Biomedical subjects
Publications and source records attributed to Min Zhang.
Oncogenic fusions both drive hematologic cancers and enable precise measurable residual disease tracking, yet whether residual fusion products can be therapeutically controlled remains incompletely defined. Emerging genomic, RNA, and proteostasis strategies now frame fusion control as a layer-matched therapeutic strategy.
The pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a class B G protein-coupled receptor (GPCR) that engages both G proteins and β-arrestins to mediate diverse signaling responses, yet how PAC1R adopts distinct intracellular conformations to achieve this transducer selectivity remains poorly understood. Here, we report the cryo-electron microscopy structure of PAC1R in complex with β-arrestin 1 (βarr1), revealing a core-engaged conformation. Comparison with the Gs-bound PAC1R structure shows that βarr1 engagement is associated with remodeling of the intracellular transmembrane bundle, including TM5 reorientation and inward movement of TM6, resulting in a receptor core geometry distinct from that of the G protein-bound state. Comparison with the βarr1-bound parathyroid hormone receptor 1 (PTH1R) structure further reveals both conserved and receptor-specific features of βarr1 engagement. Although outward displacement of the TM5 cytoplasmic end is observed in both PAC1R-βarr1 and PTH1R-βarr1 complexes, its specific direction and the resulting TM5-TM6 rearrangements differ between receptors, correlating with distinct βarr1 finger loop orientations within the receptor core. Together, these findings suggest that β-arrestin core engagement by class B GPCRs is accompanied by receptor-specific intracellular remodeling that may contribute to transducer selectivity in PAC1R.
Stroke remains a leading cause of long-term neurological disability worldwide, largely due to irreversible neuronal loss and the limited regenerative capacity of the adult mammalian brain. Neural stem cells (NSCs) in the adult brain possess the potential to generate new neurons after injury, yet the molecular mechanisms regulating their neuronal differentiation following ischemic insult remain incompletely understood. Here, integrating single-cell multi-omics analyses with spatial transcriptomics, we systematically delineated cell type-specific spatiotemporal dynamics in the striatum of a mouse model of ischemia-reperfusion injury. We identified Neurensin 1 (Nrsn1) as a gene markedly upregulated during NSC-derived neuronal differentiation in the recovery phase. Mechanistically, Foxa2 directly activates Nrsn1 transcription, whereas Nrsn1 promotes neuronal differentiation by facilitating the nuclear translocation of the chromatin-remodeling factor Smarcc1 in vitro. In vivo, both endogenous NSCs and transplanted NSCs overexpressing Nrsn1 significantly enhanced neuronal regeneration and improved functional recovery in mice subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). Collectively, these findings identify Nrsn1 as a key regulator of NSC neuronal differentiation and uncover a Nrsn1-Smarcc1 coupling mechanism that promotes neural regeneration after ischemic brain injury, highlighting a potential molecular target for strategies aimed at enhancing post-stroke recovery.
BACKGROUND: Insomnia is a prevalent sleep disorder that strongly affects one's quality of life and physical well-being. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestines, and a majority of IBD patients suffer from comorbid insomnia. However, the shared molecular features linking insomnia and IBD remain poorly characterized. METHODS: Common differentially expressed genes (DEGs) were identified in datasets of insomnia (GSE208668) and IBD (GSE179285) using the Limma package. Functional enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Protein-protein interaction (PPI) network construction and hub gene identification was subsequently performed. Furthermore, we validated the reliability of the hub genes using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). In addition, we constructed a TF-miRNA regulatory network of hub genes and assessed the abundance of immune cell infiltration in insomnia and IBD using CIBERSORT, EPIC, and xCell algorithms. Finally, we utilized the DsigDB to predict potential therapeutic candidates. RESULTS: The analysis revealed 75 upregulated and 32 downregulated common DEGs. Functional enrichment analysis revealed the inflammatory response and immune activation as pivotal drivers underlying the pathogenesis of both insomnia and IBD. Five hub DEGs, namely, IL1B, IL7R, CCR7, ITGB2, and IRF1, were subsequently screened and validated. The TF-miRNA-mRNA regulatory network consisted of 5 TFs, 14 miRNA nodes and 5 core mRNA nodes. Immune cell infiltration analysis revealed several patterns shared between insomnia and IBD. Additionally, 10 potential therapeutic drugs for insomnia and IBD were proposed. CONCLUSION: Integrative coexpression network analysis reveals convergent dysregulation of an IL1B-centered immune module (comprising IL7R, CCR7, ITGB2, and IRF1) across insomnia and IBD, a shared immune disturbance and candidate targets for simultaneous intervention upon further mechanistic validation.
The gut microbiome profoundly influences host aging, yet the specific microbes and mechanisms governing divergent aging trajectories remain elusive. In this study, we delineated enterotype-specific gut microbial remodeling during aging and developed a microbiome-based aging clock (MicroAge) to track biological aging trajectories. We identified Bifidobacterium pseudocatenulatum (B. pseudocatenulatum) as a candidate geroprotective species consistently depleted during aging across both sexes and multiple Chinese cohorts. In naturally aged mice, oral B. pseudocatenulatum monotherapy rescued intestinal homeostasis, mitigated multiorgan inflammaging, enhanced cognitive-motor performance and extended healthspan. Mechanistically, we characterized 5-aminovaleric acid betaine (5-AVAB) as a key B. pseudocatenulatum-derived metabolite whose levels decline physiologically in aging humans. 5-AVAB supplementation partially recapitulated a broad spectrum of the systemic benefits observed with B. pseudocatenulatum treatment, including improved cognitive and motor function and suppressed multiorgan inflammaging. Our findings identify the B. pseudocatenulatum-5-AVAB axis as a promising target for microbiome-based interventions to promote healthy aging.
BACKGROUND: Foot-and-mouth disease virus (FMDV) causes substantial economic losses in global livestock production; however, the key host factors supporting its early infection process remain poorly characterized. METHODS: In this study, we performed an unbiased genome-wide CRISPR/Cas9 knockout screening using porcine cells to screen and identify host factors involved in FMDV infection. RESULTS: We identified that the E3 ubiquitin ligase RNF24 supports efficient FMDV entry. RNF24 depletion inhibits viral entry and replication, whereas its overexpression enhances viral infectivity. Mechanistically, RNF24 preferentially promotes K27-linked non-degradative polyubiquitination of leupaxin (LPXN) at lysine 162, driving LPXN's trafficking to the plasma membrane. At the membrane, LPXN assembles a ternary integrin-LPXN-VP1 complex that strengthens virus-receptor interactions and promotes viral adsorption and entry. Disruption of this ubiquitination event via the LPXN K162R mutation impairs complex formation and compromises viral entry. CONCLUSION: Together, our study reveals a ubiquitin-dependent RNF24-LPXN regulatory axis that supports FMDV entry, highlights the role of non-degradative ubiquitination in viral pathogenesis, and proposes this interface as a potential target for antiviral intervention.
Steroid hormones play a pivotal role in fish sex differentiation, yet the dynamic expression patterns of key steroidogenic enzymes during this process remain incompletely characterized. Here, we combined genome-wide identification, time series transcriptomes spanning gonadal development (5-360 days post-hatch), and multiple hormone treatment experiments (17α-methyltestosterone, estrone, and etonogestrel) to investigate the Cyp11, Cyp17, Cyp19, and Cyp21 subfamilies in mandarin fish (Siniperca chuatsi). Seven steroidogenic Cyp genes were identified, showing teleost-specific expansion, with one duplicated pair (cyp17a2 and cyp2u1) exhibiting strong purifying selection. Expression profiling revealed pronounced sexually dimorphic and stage-specific patterns: During female differentiation (20-30 days), cyp19a1a and associated genes were highly expressed, coinciding with ovarian differentiation; during male differentiation (30-60 days), cyp17a2 and related genes were upregulated, aligning with testicular development. Exogenous hormone treatments further demonstrated that these genes are dynamically responsive: cyp19a1a and cyp17a2 were highly responsive to androgenic and progestogenic treatments, and their expression changes correlated closely with gonadal sex reversal phenotypes observed histologically. Collectively, this study provides a comprehensive expression atlas of steroidogenic Cyp genes during gonadal differentiation and identifies key hormonally responsive candidates for sex control in aquaculture.
Homologous replacement of genomic sequences with large DNA fragments (> 100 bp) holds great potential for crop breeding, yet an efficient method to achieve such edits is lacking in plants. Here, in rice, we developed template-jumping prime editing (TJ-PE), a recently reported PE strategy for large targeted insertion, as an efficient tool for homologous replacement with DNA fragments ranging from dozens to hundreds of base pairs, and using TJ-PE, we replaced genomic fragments of up to 340 bp with homologous fragments of the same length. In addition, our TJ-PE tool also enabled precise deletion of 944- to 2024-bp fragments in rice, with efficiencies of up to 34.6% for c. 2000-bp precise deletions. Collectively, this study expands the editing scope of PE in rice and establishes TJ-PE as a generalist tool for precise deletion and replacement of large DNA fragments.
Emerging evidence suggests that MYC binds RNAs, but its functional consequences remain unclear. Here, we integrate multiomics data and reveal that MYC broadly binds enhancer RNAs (eRNAs), which exhibit high cancer- and tissue-specific expression in cancer cell lines and patient tumors. Moreover, we developed a computational pipeline to identify potential cis-regulatory MYC-eRNA target genes, with most predicted eRNA-target pairs supported by RNA polymerase II-mediated chromatin interaction data. Among these, we functionally characterized MERG1 as an oncogenic eRNA that promotes breast cancer tumorigenesis. Mechanistically, MERG1 interacts with MYC to enhance its occupancy at the GREB1 promoter, driving chromatin remodeling and epigenetic activation. This process specifically amplifies GREB1 expression and promotes tumor progression. Last, nanoparticle-mediated delivery of antisense oligonucleotides targeting MERG1 suppresses MYC-mediated breast cancer growth. These results advance our understanding of the enhancer-driven regulation of gene expression and tumorigenesis and provide insights into the regulatory landscape of MYC in cancer.
BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.
Understanding the global regulatory mechanisms that control pathogen virulence gene expression is essential for elucidating the molecular basis of pathogenicity. N6-methyladenine (6 mA) plays a crucial role in regulating gene expression in response to various environmental stresses; however, its role in pathogen virulence remains largely unexplored. Here, we report the widespread occurrence of 6 mA across 17 nematode isolates and map its genomic landscape in six notorious agriculturally important pathogen root-knot nematodes (RKNs). We demonstrated that 6 mA is characterized by a conserved GAG motif across nematodes, but exhibits species-specific distribution patterns and distinct effects on gene expression. In particular, its enrichment in transposable elements (TEs) differs between polyploid and diploid nematodes, suggesting lineage-specific epigenetic regulation potentially associated with polyploidy. We further identified two functional 6 mA demethylases, MiNMAD-1 and MiNMAD-2, and confirmed their catalytic activity and active sites. Host-induced gene silencing (HIGS) of minmad-1 significantly increased plant resistance to three polyploid RKN species. A detailed functional analysis revealed that minmad-1 knockdown broadly affected gene expression during the parasitic stage, including genes involved in virulence, thereby reducing nematode infectivity. Together, our findings suggest 6 mA demethylase as a key epigenetic regulator of RKNs' virulence, providing new insights into nematode biology and offering promising targets for the development of sustainable control strategies.
Porcine teschovirus (PTV) is the causative agent of porcine diarrhea and multisystem disorder and poses a global threat to the health of domestic pigs. However, its epidemic and pathogenic characteristics in Tibetan pigs, which are a unique indigenous breed in the Qinghai-Tibet Plateau of China, remain largely unexplored. Here, we conducted a comprehensive investigation during 2024-2025, in which 303 diarrheic fecal samples were collected from 21 farms across eight counties in Ganzi Tibetan Autonomous Prefecture, with an average altitude of 3433 m. RT-PCR testing identified 141 PTV-positive samples, yielding a high positivity rate of 46.5% (141/303). From these positives, 27 VP1 sequences were cloned and sequenced; phylogenetic analysis revealed that 16 strains belonged to Teschovirus A, three strains were divided into Teschovirus B, and three strains formed the interspecies recombinant genotypes (PTV-15/16). Interestingly, five novel strains were classified as undefined genotypes, indicating an extensive genetic diversity among PTV strains circulating in Tibetan pigs. Furthermore, a PTV strain, designated PTV-SCgz-01, was successfully isolated in PK-15 cells, with a near-complete genomic sequence of 7081 nucleotides. Phylogenetic analysis based on the polyprotein and the VP1 genes indicated that it belonged to genotype PTV-4, whereas recombination analysis revealed that PTV-SCgz-01 is a natural recombinant with parental strains derived from HNMY (PTV-4) and China/SWU-ZG2/2018 (PTV-6). Experimental infection of 17-day-old Tibetan piglets demonstrated that this isolate induces severe watery diarrhea. Notably, the virus also caused severe pulmonary hemorrhage and mild cerebral hyperemia with neuronal degeneration, and it had a high mortality rate (40%), suggesting that strain PTV-SCgz-01 has strong pathogenic potential for 17-day-old Tibetan piglets. Our findings provide a more comprehensive molecular epidemiology of PTVs in Tibetan pigs and underscore the need for viral surveillance and control in this unique pig population.
BACKGROUND: The tumor microenvironment (TME) and migrasomes released by tumor cells significantly influence carcinogenesis and immune evasion. However, our understanding of the prognostic and therapeutic implications of migrasome and tumor microenvironment-related genes (mtmRGs) in head and neck squamous cell carcinoma (HNSCC) remains limited. METHODS: We explored the relationship between mtmRGs and HNSCC prognosis by utilizing The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Subsequently, we developed an innovative prognostic signature, and assessed its prognostic significance using the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and Cox regression analyses. To explore the underlying mechanisms, we conducted gene set variation analysis (GSVA), gene set enrichment analysis (GESA), and immune infiltration analysis. A nomogram was developed to estimate the overall survival (OS) rates for HNSCC patients. Lastly, we chose P4HA1, which was part of the signature, for additional experimental validation in vitro and in vivo. RESULTS: The mtmRGs signature effectively classifies HNSCC patients into two distinct risk subgroups, with the high-risk cohort demonstrating significantly poorer OS. The risk score serves as an independent prognostic factor for HNSCC patients; those with lower risk scores are more likely to exhibit favorable responses to immunotherapy, particularly with CTLA4 inhibitors. Furthermore, a lower risk score is significantly correlated with the sensitivity of HNSCC patients to cyclophosphamide, gemcitabine, and axitinib. CONCLUSION: This study presents an innovative gene signature associated with mtmRGs, which may be utilized both for predicting survival and directing personalized chemotherapy and immunotherapy regiments for patients with HNSCC.
Balantioides coli is a zoonotic ciliated protozoan that infects humans and other mammals. Conventional and ITS-based genotyping approaches have limitations that hinder precise molecular epidemiological investigations. The objective of this study was to develop a new β-tubulin gene-based approach to enhance the detection and genotyping of B. coli. We performed single-cell isolation and whole-genome sequencing on two B. coli isolates from pigs and two from guinea pigs. We then used the β-tubulin gene sequences to design PCR primers for the new genotyping assay. We validated the assay using 56 ITS-confirmed B. coli-positive fecal DNA samples from pigs, cattle, sheep, and guinea pigs. Phylogenetic analyses were conducted using both β-tubulin and ITS sequences. The β-tubulin-based nested PCR assay exhibited 100% detection efficiency and greater specificity than ITS-based methods. Phylogenetic analysis of the β-tubulin gene sequences classified B. coli into three genotypes (I-III). Genotype III appears to be specific to guinea pigs. Genotypes I and II were found across multiple hosts, indicating potential cross-species transmission. Of the five full-length B. coli β-tubulin sequences obtained in this study, 264 polymorphic sites (19.8%) were identified, including both synonymous and non-synonymous mutations. Frequent recombination events within the β-tubulin locus were detected, indicating substantial genetic diversity. Therefore, the β-tubulin gene is a robust marker for genotyping and epidemiological studies of B. coli. The novel nested PCR assay overcomes the limitations of ITS-based methods and has produced data revealing previously unrecognized genetic diversity and host specificity patterns of B. coli.
BACKGROUND: Elderly patients with chronic obstructive pulmonary disease (COPD) face a heightened risk of developing long coronavirus disease (COVID); however the exact clinical characteristics and underlying mechanisms remain unclear. METHODS: We enrolled 85 elderly COPD patients, of whom 43 reported newly onset persistent fatigue (the most dominant complaint of long COVID) within 1 year after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and they were allocated to the Long-COVID group. The remaining 42 patients were assigned to the Control group. Patients completed questionnaires, pulmonary function tests, chest CT, routine laboratory tests, and blood proteomic analysis. RESULTS: Long-COVID patients had a longer course of COPD (> 5 years, 76.8% vs 52.4%) and duration of SARS-CoV-2 infection (10.0 days vs 7.0 days) (All P < 0.05), higher symptom burden, worse pulmonary ventilation function and a more rapid decrease in DLCO (All P < 0.05). Proteomic analysis indicated disruptions in inflammation and energy metabolism, potentially underlying long COVID in these patients. The machine learning model identified wheezing, the duration of SARS-CoV-2 infection, EIF2S3 (eukaryotic translation initiation factor 2 subunit gamma), current FEV1/FVC (%), and the course of COPD as key features distinguishing Long-COVID patients, and exhibited excellent performance. CONCLUSION: Elderly COPD patients with a longer COPD course and duration of COVID-19 are more prone to develop long COVID, with decreased pulmonary ventilation and diffusion ability. Disordered inflammation regulation and energy metabolism may be the potential mechanisms, highlighting the importance of monitoring inflammation and metabolic dysregulation in elderly COPD patients after recovery from COVID-19.
Municipal landfills are hotspot sources of antimicrobial resistance (AMR) and are also important habitats of contaminant-degrading bacteria. However, high diversity of antibiotic resistance genes (ARGs) in landfills hinders assessing AMR risks in the affected environment. More concerned, whether there is co-selection or enrichment of antibiotic-resistant bacteria and contaminant-degrading bacteria in these extremely polluted environments is far less understood. Here, we collected metagenomic datasets of 32 raw leachate and 45 solid waste samples in 22 municipal landfills of China. The antibiotic resistome, antibiotic-resistant bacteria and contaminant-degrading bacteria were explored, and were then compared with other environmental types. Results showed that the antibiotic resistome in landfills contained 1,403 ARG subtypes, with the total abundance over the levels in natural environments and reaching the levels in human feces and sewage. Therein, 49 subtypes were listed as top priority ARGs for future surveillance based on the criteria of enrichment in landfills, mobilizable and present in pathogens. By comparing to those in less contaminated river environments, we elucidated an enrichment of antibiotic-resistant bacteria with contaminant-degrading potentials in landfills. Bacteria in Pseudomonadaceae, Moraxellaceae, Xanthomonadaceae and Enterobacteriaceae deserved the most concerns since 72.2 % of ARG hosts were classified to them. Klebsiella pneumoniae, Acinetobacter nosocomialis and Escherichia coli were abundant multidrug-resistant pathogenic species in raw leachate (∼10.2 % of total microbiomes), but they rarely carried contaminant-degradation genes. Notably, several bacterial genera belonging to Pseudomonadaceae had the most antibiotic-resistant, pathogenic, and contaminant-degrading potentials than other bacteria. Overall, the findings highlight environmental selection for contaminant-degrading antibiotic-resistant pathogens, and provide significant insights into AMR risks in municipal landfills.
Universal sample preparation for proteomic analysis that enables unbiased protein manipulation, flexible reagent use, and low protein loss is required to ensure the highest sensitivity of downstream liquid chromatography-mass spectrometry (LC-MS) analysis. To address these needs, we developed a ZnCl2 precipitation-assisted sample preparation method (ZASP) that depletes harsh detergents and impurities in protein solutions prior to trypsin digestion via 10 min of ZnCl2 and methanol-induced protein precipitation at room temperature (RT). ZASP can remove trypsin digestion and LC-MS incompatible detergents such as SDS, Triton X-100, and urea at high concentrations in solution and unbiasedly recover proteins independent of the amount of protein input. We demonstrated the sensitivity and reproducibility of ZASP in an analysis of samples with 1 μg to 1000 μg of proteins. Compared to commonly used sample preparation methods such as SDC-based in-solution digestion, acetone precipitation, FASP, and SP3, ZASP has proven to be an efficient approach. Here, we present ZASP, a practical, robust, and cost-effective proteomic sample preparation method that can be applied to profile different types of samples.
BACKGROUND: Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor). RESEARCH DESIGN AND METHODS: To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study. RESULTS: We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048-1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032-1.692; p = 0.027). CONCLUSIONS: Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.