👤 Feng Gao

Postoperative symptoms in lung cancer patients are complex and dynamic, yet recovery is highly heterogeneous. Traditional analyses often fail to capture individual recovery trajectories, limiting the ability to provide personalized care. This study aimed to identify distinct postoperative symptom trajectories and their clinical predictors using a person-centered approach. We conducted a prospective longitudinal study with 394 patients undergoing uniportal video-assisted thoracoscopic surgery (uniportal VATS) for early-stage non-small cell lung cancer. Patient-reported symptoms were collected at 1, 7, 14, and 30 days postoperatively. Latent Profile Analysis (LPA) was used to identify distinct symptom profiles, and Latent Transition Analysis (LTA) modeled the transitions between these profiles over time. Multinomial logistic regression was used to identify predictors of these transitions. LPA identified two distinct recovery profiles: a "Rapid Recovery" group (C1) and a "High-Symptom, Slow Recovery" group (C2). The first postoperative week was a critical window, with 73.0% of patients in the High-Symptom, Slow Recovery group transitioning to the Rapid Recovery group. This transition rate slowed significantly in subsequent weeks. A higher ASA classification, use of a thicker chest tube, and extensive lymph node dissection predicted a slower recovery. Conversely, better pulmonary function (FEV1%, MVV%) facilitated a faster transition, while postoperative complications were associated with a negative trajectory shift. Postoperative recovery in lung cancer patients follows predictable, heterogeneous trajectories. This person-centered approach enables the early identification of high-risk patients based on preoperative and surgical factors. Understanding these distinct pathways allows for a shift from a one-size-fits-all model to staged, personalized interventions designed to optimize symptom management and enhance patient recovery. Show less

Preschool children's activity patterns differ between weekdays and weekends. Weekdays are constrained by structured educational activities and parental commitments, which limit flexibility, while weekends provide opportunities for extra sleep (SLP), physical activity (PA), and reduced sedentary behavior (SB). This study aims to estimate optimal activity durations for both weekdays and weekends, based on the development of executive function (EF), fundamental movement skills (FMS), and physical fitness (PF) in preschool children. A total of 289 preschool children aged 3-6 years from four kindergartens in Zhejiang Province participated. PA and SLP were objectively measured using accelerometers and the Children's Sleep Quality Questionnaire. EF, which includes working memory, inhibitory control, and cognitive flexibility, was measured using the Early Years Toolbox (EYT). FMS were assessed using the test of gross motor development-3rd edition (TGMD-3), and PF was evaluated according to the National Physical Fitness Measurement Manual (Preschool Children Section). Compositional data regression models were applied to examine the relationship between 24-h movement behaviors and health outcomes on weekdays and weekends. Optimal time-use compositions for each outcome were estimated, and 3D quaternary plots were generated to define the Goldilocks Day at the center of the overlapping regions. 24-h movement behaviors were significantly correlated with EF (weekdays: F = 5.4, This study provides recommendations for time allocation on weekdays and weekends to support the healthy development of preschool children. Show less

Extensive research has documented a high comorbidity prevalence between depression and Internet gaming disorder (IGD). However, the distinct comorbidity patterns in adolescents have not been thoroughly investigated. Additionally, the longitudinal dynamics of these comorbidity patterns over time and the specific factors that may drive these transitions remain poorly understood. A total of 3,296 adolescents (1,501 boys; age baseline: 15.17 [1.44] years) were included in the current study. Latent profile analysis (LPA) was used to identify optimal comorbidity patterns of depression and IGD, while random intercept latent transition analysis (RI-LTA) was conducted to assess transitions in the comorbidity patterns over one and a half years and to identify factors influencing these transitions. Three patterns of comorbidity between depression and IGD symptoms were identified: no symptoms, low depression-high IGD symptoms, and high depression-low IGD symptoms. Results indicate that 72 % of individuals exhibited a stable symptom pattern trajectory. From Time 1 to Time 2, the probabilities of remaining in the three patterns were 78.3 %, 31.5 %, and 51.5 %, respectively. Findings also showed that sex, grade levels, boarding status, father's occupation as well as educational attainment, intra-week and weekend screen time, parent-child relationship, and perceived social support influenced the probabilities of transitions between comorbidity patterns in adolescents over time. Adopting targeted interventions for different comorbidity patterns and transitions, while considering specific influencing factors, provides insights into adolescent mental health dynamics and inform more effective prevention and support strategies. Show less

Prior evidence indicate that differences in treatment settings between patients with colorectal cancer (CRC) from high-poverty areas (HPA, ≥ 20% residents living under poverty level) and low-poverty areas (LPA) might have contributed to disparities in their health outcomes. We sought to determine whether certain hospitals predominantly provided surgical care for patients with CRC from HPAs and examine associated patient outcomes. We identified patients undergoing surgery for nonmetastatic CRC diagnosed during 1/1/2009-12/31/2019 from SEER-Medicare. We defined poverty-area-serving (PAS) hospitals as hospitals with ≥ 50% patients from HPAs. We compared in-hospital adverse events, 30 day readmission, and long-term mortality between patients from HPAs and LPAs treated at PAS and non-PAS hospitals using logistic and Cox regression. Our cohort included 81,992 patients with CRC (median age = 78 years, 53.8% female, 15.9% in HPAs) treated by 991 hospitals. The 180 (18.2%) PAS hospitals treated 64.2% of patients from HPAs versus 2.6% from LPAs. Compared with patients from LPAs treated at non-PAS hospitals, patients from HPAs treated at PAS hospitals had more frequent in-hospital adverse events (OR[95%CI] = 1.17[1.07-1.29]), 30-day readmission (OR[95%CI] = 1.33[1.20-1.47]), worse all-cause (HR[95%CI] = 1.16[1.10-1.22]), and cancer-specific mortality (HR[95%CI] = 1.23[1.15-1.32]). A group of PAS hospitals treated a significant proportion of patients with CRC from HPAs and few from LPAs and was associated with worse short- and long-term patient outcomes. These findings highlight the presence and negative impact of healthcare segregation by area-level poverty and systemic inequities faced by individuals from HPAs. Multilevel resources are needed to address quality of care and other healthcare-associated needs for individuals from disadvantaged areas. Show less

Older adults' social participation is associated with frailty, but the transition patterns and their relationship with frailty remain unclear. This longitudinal study aims to explore the latent classes and transition patterns of social participation in older adults with chronic non-communicable diseases and to assess their relationship with subsequent frailty. The data set from the China Health and Retirement Longitudinal Study (CHARLS) in 2018 (T1) and 2020 (T2) was analyzed, including 4793 older adults. Latent profile analyses (LPA) and latent transition analyses (LTA) were employed to identify latent classes and the transition probabilities of social participation at T1 and T2. The ANCOVA was employed to examine the frailty index at T2 was compared across transition patterns. The LPA results supported a 4-class model labeled as inactive group, voluntary group, social interaction group, and omni-engaged group. The probability of transition from the other groups to the inactive group was significant (33.3 %, 53.8 %, 54.4 %). Age, residence, marital status, and other demographic characteristics can significantly impact transition patterns. However, after controlling for baseline frailty and other covariates, transition patterns were not significantly associated with T2 frailty levels. The short-term (two-year) effect of qualitative shifts in social participation on frailty may be limited when pre-existing health status is accounted for. Future interventions should prioritize sustained engagement and investigate the longer-term effects of both qualitative and quantitative changes in social participation. Show less

Accumulating research has demonstrated a significant association between early-life inflammation and behavioral disorders later in life. However, the effects of early-life inflammation on aggressive behavior in adulthood remain poorly understood. Here, we show that early-life inflammation induced by lipopolysaccharide (LPS) upregulated neuronal dynamin-related protein 1 (DRP1) and impaired mitochondrial function in medial prefrontal cortex (mPFC) of adult mice, thereby increasing aggressive behavior in adulthood. We further identify that CCAAT/enhancer binding protein β (C/EBPβ) is the transcription factor of Dnm1l, which was activated by an increased release of lysophosphatidic acid (LPA) induced by early-life inflammation. Moreover, the overproduction of LPA was due to a specific increase in astrocyte-secreted autotaxin (ATX). Specific knockdown of astrocytic ATX reduced early-life inflammation-induced aggression in wild-type mice, but not in Thy1-C/EBPβ transgenic mice. Remarkably, coenzyme Q10 decreased early-life inflammation-induced aggressive behavior in adult mice. Altogether, these findings provide new insights into the molecular mechanisms by which early inflammation promotes aggressive behavior in adulthood. Show less

Acetyl-CoA synthetase 2 (ACSS2) is the obligatory gatekeeper for converting rumen-derived acetate into acetyl-CoA in ruminants. However, whether ACSS2 actively regulates the transcriptional networks governing lactation, beyond its catalytic role, remains unclear. This study aimed to elucidate the molecular characteristics of buffalo ACSS2 and investigate its function as a central node in the metabolic-transcriptional circuitry of buffalo mammary epithelial cells (BuMECs). The complete coding sequence of buffalo ACSS2 was characterized, and its expression was analyzed across lactation stages. Subcellular localization was determined via high-resolution confocal microscopy. We utilized siRNA-mediated knockdown in BuMECs to assess cell viability, triglyceride (TAG) content, and the expression of core metabolic and regulatory genes to dissect the underlying molecular mechanisms. ACSS2 expression was highly enriched in lactating mammary tissue, and the protein exhibited a dual nucleocytoplasmic distribution. ACSS2 knockdown induced a "dual collapse" of cellular function: it severely impaired lipogenesis (significantly reducing intracellular TAG and downregulating FASN, ACACA, SCD, CD36, LPL, FABP3, DGAT1, DGAT2 and AGPAT6) and arrested cell proliferation (downregulating the G1/S phase regulators CCND1, CCNE1, CDK2 and CDK4). Mechanistically, ACSS2 depletion dismantled the transcriptional machinery itself, suppressing the mRNA levels of master regulators SREBF1 and PPARG. Crucially, this collapse was accompanied by the paradoxical upregulation of the SREBP1-inhibitor INSIG1, suggesting that metabolic stress triggers an INSIG1-mediated blockade of the feedback loop. This study establishes ACSS2 as a critical metabolic checkpoint in the buffalo mammary gland, rather than a passive enzyme. We propose a model where ACSS2 maintains a reciprocal positive feedback loop with SREBP1 and PPARG. By ensuring sufficient acetyl-CoA to suppress INSIG1 and support histone acetylation (implied by nuclear localization), ACSS2 couples substrate availability to the stability of the lipogenic program and cell cycle progression. These findings reveal an evolutionarily conserved metabolic-epigenetic axis essential for high-efficiency lactation in ruminants. Show less

Familial partial lipodystrophy type 3 (FPLD3) is a rare autosomal dominant disorder caused by mutations in peroxisome proliferator-activated receptor gamma(PPARG), which encodes the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPARγ). Clinical diagnosis is challenging due to phenotypic overlap with common metabolic syndromes. We identified a novel PPARG variant in a Chinese family and performed comprehensive functional characterization to elucidate its pathogenic mechanism. The proband, a 15-year-old boy presenting with atypical fat distribution, severe insulin resistance, hypertriglyceridemia, and pancreatitis, underwent clinical evaluation and whole-exome sequencing. The identified variant was confirmed by Sanger sequencing. Its functional impact was assessed through in silico modeling, luciferase reporter assays, protein stability analysis (cycloheximide chase), and evaluation of mitochondrial function (JC-1 staining) and adipocyte gene expression in cellular models. A heterozygous PPARG c.634C>T (p.Arg212Trp, R212W) variant was identified and segregated with the phenotype. Functional studies revealed that the R212W mutant exhibits a partial loss of transcriptional activity (~40% of wild-type) while retaining ligand sensitivity. Crucially, we demonstrated that the mutant protein has significantly reduced stability due to accelerated degradation. In adipocyte models, R212W expression led to impaired mitochondrial membrane potential, depleted cellular ATP levels, and downregulated expression of key metabolic genes (glucose transporter 4[GLUT4], adiponectin[ADIPOQ], fatty acid binding protein 4[FABP4], lipoprotein lipase[LPL], perilipin 1[PLIN1]). These functional deficits were partially rescued by treatment with the PPARγ agonist rosiglitazone. We report a novel pathogenic PPARG R212W variant associated with FPLD3. Our data extend beyond a simple loss-of-function model by establishing a multi-faceted pathogenic mechanism involving protein destabilization, mitochondrial dysfunction, and cellular bioenergetic failure. The partial rescue by rosiglitazone suggests a potential therapeutic avenue. This study underscores the importance of integrating clinical phenotyping with deep functional analysis to diagnose and understand rare monogenic lipodystrophies. Show less

Tail fat deposition constitutes a distinctive adaptive phenotype in sheep. The Large-tailed Han (LTH) and Small-tailed Han (STH) breeds display pronounced divergence in tail fat storage, offering an ideal model for elucidating lipid metabolism regulation. Integrated sRNA-Seq and RNA-Seq analysis identified 521 differentially expressed genes and 144 miRNAs, which were significantly enriched in lipid metabolism pathways, including fatty acid metabolism and PPAR signaling. Key candidate genes ( Show less

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4 Show less

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited treatment options and frequent drug resistance. Novel therapeutic targets are urgently needed. We performed a druggable genome-wide Mendelian randomization (MR) analysis using blood cis-expression quantitative trait locus (eQTL) and HS genome-wide association study (GWAS) data. Colocalization, transcriptomic validation, single-cell RNA sequencing, and cell-cell communication analyses were integrated to explore gene function and cell-type specificity. We identified eight genes that showed significant associations with HS through MR analysis. Colocalization analysis further prioritized PSMA4 and MAST3 as the most promising druggable targets for HS. Specifically, PSMA4 (single nucleotide polymorphisms [SNPs] = 10; inverse-variance weighted [IVW] OR = 1.912, 95% CI: 1.492-2.450, Show less

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

Prostate cancer (PCa) is a leading cause of male cancer-related death globally. While the gut microbiota is linked to PCa, its genetic association remains unclear. We screened genetic instruments related to the gut microbiota and paired them with PCa genome-wide association study data to conduct Mendelian randomization (MR) analysis. Positive MR findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus (GEO) dataset to perform differential expression analysis, aiming to identify differentially expressed associated genes (DEAGs). We determined the importance scores of these DEAGs through four machine learning models and constructed a nomogram based on these findings, and then validated it in another group of the GEO dataset. MR analysis found 16 gut bacteria causally linked to PCa (7 risk, 9 protective), with 144 related genes. PLCL1, VSNL1, ROR2, NRXN3, and TEAD1 were identified as feature genes for constructing a nomogram that provides a quantitative prediction of the risk of PCa onset. This study indicates that there are causal links between the gut microbiota and PCa. Feature genes may affect the occurrence of PCa by inhibiting the epithelial-mesenchymal transition, proliferation, migration, and invasion of cells. Show less

This study aims to elucidate the regulatory mechanisms of host genetics on the porcine gut microbiota and their subsequent impact on the feed conversion ratio (FCR). While initial genome-wide association studies (GWAS) did not identify significant SNPs directly associated with FCR, we investigated the gut microbiota as a potential intermediate phenotype influencing feed efficiency. Nonmetric multidimensional scaling (NMDS) based on Bray–Curtis distances demonstrated a distinct separation in microbial community structure between the high-feed conversion ratio (HFCR) and low-feed conversion ratio (LFCR) groups (stress = 0.19), suggesting a link between FCR and gut microbial composition. Furthermore, a significant, albeit weak, negative correlation was observed between the genomic relatedness matrices and microbial Bray‒Curtis dissimilarity ( The online version contains supplementary material available at 10.1186/s42523-026-00527-y. Show less

Autophagy is a fundamental lysosome-dependent degradation process that maintains cellular homeostasis in response to stress. VSP34 (Vacuolar Protein Sorting 34, PIK3C3) is the only class-III phosphatidylinositol 3-kinase and generates phosphatidylinositol 3-phosphate (PI3P) for auto-phagosome nucleation and maturation. Thus, it provides a critical adaptive survival pathway for cells that are experiencing metabolic stress. The VPS34-autophagy axis plays dual roles in cancer, which depend on the context: it can restrain early tumorigenesis, but in established tumors, it can promote survival in conditions of hypoxia, nutrient deprivation, and therapeutic pressure. Moreover, VPS34 shapes the tumor microenvironment (TME) through its influence on both immune and cancer cells by modulating autophagy, cGAS-STING (cyclic GMP-AMP synthase Stimulator of Interferon Genes), and STAT1 pathways. VPS34 inhibition has been reported to induce an interferon response that increases CD8 Show less

Male infertility affects approximately one in seven couples worldwide. Prenatal cadmium (Cd) exposure has been shown to affect offspring phenotypes and increase susceptibility to diseases later in life. However, the effects of prenatal Cd exposure on multi-generational offspring fertility and the mechanisms remain unknown. A novel murine multi-generational (F1-F3 offspring) male subfertility model induced by prenatal Cd exposure was developed. The levels of testosterone and steroidogenic enzymes were also lower in these offspring's testes. The ubiquitin-dependent degradation of NR4A1, the upstream transcription factor regulating steroidogenic enzymes, was enhanced across generations upon prenatal Cd exposure. After treatment with MG132, an inhibitor of the ubiquitin-proteasome system, the levels of NR4A1 and steroidogenic enzymes were higher in offspring testes with prenatal Cd exposure. Based on the analysis of the UbiBrowser database and testicular global transcriptome, RAPSN was identified as a novel ubiquitin E3 ligase containing the RING-H2_Rapsyn domain that mediates multi-generational testicular NR4A1 ubiquitination. m Show less

Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of endothelial-to-mesenchymal transition (EndoMT), a key cell-fate process in vascular development and disease, in TAD remains poorly defined. Furthermore, the functional role of PDK4 (pyruvate dehydrogenase kinase 4) as a driver of this pathological cell-fate transition has not been elucidated. To delineate the mechanistic contribution of EndoMT to TAD, we integrated transcriptomic profiling and immunofluorescence analysis in human aortic specimens and a β-aminopropionitrile-induced murine model. Following the identification of PDK4 as a critical downstream effector of EndoMT signaling via RNA-sequencing and chromatin immunoprecipitation assays, its functional role was validated using conditional EC-specific knockout mice and adeno-associated virus-mediated endothelial gene modulation. Serum samples were collected, and ELISA was used to measure levels of endothelial injury markers for assessing EC-dysfunction. In addition, therapeutic potential was assessed using dichloroacetate, a small-molecule PDK4 inhibitor. A robust activation of the EndoMT gene program was observed in both human TAD specimens and murine aortic tissues, characterized by the loss of endothelial identity and acquisition of mesenchymal traits. Transcriptomic screening pinpointed PDK4 as a critical mediator upregulated during EndoMT. Mechanistically, we demonstrated that the transcription factor Our findings demonstrate that the pathological EndoMT program is activated in ECs by PDK4, which aggravates TAD development in β-aminopropionitrile-induced mouse models, highlighting PDK4 as a promising therapeutic target for TAD. Show less

Cellular senescence, characterized by permanent cell cycle arrest, significantly influences cancer development, immune regulation, and progression. However, the precise mechanisms by which senescence contributes to colorectal cancer prognosis remain to be fully elucidated. By integrating expression profiles of senescence-related and prognostic genes in colon adenocarcinoma (COAD) patients, we formulated and confirmed a nine-gene cellular senescence-related signature (CSRS) that integrates senescence-associated and prognosis-predictive genes using data from the CellAge, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A cell senescence-related prognostic formula was developed as follows: CSRS = (CASP2 × 0.2098) + (CDKN2A × 0.1196) + (FOXD1 × 0.1472) + (ING5 × 0.3723) + (OXTR × 0.0786) + (PHGDH × 0.1408) + (SERPINE1 × 0.1127) + (SNAI1 × 0.1034) + (LIMK1 × 0.0747). In a multivariate Cox proportional hazards model, the CSRS score, age and TNM stage were all identified as significant independent indicators for overall survival, affirming their prognostic value in colorectal cancer. The CSRS-high group exhibited significantly up-regulated senescence-associated secretory phenotype (SASP) and immune cell infiltration, whereas the CSRS-low group showed an apparent better response to immune-checkpoint inhibitor therapy. Our findings suggest CSRS score and its constituent genes represent potential biomarkers for prognosis and immunotherapeutic benefit in COAD patients. Extending this nine-gene set into a broader senescence-associated panel should be a next step toward delivering truly individualized treatment plans. Show less

The mechanisms by which the autosomal dominant disorder tuberous sclerosis complex (TSC) results in liver fibrosis remain poorly understood. KDM6A, a histone demethylase, has been implicated in the pathogenesis of fibrosis in multiple tissues. This study aimed to elucidate the molecular mechanism by which KDM6A contributed to TSC-associated fibrosis. We observed fibrogenesis, epithelial-mesenchymal transition (EMT) induction and upregulation of Kdm6a in vivo and in vitro upon Tsc1 or Tsc2 deficiency. Knockdown of Kdm6a attenuated both fibrosis and EMT phenotypes. Mechanistically, Kdm6a depletion reduced phosphorylation of ERK1/2 and downregulated Snai1 expression. Activation of the MAPK/ERK pathway with PMA restored EMT-related protein expression, confirming the functional involvement of this signaling axis. Furthermore, Tsc1 or Tsc2 deficiency promoted Kdm6a expression via the mTORC1 pathway, while Kdm6a knockdown conversely suppressed mTORC1 activity by reducing mTOR protein expression, suggesting a positive feedback loop between Kdm6a expression and mTORC1. These findings indicate that Kdm6a promotes fibrosis in TSC through the activation of the MAPK/ERK/SNAI1 signaling pathway. Moreover, the combination of mTORC1 and KDM6A inhibitors results in marked regression of fibrosis and liver lesions in TSC models, unveiling a potential treatment for TSC patients with inadequate response to mTORC1 inhibitors. Show less

Osteoarthritis (OA) represents a prevalent degenerative joint condition, in which chondrocyte dysfunction plays a key role in disease progression. Although accumulating evidence underscores the importance of cellular stemness regulation in OA development, systematic screening of related biomarkers has been insufficient. The current study sought to discover and validate potential biomarkers through bioinformatics and machine learning (ML), offering novel perspectives for early detection and therapeutic intervention in OA. The present study examined six OA-related transcriptomic profiles from the Gene Expression Omnibus (GEO) to discover and validate stemness-associated biomarkers. Differentially expressed genes (DEGs) were selected and analyzed for enriched biological functions. OA-related modules were determined via weighted gene coexpression network analysis (WGCNA). Key stemness-related genes were selected using ML algorithms, including support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and the least absolute shrinkage and selection operator (LASSO) regression. Receiver operating characteristic (ROC) analysis was implemented to determine diagnostic accuracy. Utilizing single-sample gene set enrichment analysis (ssGSEA), the link with immune cell infiltration was examined. Ultimately, immunohistochemistry was employed for experimental validation. Intersection analysis identified 56 stemness-related DEGs in OA cartilage. WGCNA analysis yielded 7 modules significantly associated with stemness genes, and a combined screening approach identified 60 candidate genes. Using four machine learning algorithms-SVM, LASSO, XGBoost, and RF-four feature genes were ultimately determined (WWP2, CDKN1A, IL11, and CRTAC1), among which WWP2, CDKN1A, and CRTAC1 showed significant differential expression between OA and normal samples and demonstrated good diagnostic performance in both the training and validation cohorts (AUC > 0.7). ssGSEA analysis revealed that the expression of these three genes was significantly correlated with specific immune cell subpopulations. Immunohistochemistry further confirmed that WWP2 and CDKN1A were downregulated in OA tissues, whereas CRTAC1 was upregulated. Through bioinformatics analysis and IHC validation, we identified three stemness-associated biomarker genes (WWP2, CDKN1A, CRTAC1) in OA. These findings may provide meaningful implications for future clinical assessment, treatment, and research on OA. Show less

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less

The increasing global aging population presents significant challenges related to cognitive decline, mental health disorders, and social isolation. Martial arts exercise emerges as a multifaceted intervention promoting mental health and cognitive vitality among older adults by integrating physical activity, cognitive engagement, and social interaction. This review synthesizes evidence on the neural mechanisms underlying the benefits of martial arts, highlighting their role in enhancing brain-derived neurotrophic factor (BDNF) expression, neuroplasticity, and neural connectivity, which support improved executive functions, memory, and emotional regulation. Both hard martial arts and soft practices, such as Tai Chi, offer distinct advantages in addressing age-related cognitive and psychosocial challenges. Additionally, martial arts foster strong social support systems, reducing loneliness and enhancing emotional resilience through community engagement and shared achievement. Physical and functional benefits, including improved strength, balance, and cardiovascular health, further contribute to overall well-being. Despite promising results, current studies are limited by heterogeneity in martial arts styles, short intervention durations, and variable methodologies. Future research should focus on long-term, standardized interventions employing advanced neuroimaging and biomarker assessments to better elucidate mechanisms and optimize training protocols. Integrating martial arts into health promotion strategies holds substantial potential for enhancing mental health, cognitive resilience, and quality of life in aging populations. Show less

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less

Jiaotaiwan (JTW) is a classic traditional Chinese medicine (TCM) prescription for treating depression, but its potential mechanisms are not fully understood. The aim of this study is to detect the levels of serum Short-chain fatty acids (SCFAs) and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP-response element binding protein (CREB)-brain derived neurotrophic factor (BDNF) signaling pathway, further revealing the scientific connotation of the antidepressant effect of JTW. In this multicenter, randomized, controlled study, 120 patients with depression were divided into the JTW (16.5 g/d) group, JTW (16.5 g/d) + selective serotonin reuptake inhibitors (SSRIs) group, and SSRIs group. Hamilton depression Scale-24 (HAMD-24) and Self-rating depression scale (SDS) were used for efficacy evaluation. Enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to evaluate the expression levels of cAMP-PKA-CREB-BDNF signaling pathway. Serum SCFAs concentrations were analyzed using liquid chromatograph-mass spectrometer (LC-MS) targeted metabolomics. After eight weeks of treatment, HAMD score and SDS score were significantly decreased in the three groups, and HAMD score in JTW + SSRIs group was significantly lower than that in SSRIs group. After treatment, the expression levels of cAMP-PKA-CREB-BDNF signaling pathway were significantly increased in the three group, with the JTW + SSRIs group showing more significant increase. After treatment, the levels of isobutyric, butyric, isovaleric, and valeric acids in the JTW + SSRIs groups were significantly higher than that before treatment, and the levels of isobutyric, and isovaleric acids in the JTW + SSRIs group was significantly higher than that in the JTW group and SSRIs groups. JTW can alleviate symptoms in patients with depression, and its antidepressant mechanism may be related to regulating serum SCFAs and cAMP-PKA-CREB-BDNF signaling pathway. Show less

The glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are important incretin receptors that are therapeutic targets for the treatment of type 2 diabetes and obesity. This study extensively characterised the metabolic phenotype of mice with global deletion of either the GLP-1R or GIPR side by side under identical conditions. Age-matched male wild-type (WT) C57Bl6NTac, GLP-1RKO or GIPRKO mice were placed on a high-fat or chow diet for 12 weeks, and a range of in vivo (weight gain, food intake, glucose tolerance, insulin tolerance, and whole-body energy metabolism) and ex vivo (white adipocyte lipolysis, brown adipose tissue and liver mitochondrial function, adipocyte and islet size, and hepatic steatosis) parameters were measured. While both WT and GLP-1RKO mice gained weight similarly on a HFD, obese high-fat-fed GLP-1RKO mice had altered glucose and insulin tolerance, and exhibited hepatic steatosis, highlighting the physiological importance of the GLP-1R in the regulation of blood glucose and lipid homoeostasis. In contrast, GIPRKO mice were partially resistant to diet-induced obesity compared to the WT mice, which was associated with a small reduction in food intake and intact epididymal and subcutaneous white adipocyte β-adrenoceptor-mediated lipolysis. Similarly, WT mice treated with a GIPR antagonist prevented weight gain due to a reduction in food intake on a HFD. These findings provide further support that the GLP-1R is important for normal glycaemic control, whereas the GIPR may play a role in the regulation of body weight. Show less

GLP-1 has become a prime target for medical treatment due to its significant therapeutic efficacy. However, the activation mechanisms of class B1 GPCRs, including glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), remain poorly understood. This study focuses on understanding the activation mechanisms of the GLP-1 receptor (GLP-1R) by investigating its conformational changes from activated/inactivated to inactivated/activated states. By analyzing the dynamic conformational changes of the receptor during activation, a closure-open transition in the extracellular domain (ECD) and a movement trend of the transmembrane helices are observed, which indicates a similarity to the activation mechanism of class A GPCRs. Furthermore, the binding characteristics of a dual agonist Tirzepatide (LY3298176) is studied in detail and it is revealed that the conserved residues contribute in a similar fashion toward binding to both GLP-1R and GIPR. Mutations in non-conserved residues in Tirzepatide affect the binding affinity, with C-terminal mutations weakening the binding affinity toward GLP-1R, while N-terminal mutations enhancing the affinity to GIPR, resulting in a biased binding mode. These findings enriched our fundamental understanding of GLP-1R/GIPR activation and provided theoretical guidance for the design and development of future peptide-based agonists and offer insights into the optimization of other dual or multi-target agonists. Show less

Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments. Show less

Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist for the treatment of diabetes, has a role in attenuating CRC growth. TZP significantly inhibited colon cancer cell proliferation promoted apoptosis in vitro and induced durable tumor regression in vivo under hyperglycemic and nonhyperglycemic conditions across multiple murine cancer models. As glucose metabolism is known to critically regulate colon cancer progression, spatial metabolomics results revealed that glucose metabolites are robustly reduced in the colon cancer regions of the TZP-treated mice. TZP inhibited glucose uptake and destabilized hypoxia-inducible factor-1 alpha (HIF-1α) with reduced expression and activity of the rate-limiting enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK-1). These effects contributed to the downregulation of glycolysis and the tricarboxylic acid (TCA) cycle. TZP also delayed tumor development in a patient-derived xenograft (PDX) mouse model accompanied by HIF-1α mediated PFKFB3-PFK-1 inhibition. Therefore, the study provides strong evidence that glycolysis-blocking TZP, besides its application in treating type 2 diabetes, has the potential for preclinical studies as a therapy for colorectal cancer used either as monotherapy or in combination with other anticancer therapies. Show less

Mahogunin ring finger 1 (MGRN1) is a membrane-tethered E3 ligase that fine-tunes signaling sensitivity by targeting surface receptors for ubiquitylation and degradation. Although MGRN1 is known to regulate the Hedgehog signaling effector Smoothened (SMO) via the transmembrane adapter multiple epidermal growth factor-like 8 (MEGF8), the broader scope of its regulatory network has been speculative. Here, we identify attractin (ATRN) and attractin-like 1 (ATRNL1) as additional transmembrane adapters that recruit MGRN1 and regulate cell surface receptor turnover. Through co-immunoprecipitation, we show that ATRN interacts with the RING domain of MGRN1. Functional assays suggest that ATRN and ATRNL1 work with MGRN1 to promote the ubiquitylation and degradation of the melanocortin receptors MC1R and MC4R, in a process analogous to its regulation of SMO. Loss of MGRN1 or ATRN leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, resulting in enhanced eumelanin production. These findings expand the known repertoire of MGRN1-regulated receptors and provide new insight into a shared mechanism by which membrane-tethered E3 ligases utilize transmembrane adapters to facilitate substrate receptor specificity. Show less