Metabolic associated fatty liver disease (MAFLD) is a globally recognized chronic metabolic disorder characterized by lipid metabolism abnormalities. Accumulating evidence indicates that exopolysaccha Show more
Metabolic associated fatty liver disease (MAFLD) is a globally recognized chronic metabolic disorder characterized by lipid metabolism abnormalities. Accumulating evidence indicates that exopolysaccharides (EPS) could modulate the gut microbiota structure and function to prevent and treat MAFLD. Herein, a novel EPS designated BVP1 was isolated from Bacillus velezensis CGMCC 24752. Structural analysis revealed that BVP1 is a neutral Ξ±-mannan consisting of a backbone of 1,2,6-linked Ξ±-D-Manp, with branches composed of T-linked Ξ±-D-Manp, 1,2-linked Ξ±-D-Manp, and 1,3-linked Ξ±-D-Manp. Animal experiments showed that BVP1 significantly alleviated hepatic steatosis, liver injury and inflammation, and enhanced antioxidant activity in MAFLD mice. Single-nucleus RNA sequencing analysis revealed that BVP1 could restore HFD-induced imbalances in liver sinusoidal endothelial cells, hepatic stellate cells, macrophages and Kupffer cells by upregulating the expression of the lipid degradation gene Cps1 and downregulating the expression of the lipid synthesis gene Acsl1 in these cell subpopulations. Interestingly, BVP1 reshaped the gut microbiota and fecal metabolite profile by enriching beneficial bacteria and associated metabolites including salicylic acid, spermidine, and 4-hydroxyphenyl acetate. Fecal microbiota transplantation experiments verified that the anti-MAFLD effects are mediated by the BVP1-modified gut microbiota. Our findings highlight the potential of BVP1 as a promising therapeutic agent for MAFLD treatment. Show less
To investigate longitudinal changes in pelvic floor support in primiparous women with pelvic organ prolapse (POP) after vaginal delivery, focusing on single- and multiple-compartment involvement. Two Show more
To investigate longitudinal changes in pelvic floor support in primiparous women with pelvic organ prolapse (POP) after vaginal delivery, focusing on single- and multiple-compartment involvement. Two hundred primiparas after vaginal delivery were prospectively enrolled and underwent pelvic floor MRI at six weeks postpartum. POP was diagnosed and classified into subgroups (single or multiple compartments involved) based on MRI findings. Primiparas with POP underwent repeat MRI at four months postpartum. Pelvic floor measurements, including injury score and functional parameters of the levator ani muscle (puborectal hiatus line, H line; muscular pelvic floor relaxation line, M line; levator hiatus area, LHA; iliococcygeus angle, ICA; levator plate angle, LPA), were assessed on MRI. Measurements were compared among POP subgroups and a normal control group (without POP) at six weeks postpartum. Additionally, changes between six weeks and four months postpartum were analyzed within POP subgroups. Based on MRI criteria, approximately 41.5% of primiparas were diagnosed with POP, predominantly cystoceles commonly associated with uterine prolapse. Functional parameters of the levator ani, except for LPA at rest, were significantly increased in POP subgroups compared to controls. At four months postpartum, M line, H line, and LPA significantly decreased, and prolapsed organs were elevated in cases with multiple compartments involved, compared to six weeks postpartum. No significant changes were observed in cases with single-compartment involvement during follow-up. A substantial proportion of primiparas experienced postpartum POP. Impaired levator ani function contributed to POP. Pelvic floor support improved during early postpartum in cases with multiple-compartment involvement. Show less
Light-responsive porous liquids (LPLs) attract significant attention for their controllable gas uptake under light irradiation, while their preparation has remained a great challenge. Here we report t Show more
Light-responsive porous liquids (LPLs) attract significant attention for their controllable gas uptake under light irradiation, while their preparation has remained a great challenge. Here we report the fabrication of type II LPLs with enhanced light-responsive efficiency by tailoring the host's functionality for the first time. The functionality of light-responsive metal-organic cage (MOC-RL, constructed from dicopper and responsive ligands) is modified by introducing the second long-chain alkyl ligand, producing MOC-RL-AL as a new host. A spatially hindered solvent based on polyethylene glycol, IL-NTf Show less
This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict na Show more
This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict natural compounds (NCs) with potential in Alzheimer's disease (AD) treatment. The NCs were identified based on activity related to seven AD-specific genes, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), and presenilin-1 (PSEN1). We implemented a computational pipeline using SELFormer and deep learning techniques, conducted optimal clustering and quantitative structure-activity relationship (QSAR) analyses, and performed a uniform manifold approximation and projection (UMAP) to categorize compounds based on bioactivity levels. Molecular docking analysis was carried out on selected compounds. To validate the computational predictions, we conducted in vitro studies using nerve growth factor (NGF)-differentiated PC12Β cells. Finally, we mapped the relationships between food sources containing the identified compounds and their target proteins. Optimal clustering analysis revealed five distinct groups of NCs, while QSAR analysis highlighted variations in molecular properties across clusters. The UMAP projection identified 17 highly active NCs (pIC This integrated computational and experimental approach offers a promising framework for identifying potential NCs for AD treatment. The results contribute to exploring effective therapeutic strategies against AD. Show less
Atherosclerotic cardiovascular disease (ASCVD) is a major threat to human life and health, and dyslipidemia with elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor, and i Show more
Atherosclerotic cardiovascular disease (ASCVD) is a major threat to human life and health, and dyslipidemia with elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor, and in the optimal LDL-C scenario, apolipoprotein B (ApoB) has a more predictive value of ASCVD risk. The study is a genome-wide association study (GWAS) based on a European population. A large GWAS dataset for atherosclerotic cardiovascular diseases was targeted, including coronary heart disease (CHD), ischemic stroke (IS), large-artery atherosclerotic stroke (ISL), small-vessel stroke (ISS), and myocardial infarction (MI). Univariate two-sample mendelian randomization (MR) analyses of ApoB and the above cardiovascular diseases were performed separately, and the association was assessed mainly using the inverse variance weighted (IVW) method, with confidence intervals for the superiority ratios set at 95%. In addition, the experiment was supplemented using MR-Egger, weighted model and weighted median (WM). Based on the results of univariate two-sample mendelian randomisation analysis, it was shown that there was a causal relationship between ApoB and CHD (ORβ=β1.710, 95% CI 1.529-1.912, Pβ=β0.010), ISL (ORβ=β1.430, 95% CI 1.231-1.661, Pβ=β2.714E-06), ISS (ORβ=β1.221, 95% CI 1.062-1.405, Pβ=β0.005) were causally related to each other and the disease prevalence ratio was positively correlated with ApoB concentration. This MR analysis demonstrated a causal relationship between ApoB and CHD, ISL, ISS, but not with the risk of developing IS and MI, which further validated the relationship between ApoB and the risk of ASCVD, and contributed to a better understanding of the genetic impact of ApoB on ASCVD, and to a certain extent, could improve the management of ApoB and reduce the prevalence of ASCVD. Show less
Bo Lin, Mengsen Li Β· 2025 Β· Frontiers in immunology Β· Frontiers Β· added 2026-04-24
Abnormalities in the Wnt/Ξ²-catenin pathway promote the development of hepatocellular carcinoma (HCC). Mutations in CTNNB1, which encodes Ξ²-catenin, are frequently found in clinical HCC samples, as are Show more
Abnormalities in the Wnt/Ξ²-catenin pathway promote the development of hepatocellular carcinoma (HCC). Mutations in CTNNB1, which encodes Ξ²-catenin, are frequently found in clinical HCC samples, as are loss-of-function mutations in signaling pathway regulators such as axis inhibition protein 1 (Axin1) and adenomatous polyposis coli (APC). The activation of the Wnt/Ξ²-catenin pathway synergizes with other oncogenic signal molecules such as c-Met or glypican-3, contributing to HCC development. Furthermore, Wnt/Ξ²-catenin pathway activation in the tumour microenvironment (TME) leads to cold tumour and resistance to immunotherapy. In this review, we discuss two models of Wnt/Ξ²-catenin signaling activation, role of Wnt/Ξ²-catenin signaling pathway in the development of HCC, the association between Wnt/Ξ²-catenin pathway and tumour angiogenesis, metastasis, and immune escape in the TME, and the targeting of this signaling pathway for HCC treatment. Show less
Childhood cancer can disrupt family functioning, increase caregiver psychological distress, and impair caregiver quality of life. While family resilience is crucial for adaptation, most research has f Show more
Childhood cancer can disrupt family functioning, increase caregiver psychological distress, and impair caregiver quality of life. While family resilience is crucial for adaptation, most research has focused on individual-level factors, neglecting heterogeneity and multilevel influences on family resilience. Guided by the Social Ecological Model (SEM), this cross-sectional observational study used latent profile analysis (LPA) to identify distinct profiles of family resilience among caregivers of children with cancer and to explore factors associated with these profiles. Between July 2022 and March 2024, 292 caregivers were recruited. Family resilience was measured using the Family Resilience Assessment Scale. LPA was employed to identify resilience profiles, and binary logistic regression was used to explore influencing factors. Two latent profiles were identified: the Low Resources-Low Positivity profile (86%) and the High Internal Resilience profile (14%). The Low Resource-Low Positivity profile demonstrated generally lower scores, especially in utilizing social and economic resources and maintaining a positive outlook. The High Internal Resilience profile showed higher scores across all family resilience dimensions, particularly in communication/problem solving, positive outlook, and meaning-making, while the use of external social and economic resources remained relatively lower. Univariate analysis showed significant differences between profiles in residence, number of siblings, caregiver education, individual resilience, social support, caregivers' physical and psychological well-being and child communication (caregiver-reported). Binary logistic regression identified having more than one child (ORβ=β3.184, 95% CI: 1.437β~β7.057, Pβ=β0.004) and higher individual resilience (ORβ=β1.095, 95% CI: 1.028β~β1.165, Pβ=β0.005) as significant predictors of High Internal Resilience profile. This study identified two distinct family resilience profiles among caregivers of children with cancer. Limited use of social and economic resources was common, while caregiver resilience and having multiple children predicted higher family resilience. Interventions should enhance caregiver coping capacity, support one-child families through peer and family programs, and improve access to social support, flexible employment, and affordable care to strengthen family resilience. Not applicable. Show less
Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia an Show more
Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia and glucose intolerance, hallmark features of type 2 diabetes. While SEC16 homologue B (SEC16B), an endoplasmic reticulum export factor, has been linked to obesity, type 2 diabetes and lipid metabolism, its role in glucose regulation remains poorly defined. This study aims to investigate SEC16B's contribution to glucose homeostasis by systematically dissecting its conserved physiological mechanisms across species. To interrogate SEC16B's role, we combined Drosophila genetics (RNA interference-mediated dSec16 knockdown) with murine models (Sec16b deletion) under standard or high-fat diet conditions. Glucose and insulin tolerance tests assessed glucose homeostasis. Mechanistic insights into beta cell dysfunction were derived from immunostaining, glucose-stimulated insulin secretion assays and RNA-seq profiling of murine pancreatic islets. Both disruption of dSec16 in Drosophila and Sec16b deletion in mice triggered glucose intolerance under standard diet conditions, recapitulating conserved metabolic dysfunction. In addition, Sec16b loss impaired glycaemic control in mice fed a high-fat diet. Mechanistically, Sec16b deficiency impairs insulin secretion by downregulating cholinergic signalling and compromising intracellular Ca Our study reveals SEC16B, a genome-wide association study-identified obesity risk gene, as an evolutionarily conserved regulator of glucose homeostasis. By linking SEC16B to cholinergic-driven insulin secretion and calcium dynamics, we resolve a mechanistic gap in beta cell dysfunction and metabolic disease. This finding provides novel insights into the mechanisms underlying glucose homeostasis and may enhance our understanding of potential treatments for metabolic diseases. Show less
Traditional approaches to assessing sleep quality in clinical nurses often overlook population heterogeneity and the complex interplay of influencing factors. This study employs Latent Profile Analysi Show more
Traditional approaches to assessing sleep quality in clinical nurses often overlook population heterogeneity and the complex interplay of influencing factors. This study employs Latent Profile Analysis (LPA) and Association Rule Mining (ARM) to identify distinct sleep quality subgroups and uncover key factor combinations, thereby informing targeted intervention strategies. A total of 1,686 nurses from 123 hospitals in Shandong Province were recruited through multistage stratified sampling. LPA was used to classify participants based on seven sleep dimensions from the Pittsburgh Sleep Quality Index (PSQI), while ARM was applied to identify frequent itemsets of sleep disorder triggers. Key influencing factors were further examined using univariate analysis and multivariate logistic regression. Three latent sleep profiles were identified: high (63.11%), moderate (34.10%), and low (2.79%) sleep quality. The low-sleep subgroup was characterized by higher proportions of being unmarried/divorced (42.55%), low monthly income (β€β3,000 CNY, 42.55%), non-permanent employment (76.60%), and severe psychological distress (44.68%). In contrast, the high-sleep subgroup featured higher rates of being married (85.62%), moderate income (3,001β7,000 CNY, 73.03%), and low psychological distress (51.32%). Key determinants included marital status (ORβ=β2.153/2.252), income (ORβ=β9.098), employment type (ORβ=β1.475), and psychological state (ORβ=β0.060β0.555). ARM revealed distinct risk combinations: βlow incomeβ+βnon-permanent employmentβ (liftβ=β3.895) for the low-sleep group; βmarriedβ+βmoderate incomeβ+βnon-permanent employmentβ+βpatient conflictβ for the moderate group; and βhigh incomeβ+βlow psychological distressβ buffering night-shift effects in the high-sleep group. By integrating LPA and ARM, this study reveals the multidimensional heterogeneity and interactive mechanisms underlying clinical nursesβ sleep quality. The findings support a stratified intervention framework combining institutional safeguards with precision strategies to enhance sleep health management in nursing populations. Show less
The genetic foundations underlying the observed disease resistance in certain indigenous pig breeds, notably the Min pigs of China, present a compelling underexplored subject of study. Exploring the m Show more
The genetic foundations underlying the observed disease resistance in certain indigenous pig breeds, notably the Min pigs of China, present a compelling underexplored subject of study. Exploring the mechanisms of disease resistance in these breeds could lay the groundwork for genetic improvements in pig immunity, potentially augmenting overall pig productivity. In this study, whole blood samples were collected from pre- and post- swine fever vaccinated Min and Large White pigs for transcriptome sequencing. The mRNA and lncRNA in both pig breeds were analyzed, and intra-group and inter-group comparisons were also conducted. The results indicated that a greater number of immune-related pathways such as the JAK-STAT and PI3K-AKT signaling were enriched in Min pigs. Furthermore, genes involved in inflammation and antiviral responses, including IL16, IL27, USP18, and DHX58, were upregulated in post-vaccination Min pigs compared to post-vaccination Large White pigs. This heightened immune responsiveness could contribute to the observed differences in disease resistance between Min pigs and Large White pigs. Show less
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial-mesenchymal transition (EMT) is a key driver Show more
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial-mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-Ξ²1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-Ξ²1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Show less
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined r Show more
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27-IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction-mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Show less
Poly(A) binding protein cytoplasmic 4 (PABPC4) has been regarded as a prognostic marker in many malignancies. In this study, we evaluated PABPC4 expression at both messenger ribonucleic acid (mRNA) an Show more
Poly(A) binding protein cytoplasmic 4 (PABPC4) has been regarded as a prognostic marker in many malignancies. In this study, we evaluated PABPC4 expression at both messenger ribonucleic acid (mRNA) and protein levels. The prognostic value of PABPC4 in patients with prostate cancer (PCa) was also investigated. The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, our analysis of Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), and 65 pairs of ribonucleic acid (RNA) sequencing data from our center were employed to detect the expression of PABPC4 in PCa tissues. Tissue microarrays (TMAs) were utilized to detect the expression of the PABPC4 protein, and survival analysis as well as risk factor analysis were conducted. In the 65 pairs of sequencing data, the expression of PABPC4 in tumor tissues was significantly higher than that in paired adjacent tissues (P<0.001), and its expression also presented significant differences among different Gleason groups (P=0.041). In the CPGEA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of PABPC4 in M1 patients was higher than that in M0 patients, although no significant statistical difference was shown (P=0.051). In the TCGA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001). The expression of pT3/4 (pathological tumor stage 3 and pathological tumor stage 4) in high-stage tumor tissues was significantly higher than that in low-stage tumor tissues (pT2) (P=0.02), the expression of pT3/4 in GSE21034 and GSE32571 tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of pT3/4 in primary tumor tissues was higher than that in metastatic tissues in GSE6752 (P<0.001). The TCGA data revealed that patients with high PABPC4 expression had poorer overall survival (OS) than those with low PABPC4 expression (P=0.04), and the TMA data indicated that patients with high PABPC4 expression had a poor prognosis (P=0.004). Our study demonstrated that PABPC4 was overexpressed at mRNA and protein levels in PCa. We found that patients with high PABPC4 expression had a shorter biochemical recurrence (BCR)-free survival and OS, showing its value as a prognostic biomarker in patients with PCa. Show less
Polychlorinated biphenyls (PCBs) are environmental pollutants associated with various health issues, including breast cancer. This study investigates potential molecular mechanisms by which PCBs may i Show more
Polychlorinated biphenyls (PCBs) are environmental pollutants associated with various health issues, including breast cancer. This study investigates potential molecular mechanisms by which PCBs may influence breast cancer progression using computational and preliminary experimental approaches. We conducted a differential expression analysis using the TCGA-BRCA dataset. PCBs-related toxicological targets were collected from the Comparative Toxicogenomics Database (CTD). Enrichment and pathway analyses identified candidate biological processes and pathways. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Single-cell expression levels of key targets were analyzed (GSE114727 dataset). Molecular docking predicted binding affinities of PCBs congeners with key targets. Cell experiments assessed gene expression changes upon PCBs exposure. We identified 52 upregulated and 24 downregulated PCBs-related toxicological targets in breast cancer. Enrichment analysis highlighted potential associations with pathways such as PI3K-Akt, MAPK, and HIF-1, including genes like BRCA1, FGFR1, IGF1, AKT1, and EGF. PPI network analysis identified key hub genes like EZH2, EGF, BRCA1, AKT1, IL6, and TNF. Single-cell analysis suggested variable expression of key targets across immune cell types. Molecular docking predicted strong binding affinities of PCB 105 with EZH2 and EGF Our integrated analysis proposes that PCBs exposure may perturb key molecular pathways in breast cancer. Computational findings implicate targets like EZH2 and EGF, while preliminary cell experiments support further investigation. These results highlight a need for mechanistic studies to confirm PCB-induced effects and their therapeutic relevance, underscoring environmental pollutants as potential risk factors in cancer. Show less
Despite the critical role of e-Health literacy (eHL) in modern healthcare, current research predominantly concentrates on conditions such as cancer and diabetes, as well as outpatient care settings. H Show more
Despite the critical role of e-Health literacy (eHL) in modern healthcare, current research predominantly concentrates on conditions such as cancer and diabetes, as well as outpatient care settings. However, there remains a significant gap in studies specifically addressing the eHL needs of patients with maintenance hemodialysis (MHD). This study aims to explore the latent categories of eHL among MHD patients and its impact on health-promoting lifestyle (HPL). A survey was conducted using a convenience sampling method involving 500 MHD patients from three tertiary hospitals in Baoding. Data were analyzed using latent profile analysis (LPA) and a mixed regression model. This study showed that MHD patients could be classified into low (23.17%), middle (49.78%), and high (27.05%) eHL groups, with the three-class model showing optimal fit (AICβ―=β―2321.213, BICβ―=β―2271.168, entropyβ―=β―0.967). MHD Patients in the high literacy group scored significantly higher in all dimensions of e-HL and overall HPL (119.58β―Β±β―13.86) compared to those in the low literacy group (91.82β―Β±β―11.73) (all The findings suggest a heterogeneous stratification of eHL among MHD patients, closely linked to HPL. Stratified intervention strategies should be developed for different patient groups to potentially improve their health behaviors. The study provides evidence-based support for personalized health management. Show less
Xiang Lian, Xiaoyan Li, Kexin Wang+3 more Β· 2025 Β· Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics Β· added 2026-04-24
To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestation Show more
To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation. Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the "ACMG Guidelines"), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X). Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c.1871ββββdel(p.Ile624del) and c.1747C>T (p.His583Tyr) in the LDLR gene (NMββββ ββ.4), while patient 2 carried the heterozygous variants c.1747C>T (p.His583Tyr) in the LDLR gene and c.6936ββββinv (p.Ile2313Val) in the APOB gene (NMβββββββ. According to the ACMG Guidelines, the LDLR gene c.1747C>T (p.His583Tyr) was classified as a pathogenic variant (PS3+PM1+PM2_supporting+PM5+PP2+PP3), and c.1871ββββdel (p.Ile624del) was classified as a pathogenic variant (PS3+PS4+PM2_supporting+PM1+PM4); the APOB gene c.6936ββββinv (p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents. Show less
The malignant transformation of odontogenic keratocysts (OKC) into cancerous odontogenic keratocysts (COKC) is exceedingly rare, and its mechanisms remain poorly understood. Studies exploring the cell Show more
The malignant transformation of odontogenic keratocysts (OKC) into cancerous odontogenic keratocysts (COKC) is exceedingly rare, and its mechanisms remain poorly understood. Studies exploring the cellular heterogeneity, molecular pathways, and clinical features of COKC are limited. In this study, we performed single-cell RNA sequencing (scRNA-seq) on three COKC samples and integrated the data with a public OKC dataset, identifying 22,509 single cells. Two COKC-specific epithelial subpopulations, Basal-C0-EXT1 and Basal-C3-HIST1H3B, were identified. These subpopulations exhibited enhanced stemness and invasive potential, respectively, suggesting their roles as key drivers of OKC carcinogenesis. Fibroblasts underwent phenotypic transitions, particularly from inflammation-associated fibroblasts (IFBs) to myofibroblasts (MFBs). Similarly, macrophage phenotypic transformation may also play a role in OKC carcinogenesis. Clinical observations of severe lesion-area pain in COKC patients suggest potential neuroinvasiveness, Supported by single-cell transcriptomic data, imaging findings, and histopathological evidence. A review of clinical data revealed that none of the COKC patients exhibited cervical lymph node metastasis. Single-cell transcriptomics suggests that this phenomenon may be associated with an active immune microenvironment in COKC, reduced epithelial-mesenchymal transition (EMT) activity, lower VEGFC expression, and upregulated MAST4 expression as a potential regulator of lymphatic metastasis. In conclusion, COKC exhibits distinct molecular, cellular, and clinical characteristics compared to OKC, featuring potent neuroinvasiveness and low lymph node metastatic potential. These findings provide important insights into the mechanisms underlying COKC development and may guide novel diagnostic and therapeutic strategies. Show less
Coronary heart disease (CHD) has a significant co-morbid association with chronic kidney disease (CKD), but identification tools for the risk of concomitant CKD in patients with CHD are still lacking. Show more
Coronary heart disease (CHD) has a significant co-morbid association with chronic kidney disease (CKD), but identification tools for the risk of concomitant CKD in patients with CHD are still lacking. The purpose of this research was to construct machine learning (ML) models for identifying undetected CKD in CHD patients. 1786 CHD patients undergoing coronary intervention were retrospectively included. Lasso regression and multifactor logistic regression were used to screen feature variables. Five ML models, ie, logistic regression (LR), support vector machine (SVM), random forest (RF), gradient boosting machine (GBM), and extreme gradient boosting (XGBoost), were constructed. Participants were divided into the training set and validation set in a 7:3 ratio. The evaluation metrics included the area under the curve, calibration curve, and decision curve. Totally, 1786 CHD patients were enrolled and split into training (70%) and validation (30%) sets. The prevalence of CKD was 21.8% (390/1786). Multivariate logistic regression analysis showed that men, advanced age, hypertension, diabetes mellitus, history of atrial fibrillation (AF), high Gensini, low hemoglobin, low plateletcrit (PCT), high triglycerides (TG), high lipoprotein(a) (Lp(a)), hyperkalemia, high uric acid to albumin ratio (UAR), high systemic inflammation response index (SIRI), low lymphocyte to monocyte ratio (LMR), and high apolipoprotein B to apolipoprotein A1 (ApoB/ApoA1) ratio were the key clinical and laboratory test indicatorsΒ of CKD. The XGBoost model performed optimally in the validation set (AUC=0.909, 95% CI 0.881 -0.937). SHapley Additive explanation analysis identified UAR, hypertension, Gensini score, age, and SIRI as the top 5 key features. The XGBoost model constructed on routine clinical data was effective in identifying CKD risk in CHD patients, with UAR as a novel strong predictor. Decision curve analysis confirmed the clinical utility of the model, indicating that it may be used to guide decisions for enhanced monitoring and early intervention over a wide range of risk thresholds. Show less
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANG Show more
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less
Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study ai Show more
The early, precise, and safe management of vulnerable atherosclerotic plaques (VAPs) remains a formidable clinical challenge. Here, we present a targeted nanotherapeutic approach in which osteopontin- Show more
The early, precise, and safe management of vulnerable atherosclerotic plaques (VAPs) remains a formidable clinical challenge. Here, we present a targeted nanotherapeutic approach in which osteopontin-targeted nanoparticles encapsulate luteolin (NPs-Lut) for the precise delivery and treatment of VAPs. This engineered system enables site-specific accumulation and sustained release of luteolin at plaque sites. We innovatively constructed an osteopontin-targeted drug delivery system designed for vulnerable atherosclerotic plaques, in which luteolin and atorvastatin were successfully encapsulated. The system demonstrated sustained-release capability in vitro, and its biosafety and histocompatibility were comprehensively evaluated both in vitro and in vivo. Moreover, therapeutic efficacy was further assessed in ApoE In vivo evaluation in ApoE This work provides a robust and translationally promising nanoplatform for the precision treatment of VAPs, offering a novel strategy for safe and effective intervention in atherosclerotic cardiovascular disease. Show less
As a chronic lipid driven arterial disease, dyslipidemia is one of the most critical risk factors for atherosclerosis (AS). The gut microbiota plays an important role in regulating host lipid metaboli Show more
As a chronic lipid driven arterial disease, dyslipidemia is one of the most critical risk factors for atherosclerosis (AS). The gut microbiota plays an important role in regulating host lipid metabolism disorders. Studies have shown that the herb "Gualou-Xiebai" (GLXB) can effectively regulate the blood lipid levels of ApoE Show less
Atherosclerosis is a primary contributor to worldwide morbidity and mortality. Failure to timely clear apoptotic cells can trigger a cascade reaction, where the necrotic core expands until the fibrous Show more
Atherosclerosis is a primary contributor to worldwide morbidity and mortality. Failure to timely clear apoptotic cells can trigger a cascade reaction, where the necrotic core expands until the fibrous cap is ruptured, and atherosclerotic plaques become vulnerable. Efferocytosis is an important method for recognizing and eliminating apoptotic cells. Nevertheless, the specific effect of efferocytosis on atherosclerosis remains uncertain. This study aimed to identify and verify the relevant characteristics of efferocytosis for detecting atherosclerosis. The data of gene expression patterns of atherosclerosis were sourced from the Gene Expression Omnibus (GEO) database, and the differential expression analyses of efferocytosis-related genes (EFRGs) were performed between the atherosclerosis samples and the control samples. Subsequently, protein-protein interaction (PPI), correlation analysis, and functional enrichment analysis were performed to reveal the interaction between molecules as well as their pathways. Machine learning (ML) was employed to determine hub genes to construct a clinical prediction model. At the same time, immune infiltration, single-cell transcriptome analysis, and cell experiments were conducted in both atherosclerosis and control samples to provide a reference for the immune cell landscape and the cell heterogeneity under this condition. The study revealed that 14 genes were closely related to efferocytosis in atherosclerosis. Among them, an ML model was used to screen 5 potential diagnostic biomarkers, including tumor necrosis factor (TNF), apolipoprotein E (ApoE), neutrophil cytosolic factor 1 (NCF1), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3 like-protein-1 (CHI3L1). Subsequent external validation indicated that, except for TNF, the other 4 genes were all upregulated. From the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, those 5 genes were all significantly associated with various immune cells. Further single-cell RNA sequencing (scRNA-seq) analysis demonstrated that those 5 genes were selectively upregulated in the macrophages of atherosclerosis lesions, which was supported by mRNA levels in cell experiments. This study clarified the association between atherosclerosis and efferocytosis, and established an effective diagnostic model. Moreover, potential treatment targets for atherosclerosis were identified, offering new insights into the potential mechanism of atherosclerosis. Show less
Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molec Show more
Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molecular scaffolds coordinating these processes remain incompletely defined. Here, we identify neurofibromin 2 (Nf2) as a critical regulator to direct CNC-derived skull morphogenesis. Genetic ablation of Nf2 in murine CNCs causes severe craniofacial anomalies, featuring declined proliferation and increased apoptosis in osteoprogenitors, impaired type I collagen biosynthesis and trafficking, and aberrant osteogenic mineralization. Mechanistically, we uncover that Nf2 serves as a molecular linker that individually interacts with FGF receptor 1 (FGFR1) and Akt through spatially segregated phosphor-sites, and structural modeling and mutagenesis identified Ser10 and Thr230 as essential residues, with Thr230 mutation selectively ablating Akt binding while preserving FGFR1 association. Strikingly, Akt inhibition phenocopied Nf2 deficiency, reducing collagen production and Nf2 phosphorylation, whereas phospho-mimetic Nf2 (T230D) rescued CNC-derived osteogenic defects in Nf2-mutant animals. Our findings underscore the physiological significance of Nf2 as a phosphorylation-operated scaffold licensing the FGFR1/AKT axis to regulate collagen type I biogenesis and trafficking, ensuring normal CNC-derived osteogenesis and craniofacial bone development, thus exposing the Nf2/FGFR1/AKT signaling axis as a therapeutic target and promising advancements in treatment of craniofacial anomalies. Show less
Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Show more
Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Fritillariae Thunbergii Bulbus, Leonuri Herba, and Forsythiae Fructus, has shown efficacy in treating cardiovascular diseases, although its mechanisms are unclear. This study aimed to explore the protective effects of QRSJF against atherosclerosis and the mechanisms involved. The composition of QRSJF was analyzed using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. An 8-week high-fat diet (HFD)-induced atherosclerosis model was established in ApoE Both low- and high-dose QRSJF effectively attenuated dyslipidemia and decreased serum inflammatory cytokine levels in HFD-fed ApoE QRSJF improves dyslipidemia and reduces atherosclerotic plaque in ApoE Show less
Cellular senescence is a hallmark for cancers, particularly in lung adenocarcinoma (LUAD). This study developed a risk model using senescence signature genes for LUAD patients. Based on the RNA-seq, c Show more
Cellular senescence is a hallmark for cancers, particularly in lung adenocarcinoma (LUAD). This study developed a risk model using senescence signature genes for LUAD patients. Based on the RNA-seq, clinical information and mutation data of LUAD patients collected from the TCGA and GEO database, we obtained 102 endotheliocyte senescence-related genes. The "ConsensusClusterPlus" R package was employed for unsupervised cluster analysis, and the "limma" was used for the differentially expressed gene (DEG) analysis. A prognosis model was created by univariate and multivariate Cox regression analysis combined with Lasso regression utilizing the "survival" and "glmnet" packages. KM survival and receiver operator characteristic curve analyses were conducted applying the "survival" and "timeROC" packages. "MCPcounter" package was used for immune infiltration analysis. Immunotherapy response analysis was performed based on the IMvigor210 and GSE78220 cohort, and drug sensitivity was predicted by the "pRRophetic" package. Cell invasion and migration were tested by carrying out Transwell and wound healing assays. According to the results, a total of 32 genes related to endotheliocyte senescence were screened to assign patients into C1 and C2 subtypes. The C2 subtype showed a significantly worse prognosis and an overall higher somatic mutation frequency, which was associated with increased activation of cancer pathways, including Myc_targets2 and angiogenesis. Then, based on the DEGs between the two subtypes, we constructed a five-gene RiskScore model with a strong classification effectiveness for short- and long-term OS prediction. High- and low-risk groups of LUAD patients were classified by the RiskScore. High-risk patients, characterized by lower immune infiltration, had poorer outcomes in both training and validation datasets. The RiskScore was associated with the immunotherapy response in LUAD. Finally, we found that potential drugs such as Cisplatin can benefit high-risk LUAD patients. In-vitro experiments demonstrated that silencing of Angiopoietin-like 4 (ANGPTL4), Gap Junction Protein Beta 3 (GJB3), Family with sequence similarity 83-member A (FAM83A), and Anillin (ANLN) reduced the number of invasive cells and the wound healing rate, while silencing of solute carrier family 34 member 2 (SLC34A2) had the opposite effect. This study, collectively speaking, developed a prognosis model with senescence signature genes to facilitate the diagnosis and treatment of LUAD. Show less
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate Show more
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Lung adenocarcinoma (LUAD) is a major cause of cancer-related morbidity and mortality globally, with challenges in prognosis and treatment due to its complex pathogenesis and heterogeneous tumor micro Show more
Lung adenocarcinoma (LUAD) is a major cause of cancer-related morbidity and mortality globally, with challenges in prognosis and treatment due to its complex pathogenesis and heterogeneous tumor microenvironment (TME). Neutrophil extracellular traps (NETs) and oxidative stress play critical roles in tumor progression: NETs promote tumor cell adhesion, migration, and immune suppression, while oxidative stress induces DNA damage and activates pro-tumor signaling pathways. Moreover, oxidative stress is an important inducer of NETs, and their crosstalk shapes the LUAD immune microenvironment. However, systematic exploration of LUAD immunotherapeutic response prediction based on NETs and oxidative stress-related genes remains lacking. The gene set related to oxidative stress was obtained from MSigDB. The gene set related to NETs was sourced from relevant literature. Transcriptomic and clinical data were integrated from The Cancer Genome Atlas (TCGA)-LUAD (training set) and GSE31210 (validation set). Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to screen gene modules and characteristic scores related to NETs and oxidative stress signatures. Differentially expressed genes (DEGs) were screened, and prognostic model was established using univariate and LASSO Cox regression. Immune infiltration was analyzed using ESTIMATE algorithm, MCP-counter and ssGSEA methods. And we developed a nomogram incorporating clinicopathological features and RiskScore model, and performed drug sensitivity analysis. Finally, the biological role of CPS1 in lung cancer cells was investigated through CCK-8, wound-healing, and Transwell experiments. 22 co-expression modules were screened, among which the brown module showed significant correlations with NETs and oxidative stress signature scores. This module was intersected with DEGs, yielding 624 overlapping genes implicated in immune-relevant pathways (like leukocyte differentiation, neutrophil activation involved in immune response). A prognostic model was established utilizing 8 key genes (ADGRE3, ARHGEF3, CD79A, CLEC7A, CPS1, EPHB2, LARGE2, and OAS3). In the TCGA database, the model demonstrated robust prognostic discrimination (area under the curve (AUC)β>β0.6), with high-risk patients exhibiting shorter overall survival (OS) (pβ<β0.05). Its stability was validated in GSE31210 (AUCβ>β0.6). The RiskScore showed negative correlations with immune infiltration (like T cells, CD8 T cells, and natural killer cells) as well as immune/stromal scores. A nomogram model combining RiskScore with N staging was developed and validated, demonstrating strong predictive accuracy through calibration and decision curve analyses. High-risk patients were more sensitive to drugs like BI-2536, BMS-509744, and Pyrimethamine. Finally, in vitro tests showed that CPS1 knockdown markedly decreased the viability, migration, and invasion of lung cancer cells. The constructed prognostic model by NETs and oxidative stress-relevant genes effectively predicts LUAD prognosis, correlates with immune microenvironment characteristics, and guides drug sensitivity, providing novel insights for LUAD prognostic assessment and personalized therapy. Show less