Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmo Show more
Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmonella based therapeutic method for targeted drug delivery and long-term treatment is herein designed to mitigate ischemic damage. We engineered an attenuated luminescent Salmonella typhimurium (S.t -ΔpG) strain with an L-arabinose-inducible pBAD system to secrete bioactive FGF21. C57BL/6 mice were used to to measure neuron apoptosis and the activity of immune cells following IS induction plus S.t-ΔpG injection. Bioluminescence imaging was applied for bacterial colonization. ELISA and glucose uptake assays were performed to detect FGF21 secretion and the bioactivity. Neurological tests, TTC staining, and TUNEL labeling were used to assess the therapeutic effects of barterially secreted FGF21. Immunofluorescence assay of FGF21/FGFR1 dominant pathway was explored to investigate neuroprotective mechanism, while IBA-1 staining, CD3/CD68 immunostaining, cytokine profiling, and hepatorenal histopathology were detected to evaluate biosecurity. S.t-ΔpG Our study presents a novel, Salmonella - based platform for targeted and sustained FGF21 delivery, offering a promising therapeutic strategy for ischemic stroke with robust efficacy and minimal systemic toxicity. Show less
A crucial aspect of the association involving inflammation and the development of cancer is the ability of cancer cells to undergo a transition into mesenchymal cells. The process is referred to as ep Show more
A crucial aspect of the association involving inflammation and the development of cancer is the ability of cancer cells to undergo a transition into mesenchymal cells. The process is referred to as epithelial-mesenchymal transition (EMT). Cytokines and chemokines, which are inflammatory agents found in the carcinoma microenvironment, induce epithelial-mesenchymal transition (EMT) changes in malignant cells. Evaluating the role of cytokines in EMT in breast carcinoma and investigating their potential therapeutic implications is the objective of this comprehensive research report. The following search criteria were applied to the Cochrane, Embase, PubMed, and Web of Science databases: "cytokines," "the cytokines," "chemokines," "EMT," "epithelial-mesenchymal transition or transformation," "breast tumor," "breast carcinoma," and "breast cancer." A body of research comprising 54 articles has demonstrated that a number of cytokines, including TNF-α, TGF-β, and IL-6, contribute to the promotion of EMT alterations in breast tumors. The epithelial markers E-cadherin and β-catenin were downregulated as a consequence of morphological changes induced by EMT; conversely, the mesenchymal markers N-cadherin, vimentin, and fibronectin were upregulated. The EMT transforming factors (EMT-TF) TWIST/ZEB/SNAI1/SNAI2 were upregulated. Pharmaceuticals with the capacity to specifically target cytokines or their epithelial-mesenchymal transition (EMT) signalling pathways have the potential to significantly reduce treatment resistance, impede the progression of cancer, and prevent the recurrence of breast cancer. Epithelial-mesenchymal transition (EMT) induced by cytokines is a factor in breast cancer progression and metastasis. Show less
Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architect Show more
Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined. We obtained genome-wide association study (GWAS) summary statistics for GERD (71 522 cases and 261 079 controls) and asthma (56 167 cases and 352 255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional Mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based MR and transcriptome-wide association study were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data. We identified a significant genetic correlation between GERD and asthma ( rg = 0.37, P = 6.19 × 10 -38 ) and a significant causal effect of GERD on asthma [odds ratio (OR) = 1.22, P = 1.54 × 10 -5 ]. Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes ( RBM6, SUOX , and MPHOSPH9 ) between GERD and asthma. scRNA-seq analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD. Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases. Show less
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were appr Show more
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From Show more
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing. Show less
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R Show more
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD. Show less
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our gen Show more
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced Show more
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunc Show more
The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts. The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling. The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders. Show less
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understandin Show more
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less
The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascu Show more
The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients. Show less
Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achiev Show more
Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achieve satisfactory outcomes. Therefore, it is imperative that we approach the progress of AMD from novel perspectives in order to explore new therapeutic strategies. We obtained transcriptomic data from the macular and the peripheral retina from patients with AMD and a control group from the Gene Expression Omnibus (GEO) database. Through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified differentially expressed genes (DEGs) that were significantly enriched in functions associated with ferroptosis. Subsequent application of machine learning techniques enabled the identification of key hub genes, whose diagnostic potential was further validated. Additionally, the expression of these hub genes was corroborated in both animal and cellular models. Finally, we performed a functional enrichment analysis of these hub genes. In the macula of patients with AMD, 452 DEGs were identified, while in the peripheral retina, 222 DEGs were discovered. Within the macula, 19 genes were associated with ferroptosis, compared to 3 in the peripheral retina. Consequently, the macular was selected as the primary focus of the study. Subsequent screening of these 19 genes using LASSO regression, Support Vector Machine (SVM), and Random Forest algorithms identified four hub genes: FADS1, TFAP2A, AKR1C3, and TTPA. Consequently, we utilized cigarette smoke extract (CSE) to either stimulate retinal pigment epithelial (RPE) cells in vitro or administer it via intravitreal injection, thereby establishing in vitro and in vivo models of AMD. Results from RT-PCR and Western blot analyses revealed an upregulation of FADS1, AKR1C3, and TTPA, while TFAP2A exhibited decreased expression. Finally, we investigated the infiltration of immune cells within the macular and performed a functional enrichment analysis of the hub genes. We identified four key ferroptosis-related genes (FRGs)-FADS1, AKR1C3, TFAP2A, and TTPA-that possess diagnostic relevance for AMD and correlate with immune cell infiltration. Moreover, significant changes in both mRNA and protein expression levels of these genes have been observed in in vitro experiments and mice models. Show less
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. Howeve Show more
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain. Show less
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a de Show more
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hep Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application. Show less
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphon Show more
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphone-poses significant challenges to students' learning and daily life. Prior research on nomophobia has predominantly adopted a variable-centered perspective. However, if nomophobia is heterogeneous across subgroups, acknowledging this heterogeneity may inform the advancement of more tailored and productive therapeutic methods. Latent profile analysis (LPA) was conducted separately among high school students (N = 446) and college students (N = 667) to identify potential subgroup heterogeneity in nomophobia. To examine cross-group similarities in nomophobia profiles, a multi-group LPA was employed. Based on multiple model fit criteria, a three-profile solution-high nomophobia, moderate nomophobia, and low nomophobia-was identified for both groups. However, the multi-group LPA provided only partial support for the similarity of nomophobia profiles across educational stages, specifically in terms of configural and dispersion similarity. While similar nomophobia profiles emerged across groups, the partial equivalence suggests that intervention strategies for nomophobia may not be universally applicable across different educational levels. Additional studies should investigate the mechanisms underlying students' nomophobia profiles and to inform differentiated interventions for educators, institutions, and policymakers. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
This study aims to investigate the molecular differences and commonalities between systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) by analyzing RNA-sequencing (RNA-seq) data. By focusi Show more
This study aims to investigate the molecular differences and commonalities between systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) by analyzing RNA-sequencing (RNA-seq) data. By focusing on differentially expressed genes and enriched pathways, the investigation seeks to identify unique biomarkers, shared pathways, and potential therapeutic targets for these autoimmune diseases. This study involved 10 patients with SSc and 24 with SLE who did not receive immunosuppressants. RNA-seq data from patients with SSc and SLE were analyzed using DESeq2 to identify differentially expressed genes. Functional and pathway enrichment analyses were conducted and comparative analyses were performed. We identified 2055 differentially expressed genes (DEGs) between patients with SSc and controls. Notably, the expression of the shared gene RGS5 was significantly downregulated in both SLE and SSc, with a more pronounced downregulation in SSc. Additionally, the expression of the key transcription factor EGR1 was upregulated in SSc, whereas that of BLK, ITGAM, and IFNG was upregulated in SLE. Network analysis identified hub genes-AP3D1, FTX, USP47, CUX1, ZC3H4, CAND1, INTS1, TRNT1, MTERF1, and SETD1B-that may play critical roles in the progression of both SLE and SSc. These findings suggest that RGS5 could serve as a shared biomarker for vascular dysfunction, while EGR1 and BLK may represent therapeutic targets in SSc and SLE. Overall, this analysis enhances understanding of distinct and overlapping gene expression signatures in SSc and SLE, providing a foundation for future targeted treatment strategies and requiring further validation in larger cohorts. Show less
Health literacy plays an important role in disease prevention and control. The aim of this study is to explore the health literacy patterns and associated factors among residents in Zhejiang Province. Show more
Health literacy plays an important role in disease prevention and control. The aim of this study is to explore the health literacy patterns and associated factors among residents in Zhejiang Province. This study included 56,863 residents aged 15-69 years from the 2024 Zhejiang Province Health Literacy Survey. Latent Profile Analysis (LPA) was used to investigate health literacy patterns, and multinomial logistic regression analysis was employed to identify associated factors. Dominance analysis was performed to compare the relative contribution of the main variables associated with health literacy. The analysis identified three distinct health literacy profiles: low literacy (15.13%), moderate literacy (32.24%), and relatively high literacy (52.63%). The low literacy group was characterized by an older demographic (with an average age of 58.71 years), lower educational attainment (20.72% had no formal education), a higher proportion of farmers (52.93%), and a significant share of low-income individuals (40.98%). Multinomial logistic regression and dominance analysis revealed that education level, age, and occupation were the most important associated factors of health literacy. The study findings highlighted the heterogeneity in health literacy among various population groups and emphasized the need for targeted interventions. This study provides empirical evidence to inform precision health promotion strategies in developed regions of China. Show less
We report a diagnostically challenging case of acute myeloid leukemia (AML) in a 2-year-9-month-old boy, presenting with diarrhea and pancytopenia. Bone marrow aspiration revealed 90% blasts exhibitin Show more
We report a diagnostically challenging case of acute myeloid leukemia (AML) in a 2-year-9-month-old boy, presenting with diarrhea and pancytopenia. Bone marrow aspiration revealed 90% blasts exhibiting cup-like nuclei and azurophilic granules, morphologically mimicking acute promyelocytic leukemia (APL).However, immunophenotyping was inconsistent with classic APL, showing positivity for CD33 and cytoplasmic myeloperoxidase (cMPO) but negativity for CD34 and HLA-DR. Molecular analysis was negative for the canonical PML::RARA fusion but identified a rare Show less
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from Show more
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less
Ttraumatic brain injury (TBI) induces oxidative stress, which contributes to neuronal damage and cognitive impairment. Apolipoprotein E (ApoE) plays a key role in neural repair and may modulate oxidat Show more
Ttraumatic brain injury (TBI) induces oxidative stress, which contributes to neuronal damage and cognitive impairment. Apolipoprotein E (ApoE) plays a key role in neural repair and may modulate oxidative stress responses. However, the relationship between ApoE expression at different stages after TBI and oxidative stress markers, as well as its association with cognitive outcomes, remains unclear. A total of 126 patients with TBI were prospectively enrolled and stratified according to the Glasgow Coma Scale (GCS) score on admission into mild ( Serum ApoE levels peaked at 24 h and slightly decreased thereafter, with overall levels increasing in proportion to TBI severity ( ApoE exhibits an injury-severity-dependent increase during the early stage of TBI, and its levels are closely associated with oxidative stress imbalance and cognitive impairment. These findings suggest that ApoE may play a critical role in both the pathological progression and neural repair following TBI. Show less
Head and neck squamous cell carcinoma (HNSCC) poses a global health challenge. The management of HNSCC is complicated by the difficulty in detecting occult lymph node metastases, leading to dilemmas i Show more
Head and neck squamous cell carcinoma (HNSCC) poses a global health challenge. The management of HNSCC is complicated by the difficulty in detecting occult lymph node metastases, leading to dilemmas in elective neck dissection decisions, which will impair patients' quality of life without improving survival for nodal negative patients. We conducted a comparative analysis of the clinical features, genomic alterations, gene expression and methylation, tumor microenvironment and cellular states between the clinically N0 and pathologically N0 (cN0-pN0) patients and occult lymph node metastatic patients. Patients with occult lymph node metastases typically present with more poorly differentiated primary tumors and higher rates of angiolymphatic and perineural invasion. We identified a distinctive genomic mutation spectrum in the primary tumors of patients with occult metastases, notably in genes such as NSD1, ARHGAP15 and SMARCA4. A whole-genome DNA hypomethylation and altered gene expression profiles are identified in occult lymph node metastatic patients. Analysis of the tumor microenvironment revealed an enrichment of CARNS1 + NK cells and CBX1 + tumor cells in occult metastatic patients. In conclusion, patients with occult lymph node metastases exhibit distinct molecular and clinical features compared with cN0-pN0 patients. Show less
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. Thi Show more
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. This study investigated the relationship between aging, immunity, and sepsis by analyzing six human aging-related gene sets (656 genes). We identified 16 aging-related differentially expressed genes (DEGs) in sepsis. Among these, ATP11B, RBBP7, DOCK10, and NUP160 demonstrated the strongest connectivity with other genes and exhibited significant predictive power. Functional enrichment analysis (GO and KEGG) revealed distinct signaling pathway profiles between high-risk and low-risk sepsis groups (stratified based on risk scores). These dysregulated pathways, associated with multiple immune cells, were primarily linked to transcriptional dysregulation in cellular processes and cancer-related pathways. Experimental validation assays corroborated the roles of ATP11B and RBBP7. Collectively, our bioinformatic and experimental findings indicate that ATP11B, RBBP7, DOCK10, and NUP160 are implicated in the pathogenesis and progression of sepsis. But their potential for sepsis biomarkers still requires further verification. Show less
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a th Show more
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a three-wave longitudinal study was designed to explore the heterogeneity of parent-child attachment networks using latent profile analysis (LPA) and random intercept latent transition analysis (RI-LTA). Participants included 2116 adolescents (ages 14-21; 53.8% girls). Results identified five stable parent-child attachment network profiles, each showing moderate but decreasing stability. Notably, adolescents who were grouped into an attachment network characterized by secure maternal attachment but insecure paternal attachment, similar to those in attachment networks with both insecure maternal and paternal attachment, scored higher levels of problematic mobile phone use than those who were grouped into attachment networks with both secure maternal and paternal attachment. Our findings fill empirical gaps and provide strong evidence supporting attachment-based interventions to reduce problematic mobile phone use. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL Show more
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1). Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study. ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality. Show less
This study aims to investigate the spectrum and prognosis of membranous nephropathy (MN) in patients with Sjögren's syndrome (SS). SS patients with biopsy-proven kidney involvement who were diagnosed Show more
This study aims to investigate the spectrum and prognosis of membranous nephropathy (MN) in patients with Sjögren's syndrome (SS). SS patients with biopsy-proven kidney involvement who were diagnosed at our center between April 2007 and February 2024 were retrospectively reviewed and analyzed. A total of 290 SS patients with kidney involvement were enrolled. The frequency of MN increased from 16.28% during the 2007-2010 period to 44.05% during the 2021-2024 period. After 2016, MN became the most common renal pathologic type, surpassing tubulointerstitial nephritis. PLA2R antibody or antigen was detected in 74 SS-MN patients, in whom 37 (50%) showed a negative result. Within the PLA2R-negative group, five out of 15 showed positivity for EXT1/EXT2 antigen and one out of eight for THSD7A antigen. Sixty-one SS patients with MN were followed up for >6 months, and 44 (72.13%) of them achieved renal complete remission (CR). Compared with PLA2R-negative patients, PLA2R-positive patients spent a longer time to achieve CR (1.46 ± 1.16 vs. 0.74 ± 0.47 years, MN has become the predominant renal pathologic type in SS. PLA2R-positivity testing followed by EXT1/EXT2 and THSD7A testing is recommended for SS-MN patients. Although most patients can achieve renal CR, the prognosis is usually poor in PLA2R-positive SS-MN patients. Show less
Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac h Show more
Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac hypertrophy. SMURF2 (SMAD-specific E3 ubiquitin ligase 2) is an important member of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) family of HECT E3 ubiquitin ligases. In this study we investigated the regulatory role of SMURF2 in cardiac hypertrophy. Experiment models were established in mice by transverse aortic constriction (TAC) in vivo, as well as in neonatal rat cardiomyocytes (NRCMs) by treatment with angiotensin II (Ang II, 1 μM) in vitro. We showed that the expression levels of SMURF2 were significantly elevated in cardiac tissues from patients with cardiac hypertrophy and the two experiment models. In NRCMs, SMURF2 knockdown or treatment with a specific SMURF2 inhibitor heclin (8 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, evidenced by reduced mRNA levels of Anp, Bnp and β-Mhc as well as cell surface. Prophylactic or therapeutic administration of heclin (10 mg·kg Show less