Biology subjects

Wang, Y.-N.

Publications and source records attributed to Wang, Y.-N..

7 recordsLinked to original sources

bioRxiv2025

Targeting STING-ATM axis overcomes radiotherapy-induced immune suppression and restores anti-tumor immunity in nasopharyngeal carcinoma

BackgroundRadiotherapy (RT) is a standard treatment for nasopharyngeal carcinoma (NPC), however, RT-induced immune suppression and tumor radioresistance limit durable cancer control, with approximately 20% of patients developing recurrence or metastasis after treatment. We investigated the molecular effects of RT on the immune landscape of NPC and identified a key role of the STING-ATM-MPO axis in RT-induced immune suppression, which is associated with regulatory T cell (Treg) expansion and radioresistance. MethodsWe analyzed leukocyte counts from 653 NPC patients before treatment and at multiple time points (week 1-2, week 3-4, and week 5-6) after RT. Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cell (PBMC) samples from stage I NPC patients (T1N0M0) treated with RT alone. Blood samples were collected before and after 18 Gy RT (in 2 Gy fractions). A randomized six-arm syngeneic mouse tumor model and in vitro cell studies were used to investigate interactions among STING-ATM signaling, immune modulation, and tumor response. ResultsIn NPC patients, RT suppressed cGAS-STING signaling in monocytes and dendritic cells but promoted immunosuppressive programs, including PD-1 signaling, checkpoint expression, regulatory T cell expansion, and upregulation of TGF{beta}1, IL-10, VEGF, PDGF, and MDSC-associated pathways. In a syngeneic mouse model, co-treatment with the STING agonist diABZI reversed these effects and improved tumor control. Bulk RNA sequencing confirmed that RT suppressed cGAS-STING and ATM signaling in both spleens and tumors. Combination treatment restored this signaling, enhanced neutrophil degranulation, and inhibited PD-1 signaling and immune checkpoints. Immunohistochemistry showed that diABZI increased ATM activation, MPO expression, and reduced Treg infiltration in spleens and tumors. ATM activation correlated positively with MPO and inversely with FOXP3 immunoreactivity, suggesting that STING-ATM-MPO activation counteracts Treg-mediated immune suppression. In vitro, diABZI activated STING-ATM signaling in PBMCs, THP-1 cells, and Jurkat T cells, while inhibiting NPC cell growth partly via CYLD upregulation. ConclusionsThese findings link RT-induced suppression to inhibition of cGAS-STING signaling. Activation of STING-ATM-MPO axis counteracts Treg-mediated immune suppression, supporting the therapeutic potential of STING agonists as radiosensitizers in NPC.

cancer biology↗

bioRxiv2025

An atlas of cell type specific regulatory effects in cattle

Understanding the genetic and molecular architecture of complex traits and artificial selection is crucial for advancing sustainable precision breeding in cattle and other livestock. Yet, how genetic variation affects cellular gene expression remains elusive in cattle. Here, by integrating 8,866 bulk RNA-seq samples and 999,192 single cells of 81 cell types in 22 bovine tissues, we presented a comprehensive atlas of regulatory variants at the cell type resolution in cattle. By colocalizing with bulk-tissue expression quantitative trait loci (beQTL), we detected 57,043 novel cell-type stratified eQTL and cell-type/state interaction eQTL in 18,153 genes, which also exhibited a stronger tissue/cell-type specificity than beQTL. By examining genome-wide associations (GWAS) of 44 complex traits, these cell-resolved eQTL were colocalized with 505 (24%) additional GWAS loci compared to beQTL. Through integrating this resource with selection signatures between dairy and beef cattle, we provided tissue/cell-specific regulatory insights into cattle breeding. Overall, the current atlas of cell-type-specific regulatory variants will serve as an invaluable resource for cattle genomics and selective breeding.

genetics↗

bioRxiv2024

All-trans retinoic acid-mediated ADAR1 degradation synergizes with PD-1 blockade to suppress pancreatic cancer

As a double-stranded RNA-editing enzyme and an interferon-stimulated gene, double-stranded RNA-specific adenosine deaminase (ADAR1) suppresses interferon signaling and contributes to immunotherapy resistance. Suppression of ADAR1 overcomes immunotherapy resistance in preclinical models, but has not yet been translated to clinical settings. By conducting a screening of a subset of the FDA-approved drugs, we found that all-trans retinoic acid (ATRA, also known as tretinoin) caused ADAR1 protein degradation through ubiquitin-proteasome pathways and concomitantly increased PD-L1 expression in pancreatic and breast cancers. In addition, the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment and unleashed antitumor immunity and thereby impeded tumor growth in pancreatic cancer mouse models. In a pilot clinical trial, a higher dose of ATRA plus the anti-PD-1 antibody nivolumab prolonged median overall survival in patients with chemotherapy-resistant pancreatic cancer compared to a lower dose of the same regimen. In this study, ATRA was the first drug to be found to cause ADAR1 degradation. We propose translation of a promising 2-pronged antitumor strategy using ATRA and nivolumab to convert immunologically "cold" into "hot" tumors susceptible to immune checkpoint blockade.

cancer biology↗

bioRxiv2022

Multiple GC-biased repetitive ITS copies in the Hirsutella sinensis genome are not generated by RIP mutagenesis involving transition point mutations

It has been hypothesized that AT-biased genotypes of Ophiocordyceps sinensis are generated through repeat-induced point mutation (RIP) and coexist as permanently nonfunctional internal transcribed spacer (ITS) pseudogenes in the genome of Hirsutella sinensis (GC-biased Genotype #1 of O. sinensis). This study examined the H. sinensis genome, which contains multiple repetitive ITS copies (GC content: 64.7{+/-}0.33%) with multiple insertion/deletion and transversion alleles, which were not generated through RIP mutagenesis that theoretically causes cytosine-to-thymine (C-to-T) and guanine-to-adenine (G-to-A) transitions. The repetitive ITS copies in the H. sinensis genome were found to be genetically and phylogenetically distinct from the AT-biased O. sinensis genotypes (GC content: 51.1{+/-}1.69%), which possess multiple transition alleles. The sequences of Genotypes #2-17, both GC- and AT-biased, are absent from the H. sinensis genome; these genotypes belong to interindividual O. sinensis fungi and differentially occur in different compartments of natural Cordyceps sinensis, with dynamic alterations in abundance occurring in an asynchronous, disproportional manner during C. sinensis maturation. Metatranscriptomic analyses of natural C. sinensis revealed the transcriptional silencing of 5.8S genes in all C. sinensis- colonizing fungi, including H. sinensis. The transcription assay reported by Li et al. [1] provided unsound, controversial evidence indicating that the 5.8S genes of AT-biased genotypes are nonfunctional pseudogenes. In addition to the single ITS locus analysis, repetitive genomic copies were also examined at multiple loci in the H. sinensis genome, and approximately 8.2% of the authentic genes had repetitive copies, including various transitions, transversions, and insertions/deletions. The transcripts for the repetitive copies, regardless of the decreases, increases, or bidirectional changes in the AT content, were identified in the H. sinensis transcriptome. These results are inconsistent with those of RIP mutagenesis, which generates pseudogenic, nonfunctional, repetitive copies. In conclusion, AT-biased genotypes of O. sinensis might have evolved through evolutionary mechanisms from a common ancestor over the long course of evolution, in parallel with GC-biased Genotype #1 H. sinensis.

molecular biology↗

bioRxiv2021

Hydrogen sulfide improves the cold stress resistance through the CsARF5-CsDREB3 module in cucumber

Hydrogen sulfide (H2S) plays a crucial role in regulating cold tolerance. But the synergistic regulation of H2S and auxin in the plant response to cold stress has not been reported. In the study, we found that sodium hydrosulfide (NaHS, an H2S donor) treatment enhanced the cold tolerance of cucumber seedlings and increased the level of auxin. CsARF5, a cucumber auxin response factor (ARF) gene was isolated and its role in regulating H2S-mediated cold stress tolerance was described. Transgenic cucumber leaves overexpressing CsARF5 were obtained. Physiological analysis indicated that overexpression of CsARF5 enhanced the cold stress tolerance of cucumber and the regulation of the cold stress response by CsARF5 depends on H2S. In addition, molecular assays showed that CsARF5 modulated cold stress response by directly activating the expression of the dehydration-responsive element-binding (DREB)/C-repeat binding factor (CBF) gene CsDREB3, which was identified as a positive regulator of cold stress. Taken together, our results suggest that CsARF5 plays an important role in H2S-mediated cold stress in cucumber. These results shed light on the molecular mechanism by which H2S regulates cold stress response by mediating auxin signaling, and will provide insights for further studies on the molecular mechanism by which H2S regulates cold stress. HighlightAuxin signaling participates in H2S-mediated cold stress through the CsARF5-CsDREB3 module in cucumber.

physiology↗

bioRxiv2020

Treating Porcine Abscesses With Histotripsy: A Pilot Study

Infected abscesses are walled-off collections of pus and bacteria. They are a common sequela of complications in the setting of surgery, trauma, systemic infections, and other disease states. Current treatment is typically limited to antibiotics with long-term catheter drainage, or surgical wash-out when inaccessible to percutaneous drainage or unresponsive to initial care efforts. Antibiotic resistance is also a growing concern. Although bacteria can develop drug resistance, they remain susceptible to thermal and mechanical damage. In particular, short pulses of focused ultrasound (i.e., histotripsy) generate mechanical damage through localized cavitation, representing a potential new paradigm for treating abscesses non-invasively, without the need for long-term catheterization and antibiotics. In this pilot study, boiling and cavitation histotripsy treatments were applied to subcutaneous and intramuscular abscesses developed in a novel porcine model. Ultrasound imaging was used to evaluate abscess maturity, for treatment monitoring and assessment of post-treatment outcomes. Disinfection was quantified by counting bacteria colonies from samples aspirated before and after treatment. Histopathological evaluation of the abscesses was performed to identify changes resulting from histotripsy treatment and potential collateral damage. Cavitation histotripsy was more successful in reducing the bacterial load while having a smaller treatment volume compared with boiling histotripsy. The results of this pilot study suggest focused ultrasound may lead to a technology for in situ treatment of acoustically accessible abscesses.

bioengineering↗

bioRxiv2020

A porcine bimicrobial abscess model for testing interventional treatments

BackgroundAbscess formation is a host defense mechanism to contain the spread of infection. Abscesses can affect any part of the body and are common sequelae to complications of trauma, surgery, systemic infections and other disease states. Most models for abscesses are in small animals. Pursuant to the goal of developing more advanced treatments for abscesses, we sought to develop a large animal model which would reasonably mimic a fluid-filled human abscess. MethodsDomestic swine were inoculated with a bimicrobial mixture of Bacteroides fragilis (B. fragilis) and Escherichia coli (E. coli) supplemented with an irritant (dextran). Inoculations were performed under ultrasound guidance in the muscle, subcutaneously or intradermally within the same animal. Fourteen days after inoculation, lesions were imaged with ultrasound, resected and prepared for histological evaluation. ResultsInjection of bimicrobial (aerobic and anaerobic) bacterial mixtures at multiple sites in a pig produced multiple lesions with histological features similar to encapsulated and multiloculated/multichamber abscesses often observed clinically in humans. Important salient features include the formation of a connective tissue capsule surrounding histologically nearly amorphous pus. ConclusionsThis paper provides the first description of a pig model for multiloculated abscesses. This animal model could potentially enable the evaluation of new technologies to replace or augment the current standard of care (image-guided percutaneous abscess drainage with antibiotics).

microbiology↗