Biomedical subjects

Wei Hu

Publications and source records attributed to Wei Hu.

At least 19 recordsLinked to original sources

PubMed2026

FOS Regulates Myogenic and Adipogenic Differentiation via Extracellular Matrix Signaling.

In the livestock industry, intramuscular fat deposition is a key factor influencing meat tenderness and flavor. Although FOS (Fos proto-oncogene, AP-1 transcription factor subunit) has been implicated in the regulation of cell proliferation and differentiation, its differential roles in myogenic and adipogenic regulation remain unclear. In this study, we revealed that FOS markedly enhanced myogenic differentiation while inhibiting adipogenic differentiation in muscle stem cells, indicating that it exerts distinct effects on muscle development and intramuscular fat deposition. Mechanistically, FOS modulated extracellular matrix signaling by regulating FAK and PXN phosphorylation, acting as a molecular regulator between the muscle and fat lineages. Furthermore, exon SNPs in FOS were associated with slaughter weight and backfat thickness, and the mutant genotypes weakened its antiadipogenic effect. Collectively, these findings suggest that FOS is an important regulator of myogenic and adipogenic differentiation and is a potential candidate gene for the genetic improvement of meat quality traits.

Animals↗

PubMed2026

Genome-wide CRISPR screen reveals PEX11B as a host restriction factor against ORFV through membrane fluidity regulation.

Host-pathogen interactions are shaped by cellular restriction factors that direct antiviral defenses. We built the first ovine genome-wide CRISPR knockout library in sheep testis (OA3.Ts) cells, targeting all protein-coding genes. Using this platform, we identified PEX11B, a peroxisomal membrane regulatory protein, as a strong restriction factor against orf virus (ORFV) infection. Removing PEX11B increased viral susceptibility and triggered severe cytopathic effects with membrane fusion and syncytia formation. Mechanistic studies showed that PEX11B knockout harmed peroxisomal integrity and disrupted lipid metabolism. This led to greater plasma membrane fluidity, creating a proviral environment that allowed more viral entry and replication. These results reveal a new antiviral function for PEX11B in blocking viral infection and underscore the importance of peroxisomal regulation in host-virus interactions.

Animals↗

PubMed2026

Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.

Within days of exposure to chronic viral infections, activated CD8+ T cells differentiate into Tcf1-Slamf6loTim3hi exhaustion-prone effector T (TEX_EFF) cells or self-renewing Tcf1+Slamf6hiTim3lo precursor exhausted T (TPEX) cells. Here we showed that early CD8+ TEX cell fates were imprinted by forming subset-specific, self-associating chromatin hubs. Chromatin hub assembly coincided with effector or stemness gene induction and identified the transcription cofactors Id2 and Id3 as key regulators that promoted CD8+ TEX_EFF and CD8+ TPEX cell fates, respectively. Id2 drove CD8+ TEX_EFF cell specification by activating effector genes, while suppressing genes involved in exhaustion and stemness. In contrast, Id3-repressed effector genes but upregulated IL-7Rα and AhR, thereby maintaining the CD8+ TPEX cell pool. Mechanistically, Id2 and Id3 exhibited a distinct impact on the chromatin accessibility landscape in early CD8+ TEX cells by engaging Runx3 and Tcf1 transcription factors along with E proteins. These findings indicated that reshaping chromatin architecture represents a critical means for specifying CD8+ TEX cell fates and ensuring lineage stability.

Animals↗

PubMed2026

Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.

Exhausted CD8+ T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8+ TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8+ TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8+ TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8+ TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation.

CCCTC-Binding Factor↗

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2025

Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity.

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4+ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4+ and CD8+ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.

Animals↗

PubMed2025

RNAi screening of uncharacterized genes identifies promising druggable targets in Schistosoma japonicum.

Schistosomiasis affects more than 250 million people worldwide and is one of the neglected tropical diseases. Currently, the treatment of schistosomiasis relies on a single drug-praziquantel-which has led to increasing pressure from drug resistance. Therefore, there is an urgent need to find new treatments. The development of genome sequencing has provided valuable information for understanding the biology of schistosomes. In the genome of Schistosoma japonicum, approximately 11% of the protein-coding sequences are uncharacterized genes (UGs) annotated as "hypothetical protein" or "protein of unknown function." These poorly understood genes have been unjustifiably neglected, although some may be essential for the survival of the parasites and serve as potential drug targets. In this study, we systematically mined the highly expressed UGs in both genders of this parasite throughout key developmental stages in their mammalian host, using our previously published S. japonicum genome and RNA-seq data. By employing in vitro RNA interference (RNAi), we screened 126 UGs that lack homologs in Homo sapiens and identified 8 that are essential for the parasite vitality. We further investigated two UGs, Sjc_0002003 and Sjc_0009272, which resulted in the most severe phenotypes. Fluorescence in situ hybridization demonstrated that both genes were expressed throughout the body without sex bias. Silencing either Sjc_0002003 or Sjc_0009272 reduced the cell proliferation in the body. Furthermore, in vivo RNAi indicated both genes are required for the growth and survival of the parasites in the mammalian host. For Sjc_0002003, we further characterize the underlying molecular cause of the observed phenotype. Through RNA-seq analysis and functional studies, we revealed that silencing Sjc_0002003 reduces the expression of a series of intestinal genes, including Sjc_0007312 (hypothetical protein), Sjc_0008276 (vha-17), Sjc_0002942 (PLA2G15), and Sjc_0003646 (SJCHGC09134 protein), leading to gut dilation. Our work highlights the importance of UGs in schistosomes as promising targets for drug development in the treatment of the schistosomiasis.

Schistosoma japonicum↗

PubMed2007

Insight into the host-parasite interplay by proteomic study of host proteins copurified with the human parasite, Schistosoma japonicum.

The tegument proteins of schistosome have attracted the most attention in studies of host-parasite interplay, while the host proteins acting at the host-parasite interface remained largely elusive. Here, we undertook a high-throughput proteomic approach to characterize the schistosome-adsorbed host proteins. Fifty five distinct host proteins were confidently identified in S. japonicum samples, including cercaria, schistosomula, adults, eggs, and miracidia, together with tegument and eggshell preparations, of which 23 and 38 host proteins were identified in adult worms and eggs, respectively. Among the schistosome-adsorbed host proteins, host neutrophil elastases were found in the granuloma initiated by schistosome egg deposition, implying that the host innate immune molecules could participate in the granuloma formation for fighting against schistosome invasion, except for the adaptive immune system. In addition, some host proteins, such as proteinase inhibitor and superoxide dismutase, might be utilized by schistosome to counteract or attenuate the host attacks. These parasite-adsorbed host proteins will provide new insights into the host immune responses against schistosome infection, the evasive behavior of the adult worms, and the granuloma formation, which could render an in-depth understanding for the host-parasite interplay.

Animals↗

PubMed2006

Adaptation of salt-tolerant Myxococcus strains and their motility systems to the ocean conditions.

More and more studies have indicated that myxobacteria are able to live in seawater conditions, which, however, can decrease the fruiting body formation ability and also the adventurous (A) and social (S) motility systems of the myxobacteria. To learn the adaptation mechanism of the salt-tolerant myxobacteria to marine conditions, we analyzed 10 salt-tolerant Myxococcus strains of their fruiting body formation and motility. The isolates were from marine samples and possessed different levels of salt tolerance. They had the dual motility system and formed fruiting bodies in the presence of suitable seawater concentrations. Some high salt-tolerant strains even lost their fruiting abilities in the absence of seawater. In response to the presence of seawater, the S-motility was found to be increased in the high salt-tolerants but decreased in the low salt-tolerants. The A-motility, on the other hand, was observed in all the salt-tolerant Myxococcus strains, but increased or decreased in response to the presence of seawater. Perceived shifts of fruiting body formation abilities and motilities discovered in the salt-tolerant Myxococcus strains suggested an ecological adaptation of myxobacterial social behaviors to the marine environments.

Adaptation, Physiological↗

PubMed2006

Expression of CD40 and growth-inhibitory activity of CD40 ligand in ovarian cancer cell lines.

OBJECTIVE: Soluble recombinant human CD40 ligand trimer (rhuCD40Lt) has shown antitumor activity in preclinical and clinical studies. We evaluated the effect of rhuCD40Lt on epithelial ovarian carcinoma (EOC) cell lines. METHODS: Expression of the receptor, CD40, was determined by reverse transcriptase-polymerase chain reaction and flow cytometry, and antiproliferative effects of rhuCD40Lt, either alone or in combination with recombinant interferon-gamma (rIFN-gamma), were examined in 8 EOC lines. RESULTS: Expression of CD40 was elevated in 5 out of 8 EOC cell lines examined by flow cytometry, and the presence of CD40 transcripts was detected by RT-PCR in all 8 cell lines. CD40 expression was increased by rIFN-gamma, but treatment with rhuCD40Lt decreased CD40 expression in 4 of the 5 lines that had shown elevated CD40 expression. rhuCD40Lt had a growth-inhibitory effect on 2774 cells, which also exhibited the highest level of CD40 expression. Growth-inhibitory effect of rhuCD40Lt was additive with rIFN-gamma on 2774, NMP-1, a cisplatin-resistant subline of OVCAR3, and HEY cell lines. The number of apoptotic tumor cells was increased following treatment with rhuCD40Lt. CONCLUSIONS: CD40 is expressed on EOC cell lines, and expression was found at the transcript level in all of the EOC lines examined. rIFN-gamma enhances CD40 expression, though a decrease in CD40 expression was observed following treatment with rhuCD40Lt. Growth-inhibitory activity of rhuCD40Lt on EOC lines that express CD40 could be enhanced when rhuCD40Lt treatment was combined with rIFN-gamma. These results suggest that future studies of the combination of rhuCD40Lt and rIFN-gamma might warrant consideration.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Solution structure and backbone dynamics of an endopeptidase HycI from Escherichia coli: implications for mechanism of the [NiFe] hydrogenase maturation.

[NiFe] hydrogenases are metalloenzymes involved in many biological processes concerning the metabolism of hydrogen. The maturation of the large subunit of these hydrogenases requires the cleavage of a peptide at the C terminus by an endopeptidase before the final formation of the [NiFe] metallocenter. HycI is an endopeptidase of the M52 family and responsible for the C-terminal cleavage of the large subunit of hydrogenase 3 in Escherichia coli. Although extensive studies were performed, the molecular mechanism of recognition and cleavage of hydrogenase 3 remains elusive. Herein, we report the solution structure of E. coli HycI determined by high resolution nuclear magnetic resonance spectroscopy. This is the first solution structure of the apo form of endopeptidase of the M52 family reported thus far. The overall structure is similar to the crystal structure of holo-HybD in the same family. However, significant diversity was observed between the two structures. Especially, HycI shows an open conformation at the putative nickel-binding site, whereas HybD adopts a closed conformation. In addition, we performed backbone dynamic studies to probe the motional properties of the apo form of HycI. Furthermore, the metal ion titration experiments provide insightful information on the substrate recognition and cleavage processes. Taken together, our current structural, biochemical, and dynamic studies extend the knowledge of the M52 family proteins and provide novel insights into the biological function of HycI.

Crystallography, X-Ray↗

PubMed2006

Clonorchis sinensis: development and evaluation of a nested polymerase chain reaction (PCR) assay.

Clonorchis sinensis is a fish-borne trematode endemic to East Asia, which infects over 35 million people globally. In the study described here, we developed a nested polymerase chain reaction (PCR) method for the specific and reliable detection of C. sinensis. The primers designed from the nucleotide sequence data derived in this study were evaluated for their specificity and sensitivity for the detection of C. sinensis. The specific amplification products were obtained only with C. sinensis and no amplifications occurred with the DNA of closely related trematodes including Opisthorchis viverrini demonstrating the specificity of the assay. The novel PCR method described here will be useful for the quarantine of fishery products and evaluation of transmission status of clonorchiasis in the endemic areas.

Animals↗

PubMed2006

Perturbative analysis of generally nonlocal spatial optical solitons.

In analogy to a perturbed harmonic oscillator, we calculate the fundamental and some other higher order soliton solutions of the nonlocal nonlinear Schödinger equation (NNLSE) in the second approximation in the generally nonlocal case. Comparing with numerical simulations we show that soliton solutions in the second approximation can describe the generally nonlocal soliton states of the NNLSE more exactly than that in the zeroth approximation. We show that for the nonlocal case of an exponential-decay type nonlocal response the Gaussian-function-like soliton solutions cannot describe the nonlocal soliton states exactly even in the strongly nonlocal case. The properties of such nonlocal solitons are investigated. In the strongly nonlocal limit, the soliton's power and phase constant are both in inverse proportion to the fourth power of its beam width for the nonlocal case of a Gaussian function type nonlocal response, and are both in inverse proportion to the third power of its beam width for the nonlocal case of an exponential-decay type nonlocal response.

Journal Article↗

PubMed2006

Evolutionary diversity of ketoacyl synthases in cellulolytic myxobacterium Sorangium.

The diversity of type I polyketide synthases (PKSs) in cellulolytic myxobacterium Sorangium was explored by assaying the ketoacyl synthases (KSs) in 10 Sorangium strains with two degenerate primer sets and 64 different KS fragments were obtained. For their deduced amino acid sequences, eight were identical to three known KSs from Sorangium and Magnetospirillum, while the others showed 54-83% identities to the modular KS domains reported from various microorganisms. Parts of the Sorangium KSs tightly share the clade with Actinobacteria excluding any other analyzed myxobacterial KSs, or with Cyanobacteria /Myxobacteria. Parts are widely located in the three functional groups - "Loading", "NRPS/PKS" and "Trans-AT". Sorangium KSs in the Actinobacteria, Cyanobacteria/Myxobacteria, or "Loading" clade further evolved independently on its own genus. Notably, the modular KSs from other Myxobacteria genera, i.e. Myxococcus, Stigmatella, Melittangium, Cystobacter and Angiococcus are often distributed crosswise and form non-Sorangium blend subgroups. "NRPS/PKS" and "Trans-AT" are two rather diverse groups and the Sorangium KSs in these clades evolved crosswise with other taxa lineages. The results presented in this paper suggest that the inherent genetic strategies, together with frequent gene importing from many organisms (HGT) have contributed to the evolution of modular PKSs in Sorangium. These findings reinforce that Sorangium strains are really excellent creators for novel and diverse polyketides.

Evolution, Molecular↗

PubMed2006

Reconstruction and in silico analysis of the MAPK signaling pathways in the human blood fluke, Schistosoma japonicum.

At present, little is known about signal transduction mechanisms in schistosomes, which cause the disease of schistosomiasis. The mitogen-activated protein kinase (MAPK) signaling pathways, which are evolutionarily conserved from yeast to Homo sapiens, play key roles in multiple cellular processes. Here, we reconstructed the hypothetical MAPK signaling pathways in Schistosoma japonicum and compared the schistosome pathways with those of model eukaryote species. We identified 60 homologous components in the S. japonciumMAPK signaling pathways. Among these, 27 were predicted to be full-length sequences. Phylogenetic analysis of these proteins confirmed the evolutionary conservation of the MAPK signaling pathways. Remarkably, we identified S. japonicum homologues of GTP-binding protein beta and alpha-I subunits in the yeast mating pathway, which might be involved in the regulation of different life stages and female sexual maturation processes as well in schistosomes. In addition, several pathway member genes, including ERK, JNK, Sja-DSP, MRAS and RAS, were determined through quantitative PCR analysis to be expressed in a stage-specific manner, with ERK, JNK and their inhibitor Sja-DSP markedly upregulated in adult female schistosomes.

Amino Acid Sequence↗

PubMed2006

Angiopoietin-related growth factor (AGF) supports adhesion, spreading, and migration of keratinocytes, fibroblasts, and endothelial cells through interaction with RGD-binding integrins.

Angiopoietin-related growth factor (AGF) is a newly identified member of angiopoietin-related proteins (ARPs)/angiopoietin-like proteins (Angptls). AGF has been considered as a novel growth factor in accelerating cutaneous wound healing, as it is capable of stimulating keratinocytes proliferation as well as angiogenesis. But in our paper, we demonstrate that AGF stimulates keratinocytes proliferation only at high protein concentration, however, it can potently promote adhesion, spreading, and migration of keratinocytes, fibroblasts, and endothelial cells. Furthermore, we confirm that the adhesion and migration cellular events are mediated by RGD-binding integrins, most possibly the alpha(v)-containing integrins, by in vitro inhibition assays using synthetic competitive peptides. Our results strongly suggest that AGF is an integrin ligand as well as a mitogenic growth factor and theoretically participates in cutaneous wound healing in a more complex mechanism.

Angiopoietin-Like Protein 6↗

PubMed2006

The solution structure of Escherichia coli Wzb reveals a novel substrate recognition mechanism of prokaryotic low molecular weight protein-tyrosine phosphatases.

Low molecular weight protein-tyrosine phosphatases (LMW-PTPs) are small enzymes that ubiquitously exist in various organisms and play important roles in many biological processes. In Escherichia coli, the LMW-PTP Wzb dephosphorylates the autokinase Wzc, and the Wzc/Wzb pair regulates colanic acid production. However, the substrate recognition mechanism of Wzb is still poorly understood thus far. To elucidate the molecular basis of the catalytic mechanism, we have determined the solution structure of Wzb at high resolution by NMR spectroscopy. The Wzb structure highly resembles that of the typical LMW-PTP fold, suggesting that Wzb may adopt a similar catalytic mechanism with other LMW-PTPs. Nevertheless, in comparison with eukaryotic LMW-PTPs, the absence of an aromatic amino acid at the bottom of the active site significantly alters the molecular surface and implicates Wzb may adopt a novel substrate recognition mechanism. Furthermore, a structure-based multiple sequence alignment suggests that a class of the prokaryotic LMW-PTPs may share a similar substrate recognition mechanism with Wzb. The current studies provide the structural basis for rational drug design against the pathogenic bacteria.

Amino Acid Sequence↗

PubMed2006

Transcriptomics tool for the human Schistosoma blood flukes using microarray gene expression profiling.

We report the design, fabrication, and validation of a microarray covering the majority of the Schistosoma japonicum and Schistosoma mansoni transcriptomes. The oligonucleotide microarray contains 12,166 S. mansoni and 7055 S. japonicum target sequences. A confidence threshold of <or=0.001 (P value) was used in all analyses. The cross hybridization potential of the microarray was representative of 10,362 probes detected in both channels, while 12,052 probes hybridised to S. japonicum and 11,254 probes hybridised to S. mansoni. Differential hybridisation consisted of 3422 probes to S. mansoni mRNA and 3103 probes to S. japonicum mRNA. Important biological functions, such as transport, metabolism, immune evasion and host-parasite immunological interplay, cell communication, and sexual maturation are represented on this microarray. This is the first microarray commercially manufactured for studying schistosomes, and the large size and verified quality of the resource demonstrate its power for characterising the schistosome transcriptome.

Animals↗