👤 Guo Nan Yin

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have revolutionized cancer therapy, yet primary and acquired resistance remain major clinical obstacles. Dysregulated angiogenesis fuels the development of an immunosuppressive tumor microenvironment, while crosstalk between immunity and angiogenesis further propels tumor immune evasion and treatment resistance. The present study aimed to establish a penpulimab-resistant model, delineate anti-PD-1 resistance traits via single-cell RNA sequencing, and unravel the precise mechanisms through which anlotinib-an anti-angiogenic agent-mitigates penpulimab resistance. These findings offer insights to guide clinical management of immune-pretreated patients. Single-cell sequencing analyses demonstrated that anlotinib reverses penpulimab resistance by reprogramming the tumor immune microenvironment, thereby boosting PD-1 blockade efficacy via modulation of immune infiltration and tumor signaling pathways. Identifying Apoe⁺ M2 macrophages, Srgn⁺ M1 macrophages, and Cxcl2⁺ T cells provides key cellular and molecular targets for developing clinically actionable immunotherapies. Taken together, this work validates the preclinical potential of anlotinib combined with immunotherapy for immunotherapy-resistant tumors. Show less

To investigate the effects of SLCO1B1, apolipoprotein E (APOE) and ABCG2 gene polymorphisms on the lipid-modulating efficacy of rosuvastatin. Systematic searches were conducted in PubMed, Cochrane Library, Embase, Web of Science, PharmGKB, CNKI, VIP, and Wanfang databases (from database establishment to 1 March 2025). Studies on the correlation between SLCO1B1, APOE, ABCG2 gene polymorphisms and the lipid-modulating efficacy of rosuvastatin were collected, and meta-analysis was performed using RevMan 5.4 software. A total of 16 studies involving 6167 patients were included, covering APOE (p.C130R/rs429358, p.R176C/rs741), SLCO1B1 (p.V174A/rs4149056, p.N130D/rs2306283), and ABCG2 (p.Q141K/rs2231142) genes. The results showed that SLCO1B1 [AG+GG vs. AA, mean difference = -4.36, 95% confidence interval (CI): -7.92 to -0.80, P = 0.02], APOE (E2 vs. E3, mean difference = -5.58, 95% CI: -8.04 to -2.51, P < 0.00001] and ABCG2 (CA+AA vs. CC, mean difference = -7.07, 95% CI: -9.47 to -4.68, P < 0.00001) genotypes all significantly affected statin-induced low-density lipoprotein cholesterol (LDL-C) reduction; patients with ABCG2 CA+AA genotype had statistically significant differences in total cholesterol level changes (mean difference = -7.15, 95% CI: -8.78 to -5.53) and triglyceride level changes (mean difference = -7.37, 95% CI: -10.91 to -3.83) (both P < 0.05). The lipid-lowering efficacy of rosuvastatin (especially the reduction of LDL-C level) is significantly affected by the polymorphisms of SLCO1B1 (c.388A>G), ApoE (c.388T>C, c.526C>T) and ABCG2 (c.421C>A) genes. Show less

Mounting evidence implicates inflammation as a key factor in Alzheimer’s disease (AD) development. We previously identified pro-inflammatory soluble epoxide hydrolase (sEH) metabolites to be elevated in plasma and CSF of AD participants and to be associated with lower cognition in non-AD subjects. Soluble epoxide hydrolase is a key enzyme converting anti-inflammatory epoxy fatty acids to pro-inflammatory diols, reported to be elevated in multiple cardiometabolic disorders. Here we analyzed over 700 fasting plasma samples from the baseline of Alzheimer’s Disease Neuroimaging Initiative (ADNI) 2/GO study. We applied targeted mass spectrometry method to provide absolute quantifications of over 150 metabolites from oxylipin and endocannabinoids pathway, interrogating the role for inflammation/immune dysregulation and the key enzyme soluble epoxide hydrolase in AD. We provide further insights into the regulation of this pathway in different disease stages, APOE genotypes and between sexes. Additionally, we investigated in mild cognitive impaired (MCI) participants, metabolic signatures that inform about resilience to progression and conversion to AD. Key findings include I) confirmed disruption in this key central pathway of inflammation and pointed to dysregulation of sEH in AD with sex and disease stage differences; II) identified markers of disease progression and cognitive resilience using sex and ApoE genotype stratified analysis highlighting an important role for bile acids, lipid peroxidation and stress response hormone cortisol. In conclusion, we provide molecular insights into a central pathway of inflammation and links to cognitive dysfunction, suggesting novel therapeutic approaches that are based on targeting inflammation tailored for subgroups of individuals based on their sex, APOE genotype and their metabolic profile. The online version contains supplementary material available at 10.1186/s13195-025-01939-9. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder underlying most cardiovascular events sialic acid (SIA), a terminal metabolite of glycolipid catabolism, modulates vascular injury, but its role in endothelial dysfunction remains unclear. To investigate whether N-acetylneuraminic acid (Neu5Ac) accelerates AS development. ApoE Show less

Disruption of circadian rhythms is increasingly recognized as a contributor to cognitive dysfunction, but its role in gestation-associated cognitive changes remains unexplored. Here we combine human cognitive screening with a comprehensive longitudinal mouse model to investigate whether gestational cognitive impairment and postpartum recovery are coupled with disruption and restoration of hippocampal circadian rhythms. Cognitive function was assessed in pregnant and postpartum women using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). In mice, four reproductive stages were compared: control, gestation, 1 month postpartum, and 3 months postpartum. Serum gonadotropins and sex hormones levels were quantified using ELISA. Home-cage locomotor activity was recorded over 48 h under a 12 h:12 h light-dark cycle. Hippocampal-dependent memory was evaluated using the novel object recognition test and Barnes maze at Zeitgeber times ZT6 (day) and ZT18 (night). Hippocampal amyloid β (Aβ) deposition was visualized via immunofluorescence; protein expression of amyloid precursor protein (APP), β-site amyloid precursor protein cleaving enzyme-1 (BACE1), and phosphorylated tau was measured by Western blots. Hippocampal clock gene expression was quantified by RT-qPCR at six time points; circadian parameters (mesor, amplitude, acrophase) were derived by cosinor analysis and compared between groups. Human cognitive screening confirmed modest gestational decline with postpartum recovery. In mice, gestation disrupted daily locomotor activity rhythms and reduced nocturnal preference; both partially recovered by 1 month and fully by 3 months postpartum. Behaviourally, pregnancy impaired the normal day-night difference and performance in novel object exploration and Barnes maze, which recovered progressively. At the molecular level, gestation increased hippocampal APP and BACE1 expression, elevated Aβ42 deposition, and induced tau hyperphosphorylation at multiple sites-hallmarks of Alzheimer's disease-related pathology. These alterations partially reversed by 1 month postpartum and normalized by 3 months. Hippocampal clock genes maintained 24 h rhythmicity, but gestation induced gene-specific phase shifts, amplitude reductions, and mesor alterations. These parameters showed gradual, gene-dependent normalization postpartum. Gestational cognitive impairment and postpartum recovery are associated with reversible disruption and restoration of both hippocampal circadian rhythms and Alzheimer's disease-related molecular pathology. These findings are correlational in nature and provide a foundation for future causal investigations. Show less

Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. Show less

Distant metastasis of colorectal cancer (CRC) is strongly driven by metabolic reprogramming and epithelial-mesenchymal transition (EMT). Increasing evidence suggests that these two processes form a reinforcing positive feedback loop; however, the integrated regulatory mechanism and its potential for pharmacological intervention remain insufficiently understood. This study aimed to elucidate the mechanistic coupling between autophagy, metabolic reprogramming, and EMT, and to develop a targeted pharmacological strategy capable of disrupting this positive feedback loop. We systematically constructed and validated an autophagy-metabolism-phenotypic transformation regulatory axis centered on ATG4B and PKM2, and evaluated the therapeutic efficacy of Curcumol as a pathway-specific natural compound intervention. Biochemical assays, protein-protein interaction analyses, and functional experiments were performed to determine how ATG4B regulates PKM2 Tyr105 phosphorylation, nuclear translocation, and glycolytic activity. Curcumol was applied to assess its ability to activate ATG4B-dependent autophagy and inhibit PKM2 activation. Anti-tumor efficacy was validated using colorectal cancer organoids, orthotopic implantation, and liver metastasis mouse models. ATG4B was identified as a core autophagy enzyme that directly binds to and shields the PKM2 Tyr105 site, preventing FGFR1-mediated phosphorylation and nuclear translocation. This blockade suppressed the Warburg effect, reduced lactate production, and synergistically inhibited EMT progression. Curcumol activated ATG4B-dependent autophagy, inhibited PKM2 activation, and effectively disrupted the metabolism-EMT positive feedback loop. In multiple CRC models, Curcumol markedly suppressed tumor growth and metastasis, supporting its therapeutic potential. This study reveals the ATG4B-PKM2 axis as a critical regulatory node linking autophagy, metabolic reprogramming, and EMT. Targeting this axis with Curcumol provides a precise strategy to interrupt metabolism-phenotype coupling, offering a mechanistically grounded and translationally promising approach for inhibiting CRC progression and metastasis. Show less

Periodontitis is a prevalent chronic infectious condition affecting the oral cavity. This research was conducted to analyze the role of GATA6 in LPS-stimulated human periodontal ligament cells (hPDLCs). Dysregulated genes associated with periodontitis were acquired from the GEO database (GSE23586). Cell viability was measured utilizing the MTT assay, while apoptosis was analyzed through flow cytometry. The expression levels of mRNA and proteins were examined using qRT-PCR and Western blot techniques, respectively. Levels of IL-1β, IL-6, and TNF-α were measured using specific ELISA kits. The mouse periodontitis model was established to evaluate the effect of GATA transcription factor 6 (GATA6) in vivo.The results demonstrated that GATA6 was downregulated in periodontitis and LPS-stimulated hPDLCs. Overexpression of GATA6 enhanced cell viability, while inhibited apoptosis in hPDLCs. It also reduced the levels of IL-1β, IL-6, and TNF-α in LPS-stimulated hPDLCs. Additionally, after transfection with a GATA6 overexpression vector, the expressions of Caspase 3 and Bax proteins were suppressed, while Bcl2 was upregulated. Furthermore, in LPS-stimulated hPDLCs, the protein levels of Notch1, Hey1, and Hey2 were enhanced after GATA6 overexpression. Silencing of Notch1 neutralized the effects of GATA6 in LPS-stimulated hPDLCs. In addition, GATA6 overexpression alleviated the progression of periodontitis in vivo. In conclusion, GATA6 alleviated the progression of periodontitis by activating the Notch signaling pathway. Show less

Steroid-refractory (SR) disease develops in a substantial fraction of patients with grade II-IV acute graft-versus-host disease (aGvHD) and is associated with poor long-term survival. Improved mechanistic insight is needed to identify reliable predictors of steroid resistance. We retrospectively profiled peripheral blood collected prior to glucocorticoid treatment from allogeneic hematopoietic cell transplantation recipients without aGvHD, with steroid-sensitive aGvHD, and with SR-aGvHD using an integrated multi-omics approach, and validated findings in an independent multicenter cohort. Mass cytometry revealed expansion of activated CD28+ CD8+ effector-memory T (Tem) cells in SR-aGvHD. Absolute counts of these cells at neutrophil engraftment predicted subsequent steroid resistance in the multicenter cohort and performed comparably to established clinical classifiers. This phenotype was associated with a proinflammatory milieu enriched for IL-2, IL-27, and IFN-γ. Single-cell RNA sequencing and functional assays implicated a STAT1-glucocorticoid receptor (GR) regulatory axis in which inflammatory cytokines induce STAT1 phosphorylation and suppress GR expression, consistent with intrinsic glucocorticoid resistance. JAK inhibition rescued cytokine-induced steroid resistance in vitro, while in SR-aGvHD patients, clinical response to ruxolitinib was accompanied by reduced STAT1 activation, restoration of GR expression, and contraction of the expanded CD8+ Tem pool. These findings identify immune dysregulation at SR-aGvHD centered on CD8+ Tem cells with a STAT1-dependent GR deficit and support a mechanistic link to steroid refractoriness. CD28+ CD8+ Tem cell counts may serve as a biomarker of SR-aGvHD and inform development of pre-emptive, pathway-targeted strategies. Show less

Neonatal regulatory T (Treg) cells in secondary lymphoid organs have greater proliferative capacity and more potent suppressive functions than adult Treg cells. However, the phenotypic and functional features of Tregs in neonatal nonlymphoid organs are not well understood. Our prior work demonstrated that thymus-derived Treg cells entering the neonatal mouse liver enhance immune tolerance and periportal liver maturation. Compared to splenic Treg cells, these hepatic Tregs have faster turnover and superior suppression of naïve T-cell proliferation. To further define this population, we conducted single-cell transcriptomic and immunophenotypic analyses of liver- and spleen-derived Tregs from neonatal and adult mice. Our analysis revealed a distinct T-box transcription factor Tbx21 (T-bet) Show less

Skeletal muscle atrophy is a common complication of heart failure, with myocardial infarction (MI) being the primary cause. Yet, the mechanisms linking post-MI cardiac insufficiency to muscle atrophy have remained unclear. The molecular basis for the beneficial effects of exercise on exercise intolerance in MI patients also remains absent. Serum IL-27 levels were measured in 48 MI patients and correlated with cardiac injury markers. Along with this, a rat model of post-MI cardiac insufficiency was used to assess skeletal muscle mass, cross-sectional area (CSA) of muscle fibers, and the expression of atrophy-related (MAFbx, MuRF-1) and differentiation-related markers (MyoD, Myogenin). The impact of exercise on muscle atrophy, cardiac inflammation, and IL-27 expression was then evaluated, with a focus on macrophage polarization. Serum IL-27 level was significantly elevated in MI patients and that it was positively correlated with myocardial injury and cardiac insufficiency. In post-MI rats, skeletal muscle mass and CSA of muscle fibers were reduced. Meanwhile, the expression level of myogenic markers was downregulated, while that atrophy markers was upregulated. IL-27 treatment promoted catabolism in L6 myotubes, and of note, HIF-1α overexpression in macrophages enhanced IL-27 secretion, and increased MAFbx and MuRF-1 expression. IL-27 level was also elevated in the heart, serum, and gastrocnemius muscle of MI rats. Exercise counteracted these effects by promoting M2-like macrophage polarization and suppressing HIF-1α, thereby reducing IL-27 expression. Furthermore, exercise ameliorated IL-27-induced muscle atrophy via the WSX-1/gp130/pSTAT3 signaling axis. IL-27 contributes to muscle atrophy in post-MI cardiac insufficiency. Exercise attenuates IL-27-driven muscle wasting by modulating inflammation and promoting M2-like macrophage polarization. These findings provide insights into the mechanisms of MI-induced muscle atrophy and highlight the therapeutic potential of exercise in cardiac rehabilitation. [Image: see text] The online version contains supplementary material available at 10.1186/s12967-025-07527-7. Show less

To identify latent self-management profiles in people living with HIV (PLWH) with dyslipidemia and factors associated with profile membership, thereby facilitating targeted clinical intervention. A cross-sectional survey was conducted from December 2024 to June 2025 among 333 PLWH with dyslipidemia at Nanjing Second Hospital. Data were collected via sociodemographic/disease-related questionnaire, the HIV Self-Management Scale (HIVSMS), and the Health Literacy Management Scale (HLMS). Latent profile analysis (LPA) was performed in Mplus 8.3, and multinomial logistic regression was used to examine factors associated with profile membership. Fit indices (entropy = 0.993) supported a three-profile solution: low self-management-low social support-seeking (C1, 42.3%), moderate self-management-stable (C2, 37.8%), and high self-management-emotion regulation dominant (C3, 19.8%). Seeking social support was relatively low across profiles. Compared with C1, C2 membership was significantly associated with higher education and income, lipid-lowering medication use (OR 3.735, 95% CI 1.597-8.736), and CD4 350-500 cells/μL, and was less likely among participants with VL >1000 copies/mL or chronic comorbidities (all P < 0.05). Compared with C1, C3 membership was significantly associated with HIV infection duration ≥5 years, higher education and income, CD4 >500 cells/μL, and higher HDL-C, and was less likely among those with VL >1000 copies/mL (OR 0.037, 95% CI 0.004-0.380) or chronic comorbidities (all P < 0.05). Compared with C2, C3 membership was independently associated with higher health literacy (HL) (OR 1.038 per point, 95% CI 1.012-1.064) and was less likely among those with LDL-C ≥3 mmol/L (P < 0.05). We identified three distinct self-management profiles among PLWH with dyslipidemia. Profile membership was significantly associated with HL and socioeconomic, HIV-related, lipid-related, and comorbidity factors, supporting the need for profile-tailored strategies to improve self-management. Show less

Phytate (phytic acid, or InsP6), the primary phosphorus storage compound in plants, plays essential roles in nutrient homeostasis and cellular signaling. However, its strong metal-chelating properties make cytosolic accumulation cytotoxic, necessitating its sequestration into vacuoles for safe storage. Here, we present the cryo-EM structures of the rice vacuolar phytate transporter, OsMRP5, captured in distinct functional states. These structures reveal the molecular basis of OsMRP5 function as an ATP-binding cassette (ABC) transporter. OsMRP5 employs a specialized substrate-recognition mechanism, uniquely adapted to bind the fully hydrophilic InsP6 through extensive electrostatic and hydrogen-bonding interactions within two distinct, highly polar binding sites in its central cavity. A distinctive electropositive tunnel, positioned above the central cavity, forms a continuous pathway connecting the InsP6-binding pocket to the vacuolar export site. This tunnel likely generates an electrostatic attraction that facilitates the movement of the highly anionic InsP6 through the transporter. By mapping mutations from low-phytic acid (lpa) crop variants onto the OsMRP5 structures, we pinpoint their conserved locations critical for transporter function and validate their impact experimentally. These results reveal how OsMRP5 recognizes and transports the highly charged InsP6 molecules into vacuoles, providing a molecular framework for targeted manipulation of this agriculturally important transporter. Show less

This study examined the heterogeneous nature of dual-career stress and its asymmetric associations with on adolescent athletes, aiming to: (1) identify distinct stress profiles based on academic, training, and role-conflict stressors; (2) assess whether stress associations vary across levels of athletic burnout and academic performance; and (3) test whether stress profiles moderate these relationships. A two-wave longitudinal study included 843 adolescent male football players in China. Latent Profile Analysis (LPA) categorized participants using three stressor subscales at Time 1. Quantile Regression (QR) at Time 2 (6 months later) analyzed the association between total stress and athletic burnout and academic performance across five quantiles (τ = 0.10-0.90), with stress profile as moderator, controlling for social support, time management, and demographics. LPA revealed four profiles: Balanced Moderates (37.2%), Academically Overwhelmed (28.1%), Sport-Centric Strained (22.0%), and Dual-Track Distressed (12.7%). QR showed the positive association between stress and burnout increased across quantiles (β = 0.41 at τ = 0.10 to 0.78 at τ = 0.90), with the strongest association observed among already burnt-out athletes most. For academic performance, the negative association between stress and performance was strongest at lower quantiles (β = -0.71 at τ = 0.10) and weaker at higher quantiles (β = -0.29 at τ = 0.90). Stress profiles significantly moderate these relationships: the Dual-Track Distressed profile showed the strongest association with on burnout (β = 0.89), while Academically Overwhelmed and Dual-Track Distressed profiles showed the strongest negative association with on academic performance (β = -0.79 and -0.92, respectively). Dual-career stress experiences and impacts are highly heterogeneous. Adolescents cluster into meaningful stress profiles, and stress is most strongly associated with negative outcomes among those already at extremes of burnout or poor academic performance. Findings underscore the need for personalized interventions tailored to athletes' specific stress profiles and outcome levels, supporting holistic development in dual-career contexts. Show less

Adolescence is a critical period for rapid emotional and cognitive development. Depression and cognitive impairment frequently co-occur in this population, yet their comorbidity patterns and symptom-level interactions remain insufficiently explored. A total of 2,244 students (mean age = 16.8 ± 0.84 years; 1,218 males, 1,026 females) from a high school in Heilongjiang Province, China, were recruited. Depressive symptoms and cognitive impairment were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Perceived Deficits Questionnaire–Depression (PDQ-D). Latent profile analysis (LPA) was applied to identify subgroups, followed by network analysis to examine central symptoms (expected influence, EI), bridge symptoms (bridge expected influence, BEI), and network differences (NCT). The optimal LPA model identified three comorbidity subgroups: low, moderate, and high. NCT revealed significant differences in network structure and global strength between the low–moderate (S = 1.514, Adolescent Depression and Cognitive Impairment can be classified into low, moderate, and high comorbidity subgroups. Somatic symptoms emerged as the central symptom, while prospective memory impairment and interpersonal problems were identified as key bridge symptoms, suggesting potential intervention targets for early screening and stratified treatment. Not applicable. The online version contains supplementary material available at 10.1186/s12888-026-07946-w. Show less

This study, adopting a person-centered approach and using network analysis, explores latent subtypes of Junzi personality among college students and their links to Receptiveness to Opposing Views, offering empirical backing for the ancient Chinese idea of "Junzi harmonize yet remain distinct." Traditional variable-centered methods often fail to fully expose the underlying typological structure due to the possible heterogeneous combinations in Junzi personality dimensions. Thus, a person-centered latent profile analysis (LPA) was used to pinpoint typical personality trait patterns. With 1116 college students as participants, the study employed the Junzi Personality Questionnaire Based on Confucian Thought and the Receptiveness to Opposing Views Scale. LPA identified three personality types: The Moderate Type (50%), The Daring-Aggressive Type (15%), and The Virtuously-Accomplished Type (35%). Regression analysis showed significant correlations between gender, age, and personality type, with The Virtuously-Accomplished Type scoring notably higher in Receptiveness to Opposing Views. Network analysis further revealed distinct differences in the network structures of Receptiveness to Opposing Views among the three types: The Moderate Type centered on "derogation of opponents," "refraining from what should not be done," and "respectfulness and propriety"; The Daring-Aggressive Type focused on "conversancy with righteousness and cherishment of benign rule," "derogation of opponents," and "respectfulness and propriety"; while The Virtuously-Accomplished Type highlighted "negative emotions" and "wisdom, benevolence, and courage," with "taboo issues" at the periphery in all datasets. The findings uncover the heterogeneity of Junzi personality and its varied associations with Receptiveness to Opposing Views, providing insights for understanding harmonious interactions in diverse settings. Show less

To investigate the association between vaginal microbiota structure in early pregnancy and gestational diabetes mellitus (GDM) and to characterize microbial signatures for early screening for GDM. The present study was a nested case-control study recruiting pregnant women from the Nanjing Gulou Maternal-Child Health Center, China. Vaginal swabs were collected before 20 weeks of gestation for 16S rRNA sequencing. Following 1:3 propensity score matching, 45 GDM cases and 135 controls were enrolled. The final analysis included 42 GDM cases and 121 controls. A random forest model was used to explore the genera of vaginal differential microbiota associated with GDM. Based on these findings, latent profile analysis (LPA) was conducted to explore potential types of vaginal microbiota, and logistic regression was used to analyze the association between vaginal microbiota types and GDM. The GDM group exhibited elevated alpha diversity (Chao1 index, The composition and structure of vaginal microbiota in early pregnancy are different in the two groups. The vaginal microbiota in early pregnancy, which is characterized by co-dominated by The online version contains supplementary material available at 10.1186/s12866-026-04910-2. Show less

This study aims to identify the 24-h movement behavior patterns of preschool children using Latent Profile Analysis based on Compositional Data Analysis (CoDA), and to examine their associations with physical fitness. The study employs a cross-sectional design. A total of 329 healthy children aged 4-6 years were selected. Accelerometers (ActiGraph wGT3-BT, Pensacola, FL, USA) were used to measure light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), and sedentary behavior (SB), while sleep was assessed through parent and teacher questionnaires. The assessment of physical fitness was conducted in accordance with the "Chinese National Physical Fitness Test Standards" (Preschooler Section). To address the multicollinearity problems among components of physical activity (PA), CoDA was first applied, subsequently, Latent Profile Analysis was utilized to categorize 24-h movement behavior patterns, while a Generalized Ordered Logit Model (GOLM) was applied to investigate their associations with physical fitness. Three distinct behavioral patterns emerged from the analysis: the "brown bear group" (moderate PA and SB, high SP, N = 176, 53.5%), the "cheetah group" (high PA/MVPA, low SB, moderate SP, N = 102, 31%), and the "koala group" (low PA, high SB, lower SP, N = 51, 15.5%). After adjusting for potential confounding factors, it was found that compared with the "koala group", the "brown bear group" and the "cheetah group" exhibited higher levels of physical fitness, with the probability of improving their physical fitness rating being 3.69 times and 6.36 times that of the "koala group," respectively. This study highlights the significant impact of active and healthy activity patterns on the physical fitness of preschool children, providing a foundation for formulating personalized preventive and interventional approaches in early childhood. Show less

TyHGB is a novel insulin resistance (IR)-related indicator, and its association with coronary heart disease (CHD) remains unclear. Additionally, studies have shown a close correlation between the diagonal earlobe crease (DELC) and CHD, yet it has not been fully applied in clinical practice to date. Therefore, this study constructed and validated a diagnostic model for CHD by combining TyHGB and DELC. A total of 1664 patients suspected of CHD who underwent coronary angiography (CAG) in the Department of Cardiology, Chengde Central Hospital from September 2021 to April 2025 were recruited for this study. Participants were categorized into a CHD group ( Age, sex, hypertension, diabetes, CR, Lp(a), TyHGB, and DELC were identified as independent risk factors for CHD through multivariate logistic regression analysis ( Both TyHGB and DELC have been identified as independent risk factors for CHD, with a linear relationship observed between TyHGB levels and CHD risk. A diagnostic model for CHD, developed by integrating TyHGB, DELC, and traditional risk factors, demonstrates strong diagnostic efficacy. The online version contains supplementary material available at 10.1186/s12944-026-02880-y. Show less

The Climate Change Anxiety Scale (CCAS) is an emerging psychometric instrument designed to assess climate change anxiety (CCA). This study aimed to preliminarily identify reference cutoff scores and core items of the CCAS in a Chinese adult population. We conducted an online cross-sectional survey in China between May and June 2024, recruiting 653 Chinese adults (mean age = 32.62 ± 7.40 years; 53.8% female) via Wenjuanxing. CCA was assessed using the CCAS. External variables included generalized anxiety (Chinese GAD-7), self-rated sleep quality (single-item, past week), and self-reported experience of meteorological disasters (yes/no). Latent profile analysis (LPA) and receiver operating characteristic (ROC) analyses were used to derive reference cutoff scores, and network analysis was applied to identify core items. LPA supported a two-profile solution and yielded an overall reference cutoff score of 27.5, above which participants were categorized as having elevated CCA risk. Participants classified as high risk reported higher generalized anxiety, poorer sleep quality, and a higher likelihood of meteorological disaster experience. Sex-stratified analyses indicated different optimal cutoffs: 28.5 for males (sensitivity = 1.000; specificity = 0.982) and 26.5 for females (sensitivity = 0.986; specificity = 0.986). Network analysis further suggested that the item Show less

About 20-40% of prostate cancer (PCa) develop biochemical recurrence (BCR) after surgery, and propionate metabolism may contribute to tumor progression. BCR remains a major clinical challenge in PCa, as current tools based on histopathology and prostate-specific antigen (PSA) fail to capture the molecular heterogeneity driving the disease. While metabolic reprogramming is known to facilitate post-treatment adaptation, the specific role of propionate metabolism in this context remains largely unexplored. Therefore, this study aimed to systematically investigate propionate metabolism-related genes (PMRGs) to develop a novel prognostic model for the improved early prediction of recurrence. In this study, The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD), GSE70770 and 412 PMRGs were employed. Differentially expressed genes (DEGs) in PCa and control and DEGs2 in BCR and no BCR samples obtained by differential analysis were intersected with PMRGs to get candidate genes. After Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, biomarkers were identified to construct risk models. Biomarkers including In this study, PMRGs were regarded as biomarkers in PCa for risk model construction, which suggest that propionate metabolism represents a biologically relevant axis in PCa recurrence and may offer a novel framework for biomarker-driven risk assessment. Show less

The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. 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

Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells. Together, our results indicate that LYPLAL1 loss-of-function protects against MASLD in Europeans and in vitro, LYPLAL1 is an esterase for short-chain substrates which is involved in the regulation of mitochondrial β-oxidation and uptake of fatty acids, influencing lipid accumulation in the liver. Show less

Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear. To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7 First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM. Show less

The formation of subendothelial macrophage-derived foam cells is a key driver of atherogenesis and contributes to the onset and progression of atherosclerosis (AS). The METTL3 gene, a central mediator of N6-methyladenosine (m6A) RNA methylation, serves as a critical regulatory node at the inflammation-metabolism nexus in immune pathophysiology. This study aimed to investigate the METTL3-mediated regulatory mechanisms in subendothelial macrophage-derived foam cells formation and their association with necrosis and the pro-inflammatory properties of AS lesions. METTL3 expression was significantly higher in human carotid artery plaques compared to non-plaques. Macrophages treated with ox-LDL had an upregulated METTL3 expression, while its knockdown reduced lipid accumulation, foam cell formation, and inflammatory responses in macrophages. Myeloid Mettl3 knockout AS mice exhibited attenuated AS lesions. METTL3 knockdown elevated ABCA1, LXR-α, and ZNF771 expression. Gain- and loss-of-function studies demonstrated that METTL3 modulates lipid accumulation and inflammation partly through the ZNF771/LXR-α/ABCA1 axis. YTHDF2 knockdown increased ZNF771 levels, indicating that METTL3 cooperates with YTHDF2 to suppress ZNF771 expression, thereby inhibiting LXR-α transcription. Macrophage METTL3 exacerbates AS by suppressing cholesterol efflux and amplifying inflammation through YTHDF2-mediated downregulation of ZNF771, which attenuates the LXR-α/ABCA1 axis. Our study identifies a novel METTL3-dependent mechanistic link between foam cell pathology and plaque destabilization. Show less

Langya chickens, a Chinese indigenous breed, exhibit rich genetic resources but relatively low egg production performance. To investigate the genetic basis of egg production traits, we performed low-depth genome resequencing of 1,183 Langya hens and evaluated six phenotypic traits, including age at first egg (AFE), egg number at different laying stages-EN1 (from first egg to 26 weeks), EN2 (27-36 weeks), EN3 (37-43 weeks), total egg number at 43 weeks (E43), and maximal clutch length (MCL). Genetic parameter analysis revealed that MCL exhibited high heritability (0.42) and strong genetic correlations with both egg production and AFE, suggesting its potential as a more effective selection indicator for egg production traits. Genome-wide association studies identified a total of 245 SNPs associated with these traits. Notably, a 6.58 Mb region on chromosome 5 (GGA5, 40.03-46.61 Mb) was enriched for multiple traits and in strong linkage disequilibrium. Candidate genes in this core region, including TSHR, GTF2A1, DIO2, STON2, NRXN3, KCNK10, EML5, and FOXN3, were implicated in transcriptional regulation, thyroid hormone signaling, neuroendocrine modulation, and ovarian function. Additional trait-specific candidate genes, such as ATG2B for EN2, FMNL1 for EN1/EN2, TDP1 for E43, and TPMT for MCL, were also identified. Functional enrichment analyses highlighted pathways related to cellular processes, lipid metabolism, and signal transduction. These findings provide genomic insights into the molecular mechanisms underlying egg production traits and offer valuable candidate genes for marker-assisted breeding in Langya chickens. Show less

Although large-scale studies and potential pathways of genes on intramuscular fat (IMF) in livestock have been reported, research on circRNAs in yaks-a unique, low-IMF-content animal species that is native to the Qinghai-Tibetan Plateau-is still lacking. Based on previous high-throughput sequencing results on Show less

Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the synergistic effects of tirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a potential way for better maintenance of metabolic homeostasis in obesity management. Show less