👤 J-X She

Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less

Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanisms underlying lifespan and sarcopenia remain unclear. This study aimed to identify genes associated with longevity and muscle weakness and to characterize their shared genetic architecture. We integrated the largest genome-wide association studies (GWAS) on longevity (age > 90th: n = 11 262 cases; age > 99th: n = 3484 cases) and muscle weakness (European Working Group on Sarcopenia in Older People (EWGSOP): n = 48 596 cases; Foundation for the National Institutes of Health (FNIH): n = 20 335 cases) with Genotype-Tissue Expression (GTEx) v8 multi-tissue expression quantitative trait locus (eQTL) data. Gene-trait associations were evaluated using multi-tissue and single-tissue TWAS, and validated using Multi-marker Analysis of GenoMic Annotation (MAGMA). Mendelian randomization (MR) and colocalization were applied to test causality and shared variants. Cross-trait genetic correlation was estimated with LDSC, and pleiotropic loci were identified by pleiotropy analysis under the composite null hypothesis (PLACO) followed by Functional Mapping and Annotation (FUMA)/MAGMA annotation. Across TWAS approaches, APOC1 and TOMM40 were identified as longevity-associated genes, while DYM and TGFA were susceptibility genes for muscle weakness. In MR analysis, higher expression of APOC1 and TOMM40 increased the odds of longevity (OR > 1, p < 0.05), whereas higher expression of DYM and TGFA reduced the risk of muscle weakness (OR < 1, p < 0.05). Colocalization supported shared causal variants for APOC1 (rs429358, PP.H4 = 0.81) and TOMM40 (rs429358, PP.H4 = 0.85) with longevity (age > 90th survival percentile), and for DYM and TGFA with muscle weakness defined by both EWGSOP and FNIH (PP.H4 > 0.80). A significant negative genetic correlation was observed between longevity and muscle weakness (Rg < 0, p < 0.05). Cross-trait pleiotropy analysis identified several pleiotropic genes (PVRL2, PPP1R9A, SLC39A8 and the TOMM40/APOE/APOC1 gene cluster) that influence both longevity and muscle weakness. We identified susceptibility genes for longevity (APOC1, TOMM40) and muscle weakness (DYM, TGFA) and uncovered shared pleiotropic loci linking aging and muscle decline. These findings improve the understanding of the genetic architecture underlying aging-related phenotypes and provide potential molecular targets for promoting healthy aging and reducing late-life disability. Show less

DHX36 plays a crucial role in regulating transcriptional and post-transcriptional processes through its interaction with G-quadruplexes (G4s). The mechanisms by which DHX36 regulates G4s vary across different cell types and physiological conditions. Oocyte-specific conditional knockout (CKO) mice were utilized to study the impact of DHX36 deficiency on female fertility. The results show that the CKO mice exhibit severely impaired hormone response, ovulation, and complete infertility. The CKO germinal vesicle (GV) oocytes display large nucleoli, aberrant chromatin configuration, decreased chromatin accessibility, disturbed transcriptome, and inhibited meiosis progression. Following fertilization, the embryos derived from the CKO oocytes arrest at the zygote or 2-cell stage. Notably, we observed inadequate rRNA transcription in growing GV oocytes, as well as insufficient pre-rRNA processing and translation activity in fully-grown GV oocytes. Using a G4 probe and antibody, we found increased G4s formation at the chromatin and cytoplasm of CKO GV oocytes; these G4s mainly originate from the rDNA and pre-rRNA. Furthermore, the distribution of DHX36 was found to be spatiotemporally synchronized with that of pre-rRNA and G4s in early mouse embryos. In vitro experiments confirmed that DHX36 directly binds with pre-rRNA through the RHAU-specific motif (RSM). Overexpression of DHX36 could partially alleviate the pre-rRNA accumulation in fully-grown CKO oocytes. In conclusion, this study highlights the physiological significance of DHX36 in maintaining female fertility, underscoring its critical role in rRNA homeostasis and chromatin configuration through G4-unwinding mechanism in mouse oocytes. Show less

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less

Cancer-related fatigue (CRF) is a multifaceted and subjective phenomenon that significantly impacts patients on physical, emotional, and mental levels. This study aims to identify specific subtypes of Cancer-related fatigue (CRF) in patients with Hepatocellular Carcinoma (HCC) and to explore the factors influencing each subtype. This cross-sectional study enrolled 220 participants from a tertiary cancer hospital. Latent Profile Analysis (LPA) and multinomial logistic regression were conducted to identify distinct fatigue profiles and to explore the influencing factors for different categories of CRF among the patients. The analysis revealed three potential categories of CRF severity: Physical balance -Low fatigue (20.1%); Physical imbalance -Moderate fatigue (69.6%); and Physical prominent -High fatigue (10.2%). It was found that the severe insomnia the greater the probability of patients belonging to the Physical prominent -High fatigue (OR = 1.299, 95%CI: 1.188-1.419). Has partner (OR = 5.171, 95%CI: 1.739-15.377), the severe financial stress (OR = 2.570, 95%CI: 1.209-5.463) and the moderate ISI (OR = 1.212, 95%CI: 1.136-1.292) were associated with the Physical imbalance - Moderate fatigue group. Protective factors for the Physical balance - Low fatigue group included higher scores in the physical activity Index (OR = 0.930, 95%CI: 0.870-0.995), Hope Index (OR = 0.647, 95%CI: 0.552-0.758), General self-efficacy (OR = 0.874, 95%CI: 0.793-0.965), Body Mass Index (OR = 0.799, 95%CI: 0.552-0.758), and Child-Pugh A classification (OR = 0.310, 95%CI: 0.119-0.808). CRF in patients with HCC demonstrates significant heterogeneity. It is conducive to the clinical identification of CRF risk characteristics and the design of personalized intervention measures. Show less

The relationship between high-density lipoprotein (HDL) and atherosclerotic risk remains incompletely elucidated, potentially due to the inherent heterogeneity of HDL particles. Hypertriglyceridemia is associated with alterations in HDL composition. This study investigated the impact of elevated triglycerides (TG) on HDL and its association with coronary artery disease (CAD) risk using a large prospective cohort study and Mendelian randomization (MR). We found that elevated TG was associated with reduced HDL particle size, decreased concentrations of HDL components, and increased triglycerides in HDL (HDL-TG) (all P for trend < 0.001). The protective effects of HDL particle concentration and HDL cholesterol on CAD are attenuated with increasing serum TG levels. An independent and positive association between HDL-TG levels and incident CAD events (hazard ratio [HR] per 1 standard deviation increase: 1.066, 95% CI: 1.052-1.080, P < 0.001) was confirmed even after adjustment for established cardiovascular disease risk factors. MR analyses supported a causal role for HDL-TG in CAD development (inverse-variance weighted [IVW] method: odds ratios [ORs] of 1.120 (95% CI: 1.053-1.192, P < 0.001) and 1.141 (95% CI: 1.032-1.263, P = 0.010) for dataset groups 1 and 2, respectively). Drug-target MR analyses suggested a potential association between omega-3 fatty acids (OM3-FA) and lower HDL-TG levels, with LPL and DGAT2 as key pharmacological targets. Our findings suggest that elevated TG contributes to adverse alterations in HDL, elevating CAD risk. HDL-TG is an independent positive risk factor for CAD and a potential causal contributor to CAD development. OM3-FA supplementation may offer a therapeutic strategy for mitigating the CAD risk associated with elevated HDL-TG. Show less

Egg performance significantly impacts the development of the local goose industry. The hypothalamus plays an essential role in the egg production of birds. However, few potential candidate genes and biological functions related to egg production in geese have been identified in hypothalamus tissue. In this study, 115 geese were raised and observed for 5 months during the laying period. To understand the regulation mechanism of egg production, the hypothalamus transcriptome profiles of these geese were sequenced using RNA-seq. The hypothalamus samples of four high egg production (HEP) and four low egg production (LEP) geese were selected and collected, respectively. A total of 14,679 genes were identified in the samples. After multiple bioinformatics analyses, Gene Ontology (GO) annotations indicated that genes related to egg production were mainly enriched in biological processes of "response to light stimulus," "sensory system development," and "visual perception." Six potential candidate genes ( Show less

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism. Show less

Thymic epithelial tumors (TETs) are infrequent malignancies that arise from the anterior mediastinum. Therapeutic options for TETs, especially thymic carcinoma (TC), remain relatively constrained. This study aims to investigate the oncogenic hub gene and its underlying mechanisms in TETs, as well as to identify potential therapeutic targets. Weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis were utilized to identify significant oncogenes using The Cancer Genome Atlas (TCGA) database. LASSO logistic regression analysis was performed to assess the association between hub genes and clinical parameters. The influence of the hub gene on promoting epithelial-mesenchymal transition (EMT), tumor progression, and regulating cancer stem cell-like properties was assessed both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) was utilized to analyze the alterations in the tumor and its microenvironment following the administration of the hub gene's inhibitor. Multiplex immunohistochemistry (mIHC) was employed to validate the results. The potential mechanism was further elucidated through the utilization of Cleavage Under Targets and Tagmentation (CUT&Tag), RNA-sequencing, chromatin immunoprecipitation (ChIP), CUT&RUN, luciferase reporter assay, co-immunoprecipitation (Co-IP), mass spectrometry (MS) and phosphoproteomic assays. SNAI1 was identified as a hub transcription factor for TETs, and its positive correlation with the invasiveness of the disease was confirmed. Subsequent experiments revealed that the upregulation of SNAI1 augmented the migration, invasion, and EMT of TET cell lines. Furthermore, we observed that the overexpression of SNAI1 sustained cancer stem cell-like properties. ScRNA-seq demonstrated that the use of a SNAI1 inhibitor inhibited the transition of macrophages from M1 to M2 phenotype, a finding further validated by multiplex immunohistochemistry (mIHC). Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) was identified as one of the downstream targets of SNAI1 through CUT&Tag and RNA-sequencing, a finding validated by ChIP-qPCR, CUT&RUN-qPCR, luciferase reporter and immunofluorescence assays. Co-IP, MS and phosphoproteomic assays further confirmed that PIK3R2 directly interacted with phosphorylated EphA2 (p-EphA2), facilitating downstream GSK3β/β-catenin signaling pathway. The tumorigenic role of SNAI1 through the PIK3R2/p-EphA2 axis was preliminarily validated in TETs. A potential therapeutic strategy for TETs may involve the inhibition of SNAI1. Show less

The development of site-specific, target-selective and biocompatible small molecule ligands as a fluorescent tool for real-time study of cellular functions of RNA G-quadruplexes (G4s), which are associated with human cancers, is of significance in cancer biology. We report a fluorescent ligand that is a cytoplasm-specific and RNA G4-selective fluorescent biosensor in live HeLa cells. The in vitro results show that the ligand is highly selective targeting RNA G4s including VEGF, NRAS, BCL2 and TERRA. These G4s are recognized as human cancer hallmarks. Moreover, intracellular competition studies with BRACO19 and PDS, and the colocalization study with G4-specific antibody (BG4) in HeLa cells may support that the ligand selectively binds to G4s in cellulo. Furthermore, the ligand was demonstrated for the first time in the visualization and monitoring of dynamic resolving process of RNA G4s by the overexpressed RFP-tagged DHX36 helicase in live HeLa cells. Show less

Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXRα) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXRα acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXRα and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXRα Show less

In recent years, peri-organ fat has emerged as a diagnostic and therapeutic target in metabolic diseases, including diabetes mellitus. Here, we performed a comprehensive analysis of epicardial adipose tissue (EAT) transcriptome expression differences between diabetic and non-diabetic participants and explored the possible mechanisms using various bioinformatic tools. RNA-seq datasets GSE108971 and GSE179455 for EAT between diabetic and non-diabetic patients were obtained from the public functional genomics database Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were identified using the R package DESeq2, then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed. Next, a PPI (protein-protein interaction) network was constructed, and hub genes were mined using STRING and Cytoscape. Additionally, CIBERSORT was used to analyze the immune cell infiltration, and key transcription factors were predicted based on ChEA3. By comparing EAT samples between diabetic and non-diabetic patients, a total of 238 DEGs were identified, including 161 upregulated genes and 77 downregulated genes. A total of 10 genes (IL-1β, CD274, PDCD1, ITGAX, PRDM1, LAG3, TNFRSF18, CCL20, IL1RN, and SPP1) were selected as hub genes. GO and KEGG analysis showed that DEGs were mainly enriched in the inflammatory response and cytokine activity. Immune cell infiltration analysis indicated that macrophage M2 and T cells CD4 memory resting accounted for the largest proportion of these immune cells. CSRNP1, RELB, NFKB2, SNAI1, and FOSB were detected as potential transcription factors. Comprehensive bioinformatic analysis was used to compare the difference in EAT between diabetic and non-diabetic patients. Several hub genes, transcription factors, and immune cell infiltration were identified. Diabetic EAT is significantly different in the inflammatory response and cytokine activity. These findings may provide new targets for the diagnosis and treatment of diabetes, as well as reduce potential cardiovascular complications in diabetic patients through EAT modification. Show less

Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in Show less

During peripartum period, dairy cows are highly susceptible to energy metabolism disorders such as fatty liver and ketosis. Angiopoietin-like protein 4 (ANGPTL4) and fibroblast growth factor 21 (FGF21), known as hepatokines, play important roles in lipid metabolism. The purposes of our study were to evaluate variations of serum ANGPTL4 and FGF21 concentrations in periparturient dairy cows and changes in these serum analyte concentrations of energy-related metabolic disorders in early lactation dairy cows. This study was divided into two experiments. Experiment I: Blood parameters were measured in healthy periparturient Holstein cows from 4 wk antepartum to 4 wk postpartum (n = 219). In this experiment, weekly blood samples were obtained from 4 wk before the expected calving date through 4 wk after calving. Experiment II: Blood parameters were measured in healthy cows (n = 30) and cows with clinical ketosis (n = 29) and fatty liver (n = 25) within the first 4 wk of lactation. In the present study, all blood samples were collected from the coccygeal vein in the early morning before feeding. Serum ANGPTL4 and FGF21 concentrations peaked at parturition, and declined rapidly over the following 2 wk Serum ANGPTL4 and FGF21 concentrations were positively correlated with serum non-esterified fatty acids (NEFA) concentration (r = 0.856, P = 003; r = 0.848, P = 0.004, respectively). Cows with clinical ketosis and fatty liver had significantly higher serum ANGPTL4 and FGF21 concentrations than healthy cows (P < 0.01). Serum ANGPTL4 and FGF21 concentrations were elevated during peripartum period, suggesting that energy balance changes that were associated with parturition contributed significantly to these effects. Although FGF21 and ANGPTL4 could play important roles in the adaptation of energy metabolism, they may be involved in the pathological processes of energy metabolism disorders of dairy cows in the peripartum period. Show less

Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases. Show less

WWP2 (WW domain-containing protein 2) is an E3 ubiquitin ligase belonging to the NEDD4-like protein family involved in various cell regulations, such as carcinogenesis, transcription control and cellular transport. Compared with homologues, WWP2 is difficult to express and no practical protocols have been developed for WWP2 preparation in large scale. Recently, domain structures of homologues of WWP2 have been determined by crystallography and NMR, but none for WWP2 has been attained. In this work, through a combination of extensive screening of ∼100 constructs, expression strategies and host systems, we have found a soluble HECT domain truncation (WHP2) of WWP2 which is amendable for preparation scale expression in Escherichia coli. We have also established a relatively simple purification process to achieve highly pure WHP2 protein by employing immobilized metal-affinity chromatography followed by salting out, ion exchange chromatography and finally, size exclusion chromatography. We are able to obtain about 60mg/L of the soluble WHP2. The identity and structure of the expressed WHP2 have been analyzed by mass spectrometry and circular dichroism. The native ability of WHP2 to bind different partners has been revealed by pull-down assay. Show less

To investigate the effects of 2-methoxyestradiol (2-ME) on 2 myeloid leukemia cell lines HL-60 and U937, and to explore its mechanisms. Human myeloid leukemia cells HL-60 and U937 were used. Measurement of mitochondrial membrane potential (Dym) was performed using 5,5',6,6'-Tetrachloro-1,1',3,3'- tetraethylbenzimidazolylcarbocyanine iodide ( JC-1). Apoptosis and cellular nitric oxide (NO) were detected by flow cytometry using Annexin V and NO sensor dye. Superoxide anion was measured with a fluorescent plate reader by dihydroethidium (DHE). Cytotoxicity was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay. 2-ME resulted in viability decrease in a dose-dependent manner. 2-ME treatment also generated reactive oxygen species (ROS), including NO and superoxide anions, which resulted in mitochondria damage. 2-ME-induced apoptosis was correlated with an increase in ROS. The quenching of ROS with N-acetyl-L-cysteine protected leukemia cells from 2-ME cytotoxicity and prevented apoptosis induction by 2-ME. Furthermore, the addition of manumycin, a farnesyltransferase inhibitor, significantly enhanced apoptosis induced by 2-ME. Cellular ROS generation plays an important role in the cytotoxic effect of 2-ME. It is possible to use ROS generation agents, such as manumycin, to enhance the antileukemic effect. The combination strategy needs further in vivo justification and may have potential clinical application. Show less

The pathogenic mechanisms underlying Batten disease are unclear. Patients uniformly possess autoantibodies against glutamic acid decarboxylase (GAD) that are predominantly reactive with a region of GAD (amino acids 1 to 20) distinct from subjects with autoimmune type 1 diabetes or stiff-person syndrome. Batten patients did not possess autoantibodies against other type 1 diabetes-associated autoantigens and human leukocyte antigen genotypes revealed no specific associations with this disease. Show less