👤 Zhuangfei Tian

Physical activity, grip strength, sedentary behaviors, and sleep duration were found to be associated with risk of developing stroke and dementia. However, the combined influence of these factors on stroke and dementia remains unclear. To investigate the combined influence of these multiple lifestyle and functional factors on risk of stroke and dementia and their subtypes and to investigate the potential interaction between combined factors and the apolipoprotein E gene ε4 allele ( Data were obtained from the UK Biobank, including 474,983 participants. A score ranging from 0 to 4 was assigned based on adherence to healthy factors: meeting physical activity recommendations, grip strength above the sex-specific median, sleep duration of 7–8 h/day, and sedentary time < 6 h/day. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for incident stroke and dementia, adjusting for potential confounders. Over a median follow-up of 10.1 years, 4,992 incident strokes and 2,120 dementias were recorded. Compared with participants with 0–1 healthy factor, adjusted HRs (95% CIs) for total stroke were 0.85 (0.79–0.92), 0.71 (0.66–0.77), and 0.65 (0.59–0.72) for those with 2, 3, and 4 healthy factors, respectively (P-trend < 0.001). Similar inverse associations were observed for ischemic stroke and intracerebral hemorrhage but not subarachnoid hemorrhage. For dementia, HRs (95% CIs) were 0.74 (0.66–0.83), 0.64 (0.56–0.71), and 0.43 (0.39–0.51) across increasing numbers of healthy factors ( The cumulative association of multiple healthy factors with reduced risk of stroke and dementia highlights the importance of adopting a lifestyle with more elements of healthy factors for the prevention of these neurological diseases. The online version contains supplementary material available at 10.1186/s12889-025-25305-4. Show less

Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This study comprehensively identified ASassociated genes by integrating data from the Gene Expression Omnibus (GEO) database and expression quantitative trait locus (eQTL) analyses, complemented by Mendelian randomization (MR) analysis, followed by experimental validation of their functional roles. Results indicated significant upregulation of CLEC5A and ISG20 in patients with AS, with MR analysis revealing positive causal relationships between both genes and AS risk (CLEC5A: OR = 1.001, P = 0.047; ISG20: OR = 1.001, P = 0.030), while HOXA2 showed a negative causal association. Functional enrichment analysis highlighted CLEC5A and ISG20's involvement in immune responses, inflammatory pathways, and lipid metabolism regulation. Experimental validation in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages and apolipoprotein E-deficient (ApoE This study represents the first to elucidate the molecular mechanism by which ISG20 promotes AS progression through macrophage lipid accumulation and inflammatory responses, positioning it as a potential novel therapeutic target for AS. Show less

The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptors and act as universal adaptor proteins to mediate the activation of key downstream signaling pathways. However, it remains unclear whether and how Gαi1/3 proteins mediate Wnt/β-catenin signal transduction. In this study, we utilized single-cell sequencing analysis and employed viral transfection and gene editing techniques to alter the expression of Gαi1/3 in mouse embryonic osteoblast precursor cells. We examined the relationship between Gαi1/3 expression and the Wnt/β-catenin signaling pathway. Immunoprecipitation and confocal experiments were conducted to further explore the mechanisms by which Gαi1/3 exerts its functions. Osteogenic-related protein levels were detected by Western blotting, and the effects of Gαi1/3 proteins on osteogenic function were examined through alkaline phosphatase and Alizarin red staining. Additionally, micro-CT was used to compare bone mass in mice with different levels of Gαi1/3 expression, showing the relationship between Gαi1/3 and bone formation. Our findings indicate that Gαi1/3 proteins are significantly inversely correlated with age. Gαi1/3, rather than Gαi2, mediates the Wnt/β-catenin signaling pathway and promotes osteogenesis. Mechanistically, Gαi1/3 interacts with Axin1 and recruits it to the cell membrane, leading to inactivation of the β-catenin degradation complex. This results in β-catenin accumulation and nuclear translocation, where it activates the transcription of osteogenic genes. In vivo experiments further confirm that knockdown of Gαi1/3 significantly inhibits bone formation in mice. Our study identified Gαi1/3 as key regulatory proteins in Wnt/β-catenin signaling-mediated osteogenesis, and further elucidated its molecular mechanism in bone formation, which may provide a new therapeutic target for osteoporosis. Show less

Patients with Alzheimer's disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a Show less

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its degradation through ubiquitin-proteasome and autophagy-lysosomal pathways. BAG3 Show less

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD. Show less

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans. Show less

More than the sparse infiltration in glioblastoma, cytotoxic T lymphocytes (CTLs) also function inefficiently and overexpress the inhibitory markers, especially the identified NK cell receptor (NK1.1). However, most studies solely focus on how to augment tumor-infiltrating CTLs and overlook their killing maintenance. Metalloimmunotherapy has been proven to improve the functionalities of CTLs, but it has barely adapted to glioblastoma due to the severe limitations of safe delivery and the brain's physiological properties. Herein, we synthesized an amphipathic polyethylene glycol (PEG) polymer (designated as MPP) modified with the choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) and polyphenol moieties to customize a nanoeditor (Mg Show less

Obesity is a chronic inflammatory disorder, which promotes the progression of metabolic disorders. MicroRNA (miR)-6838-5p is dysregulated and participates in the progression of several disorder models. To explore the role and mechanism of miR-6838-5p in insulin resistance. Mice were fed with high-fat diet (HFD) to construct an obesity animal model. The role of miR-6838-5p was evaluated by insulin tolerance test (ITT), glucose tolerance test (GTT), homeostasis model assessment of insulin resistance (HOMA-IR) analysis, enzyme-linked immunosorbent assay (ELISA) and western blot assays. The potential target of miR-6838-5p was screened through the starBase online website and confirmed by the luciferase assay. HFD supply induced a prominent increase in the body weight, white adipose tissue (WAT) weight, the area under the curve (AUC) of GTT and ITT, HOMA-IR, the serum level of insulin and the serum concentrations and relative protein levels of interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) accompanied with reduced levels of IL-10 in mice. The level of miR-6838-5p was reduced in HFD-fed mice. Upregulation of miR-6838-5p partly reversed the above-mentioned indicators. Moreover, miR-6838-5p directly targeted to β-site amyloid precursor protein cleaving enzyme1 (BACE1) and negatively regulated the BACE1 expression. Downregulation of BACE1 improved insulin sensitivity and inflammatory mediators release involving in AKT/GSK3β signaling pathway in HFD-fed mice. Besides, overexpression of BACE1 counteracted the depressant role of miR-6838-5p overexpression in insulin resistance and inflammatory factors release in HFD-fed mice. MiR-6838-5p/BACE1 axis regulated insulin resistance and inflammatory factors release in HFD-fed mice. Show less

RNA interference (RNAi) harbors significant potential for treating neurological disorders; nevertheless, limited efficacy has been discerned. The presence of barriers within the central nervous system, coupled with the inherent instability of nucleic acids within biological conditions, poses formidable challenges in advancing effective gene delivery strategies. In this study, we designed and prepared a virus-mimic non-viral gene vector, rabies virus glycoprotein (RVG29)-decorated liposome (f(Lipo)-RVG29), to deliver small interfering RNAs to the brain. Alzheimer's disease (AD) was chosen as a model of neurodegenerative disease in this context, and b-site APP cleaving enzyme silencing siRNA (siBACE1) was used. The developed liposomal delivery system has a particle size of under 80 nm with a spherical shape, positive zeta potential, and the ability to protect siRNA against nucleases. In vitro studies demonstrate that functionalizing the cationic liposome by the RVG29 targeting ligand significantly enhances the effectiveness of gene delivery and silencing. Examination through ex vivo imaging illustrates an increased deposition of fluorescent-labeled f(Lipo)-RVG29 within brain tissue after 12 h post application. Additionally, the in vivo delivery of f(Lipo)-RVG29 carrying siRNA has substantially suppressed BACE1 expression at both mRNA and protein levels within the brain tissue. Our results suggest that the developed non-viral vector could be a promising gene carrier system combining the synergistic effect of virus-mimic RVG29 ligand with bioinspired liposome that imitates the natural lipid bilayers of cell membranes for brain-targeted RNAi therapeutics. Show less

By integrating single-cell and bulk RNA-sequencing data for esophageal cancer (ESCA), we developed and validated a seven-macrophage-gene prognostic signature (FCN1, SCARB2, ATF5, PHLDA2, GLIPR1, CHORDC1, and BCKDK). This signature effectively stratified patients into high- and low-risk groups with significantly different overall survival, achieving area under the curve (AUC) values greater than 0.7 for 1-, 2-, and 3-year survival prediction. A high-risk status correlated with an immunosuppressive tumor microenvironment, characterized by lower infiltration of B cells and CD8 + T cells, and was associated with reduced sensitivity to multiple chemotherapeutic agents, including Cisplatin and 5-Fluorouracil. Conversely, a low-risk status was linked to greater immune cell infiltration and higher predicted chemosensitivity. At the single-cell level, pseudotime analysis revealed that macrophage maturation significantly correlated with a decreasing risk score, suggesting that mature macrophages may contribute to a favorable prognosis. Furthermore, cell communication analysis identified high-risk macrophages as dominant drivers of a pro-tumorigenic microenvironment via signaling pathways, such as SPP1 and complement. In conclusion, this seven-gene signature is a robust prognostic biomarker that offers a new strategy for personalized risk assessment and treatment selection in ESCA. The online version contains supplementary material available at 10.1007/s13205-025-04452-w. Show less

Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK-mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK-mediated phosphorylation of AKT decreases ubiquitin-mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient-derived organoids (PDOs), enhances doxorubicin-induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention. Show less

Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive metabolic abnormality cause by dysfunctionality of CPS1 and often result in unfavorable outcome. In this study, we presented the detailed laboratory features and genetic analysis of two patients with heterozygous variants of CPS1, c.1927 A > G (p.Asn643Asp), c.2375 T > G (p.Met792Arg), c.3443 T > A (p.Met1148Lys) in patient 1; c.3784C > T (p.Arg1262Ter), c.3734 T > A (p.Leu1245His) in patient 2, respectively. c.1927 A > G (p.Asn643Asp) and c.2375 T > G (p.Met792Arg) are novel out of 5 variants and classified as variants of uncertain significance (VUS) under the guidelines of ACMG/AMP-ClinGen. Structure-based analysis of 4 missense variants indicates deleterious alterations to the protein. Since the employment of genetic testing as a clinical diagnostic tool, distinguishing pathogenic from polymorphic changes poses significant problems for geneticists. As recommendation for PP3/BP4, the computational tools for missense variant have been published, we performed a comparative evaluation for pathogenicity interpretation in our patients and in ClinVar database regarding CPS1 missense variants under the updated guidelines of ACMG/AMP-ClinGen. The application of computational tools under the ACMG/AMP-ClinGen criteria revealed an increased sensitivity for pathogenicity evaluation, from variants of uncertain significance (VUS) to likely pathogenic (LP) in previously reported cases; while for variants without clinic information in the ClinVar database, the pathogenicity assessment of VUS remained, and shows a more optimistic and reliable clinical application in molecular diagnosis. Show less

1. Copy number variation (CNV) is an important source for identifying genetic differences. This study compared the genome-wide CNV and their regions (CNVR) across 16 Chinese local duck breeds and detected key genes and pathways involved in growth and reproduction-related traits using this dataset.2. Breakdancer, Pindel and CNVnator were used to detect reliable CNV, and HandyCNV was used to obtain CNVR. Selection signatures were analysed in meat (MD) and egg-laying ducks (ED) compared to wild ducks (WD) using fixation and differentiation index DIsv methods. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to identify key pathways and related genes.3. Principal component analysis (PCA) using CNV data clustered 127 ducks into 4 populations: WD, MD, ED and meat+egg-type ducks (MED). In total, 237,630 CNV and 6,176 CNVR were detected across these samples. Intersection analysis identified 1,384 common CNVR and 2,105 unique CNVR. The KEGG analysis showed that common CNVR were enriched in 7 basic life activity pathways, while unique CNVR were enriched in 9 population-specific pathways. Compared to WD, MD selection signatures were found in 4 enriched pathways and 8 genes ( 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 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

Background Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1(MLN-FGFR1), also referred to as 8p11 myeloproliferative syndrome (EMS), arises from aberrant FGFR1 gene rearrangement in bone marrow hematopoietic stem cells, resulting in the transformation of myeloid/lymphoid cells into neoplastic growths. The clinical and laboratory features of affected individuals are influenced by the specific partner genes. Purpose This article aims to report a case of MLN-FGFR1 involving a novel CNTRL::FGFR1 splicing variant and to discuss its clinicopathological characteristics and treatment challenges. Methods/Results We report a case of MLN-FGFR1 in a 35-year-old male patient presenting with leukocytosis, lymphadenopathy, hepatosplenomegaly, and a mixed population of B lymphoblasts, T lymphoblasts, and monoblasts in the bone marrow and lymph nodes. Comprehensive molecular profiling, including chromosomal karyotyping, fluorescence in situ hybridization (FISH), targeted transcriptome sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing, identified a novel splicing variant of the CNTRL::FGFR1 fusion, resulting from a t(8;9)(p11;q33) translocation. This novel splicing variant involves an in-frame fusion between exon 38 of CNTRL and exon 11 of FGFR1, retaining the kinase domain of FGFR1 and leading to its constitutive activation. Despite multiple treatment regimens, the patient failed to achieve complete remission (CR). Conclusion The findings highlight the urgent need for targeted therapies, such as FGFR inhibitors, to improve outcomes in patients with FGFR1-rearranged malignancies. Show less

This article aims to analyze the safety and efficacy of Erdafitinib in the treatment of patients with advanced solid tumors harboring FGFR1-4 mutations. Search for relevant articles in databases such as PubMed, Embase, The Cochrane Library, Web of Science, and CNKI, covering the period from their establishment to October 25, 2024. Summarize the adverse drug reaction (AE) data, overall survival (OS), median progression-free survival (PFS), objective response rate (ORR), and other relevant data for patients with advanced solid tumors treated with Erdafitinib for FGFR1-4 mutations. Conduct a meta-analysis on the corresponding summarized data using the software Stata 18.0. Through our search, we identified a total of 10 articles involving 1019 patients. In urothelial carcinoma, the most prevalent adverse reactions are hyperphosphatemia (78.5%), diarrhea (56.5%), and stomatitis (51.1%). The most frequently reported adverse reactions in other solid tumors are hyperphosphatemia (66.5%), dry mouth (48.5%), and diarrhea (44.9%). Patients with urothelial carcinoma treated with Erdafitinib exhibit higher median progression-free survival (PFS) and objective response rate (ORR) compared to those treated with other solid tumor therapies. Current evidence indicates that Erdafitinib exhibits certain therapeutic efficacy in the treatment of advanced solid tumors harboring FGFR1-4 mutations, with the most pronounced therapeutic effect observed in urothelial carcinoma. The efficacy of Erdafitinib in treating other solid tumors requires further confirmation through larger-scale studies involving a broader range of FGFR1-4 mutant tumors. Show less

Parkinson's disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca Show less

Osteosarcoma (OS) is the most prevalent primary malignant bone sarcoma, characterized by its high rates of metastasis and mortality. In our previous multiomics analysis of the Shanghai General Hospital OS (SGH-OS) cohort, we identified four distinct OS subtypes, each with unique molecular characteristics and clinical outcomes. Of particular importance was the identification of the MYC-driven subtype, which exhibited the poorest prognosis and was referred to as high-risk OS. A diagnostic tool is needed for clinicians to identify high-risk OS in advance. The purpose of this study is to develop a classifier capable of accurately predicting the high-risk OS subtype using transcriptome and methylation data. In this study, using eXtreme Gradient Boosting (XGBoost) with Bayesian optimization, we developed a classification model by integrating transcriptome and methylation data from our internal SGH-OS cohort. We further validated the model's predictive performance with the external TARGET-OS cohort. Using the XGBoost algorithm, we developed a classifier incorporating nine genes (ARHGAP9, CADM1, CPE, DUSP3, FGFR1, GALNT3, IGF2BP3, KIF26A, ZFP3). In our internal cohort, the classifier exhibited excellent predictive performance, with an area under the receiver operating characteristics curve (AUC) of 0.999 and an overall accuracy of 0.989. Furthermore, the classifier successfully stratified two groups with distinct survival outcomes in the external TARGET-OS cohort. Notably, our analysis revealed a positive correlation between IGF2BP3 and MYC signaling pathways, highlighting IGF2BP3 as a potential therapeutic target in high-risk OS. Our classifier demonstrated excellent predictive performance in identifying patients with high-risk OS, offering the potential to enhance treatment decision making and optimize patient management strategies. Show less

Cardiac ischemia/reperfusion (I/R) induces systemic oxidative stress, which in turn gives rise to the development of multiple organ abnormalities, including brain injury. The paraventricular nucleus (PVN) of the hypothalamus is a cardiovascular regulatory center. Aerobic exercise is an effective intervention to protect the heart against I/R injury. However, the effect of aerobic exercise on cardiac I/R-induced neuronal injury in the PVN has not been fully elucidated. The aim of this study is to investigate whether aerobic exercise can up-regulate fibroblast growth factor 21 (FGF21) and alleviate neuronal oxidative stress and ferroptosis in the PVN caused by cardiac I/R. In vivo, after six weeks of aerobic exercise, the cardiac I/R model was established by ligating the left anterior descending (LAD) coronary artery for 30 min, followed by 2 h of reperfusion. Cardiac function and heart rate variability (HRV) were measured. Morphological changes, oxidative stress, expression of FGF21 and its downstream signaling molecules, as well as ferroptosis-related indicators in the PVN, were evaluated. In vitro, HT22 cells were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) and treated with recombinant human FGF21 (rhFGF21) and compound C to elucidate the potential mechanism. Cardiac I/R induced iron deposition, elevated expression of lipid peroxidation drivers, and impaired antioxidant capacity in the PVN, which collectively contributed to neuronal ferroptosis. Aerobic exercise up-regulated the expression of FGF21, FGFR1, and PGC-1α, maintained the phosphorylation of AMPKα, enhanced antioxidant capacity, reduced ROS and lipid peroxidation, regulated iron homeostasis, and effectively attenuated neuronal ferroptosis induced by cardiac I/R. In addition, rhFGF21 protected HT22 cells against OGD/R-induced oxidative stress and ferroptosis, which was blocked by AMPK inhibition. FGF21 plays a pivotal role in regulating neuronal oxidative stress and ferroptosis. Aerobic exercise could increase the expression of FGF21, FGFR1, and PGC-1α, maintain the phosphorylation of AMPKα, and alleviate cardiac I/R-induced neuronal oxidative stress and ferroptosis. These results confirm the protective effect of aerobic exercise against cardiac I/R-induced brain injury and provide an experimental basis for studying the relationship between exercise and the "heart-brain axis." Show less

While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC Show less

Cadmium (Cd) is a toxic heavy metal which induces vascular disorders. Previous studies suggest that Cd in the bloodstream affects vascular endothelial cells (ECs), potentially contributing to vascular-related diseases. However, the molecular mechanisms of effects of Cd on ECs remain poorly understood. Notch signaling pathway abnormalities have been implicated in ECs disruption. The present study aims to investigate the effect of low Cd concentrations on the Notch signaling pathway in ECs. Mice were treated with low concentration of Cd (2.28 mg/kg), and tissues were collected for examination of mRNA and protein levels of Notch pathway components and VE-cadherin, a major junctional protein in ECs. We found that Cd treatment increases expression of NICD1, Hes1, Hey1, Hey2 and decreases expression of VE-cadherin in brain and kidney tissues. In vitro, a low concentration of Cd (1 μM) also induces increase expression of NICD1, Hes1, Hey1, Hey2, and decrease expression of VE-cadherin in human umbilical vein endothelial cells (HUVECs). Low concentration of Cd increased the permeability of HUVECs. We also found that Notch signaling negatively regulates the expression of VE-cadherin. In addition, DAPT, a Notch pathway inhibitor, prevents Cd-induced reduction in VE-cadherin expression in HUVECs. In summary, these findings revealed that Cd exposure decreases VE-cadherin expression through activation of the Notch signaling pathway. Show less

Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less

Magnetic resonance imaging and circulating molecular testing are potential methods for diagnosing and treating Parkinson's disease (PD). However, their relationships remain insufficiently studied. Using genome-wide association summary statistics, we found in the general population a genetic negative correlation between white matter tract mean diffusivity and PD (-0.17 < Rg < -0.11, p < 0.05), and a positive correlation with intracellular volume fraction (0.12 < Rg < 0.2, p < 0.05). Additionally, 1345 circulating genes causally linked with white matter tract diffusivity were enriched for muscle physiological abnormalities (padj < 0.05). Notable genes, including LRRC37A4P (effect size = 15.7, p = 1.23E-55) and KANSL1-AS1 (effect size = -15.3, p = 1.13E-52), were directly associated with PD. Moreover, 23 genes were found linked with genetically correlated PD-IDP pairs (PPH4 > 0.8), including SH2B1 and TRIM10. Our study bridges the gap between molecular genetics, neuroimaging, and PD pathology, and suggests novel targets for diagnosis and treatment. Show less

Psychological empowerment is a critical factor for employee work well-being, particularly within high-stress professions such as policing. However, experiences of empowerment among individuals are not uniform. This study aims to identify distinct profiles of psychological empowerment among police officers and to examine their associations with perceived coworker support and work well-being. A person-centered approach was adopted. Data were collected from 505 Chinese police officers. Latent Profile Analysis (LPA) was employed to identify subgroups based on their psychological empowerment patterns. The analysis revealed two distinct profiles: a "Globally Disempowered" profile and a "Globally Empowered" profile. Perceived emotional support from coworkers was a significant predictor of profile membership, where higher levels of support increased the likelihood of belonging to the empowered group. Furthermore, officers in the high empowerment profile reported significantly greater work well-being compared to those in the low empowerment profile. The findings underscore the heterogeneity in psychological empowerment experiences within the policing context. They emphasize the pivotal role of fostering emotional peer support as a means to enhance officers' psychological empowerment and, consequently, their work well-being. Practical implications for organizational interventions are discussed. Show less

Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising intervention for Autism Spectrum Disorder (ASD), but objective markers for rTMS tolerance remain lacking. This case-control study explored gaze behavior variability toward emotional faces in ASD children undergoing rTMS, focusing on identifying subgroups associated with rTMS intolerance. Eye-tracking data (Tobii technology, preferential-looking paradigm) were collected from 104 ASD children (48 intolerant, 56 tolerant) receiving DLPFC-targeted rTMS (left high-frequency, right low-frequency). Latent Profile Analysis (LPA) identified fixation subgroups across eight conditions. Demographic (sex, age), clinical (CARS scores) differences, and profile-tolerance associations were analyzed. LPA revealed three gaze profiles: moderate non-preferential fixation (80.76%), low diverse fixation (9.62%), and increased fixation with mild variability (9.62%). Sex and CARS scores differed across profiles (age did not). Intolerance rates were 38.1%, 60.0%, and 100%, with profiles predicting rTMS intolerance (OR = 0.210, 95% CI: 0.079-0.557). ASD children exhibit heterogeneous emotional face gaze patterns. Findings highlight the need for personalized rTMS interventions, especially for those with higher CARS scores and increased emotional face fixation-at elevated intolerance risk. Show less

Exploring how different profiles of academic task values (ATVs) and academic achievement (AA) influence students' school satisfaction should enrich understanding of how school satisfaction develops in specific academic situations. This study aimed to identify profiles of ATV (attainment value [AV], utility value [UV]) and AA, as well as heterogeneous trajectories of school satisfaction, and then examine the joint predictive effects of ATV and AA on the development of school satisfaction. A total of 3548 Chinese elementary school students (M Data were collected through self-reports of ATVs and school satisfaction, while AA data were collected from final examination scores at the end of each semester. Latent profile analysis (LPA) and latent class growth analysis revealed six profiles of ATV and AA (i.e., congruent subgroups: congruent-low, congruent-high, congruent-moderate and incongruent subgroups: high ATV-low AA, lower UV-moderate AA, low ATV-moderate AA); and four heterogeneous trajectories of school satisfaction (i.e., high-decreasing, low-stable, high-stable, low-increasing). Latent transition analysis (LTA) indicated that students with congruent levels of AA and ATV were more likely to transition into the optimal school satisfaction groups (high-stable and low-increasing groups), whereas students with greater gaps between AA and ATV were more likely to transition into the adverse groups (i.e., low-stable and high-decreasing groups). These findings highlight the need for educators to tailor interventions to distinct groups to optimize students' school satisfaction. Show less

Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less

This study aimed to analyse the latent profiles of moral sensitivity of nursing students and to explore the different types of influencing factors. A cross-sectional study. Convenience sampling method was used to select nursing students from five hospitals in Zunyi City, Guizhou Province, from July to September 2024. The demographic characteristics questionnaire and the Chinese version of the Nursing Student Moral Sensitivity Scale (MSQ-ST) were used as survey tools. Latent profile analysis (LPA) was performed on the moral sensitivity of nursing students. Logistic regression was used to analyse the influencing factors of different profiles. A total of 805 nursing students completed the questionnaire, of which 787 were valid, with a validity rate of 97.76%. The results of latent profile analysis showed that the moral sensitivity of nursing students was divided into two latent profiles: "low moral sensitivity group" (18.68%) and "high moral sensitivity group" (81.32%), and the results of logistic regression analysis showed that the level of hospital, the length of internship and the frequency of training on moral education were the factors influencing the moral sensitivity of nursing students (p < 0.05). In this study, we have demonstrated that there are two categories of moral sensitivity in nursing students, and that demographic traits have an impact on moral sensitivity in nursing students. These findings may provide a valuable theoretical foundation for nursing educators in developing the moral awareness of nursing students. No patient or public contribution. Show less

The competency of specialist nurse clinical educators is crucial for the effectiveness of specialist nurse training programmes. However, variability in teaching competency and training needs among educators remains insufficiently studied, especially in the context of rapidly evolving healthcare education in China. This study aimed to identify distinct core competency profiles among clinical educators for specialist nurses, examine associated socio-demographic factors, and explore differences in training needs across profiles. A cross-sectional online survey was conducted with 3,945 specialist nurse clinical educators from 30 Chinese regions. The Chinese version of the Nurse Educator Core Competency Scale (NECCS) and a self-developed training needs questionnaire were used. Latent Profile Analysis (LPA) identified competency subgroups, while multinomial logistic regression and Kruskal-Wallis tests examined associated variables and training needs. Latent Profile Analysis identified three competency profiles: foundational (8.6%), intermediate (43.0%), and advanced (48.4%), with mean scores of 43.89, 68.24, and 91.68, respectively. Educators without prior training were significantly more likely to belong to the foundational (OR = 3.195, p < 0.001) and intermediate (OR = 1.676, p < 0.001) groups compared to those with training experience. Advanced-competency educators showed the highest demand for curriculum design training, with 75% rating it as highly necessary. In contrast, educators in the intermediate group identified clinical teaching methods and techniques as their top training need (58.7%). Those in the foundational group prioritised common pedagogical methods and instructional technologies (54.7%). Clinical educator competencies vary by background characteristics and training exposure. Tailored, competency-based training is needed to address these gaps and enhance the quality of specialist nursing education. Show less