Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progressi Show more
Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the SNP rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC. Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of the epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients. Show less
The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new ch Show more
The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new chicken 7TM receptor (Ch-7TM) was discovered in mononuclear phagocytes (MNPs) derived from chicken peripheral blood mononuclear cells (PBMCs). To explore the functions of Ch-7TM, RNA interference (RNAi) was used to silence the Ch-7TM messenger RNA (mRNA) of MNPs, using small interfering RNA (siRNA) designed with BLOCK-iT™ RNAi Designer. Herein we demonstrated that silencing of the Ch-7TM mRNA induced apoptosis of MNPs, suggesting that Ch-7TM contributed to the survival of MNPs. Moreover, chicken sera could inhibit the Ch-7TM-silencing-induced apoptosis in MNPs. The survival factor presented in fraction 16 (F16) of chicken sera was highly protective against the Ch-7TM-silencing-induced apoptosis in MNPs. The proteins from F16 were identified as vitamin D-binding protein (DBP) and apolipoprotein A-IV (ApoA-IV), which might be potential candidates for survival factors. The protective effect of vitamin D and ApoA-IV indicated that Ch-7TM might involve the intracellular oxidation-reduction balance, although more evidence is needed to confirm this function. The siRNA screening serves as an excellent model for studying the functions of chicken MNPs receptors. Show less
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu Show more
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu and Angus is a prevalent method for achieving a better marbling level. However, the molecular mechanisms governing IMF regulation in these crossbreeds remain poorly understood. To elucidate the mechanism of IMF deposition in these crossbred cattle, we conducted a comparative transcriptomic analysis of Show less
Lipopolysaccharide (LPS) from gram-negative bacteria initially induces the pro-inflammatory cytokines storm and causes inflammatory cascade responses. However, the LPS with higher dosage induced duode Show more
Lipopolysaccharide (LPS) from gram-negative bacteria initially induces the pro-inflammatory cytokines storm and causes inflammatory cascade responses. However, the LPS with higher dosage induced duodenal, cecal, hepatic, and cardiac inflammation remains elusive. Specific pathogen-free chicken embryos (n = 72) were allocated to the control, LPS groups (10 μg, 24 μg, 50 μg, 100 μg, 170 μg/egg, respectively). Fifteen day old embryonated eggs were injected abovementioned solutions via the allantoic cavity by disposable syringes. On embryonic day 19, the tissues of the embryos were collected for histopathology, RNA extraction, real-time PCR, and immunohistochemistry investigation. The results demonstrated that there was inflammatory responses (heterophils infiltration or macrophages accumulation) presented in the duodena, ceca, livers, and hearts after LPS induction. The duodenal mRNA expressions of inflammatory-associated mediators (TLR4, IFNγ, IL-1β, IL-6, IL-8, MMP9, MMP3, p38, or NF-κB1) were significantly upregulated after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Duodenal immunopositivity of TLR4, MMP9, and MMP3 significantly increased following LPS induction (24 μg or 50 μg) compared to the control group. Meanwhile, the hepatic mRNA expressions of inflammatory-associated factors (IFNγ, MMP3, IL-1β, IL-10, TNFα, IL-8, or NF-κB1) significantly increased after LPS induction (10 μg, 24 μg, 50 μg, 100 μg, or 170 μg /egg) when compared with the control group, respectively. Additionally, cardiac mRNA expression of TLR4, IFNγ, IL-1β, IL-8, IL-10, MMP3, MMP9, and TNFα was significantly increased in all five LPS groups compared to the control group. Cardiac protein expressions of TLR4 or IFNγ significantly increased when compared 100 μg LPS group with the control group. Duodenal and cecal mRNA expressions of programmed cell death-related factors presented irregular. The mRNA expression of hepatic pyroptosis-associated gene AMPKα2, Beclin-1, Bcl-2, CASP1, or CASP12 after LPS induction (10 μg, 24 μg, or 50 μg/egg) increased when compared with the control group. Furthermore, the cardiac mRNA expressions of pyroptosis-related gene CASP1 and CASP12 in five LPS groups increased when compared with the control group. Cardiac autophagy-related gene Bcl-2, ATG5, or LC3B enhanced in LPS groups (10 μg, 50 μg, or 100 μg/egg) when compared with the control group, whereas LC3A, CASP1, or Drp1 mRNA expression in five LPS groups reduced when compared with the control group, respectively. The mRNA expressions of duodenal mucosal barrier function-associated mediators Claudin 1 and PEPT1 were upregulated after LPS induction (10 μg or 50 μg/egg) when compared five LPS groups with the control group, respectively; nevertheless, duodenal Mucin 2 and SGLT1 mRNA expression reduced in four groups (24 μg, 50 μg, 100 μg, or 170μg /egg) when compared with the control group, as well as cecal mRNA expressions of Mucin 2, occludin, SGLT1.The mRNA expressions of liver permeability-related gene (claudin 1 and occludin) increased in the five groups when compared with the control group, as well as cardiac permeability and energy metabolism-related gene (AMPKα2, APOA4, PPARα, SGLT, and claudin1). In conclusion, LPS can induce duodenal, hepatic and cardiac inflammation, initiate energy deficiency, autophagy, programmed cell death, enhanced intestinal mucous barrier function, tight junction, and permeability in chicken embryos. Show less
The purpose of this study is to explore the effect of physical activity on the executive function of 5-6-year-old children and to provide a theoretical and empirical basis for further research on impr Show more
The purpose of this study is to explore the effect of physical activity on the executive function of 5-6-year-old children and to provide a theoretical and empirical basis for further research on improvements in the executive function of children caused by physical activity. A total of 170 children (5-6 years old) from several kindergartens were selected via multistage stratified sampling. All the children wore 7-day accelerometers (ActiGraph GT3X) to measure their daily physical activities. Parents completed the preschool children's executive function questionnaire (BRIEF-P) to assess their daily executive function. (1) The total duration of physical activity (TPA) was 110.84 ± 22.52 min/day, the duration of low-intensity physical activity (LPA) was 36.23 ± 7.53 min/day, and the duration of medium- and high-intensity physical activity (MVPA) was 74.55 ± 16.77 min/day. A total of 82.6% of the children reached the recommended amount of MVPA. (2) After adjusting for body mass index (BMI), parents' highest educational background and parents' total monthly income, MVPA was negatively correlated with children's total executive function score ( Physical activity can improve the executive function of children aged 5-6 years to some extent. MVPA can improve children's executive function and subdomains, and there is a correlation between boys' physical activity and executive function. Show less
Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CA Show more
Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma. Show less
Growing evidence suggests that lipid metabolism may play a crucial role in mood disorder pathophysiology, and the correlation between blood lipids and mood disorder remains further clarified. This pro Show more
Growing evidence suggests that lipid metabolism may play a crucial role in mood disorder pathophysiology, and the correlation between blood lipids and mood disorder remains further clarified. This prospective, population-based cohort study utilized data from the UK Biobank. The study included 268,098 and 292,121 participants who had never been diagnosed with depression or bipolar disorder and who had complete data at both the baseline and follow-up points. A principal component analysis (PCA) was conducted on seven blood lipids, and the first three principal components (PCs) were derived. Cox regression analysis was employed to examine the correlation between the risk of mood disorders and the PCs. Multiplicative interaction and sensitivity analyses were also conducted. The relationship between blood lipids and neurological biomarkers was explored using Spearman's analysis. PC1, primarily reflecting levels of Apolipoprotein B (ApoB), cholesterol, and low-density lipoprotein cholesterol (LDL-C), showed a protective effect against depression, with HRs of 0.98 (95 % CI: 0.96,1.00) in the fully adjusted Cox regression model. In contrast, PC2, characterized by opposite loadings for triglycerides and high-density lipoprotein cholesterol (HDLC), was positively associated with the risk of depression and bipolar disorder.(HR = 1.03,95 % CI: 1.01,1.06; HR = 1.11, 95 % CI: 1.01,1.23). Increased PC2 level was related to a significant increase in bipolar disorder risk among participants with high genetic risk (genetic risk score > 90 %, HR = 1.22, 95 % CI: 1.02,1.46). Complicated correlations between blood lipids and serum neuroproteins were detected. These findings suggest complex associations between blood lipid profiles and the risk of depression and bipolar disorder. Show less
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. The E3 ubiquitin ligase WWP2 has emerged as a critical regulator of tumor pathogenesis through its modulation o Show more
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. The E3 ubiquitin ligase WWP2 has emerged as a critical regulator of tumor pathogenesis through its modulation of substrate ubiquitination. However, its specific mechanistic role in HCC remains poorly understood. In this study, we found that WWP2 was significantly up-regulated in HCC patients and associated with poor prognosis. Lentivirus-mediated knockdown of WWP2 induced cellular senescence and suppressed proliferation in HCC cell lines. Mechanistically, co-immunoprecipitation and ubiquitination assays identified WWP2 as a novel E3 ubiquitin ligase for p21 that promotes its K48-linked ubiquitination and subsequent proteasomal degradation, consequently accelerating cellular senescence and restraining HCC progression. Notably, we further discovered that CMTM6 directly interacts with WWP2, thereby stabilizing p21 by preventing its WWP2-mediated ubiquitination. Accordingly, the senescence and proliferation arrest induced by WWP2 deficiency were partially reversed by CMTM6 knockdown but enhanced by concurrent CMTM6 overexpression. This functional interplay was corroborated in vivo, as WWP2 depletion enhanced tumor cell senescence and suppressed tumor growth, an effect that was partially rescued by concurrent CMTM6 knockdown. Taken together, our findings establish the WWP2-CMTM6-p21 axis as a pivotal regulatory mechanism of cellular senescence in HCC and shed new light on senescence-related therapeutic strategies for HCC. Show less
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in medi Show more
The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in mediating immune suppression. However, the precise mechanisms underlying PMN-MDSCs infiltration into the tumor immune microenvironment (TIME) and their immunosuppressive functions remain poorly understood. In this investigation, we observed that PMN-MDSCs were up-regulated during stomach carcinogenesis, with gastric cancer (GC) cells secreting CCL26 to promote the infiltration of PMN-MDSCs into the TIME via the CX3CR1 receptor. The infiltrating CX3CR1 Show less
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less
This review aims to explore the epidemiology of lipoprotein(a) [Lp(a)] by its structural and genetic make-up variation amongst ancestry groups. Lipoprotein(a) [Lp(a)] is a genetically determined lipop Show more
This review aims to explore the epidemiology of lipoprotein(a) [Lp(a)] by its structural and genetic make-up variation amongst ancestry groups. Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle, causally implicated in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Given its genetic basis, studies have shown marked ancestry-related differences in different races and ethnicities. Lp(a) plasma concentrations vary by more than 100-fold among individuals, primarily due to LPA gene polymorphisms and the number of kringle-IV type 2 (KIV2) repeats, which define apolipoprotein(a) [apo(a)] isoform size. Individuals of African descent have the highest median concentrations, followed by South Asians, with Hispanics/Latinos and East Asians having lower levels. Admixed populations display heterogeneity reflecting genetic ancestry. Despite differences in absolute levels, the relative ASCVD risk per unit increase in Lp(a) is consistent across groups, highlighting the universal atherogenicity of elevated Lp(a). Small apo(a) isoforms are associated with higher Lp(a) concentrations and risk, though isoform size is mainly a surrogate for Lp(a) burden. Despite a strong genetic basis and disproportionate burden in some populations, ancestry-specific testing guidelines are limited and testing rates remain low. Therapies targeting LPA transcription are in development, with outcome trials underway. Integrating ancestry-informed perspectives with universal risk principles is essential for equitable prevention and treatment. Routine, one-time Lp(a) testing enables cost-effective early risk stratification as Lp(a)-directed therapies emerge. Show less
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically Show more
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically identify Cpn's therapeutic targets and pathways in Western diet (WD)-induced obesity using integrated network pharmacology, transcriptomics, and experimental validation. A Western diet (WD)-induced mice model was used to evaluate the effectiveness of Cpn in ameliorating obesity. A network pharmacology analysis was then employed to identify the potential anti-obesity targets of Cpn. GO functional enrichment and KEGG pathway analysis were performed to elucidate the potential functions of the identified targets, followed by constructing a protein-protein interaction network to screen the core targets. Meanwhile, quantitative transcriptomics was conducted to validate and broaden the network pharmacology findings. Finally, molecular docking and quantitative real-time PCR assay were used for the core target validation. Cpn treatment effectively alleviated obesity-related symptoms in WD-induced mice. The metabolic pathway, insulin signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, lipid and atherosclerosis pathway, and core targets including CPS1, HRAS, MAPK14, PAH, ALDOB, AKT1, GSK3B, HSP90AA1, BHMT2, EGFR, CASP3, MAT1A, APOM, APOA2, APOC3, and APOA1 are involved in regulating the therapeutic effect of Cpn. This study comprehensively uncovers the potential mechanism of Cpn against obesity based on network pharmacology and quantitative transcriptomics, which provides evidence for revealing the pathogenesis of obesity, suggesting that Cpn is a possible lead compound for anti-obesity treatment. Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Al Show more
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less
This study aimed to identify heterogeneous patterns of medical coping modes (MCM) and to examine the moderating role of social support in the relationship between these patterns and social disability Show more
This study aimed to identify heterogeneous patterns of medical coping modes (MCM) and to examine the moderating role of social support in the relationship between these patterns and social disability in young and middle-aged patients after percutaneous coronary intervention (PCI). A cross-sectional study was conducted among 129 post-PCI patients from a single center in China. Participants completed the Medical Coping Modes Questionnaire (MCMQ), the Social Support Rating Scale (SSRS), and the Social Disability Screening Schedule (SDSS). Latent profile analysis (LPA) was used to identify distinct coping patterns. The moderation effect of social support was tested using the Johnson-Neyman technique. Two distinct coping profiles were identified via LPA: "Adaptive Copers" (55.1%), characterized by higher confrontation and lower avoidance/resignation, and "Maladaptive Copers" (44.9%), showing the opposite pattern. A counterintuitive finding emerged, with the Maladaptive Copers reporting significantly lower social disability scores. Furthermore, beyond this profile differentiation, social support demonstrated a significant U-shaped moderating effect in the coping-disability relationship. Its moderating role was statistically significant only at very low (<39.884) and very high (>52.924) levels of support. This study reveals two key findings: first, post-PCI patients are heterogeneous in coping, comprising adaptive and maladaptive subgroups; second, the impact of these coping styles on social disability is non-linearly moderated by social support. Clinicians should assess both coping profiles and social support levels to tailor interventions effectively. Show less
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphon Show more
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphone-poses significant challenges to students' learning and daily life. Prior research on nomophobia has predominantly adopted a variable-centered perspective. However, if nomophobia is heterogeneous across subgroups, acknowledging this heterogeneity may inform the advancement of more tailored and productive therapeutic methods. Latent profile analysis (LPA) was conducted separately among high school students (N = 446) and college students (N = 667) to identify potential subgroup heterogeneity in nomophobia. To examine cross-group similarities in nomophobia profiles, a multi-group LPA was employed. Based on multiple model fit criteria, a three-profile solution-high nomophobia, moderate nomophobia, and low nomophobia-was identified for both groups. However, the multi-group LPA provided only partial support for the similarity of nomophobia profiles across educational stages, specifically in terms of configural and dispersion similarity. While similar nomophobia profiles emerged across groups, the partial equivalence suggests that intervention strategies for nomophobia may not be universally applicable across different educational levels. Additional studies should investigate the mechanisms underlying students' nomophobia profiles and to inform differentiated interventions for educators, institutions, and policymakers. Show less
Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biol Show more
Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biological functions of Leiomodin 1 (LMOD1) and its behind mechanisms against breast cancer. The common DEGs (co-DEGs) between the GSE22820 and GSE29431 data sets and pivotal genes were screened out using bioinformatics methods. The biological roles of LMOD1 overexpression on malignant phenotypes were validated by functional assays and the impact on fatty acid synthesis was also elucidated in breast cancer cell lines. Additionally, colivelin, a STAT3 activator, was applied for further investigating the role of LMOD1 on the JAK2/STAT3 pathway in vitro. A total of 208 co-DEGs and 5 focal genes were screened through bioinformatics analysis, and 5 focal genes were downregulated in breast cancer cell lines. LMOD1 overexpression retarded proliferative, migratory, invasive capabilities of breast cancer cells. LMOD1 overexpression suppressed fatty acid synthesis. Furthermore, the inhibitory effects on malignant phenotypes of breast cancer cells with LMOD1 overexpression were partially abolished after colivelin treatment. Additionally, LMOD1 could impede fatty acid synthesis in breast cancer cells. Our study highlighted LMOD1 exerted as a tumor-suppressive role in breast cancer, which was correlated with restraining the JAK2/STAT3 pathway activation. Show less
Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been Show more
Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case-control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power. The trans-ancestral meta-analysis with PDFF and MASLD case-control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence. Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks. 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
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contr Show more
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contributing to stroke remains poorly understood. This study aims to investigate the association between the apoB/apoA1 ratio and intracranial or extracranial atherosclerosis. We enrolled 408 patients with acute ischemic stroke who had never been treated with statins or fibrates. Based on the images from computed tomography angiography (CTA), the patients were categorized into four groups: intracranial atherosclerosis stenosis (ICAS, n = 136), extracranial carotid atherosclerosis stenosis (ECAS, n = 45), combined intracranial and extracranial atherosclerosis stenosis (COAS, n = 73), and non-cerebral atherosclerosis stenosis (NCAS, n = 154). Demographic characteristics, clinical factors, and serum lipid levels were collected and then compared across groups. The apoB/apoA1 ratio was significantly higher in patients with ICAS, ECAS and COAS compared to those in the NCAS group. Multivariable logistic regression analysis demonstrated that the ApoB/ApoA1 ratio was independently associated with ICAS, but not with ECAS. ROC curve analysis showed that the ApoB/ApoA1 ratio had a good diagnostic ability for ICAS, with an area under the curve (AUC) of 0.764, an optimal cut-off value of 0.8122, a sensitivity of 81.3%, and a specificity of 59.8%. An higher apoB/apoA1 ratio is associated with ICAS in ischemic stroke patients. 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
Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (G Show more
Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (GWASs), the GWAS Catalog, MEGASTROKE, and Open GWAS, to identify novel genetic loci linked to IS. Our meta-analysis revealed 124 new IS-associated loci, with enrichment in genes involved in cerebrovascular function, inflammation, and metabolism. Candidate genes like Show less
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive Show more
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive of its therapeutic potential against T2DM. In this study, we evaluated the protective effects of KA against apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (LDL) (AC3RL)-induced β-cell apoptosis and its underlying mechanism of action. ApoE Show less
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining Show more
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF. Show less
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted Show more
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less