👤 Shude Xu

Feed is very important for fish farming. The appropriate composition and proportion of feed ingredients can promote the growth of fish, maintain normal physiology and behavior, and even improve the resistance ability to disease and stress, etc. The core of artificial compound feed (ACF) is the composition and proportion of lipid, protein, and carbohydrate, which are also the main nutritional components required by fish. Appropriate levels and ratios can promote fish growth and save costs, and the improper would affect the biological clock systems of fish, leading to metabolic abnormalities. This study explored the preparation of ACF for H. kuda. The composition and proportion of the three main nutrients in ACF were screened based on the synchronicity between six pairs of clock genes (Clock, Bmal1, Per1, Per2, Per3, Cry1, and Cry2) in the central and peripheral clock systems, as well as the expression of eight lipid-metabolism genes (Hmgcr, Mvk, Mvd, Lss, Fdps, Cetp, Scap, Srebp1, Srebp2) in the liver and their synergy with liver clock genes. The results showed that, based on several parameters such as gene expression cycle, relative expression level, and top phase appearance time, the best synergy between the central and peripheral circadian clock systems was observed in ACF with crude fat content of 8.80%, crude protein content more than 38.4%, and carbohydrate content of 23.5%. Based on the expression relationship between lipid metabolism genes and circadian clock genes in the liver, it was further clarified that the optimal levels of fat, protein, and carbohydrate were determined with 8.80%, 38.4%, and 23.5%, respectively. After 4 weeks of breeding validation, compared with frozen Mysis, the screened ACF fed for H. kuda showed significant advantages in body length specific growth rate (SGR Show less

Xylaria nigripes, is a rare medicinal fungus known as Wulingshen in China. It has a neutral and sweet nature and belongs to the heart and kidney meridians. Rich in a variety of bioactive ingredients, it serves as a nutrient-dense food and a therapeutic agent for disease prevention. Wuling powder, a fermented form of X. nigripes, leverages biotechnology to harness the fungus's health benefits, showing significant therapeutic efficacy clinically, offering patients a safer and more effective treatment option. This article reviews the recent progress in the biological characteristics, chemical constituents, and pharmacological effects of X. nigripes. Additionally, it evaluates the modern clinical applications of Wuling powder and the current state of product development, aiming to provide insights for its further development and utilization. Research materials were collected from databases including SciFinder, PubMed, and Web of Science, encompassing over 20 years of academic literature, including books, doctoral dissertations, and master's theses from 2004 to October 2024. The literature search integrated keywords related to "X. nigripes", "Wulingshen", "Leizhenzi", "Wuling powder", "biological characteristics", "pharmacological profile", "chemical constituents", and "clinical applications", used in both English and Chinese. This review highlights the chemical diversity and bioactivities of 82 compounds identified from X. nigripes between 2004 and October 2024. Among these, 26 compounds exhibit diverse pharmacological properties, including antioxidant, anti-inflammatory, neuroprotective, anti-tumor, and cholesteryl ester transfer protein (CETP) inhibitory activities. Both aqueous and ethanol extracts of X. nigripes demonstrate comparable bioactivities. Clinical studies have further validated the efficacy of Wuling powder (dried mycelium product of X. nigripes) in regulating mental health, alleviating insomnia, and treating related disorders. The review also explores the product development status and potential of X. nigripes, analyzing its market prospects. Furthermore, it addresses advancements in artificial cultivation and industrial production, emphasizing the importance of sustainable supply chains for ongoing research and commercial applications. X. nigripes, with its elusive specific ingredients, is recognized for its potential health benefits and has been extensively researched. Due to its notable bioactive effects on human health, X. nigripes and its application, Wuling powder, have garnered considerable attention and have undergone extensive research. Recent multidimensional and interdisciplinary research approaches have achieved a deeper understanding of the biochemical nature and pharmacological effects of X. nigripes. This has led to the accumulation of substantial practical experience in the clinical application of Wuling powder-based medicines. Concurrently, the development of health products, deep fermentation technology, artificial cultivation and deep fermentation technology of X. nigripes have been successfully achieved. It is anticipated that X. nigripes holds the potential to emerge as a pivotal resource for the development of novel pharmaceuticals and therapeutic strategies targeting various human ailments. Show less

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management. Show less

Dyslipidemia is linked to pregnancy complications, but its causal role remains uncertain. This two-sample Mendelian Randomization (MR) study investigated the causal relationship between lipid traits and pregnancy complications and evaluated the impact of lipid-modifying drug targets. Genetic instruments for lipid traits and targets for lipid-modifying drugs were obtained from the Global Lipids Genetics Consortium. Three pregnancy complications' summary statistics came from the FinnGen R9 database. Significant drug targets underwent further analysis using Expression Quantitative Trait Loci data, and mediation analysis identified potential mediators. Increased high-density lipoprotein cholesterol (HDL-C) reduced the incidence of preeclampsia (OR: 0.755, 95% CI: 0.639-0.891, p=0.001, FDR=0.012) and gestational diabetes mellitus (GDM) (OR: 0.835, 95% CI: 0.741-0.942, p=0.003, FDR=0.018). Genetic proxies for cholesteryl ester transfer protein ( Elevated HDL-C levels help prevent preeclampsia and GDM. Show less

Cholesteryl ester transfer protein (CETP) plays a key role in lipoprotein metabolism, and its activity has been linked to the risk of atherosclerosis (AS). CETP inhibitors, such as obicetrapib, represent a novel approach in immunotherapy to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) by targeting lipid metabolism. In addition, CETP vaccines are being explored as a novel strategy for the prevention and treatment of ASCVD by inducing the body to produce antibodies against CETP, which is expected to reduce CETP activity, thereby increasing high-density lipoproteins (HDL) levels. This paper provides a comprehensive overview of the structure of CETP, the mechanisms of lipid transfer and the progress of immunotherapy in the last decade, which provides possible ideas for future development of novel drugs and optimization of immunization strategies. Show less

Schizophrenia (SCZ) is a major neurodevelopmental disorder that exhibits poor response to current therapeutic interventions. Dysregulation of glutamate metabolism (GM) has been strongly associated with the development of SCZ, through mechanisms involving NMDA receptor dysfunction and neuroimmune imbalance. This study utilized Mendelian randomization (MR) to explore the causal association between 1400 blood metabolites and SCZ. Differentially Expressed GM-related Genes (GMDEGs) were identified via GEO transcriptome data integration, and consensus clustering techniques were employed to delineate the molecular subtypes. Using the key GM genes, a diagnostic model was developed and combined with CIBERSORT and MCPcounter analyses to assess immune infiltration. Moreover, the Drug Signatures Database (DSigDB) was used to identify potential targeted drugs, with their binding stability verified through Molecular Docking (MD) and dynamics simulations. Mendelian randomization identified 23 SCZ-related plasma metabolites, with glutamate exhibiting the most significant effect (P < 2.72e-31). Further analysis uncovered 25 Differentially Expressed Genes (DEGs) involved in GM, among which ASL, SLC1A5, and CLN3 were validated as the core targets. Immunoassays demonstrated that these DEGs were involved in the regulation of neutrophil and T cell infiltration. SCZ was categorized into C1 and C2 subtypes based on the expression profiles of these three hub glutamate metabolism genes. A diagnostic model integrating ASL, SLC1A5, and CLN3 was developed, which could identify potential therapeutic agents like Tanespimycin with an AUC of 0.844. Moreover, MD experiments confirmed strong binding affinities between tanespimycin and SLC1A5 (-7.7812 kcal/mol), geldanamycin and SLC1A5 (-7.1142 kcal/mol), cyclosporin A and CLN3 (-7.3049 kcal/mol). Meanwhile, molecular dynamics simulations indicated stable binding interactions. This study demonstrates the potential causal association of GM-related genes in SCZ, developed a precise diagnostic model, and proposed novel targeted therapeutic strategies. Show less

Lung adenocarcinoma (LUAD) is a major cause of cancer-related morbidity and mortality globally, with challenges in prognosis and treatment due to its complex pathogenesis and heterogeneous tumor microenvironment (TME). Neutrophil extracellular traps (NETs) and oxidative stress play critical roles in tumor progression: NETs promote tumor cell adhesion, migration, and immune suppression, while oxidative stress induces DNA damage and activates pro-tumor signaling pathways. Moreover, oxidative stress is an important inducer of NETs, and their crosstalk shapes the LUAD immune microenvironment. However, systematic exploration of LUAD immunotherapeutic response prediction based on NETs and oxidative stress-related genes remains lacking. The gene set related to oxidative stress was obtained from MSigDB. The gene set related to NETs was sourced from relevant literature. Transcriptomic and clinical data were integrated from The Cancer Genome Atlas (TCGA)-LUAD (training set) and GSE31210 (validation set). Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to screen gene modules and characteristic scores related to NETs and oxidative stress signatures. Differentially expressed genes (DEGs) were screened, and prognostic model was established using univariate and LASSO Cox regression. Immune infiltration was analyzed using ESTIMATE algorithm, MCP-counter and ssGSEA methods. And we developed a nomogram incorporating clinicopathological features and RiskScore model, and performed drug sensitivity analysis. Finally, the biological role of CPS1 in lung cancer cells was investigated through CCK-8, wound-healing, and Transwell experiments. 22 co-expression modules were screened, among which the brown module showed significant correlations with NETs and oxidative stress signature scores. This module was intersected with DEGs, yielding 624 overlapping genes implicated in immune-relevant pathways (like leukocyte differentiation, neutrophil activation involved in immune response). A prognostic model was established utilizing 8 key genes (ADGRE3, ARHGEF3, CD79A, CLEC7A, CPS1, EPHB2, LARGE2, and OAS3). In the TCGA database, the model demonstrated robust prognostic discrimination (area under the curve (AUC) > 0.6), with high-risk patients exhibiting shorter overall survival (OS) (p < 0.05). Its stability was validated in GSE31210 (AUC > 0.6). The RiskScore showed negative correlations with immune infiltration (like T cells, CD8 T cells, and natural killer cells) as well as immune/stromal scores. A nomogram model combining RiskScore with N staging was developed and validated, demonstrating strong predictive accuracy through calibration and decision curve analyses. High-risk patients were more sensitive to drugs like BI-2536, BMS-509744, and Pyrimethamine. Finally, in vitro tests showed that CPS1 knockdown markedly decreased the viability, migration, and invasion of lung cancer cells. The constructed prognostic model by NETs and oxidative stress-relevant genes effectively predicts LUAD prognosis, correlates with immune microenvironment characteristics, and guides drug sensitivity, providing novel insights for LUAD prognostic assessment and personalized therapy. Show less

Gut microbiota not only biosynthesizes branched-chain amino acids (BCAA) but also catabolizes and utilizes them, while the effects of dietary BCAA supplementation on intestinal microbiota and metabolism remain largely elusive. Therefore, the present study aimed to investigate the impacts of dietary BCAA supplementation on productive performance, egg quality, gut microbiota and metabolism in laying hens. A total of 180 Fengda No.1 laying hens aged 41 weeks were randomly assigned to five groups, with each group consisting of six replicates of six hens, and the experiment lasted for 8 weeks. The control group (Ctrl AA) was fed a basal diet, while the other four groups were supplemented with 67% leucine (High Leu), isoleucine (High Ile), both leucine and isoleucine (High Leu + Ile), or a combination of the three BCAA (High BCAA), respectively, based on the Ctrl AA. The results demonstrated that compared with Ctrl AA, both High Ile and High BCAA significantly decreased egg mass and laying rate ( Show less

Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, strongly correlates with poor prognosis in LUAD patients. Using human LUAD cell lines and a 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

DHX36 is an ATP-dependent DNA/RNA helicase that unwinds the guanine-quadruplexes (G4s) of DNA or RNA and regulates their metabolism for key biological functions. Breast cancer is a malignant tumor and effective targeted therapy drugs are limited, even though chemotherapy is generally used. In this study, we found that overexpression of DHX36 promotes breast cancer cell growth, migration, and invasion in vitro, while knocking down or knocking out reversed in vitro and in vivo. Moreover, DHX36 was highly expressed in most clinical breast tumor tissues compared with the matched healthy tissues. Accordingly, higher DHX36 expression correlated with poor recurrence-free survival (RFS) in the patients of breast cancer. These results substantiate that DHX36 might be a diagnostic and prognostic biomarker and is a proto-oncogene that promotes the growth and metastasis of breast cancer. Thus, targeting DHX36-associated G4s in genes, particularly in proto-oncogenes, might be a novel anticancer strategy. Show less

Avian leukosis (AL), a major vertically transmitted infectious disease, poses a significant challenge to the conservation and industrial development of indigenous chicken breeds in China. In this study, Chengkou mountain chickens were used as a model to systematically identify genetic markers associated with resistance to avian leukosis virus subgroup J (ALV-J) through a genome-wide association study (GWAS). Genomic DNA was extracted from 500 hens at 300 days of age, and cloacal swabs, plasma, and egg white samples were collected to assess the ALV-J infection status. A total of 325 ALV-positive (ALV+) and 175 ALV-negative (ALV-) individuals were identified. Based on 10× whole-genome resequencing and stringent quality control, 12,644,463 high-quality SNPs were obtained. GWAS revealed a significant enrichment of SNPs on chromosome 6 (Chr6), from which 218 SNPs significantly associated with ALV-J resistance and 49 candidate genes were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that many of these genes, including Show less

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) is a highly prevalent female malignancy. As the epigenomic characteristics of immune cells and cancer cells can serve as predictive indicators for the response to cancer immunotherapy, analysis of epigenetically modified genes (EpiGenes) could contribute to CESC treatment. The ssGSEA algorithm was employed to compute EpiGenes scores. Core genes that exhibited significant module association and a close correlation with EpiGenes scores were identified via the WGCNA package. Univariate Cox proportional hazards regression was performed on the core genes using the survival package, followed by gene set reduction via LASSO Cox regression. Ultimately, key genes were determined through multivariate Cox regression to establish a RiskScore model. Further, the optimal risk cutoff was determined using the survminer package to stratify CESC patients into high- and low-risk subgroups. For enrichment analysis, clusterProfiler and GSEA were utilized. Immune infiltration across risk groups was evaluated via ssGSEA, the MCPcounter algorithm, and the ESTIMATE algorithm. TIDE was employed to compare immunotherapeutic responses between the risk groups, while the pRRophetic software was utilized to predict patients' chemotherapeutic drug sensitivity. The biomarkers identified were validated by performing in vitro experiments. CEP78, DOCK7, DPY19L4, and POM121 were identified by computational analyses as the key genes for CESC and further validated through in vitro experiments. Pathway enrichment analysis revealed predominant enrichment in immune-related pathways in the high-risk group, whereas the low-risk group was more enriched in energy and metabolic pathways. A significant negative correlation was observed between CD8+ T cell abundance and RiskScore, with higher ESTIMATEScores and StromalScores in high-risk patients. Notably, the high-risk group also demonstrated lower potential sensitivity to immunotherapy but more active responsiveness to a broader spectrum of chemotherapeutic agents. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that module genes are significantly enriched in cell cycle regulatory pathways, and these genes, in conjunction with Human Papillomavirus (HPV) infection-induced cell cycle dysregulation, jointly participate in CESC pathogenesis, providing a mechanistic basis for understanding the disease. This study provided novel theoretical evidence for immunotherapy and chemotherapy selection in the management of CESC. Show less

The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed beak bean phenotypes of duck at 10, 20, 30 and 40 days of age, revealing that the most common type is the black beak bean, characterized by melanin deposition on the beak surface. This study performed single nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) to investigate the genetic basis of beak bean color, identifying signals on chromosome 1. The copy number variation region-based GWAS revealed a consistent candidate region overlapping with the SNP-based GWAS signals, further supporting the importance of this genomic region. Locus zoom analysis further refined the candidate regions to 48.5-50.5 and 50.8-52.8 Mb. Functional enrichment analysis highlighted six candidate genes within these regions: KITLG, DUSP6, GALNT4, MGAT4C, ATP2B1 and NTS. Notably, KITLG and DUSP6, which are linked to melanin production, were identified as key candidate genes for beak bean color. Our finding revealed the genetic basis of the bean color traits for the first time in ducks, providing a theoretical foundation and technological framework for enhancing duck beak coloration. Show less

Studies have found that there is tertiary lymphoid structure (TLS) in IgA nephropathy (IgAN), and the existence of TLS has an impact on renal function, creatinine, and proteinuria in patients. We aim to explore the potential molecular mechanisms and therapeutic targets of TLS in IgA nephropathy by bioinformatics methods, hoping to provide treatment methods. The datasets GSE226840, GSE237120, and GSE116626 from the Gene Expression Omnibus (GEO) database were employed to investigate the potential therapeutic targets of TLS in IgAN. The R was used to obtain the differentially expressed genes (DEGs) of three datasets, and the Venny was used to intersect the above three parts of the DEGs to obtain the common DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on obtained genes using Metascape. Protein-Protein interaction (PPI) network was constructed. The intersection of the above common differential genes and IgAN differential genes was obtained by Venny tool. The Nephroseq platform was used to screen core genes and explore their relationship with clinical features. Meanwhile, CIBERSORT was utilized to further delve into the correlation between core genes and immune cells. 92 TLS-related genes and 486 IgAN related genes were obtained, and 6 common genes were obtained after crossing the two genes. The intersection genes were verified by Nephroseq, and CDKN1A, CD83, DUSP6, and CD48 were identified as core genes. At the same time, there were differences in the composition of immune cells between the disease group and the control group when the immune infiltration analysis was performed. And by further analyzing the correlation between core genes and immune cells, the study found that the four genes were positively correlated with T cells, B cells, plasma cells, and other immune cells. By exploring the relationship between core genes and clinical features, CDKN1A and DUSP6 were negatively correlated with Glomerular Filtration Rate (GFR) and positively correlated with proteinuria in IgAN patients. CD48 was negatively correlated with GFR and positively correlated with Blood Urea Nitrogen (BUN). The four genes highly associated with TLS and IgAN were screened using GEO database in study. And CDKN1A, CD83, DUSP6 and CD48 may provide potential therapeutic targets for the treatment of TLS in IgAN. At the same time, studies have found that T cells, B cells, and macrophages may be involved in the formation of TLS in IgAN. Show less

The aim of this review is to systematically explore the critical role of dual-specific phosphatases (DUSPs) in CKD-associated cognitive impairment and their therapeutic potential. Chronic kidney disease (CKD) is a global health burden, and the cognitive impairment it induces seriously affects patients' quality of life. Studies have shown that DUSPs are involved in pathological processes such as inflammation, oxidative stress, fibrosis, and neuronal apoptosis through the regulation of signaling pathways such as MAPK, which in turn affects the cognitive function of CKD patients. Specifically, downregulation of DUSP1 and DUSP6 expression in brain tissues of CKD patients is associated with cognitive impairment, whereas upregulation of DUSP8 and DUSP16 exacerbates cognitive deficits by promoting neuroinflammation. In addition, uremic toxins (e.g., indolephenol sulfate) can further deteriorate cognitive function by altering the activity of DUSPs and interfering with central nervous system signaling. Although there are currently no clinical drugs targeting DUSPs, small molecule inhibitors, gene modulation techniques, and natural compounds have demonstrated the potential to improve cognitive function by modulating DUSPs. Future studies need to focus on optimizing the specificity and selectivity of DUSPs inhibitors and conducting rigorous clinical validation. In-depth elucidation of the mechanism of action of DUSPs in the renal-brain axis will provide an important theoretical basis for the development of novel intervention strategies for CKD-associated cognitive impairment. Show less

Cadmium (Cd) is a widely available metal that has been found to have a role in causing nonalcoholic fatty liver disease (NAFLD). However, the detailed toxicological targets and mechanisms by which Cd causes NAFLD are unknown. Therefore, the present work aims to reveal the main targets of action, cellular processes, and molecular pathways by which cadmium causes NAFLD. As shown in the bioinformatics analysis, there were 74 main targets of action for cadmium-induced NAFLD, hemopoietic cell kinase (HCK), EPH receptor A2 (EPHA2), MYC proto-oncogene (MYC), lysyl oxidase (LOX), dipeptidyl peptidase 7 (DPP7), nuclear factor erythroid 2-related factor 2 (NFE2L2), dual specificity phosphatase 6 (DUSP6), CD2 cytoplasmic tail binding protein 2 (CD2BP2), notch receptor 3 (NOTCH3), and phospholipase A2 group IVA (PLA2G4A) were screened as core genes. Testing these core genes in other databases, three differentially expressed genes, HCK, MYC, and DUSP6 were verified and used as targets for drug prediction in DsigDB; decitabine and retinoic acid were screened as potential therapeutic drugs for NAFLD based on the p-value and the combined score. The results of molecular docking showed that the predicted drugs can bind well to the core targets. In conclusion, cadmium is associated with NAFLD; the identified cadmium-toxicity targets, HCK, MYC, and DUSP6, may serve as biomarkers for the diagnosis of NAFLD and predicted drugs, decitabine and retinoic acid may have a potential role in the treatment of NAFLD. Show less

This study aimed to explore the genotype and phenotype correlation of patients with multiple osteochondroma (MO), and validate phenotypic differences in ATDC5 cell model with Mutation analysis was employed in 27 families with MO using polymerase chain reaction (PCR)-Sanger sequencing and targeted next-generation sequencing (t-NGS). ATDC5 cell model with A total of 27 pathogenic mutations were identified in Clinical research identified nine novel mutations in Show less

Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. We screened CZ CELLxGene single-cell RNA (scRNA) sequence datasets for those of adult, fetal, and mouse kidneys and analyzed the above MNTAgs' expression. In adult kidneys, most MNTAgs are present in podocytes, except PCSK6 and NCAM1. PLA2R1 is expressed significantly more than other MNTAgs in podocytes and is a major podocyte marker, consistent with PLA2R1 as the dominant MNTAg. Additionally, PLA2R1 is a top-upregulated gene in the podocytes of chronic kidney disease, acute kidney injury, and diabetic nephropathy, indicating its general role in causing podocyte injury. PLA2R1, NTNG1, HTRA1, and NDNF display podocyte-enriched expression along with elevated chromatin accessibility in podocytes, suggesting transcription initiation contributing to their preference expression in podocytes. In the fetal kidney, most MNTAgs are expressed in podocytes. While PLA2R1 is weakly present in podocytes, SEMA3B is abundantly expressed in immature and mature podocytes, supporting SEMA3B as a childhood MNTAg. In mouse kidneys, Thsd7a is the only MNTAg with a prominent level and podocyte-specific expression. 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 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

Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes-downregulation of PUFA synthesis and upregulation of histone lactylation-in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI. Show less

This study aims to investigate associations between omega-3 polyunsaturated fatty acids (PUFAs) and myopia. Two-sample Mendelian randomization (MR) was conducted to estimate the associations between plasma levels of omega-3 PUFAs and three traits of myopia, including myopia, high myopia (HM), and refractive spherical equivalent (RSE). Summary data-based Mendelian randomization (SMR) and colocalization analysis were conducted to examine the associations between the FADS1 and FADS2 genes and three traits of myopia in European populations. The cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES) was performed to explore the relationship in East Asian adolescents. In the Two-sample MR study, plasma levels of total omega-3 PUFAs (0.993[0.990, 0.996]), Docosahexaenoic acid (DHA) (0.992[0.989, 0.996]), and Eicosapentaenoic Acid (EPA) (0.969[0.955, 0.983]) were found to be significantly and inversely associated with myopia in European populations, and similar results were shown in HM and RSE. SMR ( Show less

Fatty acid desaturase 1 (FADS1) is significantly and specifically upregulated following diabetic corneal injury. However, its role in diabetic keratopathy remains unclear. This study aimed to investigate the impact of FADS1 on wound healing and functional recovery of the diabetic corneal epithelium and explore its potential mechanisms. Using high-glucose-induced corneal epithelial cells and a streptozotocin-induced type 1 diabetic mouse model, FADS1 expression was suppressed via FADS1 small interfering RNA (siRNA). Cell migration was assessed using scratch and transwell assays. Wound healing and functional recovery of the corneal epithelium were evaluated using sodium fluorescein staining, anterior segment optical coherence tomography, hematoxylin and eosin staining, and immunofluorescence staining. FADS1 knockdown promoted wound healing and functional recovery of the diabetic corneal epithelium both in vivo and in vitro. Suppression of FADS1 enhanced high-glucose-induced corneal epithelial cell migration, which was dependent on elevated levels of the upstream metabolite γ-linolenic acid. This effect was mediated through the activation of the mitogen-activated protein kinase signaling pathway and the accumulation of autophagosomes. After diabetic corneal epithelial injury, FADS1 expression is specifically upregulated. Knockdown of FADS1 promotes wound healing and functional recovery, suggesting a novel therapeutic strategy for diabetic keratopathy. Show less

Epilepsy is a prevalent neurological disorder that affects over 70 million individuals worldwide and is often associated with cognitive impairments. Despite the widespread impact of epilepsy and cognitive impairments, the genetic basis and causal relationships underlying these conditions remain uncertain, prompting us to conduct a comprehensive investigation into the molecular mechanisms involved. In this study, we utilized statistical data from the third National Health and Nutrition Examination Survey (NHANES III) to evaluate correlation and large-scale pan-phenotype genome-wide association study (GWAS) data to establish genetic correlation and causality. Leveraging multi-omics datasets, we performed a comprehensive post-analysis that included variant prioritization, gene analysis, tissue and cell type enrichment, and pathway annotation. An integrated strategy-multi-trait analysis of GWAS (MTAG), transcriptome-wide association study (TWAS), summary-data-based Mendelian Randomization (SMR), and protein quantitative trait locus (pQTL)-MR-was performed to investigate the shared genetic architecture. Based on multiple orthogonal lines of evidence, we thereby identified 40 single nucleotide polymorphisms (SNPs) and 85 genes common to both conditions. Additionally, we optimized candidate genes such as GNAQ, FADS1, and PTK2 by single-cell expression analysis and molecular pathway mechanisms, thereby highlighting potential shared genetic pathways. These findings elucidate the genetic interplay and co-occurring mechanisms between epilepsy and cognitive impairments, providing crucial insights for future research and therapeutic strategies. Show less

Elevated red blood cell distribution width (RDW) is associated with increased risk of rheumatoid arthritis (RA), but the potential interactions of RDW with genetic risk of incident RA remain unclear. This study aimed to investigate the associations between RDW, genetics, and the risk of developing RA. We analysed data from 145,025 healthy participants at baseline in the UK Biobank. The endpoint was diagnosed rheumatoid arthritis (ICD-10 codes M05 and M06). Using previously reported results, we constructed a polygenic risk score for RA to evaluate the joint effects of RDW and RA-related genetic risk. Two-sample mendelian randomization and bayesian colocalization were used to infer the causal relation between them. A total of 675 patients with RA were enrolled and had a median followed up of 5.1 years, with an incidence rate of 0.57/1000 person-years. The hazard ratio of RA was 1.89 (95% CI: 1.45, 2.47) in highest RDW quartile group compared with the lowest RDW quartile group. Individuals within the top quintile of PRS showed a significantly high risk of RA. Moreover, Participants with high genetic risk and those in highest RDW group exhibited a significantly elevated hazard ratio (7.67, 95% CI: 3.98, 14.81), as opposed to participants with low genetic risk and those in lowest RDW group. Interactions between PRS and RDW on the multiplicative and additive scale were observed. Mendelian randomization provided suggestive evidence of a bi-directional causal relationship between RDW and RA. Loci near IL6R, IL1RN, FADS1/FADS2, UBE2L3 and HELZ2 showed colocalization. Increased RDW is associated with elevated risk of incident RA especially in the high genetic risk populations, but only suggestive evidence supports a causal relationship between them. Show less

Aging is an inevitable process integrating chronological alterations of multiple organs. A growing aging population necessitates feasible anti-aging strategies to deal with age-associated health problems. We previously performed a proteomics analysis in a healthy-aging cohort, and revealed an age-related downregulation of ARMH4. Here we generate a whole-body Armh4-knockout mouse line, and investigate its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowers spontaneous mortality and extends maximum lifespan. In the female mice, Armh4 deficiency postpones sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen are substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacts with IGF1R/FGFR1 to sensitize the activation of PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways, consequently promoting protein synthesis and inhibiting autophagy. Moreover, ARMH4 is required for the maintenance of IGF1R/FGFR1 expressions through regulating the transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging. Show less

8p11 myeloproliferative syndrome (EMS) is a rare aggressive hematologic malignancy with a poor prognosis that can rapidly develop into acute leukemia. It is characterized by the translocation of fibroblast growth factor receptor-1 (FGFR1), and there is still a lack of effective and reliable treatment methods at present. This report provides a new therapeutic strategy for EMS patients diagnosed with BCR-FGFR1 fusion. This report describes a case of EMS patient with a positive BCR-FGFR1 fusion gene, whose manifestations are similar to those of chronic myeloid leukemia (CML). After diagnosis by fluorescence in situ hybridization (FISH) and RNA sequencing (RNA-seq), olverembatinib, the third-generation tyrosinase inhibitor (TKI) developed in China, was used for treatment. After monotherapy and follow-up for more than one year, partial molecular response (PR) was achieved. During this period, hematologic remission and cytogenetic remission were achieved. The treatment safety of the entire process was excellent. In summary, olverembatinib provides more treatment options for rare diseases such as 8p11 myeloproliferative syndrome. Show less

Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized fibroblast growth factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention. Show less