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
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
Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse ca Show more
Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse causality. Furthermore, the underlying mediating factors and potential therapeutic targets underlying this association are poorly understood. This study aimed to investigate the causal effect of visceral adipose tissue (VAT) on asthma risk, identify potential mediators, and quantify their effects using a Mendelian randomization (MR) framework. In this study, we employed MR approach to elucidate the impact of VAT on asthma and to assess the potential mediators. Subsequently, the association between seven lipid-lowering medication targets and asthma risk was investigated using the drug target MR method. Lastly, we conducted an observational study involving 12,120 participants to evaluate the relationship between visceral adiposity index (VAI) and asthma. The univariable MR analysis demonstrated that each standard deviation increase in genetically predicted VAT was associated with a 46 % higher risk of asthma (IVW: OR = 1.460, 95 % CI: 1.351-1.578, p = 1.471E-21). This association remained significant after adjusting for BMI in multivariable MR (OR = 1.137, 95 % CI: 1.023-1.262, p = 0.017). Mediation analysis revealed that HDL-C accounted for 4.3 % of this effect (OR = 1.016, 95 % CI: 1.001-1.033, p = 0.038). Drug-target MR indicated that activation of HMGCR and LDLR reduced asthma risk (OR = 0.846 and 0.866, respectively; both p < 0.01), whereas LPL activation increased risk (OR = 1.080, p = 0.015). Observational analysis of NHANES data (n = 12,120) confirmed that higher VAI was associated with increased asthma prevalence (OR = 1.290, 95 % CI: 1.101-1.479, p = 0.010). Our results reveal a significant association between increased visceral adipose tissue and elevated risk of asthma, which is partially mediated by high-density lipoprotein cholesterol. 3-hydroxy-3-methylglutaryl coenzyme A reductase, low-density lipoprotein receptor, and lipoprotein lipase exhibit potential as therapeutic targets for asthma. 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
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchang Show more
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchange of cholesterol (C) from HDL to ApoB-containing lipoproteins. CETP inhibition increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C) while modestly decreasing TG. Considering that CETP inhibitors block removal of TG from TG-rich lipoproteins (TRL), it is interesting that CETP inhibition decreases TG concentrations. TG levels are largely regulated by lipoprotein lipase (LPL), the enzyme primarily responsible for hydrolyzing TG. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating LPL inhibitor, while the TG-lowering apolipoprotein A5 (ApoA5) acts by suppressing ANGPTL3/8-mediated LPL inhibition. To better understand CETP biology, we studied the effects of CETP overexpression and CETP inhibition on the levels of ANGPTL3/8 and ApoA5 in circulation using dedicated immunoassays. CETP-overexpressing transgenic mice had increased TG and normal ANGPTL3/8 levels but manifested dramatically reduced ApoA5 concentrations. Administration of the CETP inhibitor evacetrapib had no effect on ANGPTL3/8 levels in CETP-overexpressing mice or in humans. However, evacetrapib administration increased ApoA5 concentrations in both species. In human subjects, evacetrapib treatment increased circulating ApoA5 levels in the late-stage ACCELERATE and ACCENTUATE studies by 160.1% and 204.7%, respectively. Our results uncover a previously unrecognized link between CETP and ApoA5 by showing that CETP overexpression reduces ApoA5 levels while CETP inhibition increases ApoA5 concentrations. Show less
In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, interleukin (IL)-27 stimulates interferon γ (IFNγ) production by CD4 and CD8 T cells and is essential for disease development. Here, Show more
In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, interleukin (IL)-27 stimulates interferon γ (IFNγ) production by CD4 and CD8 T cells and is essential for disease development. Here, we tested the role of IL-27 in cellular communication. Single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21 Show less
Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide assoc Show more
Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our gen Show more
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less
High-intensity exercise promotes visceral adipose tissue (VAT) breakdown in females via the hypothalamic ERα pathway, and exogenous lactate infusion combined with aerobic training (AT) mimics this eff Show more
High-intensity exercise promotes visceral adipose tissue (VAT) breakdown in females via the hypothalamic ERα pathway, and exogenous lactate infusion combined with aerobic training (AT) mimics this effect. However, whether lactate administration can independently mediate hypothalamic plasticity and VAT catabolism as a standalone nutritional strategy remains unexplored. Firstly, using a two-factor design (Lactate × AT) in female SD rats, we showed that long-term exogenous lactate infusion independently induced co-expression of Estrogen receptor α (ERα) and Brain-derived neurotrophic factor (BDNF) in the ventromedial hypothalamus (VMH) and elevated local field potential spectral power in specific bands. These neural adaptations were accompanied by increased resting metabolic rate, enhanced fat oxidation, and enhanced lipolysis, thereby preventing excessive VAT accumulation induced by a high-fat diet. Furthermore, pharmacological inhibition confirmed that Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α (PGC-1α) acts as a co-upstream signal of ERα and BDNF mediating this process. Our findings reveal that standalone lactate administration induces functional plasticity and metabolic reprogramming through the VMH PGC-1α-ERα pathway, independent of exercise, and effectively suppresses pathological VAT accumulation in female rats. This study identifies potential nutritional interventions and mechanistic targets for preventing female-centered obesity. 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
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
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
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether c Show more
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether causal relationships exist among these associations remains unclear, as traditional observational studies are susceptible to confounding factors. To evaluate causal relationships between kidney cancer, kidney fibrosis, and inflammatory factors using Mendelian randomization, and explore tumor microenvironment heterogeneity through single-cell analysis. Based on large-scale GWAS data, bidirectional Mendelian randomization analysis was performed to assess causal relationships between kidney cancer and kidney fibrosis, using MR Egger, inverse variance weighted (IVW), and weighted mode methods. Causal associations between kidney cancer and inflammatory factors including Axin-1, C-C motif chemokine 28, and interleukin-10 receptor subunit were analyzed. Single-cell RNA sequencing data from the GEO database (GSM4819725) was integrated for tumor microenvironment analysis. Bidirectional Mendelian randomization analysis revealed no significant causal relationship between kidney cancer and kidney fibrosis [kidney cancer→kidney fibrosis: IVW OR=0.992(95%CI: 0.913-1.077, P=0.842); kidney fibrosis→kidney cancer: IVW OR=0.922(95%CI: 0.824-1.030, P=0.151)]. However, significant positive causal associations were identified between kidney cancer and multiple inflammatory factors: Axin-1 levels [OR=1.448(95%CI: 1.107-1.894, P=0.007)], C-C motif chemokine 28 [OR=1.287(95%CI: 1.076-1.540, P=0.006)], and interleukin-10 receptor subunit [OR=1.135(95%CI: 1.032-1.248, P=0.009)]. Sensitivity analyses confirmed the robustness of results. Single-cell analysis revealed cellular heterogeneity in the tumor microenvironment, including various cell types such as immune cells, T cells, and NK cells, with pseudotime analysis demonstrating cell differentiation trajectories and dynamic gene expression changes. Mendelian randomization analysis provides genetic evidence for causal relationships between kidney cancer and inflammatory factors, while excluding direct causal associations between kidney cancer and kidney fibrosis. 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
Dysregulated fibroblast growth factor receptor (FGFR) signaling - driven by amplifications, mutations, or fusions - represents a clinically validated oncogenic driver across diverse malignancies. Pan- Show more
Dysregulated fibroblast growth factor receptor (FGFR) signaling - driven by amplifications, mutations, or fusions - represents a clinically validated oncogenic driver across diverse malignancies. Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice. However, their therapeutic efficacy is substantially limited by inevitable on-target resistance mutations and toxicities via FGFR1/4 inhibition. Next-generation FGFR isoform-selective small-molecule inhibitors are emerging and represent active research frontiers. FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed 'c' isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes re Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes remains unclear. This study aims to examine the associations of physical activity with the risk of liver cirrhosis, cancer, cardiovascular disease (CVD) incidence and mortality. 32 681 MASLD participants with accelerometer-derived physical activity data from the UK Biobank were analysed. Physical activity intensity was categorised into light (LPA), moderate (MPA) and vigorous (VPA) intensity. Cox proportional hazard and acceleration failure models were employed to assess associations between physical activity duration and outcomes. During a median follow-up of 7.5-7.9 years, 1883 deaths, 151 liver cirrhosis, 3312 cancers and 6657 CVD events were recorded. Physical activity, regardless of intensity, was consistently associated with a reduced risk of liver cirrhosis, CVD and all-cause mortality. Compared with non-MASLD individuals, our analysis indicates that longer duration of physical activity, specifically >1945 min/week of LPA or >383 min/week of MPA may theoretically eliminate the excess risk of mortality associated with MASLD. Among MASLD individuals, longer physical activity duration, regardless of intensity, was associated with reduced risks of liver cirrhosis and mortality. MPA and VPA were associated with lower CVD risk, while VPA was associated with reduced cancer risk, highlighting the potential benefits of increasing the intensity and duration of physical activity in MASLD management. 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
For workers in the industry, occupational exposure to indium compounds induces pulmonary disorders, such as interstitial pneumonia. Moreover, lung cancer has been reported in both humans and rodents e Show more
For workers in the industry, occupational exposure to indium compounds induces pulmonary disorders, such as interstitial pneumonia. Moreover, lung cancer has been reported in both humans and rodents exposed to indium compounds by inhalation. However, the biological mechanism underlying indium-induced disorders is poorly understood. Epithelial-mesenchymal transition (EMT)-the cellular process of losing epithelial and acquiring mesenchymal characteristics-is linked to fibrosis and cancer progression. Therefore, we examined whether indium exposure elicits EMT in vitro. A549 human alveolar epithelial cells treated with indium chloride at doses of 0-500 μg/mL for 24 h were used to analyze EMT marker expression and cytoarchitecture. Significant downregulation of CDH1 mRNA expression as an epithelial marker after treatments at 125, 250, and 500 μg/mL occurred dose-dependently; conversely, the mesenchymal marker SNAI1 was upregulated. Consistent with mRNAs, the expression levels of EMT marker proteins (i.e., E-cadherin, ZO1, SNAIL, and Vimentin) were changed significantly by treatment. While NF-κB signaling was activated in treated cells, indium-dependent changes of CDH1 and SNAI1 mRNA expression were not affected by BAY 11-7082, an NF-κB inhibitor, suggesting that NF-κB activation may be dispensable for indium-induced EMT. Fibroblast-like morphological characteristics, such as actin stress fiber formation and cell elongation, along with deconstruction of cell-cell adhesion complexes, were observed in treated cells. Overall, our study is the first to demonstrate that EMT is caused by indium compounds. This will contribute biologically to understanding the mechanism of EMT induction and clinically to unveiling the pathophysiology of indium lung disease. 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 balance between adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for maintaining bone homeostasis. This study aimed to investigate the role of r Show more
The balance between adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for maintaining bone homeostasis. This study aimed to investigate the role of retinoid-related orphan receptor α (RORα) in the adipogenic differentiation of BMSCs. Stable BMSC lines with RORα overexpression or knockdown were established. Adipogenic differentiation was evaluated using Oil Red O staining and by measuring the expression of adipogenic markers, including PPARγ2, LPL, LEP, FABP4, and ADIPOQ. Treatment with the RORα inhibitor SR3335 significantly promoted adipogenic differentiation, whereas the RORα agonist SR1078 exerted the opposite effect. Similarly, RORα-overexpressing (OE-RORα) BMSCs showed reduced adipogenic differentiation, while RORα knockdown BMSCs exhibited enhanced differentiation at 14 days after induction. During adipogenesis, PPARγ2 expression increased significantly, peaking at day 6 before gradually declining. Overexpression and knockdown of RORα accentuated this downregulation and upregulation, respectively, at days 6 and 12. The adipogenic marker genes lipoprotein lipase (LPL), leptin (LEP), fatty acid binding protein 4 (FABP4), and adiponectin C1Q and collagen domain containing (ADIPOQ) were markedly downregulated in RORα-overexpressing BMSCs at day 12. Moreover, RORα overexpression enhanced β-catenin nuclear translocation at day 1 post-induction and upregulated downstream WNT/β-catenin signaling molecules (Axin2, c-Myc, CD44) at day 6. Inhibition of WNT/β-catenin signaling with XAV-939 effectively reversed the suppressive effect of RORα overexpression on adipogenic differentiation and restored the expression of adipogenesis-related genes. RORα suppresses adipogenic differentiation of BMSCs, at least in part, by activating WNT/β-catenin signaling. Show less
Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, Show more
Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies. 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
Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcript Show more
Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcriptomics profile and promising biomarkers for asthma severity prediction. In discovery cohort, induced sputum cells from 3 non-severe and 3 severe asthma patients were collected and analyzed using RNA-seq. Multivariate analysis was performed to explore asthma severity-associated transcriptomics profile and differential expressed genes (DEGs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used for pathway enrichment analysis. Subsequently, based on the previous study and clinical experience, the mRNA expressions of 6 overlapped asthma severity-associated DEGs and Distinct asthma severity-associated transcriptomics profile was identified in induced sputum cells in discovery cohort. Then, 345 DEGs were found, of which 38 terms and 32 pathways were enriched using GO and KEGG, respectively. In validation cohort, the mRNA expressions of Collectively, this study provides the first identification of the association between induced sputum cells transcriptomics profile and asthma severity, indicating the potential value of transcriptomics for asthma management. The study also reveals the promising value of serum C3 for predicting asthma severity in clinical practice. Show less
Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, Show more
Hypertrophic cardiomyopathy (HCM), characterized by ventricular hypertrophy and fibrosis, frequently progresses to heart failure. Although metabolic dysregulation is implicated in HCM pathophysiology, the role of PDK4 (pyruvate dehydrogenase kinase 4), a key regulator of cardiac glucose and fatty acid oxidation, in HCM-related heart failure remains unknown. Single-nucleus RNA sequencing was performed to analyze gene expression in patients with HCM (n=12), categorized into the following groups: normal, reduced, and heart failure. We validated our findings in additional cohorts of patients undergoing septal resection or heart transplantation. Cardiac-specific Single-nucleus RNA sequencing identified distinct cardiomyocyte clusters, with cardiomyocyte cluster 4 ( Our findings highlight metabolic disturbance, specifically PDK4-driven suppression of glucose oxidation, as crucial in HCM progression to heart failure. PDK4 represents a promising therapeutic target for preventing or treating heart failure in patients with HCM. 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