS strata, risk declined monotonically across PA quartiles, with similar effect sizes and no PA × PRS interaction. Notably, participants with high PRS and high PA had lower risk than those with low PRS and low PA. BMI mediated 26.2% of the total PA association and 15.5% of the MVPA association. Accelerometer-measured MVPA robustly reduces back-pain risk, independent of genetic predisposition. Future guidelines should provide clear, intensity-specific recommendations and account for the observed nonlinear dose-response to optimize prevention. Show less
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important Show more
Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel enteric coronavirus that causes severe clinical diarrhea and intestinal pathological injury in pigs. Selective autophagy is an important mechanism of host defense against virus invasion. However, the mechanism through which SADS-CoV-mediated selective autophagy mediates the innate immune response remains unknown. Here, we report that the host protein PABPC4 can inhibit SADS-CoV replication through targeting and degrading its N protein. Furthermore, we demonstrate that PABPC4 recruits MARCHF8 (an E3 ubiquitin ligase), which ubiquitinates the N protein and is degraded via NDP52/CALCOCO2 (a selective autophagy cargo receptor). Taken together, these findings reveal a new mechanism by which PABPC4 inhibits virus replication, and reveal a new target for antiviral drug development. Show less
Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the p Show more
Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Show less
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focu Show more
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which limits the availability of targeted t Show more
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which limits the availability of targeted therapies and results in poor prognosis. Immune checkpoint blockade (ICB) therapies have emerged as promising treatments by enhancing anti-tumor immunity; however, a substantial proportion of patients with TNBC exhibit primary or acquired resistance. This resistance is largely influenced by the tumor microenvironment (TME). This study uses integrated single-cell and spatial transcriptomics to elucidate key cellular mechanisms of resistance, with particular emphasis on lipid-mediated stromal-immune interactions within the TNBC TME. This investigation encompassed analysis of single-cell RNA sequencing (scRNA-seq) data from three TNBC datasets and spatial transcriptomic data from 43 TNBC samples. Spatial niches and cell-cell interactions were identified using the Multimodal Intersection Analysis (MIA) algorithm. Experimentally, adipose-derived mesenchymal stem cells (AD-SCs) were co-cultured with MDA-MB-231 TNBC cells to generate lipid-processing CAFs (lpCAFs) and subsequently co-cultured with THP-1 macrophages. Lipid metabolism and M2 polarization of macrophages were assessed using BODIPY staining, Oil Red O, qPCR, flow cytometry and Western blotting techniques. ABCA8 ABCA8 Show less
The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, t Show more
The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, the biological basis for the association between childhood obesity and adult cholelithiasis is poorly understood, which poses a challenge for preventing adult cholelithiasis in specific biological pathways. Summary statistics of genome-wide association studies (GWASs) of childhood age-specific body mass index (BMI) at 12 time points and adult cholelithiasis derived from FinnGen were used in this study, with the former covering data from birth to 8 years. Linkage disequilibrium score regression (LDSC) analyses were used to assess the genetic correlations of age-specific childhood BMI to cholelithiasis. Two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses were utilized to explore the causal associations. As downstream analyses, summary-based Mendelian randomization (SMR) analyses, transcriptome-wide association studies (TWAS), and Bayesian colocalization were conducted to discover the shared transcriptomic signals. The GWAS summary statistics of cholelithiasis from the UK Biobank were used for sensitivity analyses. LDSC analyses revealed significant genetic correlations between 11 age-specific childhood BMIs and adult cholelithiasis (except for birth BMI). Two-sample MR and MVMR analyses indicated causal relationships between birth BMI and BMI at 8 months, 1.5 years, 7 years, and 8 years after birth and adult cholelithiasis. SMR, TWAS, and colocalization analyses identified MLXIPL as the strongest overlapping signal between age-specific BMI and adult cholelithiasis. This study provides new evidence on the relationships between childhood obesity and adult cholelithiasis, highlighting the role of early intervention for obesity in childhood at key time points. MLXIPL gene expression was identified as a potential biological pathway, suggesting potential therapeutic targets and precise intervention strategies for childhood obesity and adult cholelithiasis. Show less
Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential Show more
Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD model mice and negatively correlated with amyloid-beta (Aβ) load in patients with AD. Enhancing GLP-1 signaling through GLP-1RAs increased CaMKK2-AMPK signaling, which subsequently reduced BACE1-mediated cleavage of amyloid precursor protein (APP) and Aβ generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. Consequently, GLP-1RAs inhibited plaque formation and improved memory deficits in AD model mice. Our findings indicate that AMPK activation mediates the effects of GLP-1RAs on AD, highlighting the therapeutic potential of GLP-1RAs for the treatment of AD. Show less
Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the patho Show more
Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatme Show more
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis. Schematic diagram of the mechanism by which PEMFs treat atherosclerosis (created in BioRender). Wei, B. (2025) https://BioRender.com/undefined ). Show less
Adipogenic differentiation of adipose-derived stem cells (ADSCs) is fundamental to both adipose tissue homeostasis and clinical applications, particularly fat grafting. However, the global and stage-s Show more
Adipogenic differentiation of adipose-derived stem cells (ADSCs) is fundamental to both adipose tissue homeostasis and clinical applications, particularly fat grafting. However, the global and stage-specific transcriptional regulatory networks underlying ADSC adipogenesis remain incompletely elucidated. In this study, we integrated bulk and single-cell RNA-seq datasets across multiple time points of ADSC adipogenesis to identify core regulators of differentiation and maturation. A total of 41 genes were consistently upregulated during early differentiation, among which eight hub genes (FABP4, FASN, FABP5, ADIPOQ, PLIN1, LPL, CIDEC, and ACSL1) formed a tightly connected protein-protein interaction (PPI) module associated with lipid metabolism, lipid droplet formation, and adipocyte maturation. Further integration of differentially expressed lncRNAs and miRNAs led to the construction of a ceRNA network involving 7 mRNAs, 9 miRNAs, and 4 lncRNAs, comprising 34 predicted lncRNA-miRNA-mRNA regulatory axes. To identify temporal transcriptional regulators, we defined five genes (TTC14, MBNL2, UBR3, ABCD2, and SORT1) as early-stage inducers of adipogenesis, and four genes (UQCR11, NDUFB4, S100A10, and PRDX3) as late-stage regulators involved in maintaining the mature phenotype. These stage-specific regulators showed distinct temporal expression patterns and were validated by qPCR. GeneMANIA network analysis further revealed that early-stage regulators were enriched in lipid transport and lipase activity regulation, while late-stage regulators were associated with mitochondrial electron transport and energy metabolism. These findings highlight the stage-dependent transcriptional landscape of ADSC adipogenesis and provide candidate regulatory targets for modulating adipocyte differentiation and stability. Show less
Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and most CRCs arise from colorectal adenomas. Early detection and removal of precancerous lesions during the adenoma-carci Show more
Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and most CRCs arise from colorectal adenomas. Early detection and removal of precancerous lesions during the adenoma-carcinoma sequence can significantly reduce CRC risk. However, current clinical practice lacks rapid, noninvasive screening tools for reliable adenoma detection. Proteomic analysis was performed on serum samples from patients with inflammatory polyps (non-neoplastic), patients with adenomas, and healthy controls to identify key differentially expressed proteins capable of distinguishing adenoma patients. The alterations in these candidate proteins were further validated by ELISA to evaluate their potential as diagnostic biomarkers for colorectal adenoma. In two independent cohorts, we identified two candidate biomarkers, apolipoprotein A4 (APOA4) and filamin A (FLNA), through a multi-step selection process involving ANOVA p-value screening, sparse partial least squares discriminant analysis (sPLS-DA), and LASSO regression analysis. These candidates were subsequently validated in a third cohort using ELISA. The ELISA results for APOA4 were discordant with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) findings. In contrast, FLNA levels measured by ELISA showed a progressive decrease from healthy controls to patients with inflammatory polyps and further to those with adenomas. We propose FLNA as a potential biomarker for the diagnosis of colorectal adenomas. The areas under the ROC curves exceeded 0.7 for both key clinical comparisons: 0.810 for adenomas versus healthy controls, and 0.734 for adenomas versus inflammatory polyps. Overall, this study not only enhances our understanding of the serum proteome in colorectal adenoma but also identifies FLNA as a promising biomarker for its clinical diagnosis. Show less
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases Show more
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less
Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; howe Show more
Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis. Show less
This study aimed to investigate the association between objectively and subjectively measured 24-hour movement behaviors and physical fitness, and explore how the reallocation of time between 24-hour Show more
This study aimed to investigate the association between objectively and subjectively measured 24-hour movement behaviors and physical fitness, and explore how the reallocation of time between 24-hour movement behaviors is associated with changes in physical fitness in adolescents. A total of 690 adolescents aged 14-17 years (55% girls) were included in this cross-sectional study conducted in Foshan, China. Moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior, and sleep were assessed using accelerometers in combination with a questionnaire. Physical fitness was tested through body mass index, forced vital capacity, 50-m sprint, standing long jump, sit-and-reach, gender-specific 800/1000-m run, and pull-ups/sit-ups. MVPA was significantly associated with better performance in the 50-m sprint ( Show less