👤 Ying Jin

Digital technology is frequently regarded as a tool to alleviate loneliness and enhance mental health among older adults, yet its effectiveness remains contested. This study explores whether digital exclusion moderates the association between loneliness and depressive, and examines symptom structure and depressive subtypes. Drawing on data form the 2018 and 2020 waves of the CHARLS (N = 13,719), we employed fixed-effect and mixed-effect models to assess the effect of loneliness on depressive and the moderating role of digital exclusion. Latent profile analysis (LPA) was used to identify symptoms subtypes, while symptom network analysis assessed centrality and network stability. Loneliness significantly predicted depressive symptoms across multiple models, demonstrating robust effects. Digital exclusion was positively associated with depressive symptoms but did not exhibit a statistically significant moderating effect on the loneliness-depression relationship (p > 0.05, Δβ ≈ 0.011). LPA identified six psychologically meaningful subtypes of depression. Symptom network analysis revealed that emotional and motivational symptoms occupied central positions within the network structure, whereas loneliness, despite its strong connections, exhibited relatively low centrality. The overall network structure remained stable over two years, with the digital access group exhibiting stronger network connectivity. This study emphasizes that digital access alone is not a universal remedy for alleviating loneliness. The psychological benefits of digital technology depend on the alignment between individual motivations, usage patterns, and broader social contexts. Future research should focus on digital usage quality and contextual adaptability of interventions, promoting a shift from customization in digital mental health intervention strategies. Show less

Accelerometer-derived physical activity is associated with reduced stroke risk. The biological pathways underpinning this relationship, however, are not yet understood. Herein, we aim to identify metabolic signatures associated with accelerometer-measured PA and investigate their relationships with reduced stroke incidence. Utilizing UK Biobank accelerometer data, we derived physical activity into total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA) and linked them to 249 NMR-quantified plasma metabolites. The metabolomic signatures (TPA-/MVPA-/LPA-metabolomic signatures) were developed through internal validation followed by elastic-net regression modeling. Cox proportional hazards models evaluated activity-stroke associations (adjusted for sociodemographic/genetic factors), followed by mediation analysis to quantify metabolomic signature effects. Through UK Biobank study (N = 29445; 14.1-year follow-up with 513 stroke events), we identified 195 TPA, 173 MVPA, and 164 LPA metabolite associations (FDR < 0.05), with 107, 92, and 15 validated, respectively. Elastic net-derived physical activity-metabolomic signatures (TPA-/MVPA-metabolomic signatures) correlated with physical activity intensities (r = 0.20-0.30, P < 0.001) and were associated with reduced stroke risk: TPA-metabolomic signatures (HR = 0.61, 95% CI: 0.44-0.87); MVPA-metabolomic signatures (HR = 0.50, 95%CI: 0.29-0.88). Mediation analyses showed TPA-metabolomic signatures and MVPA-metabolomic signatures explained 12.2% and 8.5% of physical activity-stroke associations (P < 0.001), implicating specific lipoprotein subclasses and lipids as key mediators. TPA-metabolomic signatures and MVPA-metabolomic signatures, particularly the 11 key metabolites included, significantly mediate the association between accelerometer-derived physical activity and stroke risk. Show less

To develop a deep-learning model for segmenting and classifying adrenal nodules as either lipid-poor adenoma (LPA) or nodular hyperplasia (NH) on contrast-enhanced computed tomography (CECT) images. This retrospective dual-center study included 164 patients (median age 51.0 years; 93 females) with pathologically confirmed LPA or NH. The model was trained on 128 patients from the internal center and validated on 36 external cases. Radiologists annotated adrenal glands and nodules on 1-mm portal-venous phase CT images. We proposed Mamba-USeg, a novel state-space models (SSMs)-based multi-class segmentation method that performs simultaneous segmentation and classification. Performance was evaluated using the mean Dice similarity coefficient (mDSC) for segmentation and sensitivity/specificity for classification, with comparisons made against MultiResUNet and CPFNet. From per-slice segmentation, the model yielded an mDSC of 0.855 for the adrenal gland; for nodule segmentation, it achieved mDSCs of 0.869 (LPA) and 0.863 (NH), significantly outperforming two previous models-MultiResUNet (LPA, p < 0.001; NH, p = 0.014) and CPFNet (LPA, p = 0.003; NH, p = 0.023). Classification performance from per slice demonstrated sensitivity of 95.3% (95% confidence interval [CI] 91.3-96.6%) and specificity of 92.7% (95% CI: 91.9-93.6%) for LPA, and sensitivity of 94.2% (95% CI: 89.7-97.7%) and specificity of 91.5% (95% CI: 90.4-92.4%) for NH. The classification accuracy for patients from external sources was 91.7% (95% CI: 76.8-98.9%). The proposed multi-class segmentation model can accurately segment and differentiate between LPA and NH on CECT images, demonstrating superior performance to existing methods. Question Accurate differentiation between LPA and NH on imaging remains clinically challenging yet critically important for guiding appropriate treatment approaches. Findings Mamba-Useg, a multi-class segmentation model utilizing pixel-level analysis and majority voting strategies, can accurately segment and classify adrenal nodules as LPA or NH. Clinical relevance The proposed multi-class segmentation model can simultaneously segment and classify adrenal nodules, outperforming previous models in accuracy; it significantly aids clinical decision-making and thereby reduces unnecessary surgeries in adrenal hyperplasia patients. Show less

Dibutyl phthalate (DBP) is a widely distributed endocrine-disrupting chemical with potential carcinogenic properties, yet its role in head and neck squamous cell carcinoma (HNSC) remains unclear. Here, we applied an integrative framework combining network toxicology, Mendelian randomization (MR), multi-omics analyses, molecular docking, molecular dynamics simulations, and in vitro experiments to elucidate the mechanisms underlying DBP-associated HNSC. Lipoprotein lipase (LPL) was identified as the sole overlapping gene between DBP-related targets and HNSC-associated genes. MR analysis supported a potential causal relationship between LPL and HNSC susceptibility. Expression profiling demonstrated tissue- and cell type-specific patterns of LPL and its dysregulation in HNSC, with associations to tumor stage and prognosis. Genomic analyses revealed that LPL alterations were infrequent and mainly driven by copy number loss. LPL expression positively correlated with immune and stromal infiltration. Enrichment analyses implicated immune regulation and PI3K-AKT signaling. Molecular simulations showed stable DBP-LPL binding. Functionally, DBP promoted SCC9 proliferation and reduced LPL expression, and was associated with transcriptional changes in PI3K-AKT-mTOR-related genes, whereas LPL restoration mitigated these effects. These findings reveal a novel DBP-LPL axis in HNSC. Show less

Neuropathic pain (NP), a chronic disorder caused by somatosensory nervous system lesions, severely impairs the quality of life. Microglial metabolic reprogramming and neuroinflammation drive NP progression. Although ChREBP (key metabolic regulator) protects against NP, its specific mechanisms remain unclear. NP rat model was established via spared nerve injury (SNI) surgery, and mechanical allodynia was evaluated using Von Frey tests. ChREBP expression in microglia was detected through immunofluorescence, RT-qPCR, and western blot. Functional studies involved ChREBP knockdown/overexpression to assess effects on microglial polarization, neuroinflammation, neuronal excitability, pain behaviors, and fatty acid metabolism. Mechanisms were explored via dual-luciferase reporter and chromatin immunoprecipitation assays. Mechanical pain thresholds were significantly decreased on the ipsilateral side after SNI. ChREBP was upregulated in SDH microglia after SNI and in LPS-stimulated microglia in vitro. ChREBP knockdown inhibited anti-inflammatory microglial polarization, exacerbated neuroinflammation, and aggravated pain. Conversely, ChREBP overexpression promoted the anti-inflammatory phenotype, suppressed neuroinflammation, and alleviated pain. ChREBP enhanced microglial fatty acid oxidation and energy metabolism. Mechanistically, ChREBP bound to the TFBS1 site on the PGC-1α promoter to activate its transcription. PGC-1α overexpression rescued the impairments caused by ChREBP knockdown, including reduced fatty acid oxidation, suppressed anti-inflammatory polarization, elevated inflammatory factors, and increased neuronal excitability. The protective effects of ChREBP were attenuated by the fatty acid oxidation inhibitor Etomoxir. ChREBP alleviates NP by enhancing microglial fatty acid oxidation and anti-inflammatory phenotype via PGC-1α transcriptional activation, revealing a novel metabolic-immune axis for potential NP therapy. Show less

Hereditary cardiomyopathies and arrhythmias are major contributors to cardiovascular morbidity and mortality. The advent of next-generation sequencing (NGS) has made genetic testing more accessible, which is crucial for precise diagnosis and targeted therapeutic strategies. The aim of this study is to explore the landscape of genetic variants, the relationship between specific variants and clinical phenotypes, and the impact on clinical decision-making in China. A total of 1536 probands (median age, 37 years; 1025 males [66.7%]) with suspected hereditary cardiomyopathy or arrhythmia (covering 15 clinical phenotypes) are recruited from 146 hospitals across 30 provinces and cities in China. Positive results are confirmed in 390 of 1536 probands, leading to a diagnostic yield of 25.4%. Forty-two and three-tenths percent (n = 169) of family members carry the same variants as positive probands. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the predominant phenotypes, with MYBPC3 variants having the highest frequency in HCM and TTN variants in DCM. In 76.9% of the positive probands, the identified variants are helpful in clinical management, family screening, and fertility. This large-scale study provides significant insights into the genetic landscape of hereditary cardiomyopathies and arrhythmias in China. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association study data from multiple cohorts totaling nearly 3 million individuals of European ancestry and applied cross-trait genomic modeling of hepatic fat and seven cardiometabolic traits to construct an MASLD-specific polygenic architecture. We identified 128 risk variants across 100 loci and prioritized 55 effector genes, including established (e.g., Show less

Colorectal cancer (CRC) is a highly aggressive malignancy prone to liver metastasis, which significantly worsens prognosis of patients. Autophagy supports tumor cell survival by meeting metabolic demands and evading programmed cell death. This study aimed to develop a prognostic risk signature for CRC patients by integrating autophagy- and metastasis-related genes and to investigate its association with the tumor immune microenvironment and implications for immunotherapy. Weighted gene co-expression network analysis (WGCNA) identified candidate genes related to autophagy and liver metastasis. Univariate Cox and LASSO regression analyses were employed to develop a risk signature in the TCGA cohort, which was subsequently validated using an independent GEO cohort. Functional enrichment, immune infiltration, the heterogeneity and dynamics of macrophages and A prognostic risk signature incorporating six biomarkers ( In our study, we developed and validated a novel autophagy- and liver metastasis-associated prognostic signature for CRC. The risk signature effectively predicts alterations in the tumor immune microenvironment, immunotherapy, chemotherapy sensitivity and intercellular communication across different risk groups. Importantly, our findings reveal that autophagy and liver metastasis synergistically foster an immunosuppressive microenvironment, highlighting a potential target for therapeutic intervention. Show less

Metabolic‒epigenetic crosstalk critically orchestrates hepatocellular carcinoma (HCC) pathogenesis. Deciphering the precise mechanism underlying epigenetic remodeling and metabolic reprogramming in HCC may lead to novel treatment paradigms, however, the key mechanisms remain elusive. RT-qPCR, western blotting and tissue microarrary Immunohistochemistry were used to detect the expression of RasGEF domain family member 1B (RASGEF1B) in HCC and normal liver tissues. Transcriptome sequencing and high-resolution untargeted metabolomics were integrated to identify the downstream regulatory mechanism through which RASGEF1B inhibited the HCC progression. Epigenetic regulation was investigated using methylation-specific PCR and luciferase reporter assays. Bioinformatic prediction and molecular docking suggested a functional interplay among RASGEF1B, ALDH7A1, and BMI1, which was experimentally confirmed through coimmunoprecipitation, GST pull-down, and immunofluorescence assays. Protein stability and ubiquitination status of ALDH7A1 were examined using cycloheximide, immunoprecipitation assay, and an in vitro reconstituted ubiquitination system. In this study, the antitumor role of RASGEF1B was confirmed in vitro and in vivo. Transcriptomic profiling revealed that RASGEF1B overexpression significantly reduced the snail family transcriptional repressor 1 (SNAI1), a master regulator of the epithelial-mesenchymal transition. Untargeted metabolomics revealed that RASGEF1B promoted SNAI1 DNA methylation through Betaine-mediated methionine metabolic reprogramming. Further analysis confirmed that RASGEF1B competitively protected the ALDH7A1 protein from BMI1-dependent ubiquitination, thereby elevating cellular Betaine levels in HCC. This study revealed that RASGEF1B inhibited SNAI1 to suppress HCC through metabolite‒epigenetic crosstalk. Our findings potentially offer a new perspective on the classical RAS signaling framework, uncovering a metabolic‒epigenetic axis as an innovative therapeutic approach for improving clinical outcomes in patients with HCC. [Image: see text] The online version contains supplementary material available at 10.1186/s12967-026-07785-z. Show less

Wilms tumor (WT), the most common pediatric malignant renal tumor, shows high recurrence in high-risk subtypes due to chemoresistance. Tumor microenvironment (TME) remodeling, particularly M2-type tumor-associated macrophages (TAMs), contributes to chemoresistance, but underlying mechanisms remain unclear. This study explored TME-related chemoresistance mechanisms in WT and developed targeted therapeutic strategies. Clinical WT samples were analyzed for M2-type TAMs infiltration and SNRPC expression. Bioinformatics analysis of TARGET-WT data identified M2-associated genes. In vitro experiments (cell transfection, qRT-PCR, Western blot, co-culture, ChIP and dual-luciferase reporter assays) explored SNRPC’s role in regulating M2-type TAMs. Animal models (orthotopic tumor and lung metastasis) verified in vivo effects. A hybrid exosome nanosystem (DOX/siSNRPC@hEVs) was constructed and evaluated for efficacy and safety. Statistical analyses included t-test, ANOVA, and survival analysis. M2-type TAMs (CD68⁺CD163⁺) infiltration was higher in chemoresistant WT and associated with poor prognosis. SNRPC was overexpressed in chemoresistant WT, correlated with M2-type TAMs, and promoted tumor malignancy and M2-type TAMs polarization. Mechanistically, SNRPC activated NF-κB signaling, inducing CXCL17 upregulation to recruit M2-type TAMs, with partial CXCL17 release via migrasomes. DOX/siSNRPC@hEVs showed high targeting, reduced toxicity, inhibited tumor growth/metastasis, and reversed chemoresistance by reducing M2-type TAMs. The SNRPC-NF-κB-CXCL17-M2 TAMs axis drives WT chemoresistance. DOX/siSNRPC@hEVs effectively targets this axis, providing a novel strategy for high-risk WT. [Image: see text] The online version contains supplementary material available at 10.1186/s13046-026-03680-z. Show less

The gut-brain axis is increasingly recognized as a key regulator of neurological health, with microbial metabolites influencing neurotransmission, synaptic plasticity, and neuroinflammation. Probiotics such as This study aimed to integrate microbial genomics, neurotranscriptomics, and Whole-genome functional annotation, metabolic pathway prediction, and biosynthetic gene cluster analysis were performed to identify neuroactive potential. Neuronal RNA-seq datasets (n = 3 biological replicates per condition) were analyzed using differential expression, WGCNA, and GSEA to capture transcriptomic responses. Multi-omics integration (CCA, DIABLO, SPIEC-EASI) linked microbial pathways with neuronal gene modules. Genomic analysis revealed that This multi-omics study demonstrates mechanistic evidence that probiotics exert complementary neuromodulatory effects: Show less

BackgroundCurrent therapeutic strategies for Alzheimer's disease (AD) demonstrate limited efficacy in decelerating disease progression, underscoring an exigent need for the development of more potent disease-modifying therapeutics.ObjectiveThe primary aim of this research was to identify novel therapeutic targets to improve AD prognosis.MethodsFirst, we conducted a meta-analysis of brain tissue transcriptome datasets from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) associated with AD. Next, Mendelian randomization (MR) and summary-based MR (SMR) analyses were utilized to screen for potential AD drug targets. Colocalization analyses were employed to examine whether DNA methylation, gene expression, and AD risk are driven by shared single nucleotide polymorphisms (SNPs). Finally, single-gene gene set enrichment analysis (GSEA), protein-protein interaction (PPI) networks, drug prediction, and molecular docking were employed to infer potential biological mechanisms.ResultsA meta-analysis of twelve brain tissue datasets revealed 262 druggable AD-related DEGs. According to MR analysis, Show less

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less

Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4 Show less

Wenshenyang decoction (WSY) has been shown to have a considerable effect on restoring renal function and improving kidney Yang deficiency syndrome in patients with CKD. However, its mechanism remains unclear. This study aimed to integrated metabolomics and network pharmacology analysis combined with Patients were selected from a clinical trial. LC-MS (Liquid chromatography-mass spectrometry) was used to investigate the differential metabolites and pathways. Spearman correlation analysis was performed between differential metabolites and clinical phenotypes. "Drug-component-differential metabolite" network was constructed to predict the core components and hub genes, and validated by molecular docking. On this basis, the effects of core components of WSY on the viability of Human Kidney-2 cells (HK-2) induced by doxorubicin (DOX) was detected by CCK-8, and RT-qPCR (Reverse transcription quantitative polymerase chain reaction) was used to detect the mRNA expression level of hub genes and related targets. LC-MS detected 54 differential metabolites, of which 35 metabolites showed up regulated, and 19 decreased. Spearman analysis showed that the differential metabolites were correlated with the clinical phenotype. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis showed that WSY mainly affected linoleic acid metabolism, FcεRI signaling pathway, and unsaturated fatty acid biosynthesis. The "Drug-component-differential metabolite" network showed that the core components of WSY were quercetin, luteolin and kaempferol, and the hub genes were PTGS2, AKT1, MMP9, EGFR and MMP2. Molecular docking showed that they had good biological binding capacity. WSY has multi-component and multi-target properties in the treatment of CKD kidney Yang deficiency syndrome, and its mechanism may be related to anti-inflammatory and anti-fibrotic effects. This study provides a methodological reference for the treatment of CKD. Show less

This study investigated the regulatory potential of salidroside (SAL), a primary active compound in Rhodiola rosea L., on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha (HIF-1a) pathway in osteoblasts. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to validate whether the receptor activator of nuclear factor-?B ligand (RANKL) is the downstream target gene of HIF-1a in osteoblasts. The study also utilized lipopolysaccharide (LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo. Furthermore, conditioned medium (CM) from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1a pathway. Hypoxic condition-induced overexpression of HIF-1a upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells. In vivo, SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1a by downregulating the expression of RANKL, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and angiopoietin-like 4 (ANGPTL4). In the paracrine experiment, conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. RANKL emerges as the downstream target gene regulated by HIF-1a in osteoblasts. SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion. Show less

Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Show less

The potential impact of lifestyle changes such as prolonged fasting on brain health still remains unclear. Neurodegenerative diseases often exhibit two key hallmarks: accumulation of misfolded proteins such as amyloid beta oligomers (AβO) and intracellular cholesterol accumulation. In this study, we investigate how a 36-h fast affects the capacity of isolated high-density lipoproteins (HDLs) to modulate the effects of AβO and excess cholesterol in microglia. HDL from 36-h fasted individuals were significantly more effective in effluxing cholesteryl esters from treated microglia, showing a remarkable 10-fold improvement compared to HDL from the postprandial state. Furthermore, the ability of 36-h fasted HDL to mitigate the reduction of apolipoprotein E secretion in AβO- and cholesterol-loaded microglia surpassed that of postprandial HDL. In exploring differences among HDL parameters from postprandial, overnight fasted, and 36-h fasted individuals, we observed that plasma HDL-cholesterol and apolipoprotein A-I concentrations remained unchanged. However, nuclear magnetic resonance (NMR) analysis revealed reduced total HDL particle count, a decrease in the smallest HDL particles (HDL1, 7.4 nm diameter), and an increase in the largest HDL particles (HDL7, 12 nm) after the 36-h fast. Transmission electron microscopy (TEM) analysis further found an increase in even larger HDL particles (12-14 nm) in 36-h fasted individuals. Targeted mass spectrometry (MS)-based proteomics and glycoproteomics unveiled a reduction in HDL-associated apolipoprotein A-IV and disialylated apolipoprotein C-III content following the 36-h fast. These findings collectively suggest that prolonged fasting induces structural, compositional, and functional alterations in HDL particles, and influences their capacity to attenuate the effects of excess cholesterol and AβO in microglia. Show less

Global warming exacerbates heatstroke, increasing its severity and associated health risks, including fatal kidney damage. Predicting post-heatstroke organ injury remains difficult, delaying timely medical intervention. This study aims to identify potential blood biomarkers that reflect organ stress and recovery status following heatstroke. Plasma samples (n = 12) from clinically diagnosed classical (non-exertional) heatstroke patients were collected at diagnosis and recovery. Two-dimensional gel electrophoresis was used to analyze protein expression, identifying 359 protein spots. Selected proteins showing differential expression were validated by Western blotting. Here, five proteins-alpha-1 antitrypsin, alpha-1 microglobulin/bikunin precursor, apolipoprotein A-IV, clusterin, and complement component 2-show significant changes between the two timepoints. These proteins are linked to inflammatory, coagulation, and lipid metabolism pathways. Alpha-1 antitrypsin, alpha-1 microglobulin, and complement component 2 may reflect the resolution of inflammation, while apolipoprotein A-IV and clusterin indicate renal stress. The alpha-1 microglobulin-IgA complex may exert anti-inflammatory effects. Complement component 2, an initiator of the complement cascade, has not been previously reported to be associated with heat stress. The findings suggest that these proteins may serve as blood biomarkers to assess heatstroke severity and monitor recovery. Their clinical application could improve early detection of organ damage and guide intervention strategies. Show less

Cardiovascular diseases from abnormal lipid metabolism significantly increase mortality in systemic lupus erythematosus (SLE). The causal link between dyslipidemia and SLE is unclear. Lipid metabolism in patients with SLE was evaluated based on clinical data from 511 patients with SLE and 706 healthy individuals. Bidirectional Mendelian randomization (MR) was employed to assess causal links between 179 plasma lipid metabolites, lipid-lowering drug targets, and SLE risk. Genetic instruments from GWAS and eQTL data were used to evaluate CETP and APOA4 effects. Peripheral blood CETP and apolipoprotein levels in SLE patients were validated via ELISA. SLE patients exhibited reduced HDL-C (P < 0.0001), APOA1 (P < 0.0001), and APOA4 (P < 0.0001), alongside elevated triglycerides (TG, P < 0.0001), APOC3, APOD, and APOF. MR identified three lipid metabolites-PC(18:2₂₀:4), TG(56:6), and TG(58:7)-as causal factors for SLE (P < 2.79E-5). CETP inhibition significantly reduced SLE risk via HDL-C modulation (OR = 0.72, P = 3.38E-08) and influenced LDL-C, TG, and apolipoproteins. Clinical validation confirmed elevated CETP and reduced APOA4 in SLE, correlating with disease activity. APOA4 activation showed protective effects, while PCSK9 inhibition lacked relevance. Bidirectional Mendelian randomization analyses confirmed dyslipidemia as a causal antecedent to SLE, with no evidence of reverse causation. A variety of MR analyses and clinical validation indicated that targeting HDL-C regulation offers significant advantages for managing dyslipidemia in patients with SLE, with CETP identified as the optimal pharmacological target. Show less

Among individuals diagnosed with type 2 diabetes mellitus (T2DM), an abnormal accumulation of visceral fat heightens the cardiovascular risk (CVR), and the major reason for death for these people is atherosclerotic cardiovascular disease (ASCVD). This study aimed to gain further insights into the longitudinal relationship between CVR and visceral fat area (VFA) in patients with T2DM, and to compare the predictive performance of additional abdominal obesity measures and VFA for changes in CVR. This prospective cohort study included 316 patients with T2DM who were followed up for more than one year, and VFA was measured by the bioimpedance method. This study investigated the prospective association between a VFA percentage change (∆VFA, %) and CVR, and evaluated the potential nonlinear relationships between ∆VFA (%) and the increase 10-year ASCVD risk. Furthermore, the area under the pooled curve (AUC) was contrasted for both ∆VFA (%) and other abdominal obesity indices. The excessive VFA loss group showed lower low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), triglyceride-glucose index, LDL-C/HDL-C, brachial-ankle pulse wave velocity, 10-year ASCVD risk, atherogenic index of plasma, TC/HDL-C, and apolipoproteins B/apolipoproteins A-1 than the VFA gain group (all β [Formula: see text] 0, HR [Formula: see text] 1, all P [Formula: see text] 0.05) after covariate controlling. VFA reduction of more than 14.82% led to a reduction in the stated risk. Moreover, ∆VFA (%) demonstrated superior predictive value for changes in ASCVD risk, with an AUC of 0.585 (95% CI: 0.513-0.656), compared to other obesity indices. Excessive VFA reduction improved 10-year ASCVD risk in patients diagnosed with T2DM. VFA was a more effective predictor of 10-year ASCVD risk changes than other abdominal obesity measures. This investigation has been registered with the Chinese Clinical Trial Registry (ChiCTR2400086569). Show less

Despite significant evidence of a genetic contribution to strabismus, precise genetic mechanisms have not been identified. There are distinct population differences in the prevalence of strabismus and its subtypes. This study aimed to explore the genetic contributions to strabismus in different ancestral groups. Case-control. The Genome-wide association study of common variants (minor allele frequency >1%) and rare variant association study at the gene level for strabismus. Individual single nucleotide polymorphisms (SNPs) significantly associated with strabismus and genes with significant burden of rare variants in strabismus. Genome-wide association study identified one locus with 3 significant SNPs (rs2247113, rs2667037, and rs2715926) in intron 1 of Genetic associations with strabismus differed between ancestry groups, although genes in similar pathways, such as synaptic signaling and structural muscle proteins, were found in multiple groups. This highlights the importance of including diverse populations in studies of genetic associations and suggests that multiple pathways may lead to strabismus in different population groups. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Show less

Calcific aortic valve stenosis (CAVS) is steadily rising worldwide with no effective pharmacological agents available. Observational studies implicated dyslipidaemia as a risk factor for CAVS. Whether dyslipidaemia is causative for CAVS and the therapeutic potential of different lipid-modifying drug targets for CAVS treatment remains unclear. We appraised the relationship of genetically-proxied lipid traits and 12 lipid-modifying drug targets with CAVS risk using Mendelian randomization (MR). Genetic variants associated with lipid traits and variants in genes encoding lipid-modifying drug targets were retrieved from GLGC. Summary-level data for CAVS were obtained from the TARGET consortium and FinnGen. Validation analyses were performed using genetic instruments retrieved from liver-derived gene expression and circulation plasma levels of targets. Colocalisation and mediation analyses were performed to evaluate the robustness of our findings and explore potential mediators (i.e., lipoprotein a (Lp(a)), body mass index, apolipoprotein B (ApoB)). The MR analyses supported that total cholesterol and LDL-cholesterol level were independent causal risk factors. The drug-target MR analysis suggested that genetic mimicry of PCSK9 inhibition should reduce CAVS risk (OR = 0.63, 95% CI = 0.56-0.70), which was corroborated by colocalisation analysis. Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.94 per SD reduction in PCSK9 expression, 95% CI = 0.88-1.00) and circulating plasma levels of PCSK9 (OR = 0.86 per SD reduction in PCSK9 protein, 95% CI = 0.83-0.88) on CAVS risk. ApoB and Lp(a) mediated 55.9% and 4.5%, respectively, of the total effect of PCSK9 on CAVS risk. Multiple sensitivity analyses supported this observation. Our study supports total cholesterol, LDL-cholesterol as a causal factor for CAVS, and genetically proxied inhibition of PCSK9 may reduced its risk. Show less

Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanisms of carcinogenesis. Here, we developed geMER to identify candidate driver genes genome-wide by detecting mutation enrichment regions within coding and non-coding elements. We subsequently designed a pipeline to identify a core driver gene set (CDGS) that broadly promotes carcinogenesis across multiple cancers. CDGS comprising 25 genes for 25 cancers displayed instability in DNA aberrations. Variants within the TTN enrichment region may influence the folding of the I-set domain by altering local polarity or side-chain chemistry properties of amino acids, potentially disrupting its antigen-binding capacity in LUAD. Multi-omics analysis revealed that APOB emerged as a candidate oncogene in LIHC, whose genetic alterations within the enrichment region may activate key TFs, upregulate DNA methylation levels, modulate critical histone modifications, and enhance transcriptional activity in the HepG2 and A549 cell lines compared to Panc1. Additionally, CDGS mutation status was an independent prognostic factor for the pan-cancer cohort. High-risk patients tended to develop an immunosuppressive microenvironment and demonstrated a higher likelihood of responding to ICI therapy. Finally, we provided a user-friendly web interface to explore candidate driver genes using geMER ( http://bio-bigdata.hrbmu.edu.cn/geMER/ ). Show less

Breast cancer is the second most common cancer worldwide. Chemotherapy often causes dyslipidemia and obesity in breast cancer patients. Monitoring lipid profiles and body mass index (BMI) is crucial to evaluate chemotherapy's metabolic side effects, identify interventions to mitigate them, and understand health risks linked to weight changes during treatment. Shenling Baizhu Powder (SLBZP), a traditional Chinese medicine (TCM), treats spleen-stomach ailments by boosting spleen function, enhancing qi, and reducing dampness. SLBZP has potential benefits in managing chemotherapy-induced dyslipidemia and improving overall metabolic health in cancer patients. This study retrospectively examined the effects of SLBZP on blood lipid levels and BMI in breast cancer patients undergoing adjuvant chemotherapy. This study reviewed the medical records of patients who were diagnosed with breast cancer at the Breast Surgery Department of Zhejiang Provincial Hospital of Traditional Chinese Medicine from January 2022 to December 2023. Based on the inclusion criteria, a total of 180 eligible patients were included and divided into an observational group (which received SLBZP) and a control group (which did not receive SLBZP) during chemotherapy. Patients' clinical data, including age at diagnosis, menopausal status, tumor location, smoking and drinking habits, tumor molecular type, tumor node metastasis (TNM) stage, chemotherapy drugs, targeted therapy, lipid levels, and BMI before and after chemotherapy, were collected. Statistical analyses were conducted using SPSS 25.0. After chemotherapy, the control group showed significant increases in total cholesterol (TC) (P=0.03), triglyceride (TG) (P=0.001), low-density lipoprotein cholesterol (LDL-C) (P=0.02), and apolipoprotein B (ApoB) (P=0.01) levels. In the observational group, the TC, TG, and LDL-C levels remained stable (P>0.05), but the high-density lipoprotein cholesterol (HDL-C) (P=0.001) and apolipoprotein A1 (ApoA1) (P<0.001) levels significantly decreased, and BMI (P=0.02) significantly increased. The subgroup analysis revealed that the taxane followed by anthracycline subgroup showed significant increases in BMI (P=0.007) and significant decreases in the HDL-C (P=0.007) and ApoA1 (P<0.001) levels, while the taxane subgroup showed a significant decrease in the HDL-C level post-chemotherapy (P=0.003). In the control group, the TG (P=0.002) and LDL-C (P=0.02) levels were significantly elevated in the taxane followed by anthracycline subgroup post-chemotherapy. No significant changes were observed in BMI or the other lipid indexes in the remaining chemotherapy drug regime subgroups (P>0.05). Chemotherapy increased the TC, TG, LDL-C, and ApoB levels in breast cancer patients, but SLBZP mitigated dyslipidemia. The patients who received SLBZP also showed increased BMI post-chemotherapy, which was likely due to reduced gastrointestinal side effects. Taxane-based chemotherapy drugs had greater effects on blood lipids and BMI, while anthracycline-based drugs did not significantly affect blood lipids and BMI. Show less

The relationship between serum lipids and prognosis of pancreatic cancer has not been confirmed. Our purpose in the study was to investigate the associations between serum lipids level and prognosis in patients with pancreatic cancer. A retrospective study was performed on 286 pancreatic cancer patients who admitted to our hospital from January 1, 2017 to December 31, 2021. Serum lipids level were recorded. Clinical-pathological characteristics, oncologic outcomes, progression free survival (PFS) and overall survival (OS) were collected. The prognostic significance was determined by Kaplan-Meier analysis and Cox proportional hazards regression model. Regarding serum lipids level, compared to normal apolipoprotein B/ apolipoprotein A (ApoB/ApoA1), high ApoB/ApoA1 level indicated a shorter OS (HR:2.028, 95% CI: 1.174-2.504, P = 0.011) and a shorter PFS (HR:1.800, 95% CI: 1.076-3.009, P = 0.025). Other serum lipid molecules were not associated with PFS and OS. ApoB/ApoA1 might be an independent prognostic factor of pancreatic cancer. Show less

High-abundance serum proteins, mostly modified by N-glycans, are usually depleted from human sera to achieve in-depth analyses of serum proteome and sub-proteomes. In this study, we show that these high-abundance glycoproteins (HAGPs) can be used as valuable standard glycopeptide resources, as long as the structural features of their glycans have been well defined at the glycosite-specific level. By directly analyzing intact glycopeptides enriched from serum, we identified 1322 unique glycopeptides at 48 N-glycosites from the top 12 HAGPs (19 subclasses). These HAGPs could be further classified into four major groups based on the structural features of their attached N-glycans. Immunoglobins including IGHG1/2/3/4, IGHA1/2 and IGHM were mostly modified by core fucosylated and bisected N-glycans with rarely sialic acids. Alpha-1-acid glycoproteins (ORM1/2) and haptoglobins (HP) were mainly modified by tri-and tetra-antennary (40 %) N-glycans with antenna-fucoses and sialic acids. Complement components C3 and C4A/B were highly modified by oligo-mannose glycans. The other HAGPs including SERPINA1, A2M, TF, FGB/G and APOB mainly contain bi-antennary complex glycans with the common core structure and (sialyl-) LacNAc branch structures. These HAGPs are easily detected by LC-MS analysis and therefore could be used as standard glycopeptides for glycoproteomic methodology studies as well as possible clinical utilities. Show less

Despite increasing heavy metal pollution, traditional epidemiology often fails to link exposure to health outcomes. This study used multi-omics to investigate associations between heavy metal exposure and health. Blood and urine samples from 294 participants in heavy metal-exposed and control areas were analyzed, revealing key biomarkers. Meta P analysis revealed consistent trends in apolipoprotein C3 (APOC3) expression, and mediation analysis showed significant effects of APOC3 and zinc-alpha-2-glycoprotein (ZA2G) on metabolites: the mediating effect of APOC3 from blood cadmium to serotonin was 0.023 (P < 0.001) and that to 3-phosphoglyceric acid (3PG) was 0.0125 (P = 0.002). Mendelian randomization confirmed the positive impact of APOC3 and Complement Factor I (CFAI) and the negative effect of ZA2G on metabolites, with apolipoprotein H (APOH) methylation significantly altering APOC3 (β = -0.22, P = 0.017), CFAI (β = 0.176, P = 0.035), and ZA2G (β = 0.139, P = 0.048) protein levels. Liver function variables, including albumin, total protein, calcium, and lactate dehydrogenase, correlated with 3PG and serotonin levels in the exposed areas. Sex-specific analysis showed that men exhibited stronger compensatory mechanisms via CFAI and myo-inositol, while women's greater vulnerability to heavy metal exposure highlighted the need for targeted interventions. These findings suggest APOH methylation affects APOC3, CFAI, and ZA2G levels, elevating 3PG, inosine monophosphate, and serotonin levels and harming liver function via lipolysis, supporting the use of these markers in health monitoring, therapies, and policies to limit heavy metal risks. Show less

Cribriform morular thyroid carcinoma (CMTC) is a rare malignant thyroid carcinoma, mainly seen in young Asian women. CMTC is related to the activation of the WNT/β-catenin signaling pathway, so CMTC is usually closely related to familial adenomatous polyposis (FAP). The patient was a 13-year-and-11-month-old girl with a right neck mass. After total thyroidectomy and bilateral lymph node dissection, the tumor's pathological report is CMTC, and 31 lymph nodes exhibited metastatic carcinoma. Adenomatous polyposis coli (APC) gene mutation has been detected. CMTC has typical cribriform and morular structures under microscope. It is associated with the WNT/β-catenin signaling pathway through inactivating mutations in the APC, CTNNB1, and AXIN1 genes, thereby enabling WNT gene expression and participating in proliferation, invasion, dedifferentiation, and tumorigenesis. CMTC is usually closely related to FAP. It requires clinical attention, and the patient's intestinal condition still needs to be closely monitored after surgery. Show less