👤 Hong Ling

Silica exposure precipitates irreversible lung injury; however, its long-term neurological sequelae—and the microglial mechanisms underlying these effects—remain poorly understood. Here, we demonstrate that inhaled crystalline silica induces persistent hippocampal inflammation, anxiety- and depression-like behaviors, and neuronal loss in mice. Bulk RNA sequencing, immunophenotyping, and pharmacological depletion studies revealed that microglia are the primary source of complement C1q in silica-exposed brains. Mechanistically, silica-induced lipocalin-2 (LCN2) engages the melanocortin-4 receptor (MC4R) on microglia, activating a cAMP/PKA/NF-κB cascade that transcriptionally upregulates C1q. Pharmacological blockade of MC4R (using PF) abolished C1q overproduction, normalized brain-derived neurotrophic factor levels, and restored both synaptic integrity and behavioral performance. Our findings establish the LCN2–MC4R–C1q axis as a critical microglial pathway in silica-related neurotoxicity and identify MC4R antagonism as a promising, readily translatable intervention for occupational neuroinflammation. The online version contains supplementary material available at 10.1186/s12974-026-03695-5. Show less

Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abnormally elevated levels of amyloid-β (Aβ) deposition and tau phosphorylation. Given the rapid rate of population aging, many scientists are investigating AD, focusing on its pathogenic mechanisms and potential treatments. Unfortunately, to date, no highly effective therapeutic strategies have emerged. Intriguingly, multiple studies have revealed alterations in the gut microbiome of individuals with AD, suggesting it may serve as a novel avenue for investigating AD pathogenesis. Show less

Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. However, adaptive changes in respiratory metabolism and molecular mechanisms in lung tissues of small mammals under extreme water shortage conditions remain unclear. This study hypothesized that small desert mammals can adapt to extreme water shortage environments by regulating the plasticity of lung tissue gene expression and respiratory metabolism. Using 29 wild-caught Siberian jerboas ( Show less

Residual cardiovascular risk persists in statin-treated patients with coronary artery disease (CAD), even when low-density lipoprotein cholesterol (LDL-C) targets are met. Excess apolipoprotein B (apoB), defined as measured apoB minus LDL-C-predicted apoB, may capture atherogenic particle burden beyond LDL-C, but its prognostic value for long-term mortality in secondary prevention remains uncertain. We conducted a pooled analysis of two nationwide Chinese cohorts (CIN-II and RED-CARPET) comprising 68,616 statin-treated CAD patients. Excess apoB was calculated using an internal reference population (triglycerides ≤ 1.0 mmol/L). Associations with all-cause and cardiovascular mortality were assessed using multivariable Cox models, with adjustment for clinical covariates including nutritional status. External validation was performed in 13,702 participants from the UK Biobank. Over a median follow-up of 5.2 years, 10,835 deaths occurred (5,090 cardiovascular). Each 1-standard deviation (15.4 mg/dL) increase in excess apoB was associated with a 12% higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.12, 95% CI 1.06-1.18) and a 24% higher risk of cardiovascular mortality (aHR 1.24, 95% CI 1.15-1.34). Patients in the highest excess apoB quartile (≥ 11.5 mg/dL) had significantly worse survival. Notably, these associations persisted consistently across all achieved LDL-C strata (< 2.0 to > 4.0 mmol/L). These findings were robustly confirmed in the external validation cohort. Excess apoB is an independent predictor of long-term mortality in statin-treated CAD patients, even among those with well-controlled LDL-C. Its incorporation into risk assessment could improve prognostic stratification and guide personalized management in secondary prevention. CIN-II: ClinicalTrials.gov, NCT05050877 (Retrospectively registered, 21 September 2021); RED-CARPET: Chinese Clinical Trial Registry, ChiCTR2000039901 (Prospectively registered, 14 November 2020). The UK Biobank study is covered by generic ethical approval from the NHS National Research Ethics Service (Ref: 99231). Show less

Protocatechuic acid (PCA), a natural compound found in a variety of Chinese herbal medicines and plant foods, has been documented to inhibit atherosclerosis partially by reducing inflammation burden in arterial endothelial cells. Interestingly, in vitro studies showed that PCA at physiologically reachable concentrations does not affect inflammation burden in TNF-α-stimulated aortic endothelial cells, whereas it increases the content of exosomal miR-10b secreted by macrophages that have engulfed apoptotic cells (efferocytic macrophages). This study was aimed at investigating whether the in vivo anti-inflammatory effect of PCA in arterial endothelial cells was due to the uptake of efferocytic macrophage exosomal miR-10b. A transwell co-culture system of aortic endothelial cells with efferocytic macrophages was used to evaluate the effect of PCA on NF-κB-mediated inflammation in aortic endothelial cells. An inhibitor of exosome secretion, GW4869, was applied to confirm the role of exosomes played in the anti-inflammatory effect of PCA. The aortic endothelial cells were administrated with exosomes isolated from PCA-treated efferocytic macrophages or miR-10b mimic or antagomir to ascertain the role of miR-10b in downregulating inflammation effect of PCA. Bioinformatics analyses, loss-of- and gain-of-function assays and luciferase reporter gene assays were performed to identify targeting relationship between miR-10b and mitogen-activated protein kinase kinase kinase 7 (MAP3K7)/β-transducin repeat-containing protein (β-TrCP). Besides, Apoe PCA at physiologically reachable concentrations inhibited NF-κB-mediated inflammation in TNF-α-stimulated aortic endothelial cells co-cultured with efferocytic macrophages, in which treatment of GW4869 reversed this effect. Exosomes isolated from PCA-treated efferocytic macrophages inhibited inflammation and increased miR-10b levels in aortic endothelial cells. Mechanistically, exosomal miR-10b post-transcriptionally repressed MAP3K7 and β-TrCP, both of which promote NF-κB activation. Knockdown of Map3k7 and Btrc with siRNA in aortic endothelial cells abolished the inhibitory effects of exosomes isolated from PCA-treated efferocytic macrophages on NF-κB-mediated inflammation. Consistently, oral administration of PCA increased miR-10b level and inhibited Map3k7 and Btrc mRNA expression as well as inflammation in aortic endothelial cells in Apoe Our current findings suggest that PCA could transfer exosomal miR-10b from efferocytic macrophages to endothelial cells and thus inhibit NF-κB-mediated inflammation in arterial endothelial cells through repressing MAP3K7 and β-TrCP, two new targets of miR-10b. Show less

Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis. Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD. Show less

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research. Show less

Approximately 10% of breast cancer cases are hereditary and associated with germline BRCA1/2 mutations. To characterize the somatic alteration landscape and HRD-related genomic features, we analyzed next-generation sequencing and clinical data from 1,243 breast cancer patients treated at Tianjin Cancer Hospital Airport Hospital between October 2021 and November 2024. We compared mutation patterns and clinicopathological features between patients with and without germline BRCA (gBRCA) mutations and further assessed somatic alterations and homologous recombination deficiency (HRD) in those carrying pathogenic variants. PIK3CA mutations were significantly more frequent in the Non-Germline and non-gBRCA groups than in the Germline and gBRCA groups (49% vs. 6%; 47% vs. 0%; both P < 0.001), indicating mutual exclusivity with gBRCA mutations. Conversely, PTEN alterations co-occurred in 30% of gBRCA cases, while TP53 mutations were mutually exclusive with MDM2 and FGFR1. HER2 amplification was identified in 10% of gBRCA-mutated tumors, and somatic alterations in non-gBRCA tumors were enriched in endocrine-resistance pathways. HRD scores were markedly higher in gBRCA patients than in non-gBRCA patients (median 59 vs. 24.5, P = 0.015), driven by significant increases in large-scale state transitions (LST) and telomeric allelic imbalance (TAI). The overall gBRCA1/2 mutation frequency was 15.61%, and two previously unreported variants, BRCA1 NM₀₀₇₂₉₄.3:c.4185G>A and BRCA2 NM₀₀₀₀₅₉.3:c.439C>A, were identified in the Chinese population. These findings provide a biological rationale to explore AKT1/HER2-targeted combinations with PARP inhibition in future studies for gBRCA-mutated breast cancer and provide the first evidence of PIK3CA-gBRCA mutual exclusivity in Chinese patients. The elevated HRD scores further underscore the presence of homologous recombination deficiency in the gBRCA group. Show less

To investigate the association between quantitative retinal vascular parameters and coronary artery disease (CAD) and to evaluate the efficacy of a retinal phenotype-based diagnostic model as a non-invasive tool for early CAD screening. A retrospective cross-sectional study. A single-centre study conducted at the Cardiovascular Center of Beijing Tongren Hospital, Capital Medical University, China, between January and October 2024. 417 patients with suspected angina undergoing their first coronary angiography (CAG) were enrolled. Inclusion criteria were age >18 years and high-quality fundus photography within 24 hours pre-CAG. Major exclusions were prior coronary interventions, severe systemic/valvular heart diseases and ocular conditions impairing retinal vascular visualisation. The primary outcome was the association between quantitative retinal vascular parameters and the presence of CAD (defined as ≥50% stenosis). Secondary outcomes included the diagnostic performance area under the receiver operating characteristic curve (AUROC) of three predictive models: one based on quantitative retinal vascular parameters alone, one based on traditional risk factors and a combined model integrating both retinal and clinical variables. This study enrolled 417 patients undergoing initial CAG. Compared with non-CAD controls (n=190), patients with CAD (n=227) had higher prevalence of hypertension, dyslipidaemia and diabetes, along with elevated levels of fasting blood glucose, lipoprotein(a) (Lp(a)), triglyceride (TG) and glycated haemoglobin (HbA1c) (all p<0.05). Quantitative fundus analysis revealed that multiple retinal vascular parameters were independently associated with CAD after multivariable adjustment, including fractal dimension (FD), vessel density (VD) and specific zonal measures of vessel diameter and tortuosity (all p<0.05). Multivariable logistic regression incorporating both fundus and clinical variables identified the following independent predictors of CAD: a decrease in FD (OR=0.26, 95% CI 0.16 to 0.41, p<0.01), reduced optic disc long-to-short axis ratio (OR=0.04, 95% CI 0.004 to 0.46, p=0.01) and optic disc-to-macula distance (OR=0.91, 95% CI 0.86 to 0.97, p<0.01), male sex, dyslipidaemia and elevated levels of Lp(a), TG, low-density lipoprotein cholesterol and HbA1c (all p<0.05). The final diagnostic model achieved an AUROC of 0.802 (95% CI 0.76 to 0.845), with a sensitivity of 0.797 and a specificity of 0.679 at the optimal cut-off. Internal validation via bootstrap resampling (1000 iterations) confirmed the robustness of the identified predictors. Our findings, derived from an artificial intelligence-based fully automated quantitative retinal vascular parameters measurement method, revealed that multiple quantitative fundus parameters-including FD, VD and other morphological parameters were significantly associated with CAD risk. The CAD diagnostic model we developed demonstrates strong performance and high interpretability, making it suitable for early CAD screening and diagnosis. Show less

This cross-sectional study involved secondary data analysis to: (1) examine relationships between psychosocial factors (autonomous motivation for physical activity [PA], PA self-efficacy, social support for PA) and various levels of PA intensity (light PA [LPA], moderate PA [MPA], vigorous PA [VPA]), and moderate-to-vigorous PA [MVPA]) in adolescents aged 10-14 years in the U.S.; and (2) investigate the influence of demographic, physiological, and activity-related characteristics (age, sex, race/ethnicity, body mass index [BMI], annual family income, cardiorespiratory fitness [CRF; estimated maximal oxygen uptake: VO2 max], current sports or cheerleading team participation, and non-sport PA program participation) on various PA intensities. In 2022-2024, adolescents completed demographic and psychosocial surveys and wore accelerometers to assess PA. Of 935 adolescents enrolled, 623 (66.6%) provided valid accelerometer data (≥4 days). Structural equation modeling was used. MPA, VPA, and MVPA were positively associated with male sex, higher CRF, and sports or cheerleading team participation. Age and BMI z-score were negative predictors of MVPA and VPA. MPA was negatively associated with age, and LPA was negatively associated with annual family income. Social support for PA predicted autonomous motivation for PA and PA self-efficacy. Indirect effects of social support on the various levels of PA intensity via autonomous motivation or PA self-efficacy were not significant. Strengthening social support for PA may enhance adolescents' autonomous motivation for PA and PA self-efficacy to help them increase PA. However, indirect effects on the PA levels were not statistically significant. Findings underscore the promise and limitations of psychosocial pathways.ClinicalTrials.gov Identifier NCT04213014. Show less

To assess the predictive value of serum lipoprotein(a) [Lp(a)] for contrast-induced nephropathy in patients with type 2 diabetes mellitus (T2DM). Consecutive T2DM patients who underwent coronary angiography (CAG) or percutaneous coronary intervention (PCI) between January 2019 and December 2021 were enrolled. Baseline Lp(a) was measured before the operation. CIN was defined as an increase in serum creatinine of more than 25% or 44 μmol within 72 h of contrast administration. The relationship between Lp(a) and CIN risk was analyzed. A total of 928 T2DM patients were included. CIN developed in 11.1% (103/928) of patients. The Lp(a) level was significantly higher in patients with CIN than in non-CIN patients (311.12 ± 278.66 vs. 254.19 ± 274.56 mg/L, A higher serum Lp(a) level indicates an increased risk of CIN in T2DM patients undergoing CAG or PCI and can serve as an independent predictor of CIN in this population. This study's findings will aid in the clinical prevention and treatment of contrast agent-induced kidney disease. Show less

Lipoprotein(a) [Lp(a)] and diabetes mellitus (DM) are independent risk factors for worse outcomes in coronary artery disease (CAD) patients. Evidence of their joint association is limited. We aimed to investigate the combined effect of elevated Lp(a) and DM on survival outcomes in CAD patients. This study included 65 547 CAD patients (62.6 ± 10.7 years, 27.7% female) from CIN-II and RED-CARPET cohorts. Patients were stratified into four groups by Lp(a) levels (< or ≥ 30 mg/dL) and DM status. Multivariable Cox regression models estimated associations with cardiovascular and all-cause mortality, examining additive and multiplicative interactions. During a median follow-up of 5.5 years, 10 686 (16.3%) patients died from all causes and 5106 (7.8%) died from cardiovascular causes. Patients with Lp(a) ≥ 30 mg/dL and DM were independently associated with cardiovascular mortality (adjusted hazard ratio [aHR]: 1.28, 95% CI: 1.20-1.35; aHR: 1.53, 95% CI: 1.44-1.62, all p < 0.001, respectively). Compared to patients with Lp(a) < 30 mg/dL without DM, the aHRs were 1.26 (95% CI: 1.16-1.36, p < 0.001), 1.51 (95% CI: 1.40-1.62, p < 0.001) and 2.00 (95% CI: 1.83-2.18, p < 0.001) for those with Lp(a) ≥ 30 mg/dL without DM, Lp(a) < 30 mg/dL with DM and Lp(a) ≥ 30 mg/dL with DM, respectively. Significant additive interaction between elevated Lp(a) and DM on cardiovascular mortality was observed, with 12% of the excess risk attributed. Similar associations were observed in all-cause mortality. In patients with CAD, elevated Lp(a) and DM act synergistically to increase the risk of cardiovascular and all-cause mortality, suggesting that both risks should be considered to integrate management. Show less

Sepsis triggered by lipopolysaccharide (LPS) is a life-threatening condition. Inspired by the specific capture mechanism of innate proteins like LBP and CD14, we develop oxidized chitosan microspheres functionalized with hyperbranched polylysine (OCS-HBPL) as a sepsis detoxification agent. Isothermal titration calorimetry (ITC) reveals that HBPL-LPS binding is an enthalpy-driven process, distinct from the entropy-driven interaction of linear polylysine (LPL)-LPS. Validated by surface plasmon resonance (SPR), HBPL demonstrates superior affinity with a dissociation constant (K Show less

Recent studies highlight the role of uric acid in tumor development, but its impact on prostate cancer (PCa) remains underexplored. This study aimed to investigate how uric acid influences PCa prognosis by analyzing transcriptomic data on PCa and uric acid-related genes (UARGs) from public databases. Differential expression analysis, protein-protein interaction (PPI) network, univariate Cox regression, and machine learning were used to identify prognostic genes. A risk model was then constructed based on these genes. Six prognostic genes (AHSG, AOX1, APOC1, LPL, NKX2-2, NKX6-1) were identified through the analysis of 1 433 differentially expressed genes (DEGs) and 3 806 UARGs. The risk model showed strong predictive ability, with the high-risk group (HRG) exhibiting poorer prognosis. Additionally, 10 immune cell types were significantly different between risk groups, with the HRG showing higher tumor mutation burden. A total of 8 drugs were found to correlate with risk scores. Enrichment analysis revealed that AHSG, AOX1, and APOC1 were linked to oxidative stress and Parkinson's disease, while NKX2-2 and NKX6-1 were associated with RNA degradation. These findings suggest that oxidative stress may be a key mechanism in PCa progression. This study offers a novel perspective on PCa treatment by identifying 6 prognostic genes and providing a prognostic risk model. Show less

Excessive fat deposition compromises the health of companion animals and the carcass quality of food-producing livestock. Follicle-stimulating hormone (FSH) has been demonstrated to play a critical regulatory role in fat deposition, with its function dependent on binding to its cognate receptor (FSHR) in target organs. In this study, female Sprague-Dawley (SD) rats were immunized with subunit vaccines targeting FSHβ and FSHR, respectively, and obesity was induced by a high-fat diet (HFD) to investigate the effects of these vaccines on adipose deposition in female mammals. The results revealed that active immunization against FSHβ and FSHR effectively suppressed HFD-induced obesity and the elevated serum triglyceride levels. Histological observations found that FSHβ and FSHR immunity decreased adipocyte hypertrophy and increased the cross-sectional area of skeletal muscle fibers caused by HFD, partially ameliorated HFD-associated hepatic sinusoidal spaces and vacuolated steatosis in the cytoplasm. RT-qPCR results indicated that FSHβ and FSHR immunization inhibited lipid synthesis by downregulating adipogenic-related genes, including C/ebpα, Creb, Pparγ, Lpl, and Perilipin. These findings suggest that both vaccines can mitigate HFD-induced adipose deposition in rats, with the FSHR vaccine exhibiting more pronounced effects. This study provides a novel strategy to mitigate pet health deterioration caused by excessive obesity and the decline in carcass quality of food-producing livestock. Show less

In this study, we used optical genome mapping (OGM), conventional karyotyping, and next-generation sequencing to analyze cytogenomic alterations in 91 cases of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Whereas karyotyping detected abnormal karyotypes in 55% of cases, OGM identified cytogenetic abnormalities in 97.8% of the cases and provided clinically relevant information beyond karyotyping in ∼70% of cases. OGM detected gene rearrangements in 80% of cases, including 24 recurrent gene fusions and 21 previously unreported putative gene fusions in T-ALL. Copy number variants were detected in 93% of cases, with interstitial deletions the most common. Gene mutations were detected in 93% of cases, with NOTCH1 being most frequent (in 57% of cases). Combining all data, most T-ALL cases harbored 3 or more cytogenomic aberrations. Specific cytogenomic alterations differed among T-ALL subtypes as follows: rearrangements of BCL11B and PICALM::MLLT10, deletions of 7p, and mutations involving DNMT3A, WT1, TET2, IDH2, and FLT3 were common in early T-precursor and near-early T-precursor subtypes. Rearrangements of TLX1, KMT2A, STIL::TAL1, and NUP214::ABL1, deletions of 9p, and FBXW7 mutations were frequently associated with the cortical subtype. We conclude that integration of OGM and next-generation sequencing with karyotyping enables comprehensive cytogenomic profiling of T-ALL that improves detection of clinically relevant genomic alterations and may inform disease classification and future studies of risk stratification. Show less

Autophagy regulates intermittent hypoxia (IH)-induced obstructive sleep apnea-hypopnea syndrome (OSAHS). We investigated the effects of IH and its withdrawal on cognitive function, autophagy, and lysophagy in OSAHS. An OSAHS rat model was established, and rats were divided into five groups: normoxia control, IH-4w (4-week IH), IH-6w (6-week IH), IH-8w (8-week IH), and IH-8w + 4w (8-week IH and 4-week normoxia). The cognitive behavior; mitochondrial and lysosomal morphology of the hippocampal tissue; mitochondrial respiratory function, permeability, and membrane potential; lysosomal function; autophagy- and lysophagy-related protein levels; and hypoxia-associated autophagy gene expression in rats were assessed. The cognitive function of rats in the IH-4w, IH-6w, and IH-8w groups was significantly impaired. In IH-8w cells, mitochondrial function was damaged with swollen morphology and decreased quantity, respiration, permeability, and membrane potential, along with significantly increased mitophagy-related protein ATG5 and LC3II/LC3 levels and decreased p62 levels. Expression of hypoxia-associated autophagy genes Becn1, Hif1, Bnip3, Bnip3l, and Fundc1 was significantly higher in the IH-8w group. Significantly increased LAMP2, CTSB, and ACP2 levels in IH-8w cells further indicated impaired lysosomal function. Lysophagy-related protein LAMP1, LC3II/LC3I, and TFEB levels were significantly increased in the IH-8w group, whereas p62 level was significantly decreased. The above listed evidence indicated damage to the mitochondria and lysosomes, as well as stimulation of mitophagy and lysophagy in IH-treatment OSAHS rat model. After withdrawing IH and culturing for 4 weeks in normal conditions, the cognitive function of rats improved, and mitophagy and lysophagy decreased. Our findings indicate that IH impairs cognitive function and promotes mitophagy and lysophagy in an OSAHS rat model, and IH withdrawal recovered the above effects. Show less

The Golgi apparatus (GA) serves as the center of protein and lipid synthesis and modification within cells, playing a crucial role in regulating diverse cellular processes as a signaling hub. Dysregulation of GA function can give rise to a range of pathological conditions, including tumors. Notably, mutations in Golgi-associated genes (GARGs) are frequently observed in various tumors, and these mutations have been implicated in promoting tumor metastasis. However, the precise relationship between GARGs and glioma, a type of brain tumor, remains poorly understood. Therefore, the objective of this investigation was to assess the prognostic significance of GARGs in glioma and evaluate their impact on the immune microenvironment. The expression of GARGs was obtained from the TCGA and CGGA databases, encompassing a total of 1564 glioma samples (598 from TCGA and 966 from CGGA). Subsequently, a risk prediction model was constructed using LASSO regression and Cox analysis, and its efficacy was assessed. Additionally, qRT-PCR was employed to validate the expression of GARGs in relation to glioma prognosis. Furthermore, the association between GARGs and immunity, mutation, and drug resistance was investigated. A selection of GARGs (SPRY1, CHST6, B4GALNT1, CTSL, ADCY3, GNL1, KIF20A, CHP1, RPS6, CLEC18C) were selected through differential expression analysis and Cox analysis, which were subsequently incorporated into the risk model. This model demonstrated favorable predictive efficiency, as evidenced by the area under the curve (AUC) values of 0.877, 0.943, and 0.900 for 1, 3, and 5-year predictions, respectively. Furthermore, the risk model exhibited a significant association with the tumor immune microenvironment and mutation status, as well as a diminished sensitivity to chemotherapy drugs. qRT-PCR analysis confirmed the up-regulation or down-regulation of the aforementioned genes in glioma. The utilization of GARGs in our constructed model exhibits a high level of accuracy in prognosticating glioma and offers promising avenues for the development of therapeutic interventions targeting glioma. Show less

Myocardial infarction (MI) is one of the most serious cardiovascular diseases in the world. Nevertheless, the majority of diagnostic procedures conducted subsequent to the illness do not provide any means to prevent several risks associated with MI. Blood and urine tests are frequently employed in clinical examinations to detect cardiovascular diseases at an early stage. Mendelian randomization (MR) is commonly employed to explore disease-trait relationships and uncover therapeutic targets. Our goal was to explore the genetic links between 35 blood and urine biomarkers and MI. Blood and urine biomarker MR correlations with MI risk were studied. In version R10, the UK Biobank and Finnish databases included blood and urine marker data and MI data (26,060 cases and 343,079 controls). We performed bidirectional 2-sample MR with 4 methods: inverse variance weighted, MR-Egger, weighted median, and weighted mode. Final causal associations were determined by inverse variance weighted. Sensitivity analyses (heterogeneity, pleiotropy) were conducted. MR-PRESSO and PhenoScanner were used to exclude invalid instruments. We used multivariate MR to filter the most important genes without including other positive genes. To identify positive gene pathways and gene networks that cause MI, we employed GeneMANIA for gene prediction. The findings revealed a positive genetic association between the 8 blood and urine biomarker levels and an elevated risk of MI. There are apolipoprotein B (APOB), glycated hemoglobin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, sex hormone-binding globulin, triglycerides, and urate. Moreover, APOB, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol selectively affect MI through the rejection of other positive gene stems. Finally, APOB and numerous genes strongly impact MI development. APOB collaborates with related genes to regulate plasma lipoprotein particle levels, sterol homeostasis, organization, lipid homeostasis, and remodeling in MI. Our research further reveals the causal relationship between MI and blood/urine biomarkers, providing a new perspective for the prevention, diagnosis, and treatment of MI. Blood and urine marker tests can subsequently be conducted based on these results to detect MI and study the underlying mechanisms linking these metabolites to MI. Show less

Neurovascular biomarkers have the potential to enhance early diagnosis of Alzheimer's disease (AD) and AD-related dementias (ADRD), as cerebrovascular alterations often precede neurodegeneration. However, their clinical application remains challenging due to insufficient specificity, heterogeneity, and technical limitations. Here, we report that vessel- and cortical layer-specific parameters exhibit promising diagnostic sensitivity for neurovascular impairments in an AD/ADRD mouse model, apolipoprotein E (APOE) 4 knock-in (KI), compared to APOE3-KI at 12 months of age. Using two in vivo imaging modalities, 3D capillary-resolution optical Doppler tomography and laser speckle contrast imaging, we measured 36 morphological and functional vascular parameters and evaluated their diagnostic performance using a machine-learning Support Vector Machine classifier. APOE4 mice showed significant alterations including reduced venular and arterial cerebral blood flow velocities and diameters, increased vascular tortuosity, layer-dependent decreases in vascular density, and impaired cerebrovascular reactivity. Venule- and microcirculation-related parameters and dynamic vasoactivity to brain stimuli demonstrated high diagnostic accuracy (~ 90%). Together, these findings provide in vivo evidence for early, cortical layer-specific neurovascular dysfunction caused by APOE4 that increases the susceptibility to dementia and highlight the potential of combining neurovascular biomarkers from optical imaging with AI-based classifier for identification of increased AD/ADRD risk. Show less

Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less

Estimated pulse wave velocity (ePWV), a noninvasive marker of arterial stiffness, reflects vascular aging and has been associated with increased coronary artery disease (CAD) risk. However, the interplay between ePWV and genetic factors, including polygenic risk score (PRS) and apolipoprotein E genotypes, in determining CAD susceptibility remains unclear. We analyzed data from the HRS (Health and Retirement Study), including 5856 participants (4741 White and 1115 Black individuals) without baseline CAD. ePWV was calculated, and genetic risk was assessed using PRS and apolipoprotein E genotyping. Cox proportional hazards models evaluated the associations between ePWV, genetic predisposition, and CAD incidence, with stratified analyses by race and sex. Mediation analyses explored underlying mechanisms. Elevated ePWV (≥10 m/s) was significantly associated with increased CAD risk (hazard ratio [HR], 1.50 [95% CI, 1.25-1.81], Vascular aging and genetic predisposition interact in complex ways to influence CAD risk, with notable variations across racial and sex subgroups. These findings highlight the need for personalized prevention strategies incorporating both vascular health and genetic risk profiling. Show less

Disruption of photoreceptor-retinal pigment epithelium (RPE) interface with loss of photoreceptor outer segments (POSs) in the retina is a pathological hallmark of several neurodegenerative and retinal diseases including lysosomal storage disorder's like CLN3 disease. However, the retina is a functional composite Acid ceramidase deficiency and consequently altered sphingolipid signaling promotes disease phenotype(s) in a lysosomal storage disorder, CLN3 disease. Show less

Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection. Show less

The abnormal accumulation of lipid droplets in clear cell renal cell carcinoma (ccRCC) is related to metabolic reprogramming. However, the mechanism between metabolic reprogramming and tumor progression in ccRCC remains to be explored. Utilize multiple omics technologies to predict the relationship between fatty acid metabolism and tumor progression, and identify the key regulatory proteins and mechanisms. The role of proteins in influencing tumor progression and fatty acid metabolism was explored from both in vivo and in vitro. The mechanism of the regulatory protein was analyzed and verified by co-immunoprecipitation and mass spectrometry. Multimodal analysis revealed that fatty acid desaturase 3 (FADS3), as a key molecule connecting fatty acid metabolism and Epithelial-mesenchymal transition (EMT), was upregulated in clinical samples of ccRCC and participated in the immune regulation, and was positively correlated with clinical stage and poor prognosis. Functionally, FADS3 promoted cell proliferation and EMT in vivo and in vitro as well as sunitinib resistance, and induced fatty acid synthesis and lipid droplet storage. Mechanistically, FADS3 activates the phosphorylation of Smad2/3 through autocrine Transforming Growth Factor-β (TGF-β). The lipid droplets induced by FADS3 could act as a reservoir of acetyl-CoA, promoting the acetylation of Smad2 and inducing the upregulation of TGF-β receptors, thereby promoting the proliferation and EMT. Our study confirmed FADS3 as a key intermediate protein regulating fatty acid metabolism and tumor progression, which was expected to be a potential diagnostic and prognostic biomarker for ccRCC. Show less

Although low-density lipoprotein cholesterol (LDL-C) is established as the primary cardiovascular disease (CVD) risk factor, some individuals with LDL-C within desirable limits still develop coronary artery disease (CAD). Lipoprotein(a) (Lp(a)) has emerged as a genetically determined independent risk factor for CVD. This study aims to investigate Lp(a) by determining its association with coronary artery stenosis severity, identifying its ethnic-specific genetic determinants and assessing its relationship with an energy-dense dietary pattern. The PUTRA-CV study is a 3-year, multicentre, case-control observational study involving adult patients who have undergone coronary angiography. The primary outcome is the association between Lp(a) levels and the severity of angiographic CAD (assessed by Gensini or Syntax score). Secondary outcomes include the frequencies of Lp(a)-associated single nucleotide polymorphisms (SNPs) (rs10455872 and rs3798220) and the association between dietary patterns and Lp(a) levels. Lp(a) will be measured using a particle-enhanced immunoturbidimetric method, and SNPs will be genotyped using high-resolution melting. Dietary intake will be assessed using a validated semiquantitative food frequency questionnaire. Data will be analysed using SPSS. Descriptive statistics will be used to summarise population characteristics. Bivariate analyses will use chi-square (χ2), independent t-tests or Mann-Whitney U tests as appropriate. The independent association between Lp(a) and coronary artery stenosis severity will be determined using multivariable logistic regression, adjusting for confounders. Empirically driven dietary patterns will be derived using reduced rank regression, and their association with Lp(a) will be assessed. For genetic analysis, allele frequencies of the Ethical approval has been obtained from the ethics committees of the Ministry of Health Malaysia (NMRR ID-24-00877-2ID-IIR), Universiti Putra Malaysia (JKEUPM-2024-246), Universiti Teknologi MARA (REC/07/2024-OT/FB/2) and Universiti Malaya Medical Centre (MREC ID NO: 2 02 453-13692). The findings will be disseminated via peer-reviewed journals and conferences. Show less

Lung adenocarcinoma (LUAD), the predominant histological subtype of non-small cell lung cancer, demonstrates critical regulatory involvement of RNA-binding proteins (RBPs) and circular RNAs (circRNAs) in tumorigenic processes. Emerging evidence highlights the circRNA-autophagy regulatory axis as a crucial modulator of cancer progression. This study systematically investigates the functional interplay within the RBP-circRNA-autophagy network in LUAD pathogenesis. Employing RNA pull down, mass spectrometry and RNA immunoprecipitation facilitated the exploration of the circRAPGEF5 binding protein. M6A methylation RNA immunoprecipitation-PCR was utilized for m6A analysis. Immunofluorescence (IF) and fluorescence in situ hybridization (FISH) assays were conducted to ascertain the subcellular localization of target genes. Employing mRFP-GFP-LC3 fluorescent lentivirus labelling facilitated the monitoring of autophagy flow levels. Xenografts in mice were instrumental in affirming the role of circRAPGEF5. Through comprehensive molecular profiling, we identified elevated circRAPGEF5 expression in LUAD cells, which significantly suppressed autophagic flux while promoting malignant phenotypes including enhanced proliferation, migration, and invasion. Mechanistic investigations revealed that circRAPGEF5 directly interacts with the KH3-4 functional domain of Insulin-like Growth Factor 2 mRNA-Binding Protein 2 (IGF2BP2), an m6A reader protein. This interaction facilitated IGF2BP2-mediated stabilization of NUP160 mRNA, a nuclear pore complex component. Genetic ablation of NUP160 through RNA interference effectively restored autophagic activity, thereby attenuating the aggressive biological behaviors of LUAD cells. In vivo validation using xenograft models demonstrated that the circRAPGEF5/IGF2BP2/NUP160 signaling axis promotes tumor growth and metastatic dissemination through autophagy suppression. Our findings reveal a novel epigenetic regulatory mechanism wherein m6A-modified circRAPGEF5 orchestrates autophagy inhibition via IGF2BP2-dependent stabilization of NUP160 transcripts, ultimately driving LUAD progression and metastasis. These results establish the circRAPGEF5/IGF2BP2/NUP160 axis as a potential therapeutic target for LUAD intervention. 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 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