Prediction of lymph node metastasis in patients with papillary thyroid cancer based on radiomics analysis and intraoperative frozen section analysis: A retrospective study.

INTRODUCTION: To evaluate the diagnostic efficiency among the clinical model, the radiomics model and the nomogram that combined radiomics features, frozen section (FS) analysis and clinical characteristics for the prediction of lymph node (LN) metastasis in patients with papillary thyroid cancer (PTC). METHODS: A total of 208 patients were randomly divided into two groups randomly with a proportion of 7:3 for the training groups (n = 146) and the validation groups (n = 62). The Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for the selection of radiomics features extracted from ultrasound (US) images. Univariate and multivariate logistic analyses were used to select predictors associated with the status of LN. The clinical model, radiomics model and nomogram were subsequently established by logistic regression machine learning. The area under the curve (AUC), sensitivity and specificity were used to evaluate the diagnostic performance of the different models. The Delong test was used to compare the AUC of the three models. RESULTS: Multivariate analysis indicated that age, size group, Adler grade, ACR score and the psammoma body group were independent predictors of lymph node metastasis (LNM). The results showed that in both the training and validation groups, the nomogram showed better performance than the clinical model, albeit not statistically significant (p > .05), and significantly outperformed the radiomics model (p < .05). However, the nomogram exhibits a slight improvement in sensitivity that could reduce the incidence of false negatives. CONCLUSION: We propose that the nomogram holds substantial promise as an effective tool for predicting LNM in patients with PTC.

Beneficial effects of the first case of washed microbiota transplantation for postorgasmic illness syndrome: a case report.

Introduction: Postorgasmic illness syndrome (POIS) is characterized by allergic symptoms and flu-like illness after ejaculation. There are still no effective treatments for POIS. Aim: To report the first case of washed microbiota transplantation (WMT) to treat patient with POIS. Methods: Data were collected from a patient with POIS who had received 3 courses of WMT: self-rating scale of POIS symptoms, Self-rating Anxiety Scale, Self-rating Depression Scale, and Symptom Checklist 90. The patient's stool samples for 16sDNA sequencing were collected 1 month after WMT. Results: POIS symptoms improved after WMT. Scores decreased from baseline after WMT: self-rating scale of POIS symptoms (before WMT, 16; after first, 16; after second, 8; after third, 9), Self-rating Anxiety Scale (45, 42.5, 37.5, 45), Self-rating Depression Scale (63.75, 58.75, 47.5, 50), and Symptom Checklist 90 (143, 140, 109, 149). Characteristics of the patient's gut microbiota changed. At the genus level, the relative abundance of beneficial bacteria increased, and some opportunistic pathogenic bacteria decreased. Conclusion: WMT may be an effective and safe choice for the treatment of patients with POIS by changing the gut microbiota of the host.

Age Encoded Adversarial Learning for Pediatric CT Segmentation.

Organ segmentation from CT images is critical in the early diagnosis of diseases, progress monitoring, pre-operative planning, radiation therapy planning, and CT dose estimation. However, data limitation remains one of the main challenges in medical image segmentation tasks. This challenge is particularly huge in pediatric CT segmentation due to children's heightened sensitivity to radiation. In order to address this issue, we propose a novel segmentation framework with a built-in auxiliary classifier generative adversarial network (ACGAN) that conditions age, simultaneously generating additional features during training. The proposed conditional feature generation segmentation network (CFG-SegNet) was trained on a single loss function and used 2.5D segmentation batches. Our experiment was performed on a dataset with 359 subjects (180 male and 179 female) aged from 5 days to 16 years and a mean age of 7 years. CFG-SegNet achieved an average segmentation accuracy of 0.681 dice similarity coefficient (DSC) on the prostate, 0.619 DSC on the uterus, 0.912 DSC on the liver, and 0.832 DSC on the heart with four-fold cross-validation. We compared the segmentation accuracy of our proposed method with previously published U-Net results, and our network improved the segmentation accuracy by 2.7%, 2.6%, 2.8%, and 3.4% for the prostate, uterus, liver, and heart, respectively. The results indicate that our high-performing segmentation framework can more precisely segment organs when limited training images are available.

Transcriptomic and functional analyzes reveal that the brassinosteroid insensitive 1 receptor (OsBRI1) regulates cold tolerance in rice.

Brassinosteroids (BR) play crucial roles in plant development and abiotic stresses in plants. Exogenous application of BR can significantly enhance cold tolerance in rice. However, the regulatory relationship between cold tolerance and the BR signaling pathway in rice remains largely unknown. Here, we characterized functions of the BR receptor OsBRI1 in response to cold tolerance in rice using its loss-of-function mutant (d61-1). Our results showed that mutant d61-1 was less tolerant to cold stress than wild-type (WT). Besides, d61-1 had lower levels than WT for some physiological parameters, including catalase activity (CAT), superoxide dismutase activity (SOD), peroxidase activity (POD), peroxidase activity (PRO), soluble protein, and soluble sugar content, while malondialdehyde content (MDA) and relative electrical conductivity (REC) levels in d61-1 were higher than those in WT plants. These results indicated that the loss of OsBRI1 function resulted in decreased cold tolerance in rice. In addition, we performed RNA sequencing (RNA-seq) of WT and d61-1 mutant under cold stress. Numerous common and unique differentially expressed genes (DEGs) with up- and down-regulation were observed in WT and d61-1 mutant. Some DEGs were expressed to various degrees, even opposite, between CK1 vs. T1 (WT) and CK2 vs. T2 (d61-1). Among these specific DEGs, some typical genes are involved in plant tolerance to cold stress. Through weighted correlation network analysis (WGCNA), 50 hub genes were screened in the turquoise and blue module. Many genes were involved in cold stress and plant hormone, such as Os01g0279800 (BRI1-associated receptor kinase 1 precursor), Os10g0513200 (Dwarf and tiller-enhancing 1, DTE1), Os02g0706400 (MYB-related transcription factor, OsRL3), etc. Differential expression levels of some genes were verified in WT and d61-1 under cold stress using qRT-PCR. These valuable findings and gene resources will be critical for understanding the regulatory relationships between cold stress tolerance and the BR signaling pathways in rice.

Bibliometric and visualized analysis of hydrogels in organoids research.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

MIBPred: Ensemble Learning-Based Metal Ion-Binding Protein Classifier.

In biological organisms, metal ion-binding proteins participate in numerous metabolic activities and are closely associated with various diseases. To accurately predict whether a protein binds to metal ions and the type of metal ion-binding protein, this study proposed a classifier named MIBPred. The classifier incorporated advanced Word2Vec technology from the field of natural language processing to extract semantic features of the protein sequence language and combined them with position-specific score matrix (PSSM) features. Furthermore, an ensemble learning model was employed for the metal ion-binding protein classification task. In the model, we independently trained XGBoost, LightGBM, and CatBoost algorithms and integrated the output results through an SVM voting mechanism. This innovative combination has led to a significant breakthrough in the predictive performance of our model. As a result, we achieved accuracies of 95.13% and 85.19%, respectively, in predicting metal ion-binding proteins and their types. Our research not only confirms the effectiveness of Word2Vec technology in extracting semantic information from protein sequences but also highlights the outstanding performance of the MIBPred classifier in the problem of metal ion-binding protein types. This study provides a reliable tool and method for the in-depth exploration of the structure and function of metal ion-binding proteins.

Effect of Compounded Aluminum Hydroxide Flame Retardants on the Flammability and Smoke Suppression Performance of Asphalt Binders.

Compounded aluminum hydroxide (ATH) flame retardants have been widely used for their low cost and environmentally friendly characteristics. However, previous research lacks a systematic and comprehensive comparison. In addition, the combustion characteristics and phase characterization of asphalt binders are not taken into account either. In this work, flame retardants, for instance, APP, Sb2O3, ZB, and LDHs, were compounded with ATH. The flame retardant behavior, together with the smoke suppression behavior, of asphalt binders with compounded flame retardants was determined by LOI and CCT. Furthermore, mechanisms on flame retardants were investigated. It was found that ATH compounded with ZB significantly reduced the heat smoke release and suppressed the formation of toxic volatiles during asphalt combustion. This was because ATH/ZB facilitated the formation of polyaromatic structures and improved the resistance of the char layer. ATH compounded with APP showed an antagonistic effect in the limiting oxygen test because the reaction between ATH and APP inhibited and delayed the decomposition of ATH during asphalt combustion with more aluminum phosphate presenting relatively poor barrier properties produced.

Application of organoids in otolaryngology: head and neck surgery.

PURPOSE: The purpose of this review is to systematically summarize the application of organoids in the field of otolaryngology and head and neck surgery. It aims to shed light on the current advancements and future potential of organoid technology in these areas, particularly in addressing challenges like hearing loss, cancer research, and organ regeneration. METHODS: Review of current literature regrading organoids in the field of otolaryngology and head and neck surgery. RESULTS: The review highlights several advancements in the field. In otology, the development of organoid replacement therapies offers new avenues for treating hearing loss. In nasal science, the creation of specific organoid models aids in studying nasopharyngeal carcinoma and respiratory viruses. In head and neck surgery, innovative approaches for squamous cell carcinoma prediction and thyroid regeneration using organoids have been developed. CONCLUSION: Organoid research in otolaryngology-head and neck surgery is still at an early stage. This review underscores the potential of this technology in advancing our understanding and treatment of various conditions, predicting a transformative impact on future medical practices in these fields.

Research progress and application of single-cell sequencing in head and neck malignant tumors.

Single-cell sequencing (SCS) is a technology that separates thousands of cells from the organism and accurately analyzes the genetic material expressed in each cell using high-throughput sequencing technology. Unlike the traditional bulk sequencing approach, which can only provide the average value of a cell population and cannot obtain specific single-cell data, single-cell sequencing can identify the gene sequence and expression changes of a single cell, and reflects the differences between genetic material and protein between cells, and ultimately the role played by the tumor microenvironment. single-cell sequencing can further explore the pathogenesis of head and neck malignancies from the single-cell biological level and provides a theoretical basis for the clinical diagnosis and treatment of head and neck malignancies. This article will systematically introduce the latest progress and application of single-cell sequencing in malignant head and neck tumors.

Nano-induced endothelial leakiness-reversing nanoparticles for targeting, penetration and restoration of endothelial cell barrier.

Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. STATEMENT OF SIGNIFICANCE.

PM2.5 induces lung inflammation and fibrosis via airway smooth muscle cell expression of the Wnt5a/JNK pathway.

Background: In recent years, particulate matter 2.5 (PM2.5) exposure has been considered a key dangerous factor in chronic obstructive pulmonary disease (COPD). The dysfunction of airway smooth muscle cells (ASMCs) facilitates lung inflammation and fibrosis in COPD. Therefore, we explored whether PM2.5 could promote the inflammatory response and fibrosis in ASMCs in vivo and in vitro via the wingless-related integration site 5a (Wnt5a)/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Methods: Wnt5a expression in the bronchoalveolar lavage fluid (BALF) of COPD patients exposed to PM2.5 was measured by enzyme-linked immunosorbent assay (ELISA). Mice were intratracheally injected with PM2.5 and a Wnt5a antagonist (BOX5). ASMCs were transfected with Wnt5a small interfering RNA (siRNA), BOX5 and the JNK inhibitor SP600125 before PM2.5 stimulation. Hematoxylin and eosin (H&E) staining was performed to measure the inflammatory response and airway fibrosis. The production of Wnt5a/JNK/NF-KB pathway factors was analyzed by Western blotting. The secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α (TNF-α) was measured by ELISA. The expression levels of alpha smooth muscle actin (α-SMA), collagen I and collagen III were assessed by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting. Results: We found that the increase in Wnt5a expression in the BALF of COPD patients was positively correlated with the levels of PM2.5 exposure. The Wnt5a/JNK/NF-κB pathway was activated in the lung samples of PM2.5-induced model mice and PM2.5-exposed ASMCs, which promoted the production of α-SMA, collagen I and collagen III and increased the secretion of IL-6, IL-8 and TNF-α. Furthermore, our results showed that BOX5 could prevent these effects. Wnt5a siRNA blocked the activation of the Wnt5a/JNK/NF-κB pathway and inhibited the effects of PM2.5 on fibrosis and inflammation in ASMCs. SP600125 blocked the phosphorylation of NF-κB and inhibited inflammation and fibrosis in PM2.5-exposed ASMCs. Conclusions: These findings suggest that PM2.5 stimulation of ASMCs induces pulmonary inflammatory factor expression and collagen deposition during COPD via the Wnt5a/JNK pathway, which indicates that modulating the Wnt5a/JNK pathway could be a promising therapeutic strategy for PM2.5-induced COPD.

A Randomized, Double-Blind, Active Control, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Liztox® versus Botox® in Post-Stroke Upper Limb Spasticity.

Botulinum toxin type A (BTX-A) injection is a commonly used therapeutic intervention for upper limb spasticity in stroke patients. This study was designed as a randomized, active-drug-controlled, double-blind, multicenter, phase 3 clinical trial to evaluate the safety and efficacy of Liztox® in comparison to onabotulinum toxin A (Botox®) for individuals with post-stroke upper limb spasticity. The primary outcome was the alteration in wrist flexor muscle tone from the initial assessment to the fourth week, evaluated using the modified Ashworth scale (MAS). Secondary outcomes included MAS score changes for the wrist at weeks 8 and 12 from baseline; MAS score changes for finger and elbow flexors; and changes in the Disability Assessment Scale (DAS), Subject's Global Assessment (SGA), the Investigator's Global Assessment (IGA), and Caregiver Burden Scale (CBS) at weeks 4, 8, and 12 from baseline. The MAS score for wrist flexor spasticity decreased by -1.14 ± 0.59 in the Liztox® group and -1.22 ± 0.59 in the Botox® group from baseline to week 4. The difference [97.5% confidence interval (CI)] between the test and control groups was 0.08 [-∞, 0.26], confirming the non-inferiority of the test group compared to the control group. Furthermore, there were consistent improvements in the IGA, SGA, and CBS scores across all assessment intervals, with no statistically significant variances detected between the two groups. No safety-related concerns were reported during the study. In conclusion, Liztox® injection proved to be a secure and efficacious intervention for managing upper extremity spasticity in post-stroke patients.

Millimeter-Wave and Short-Range Wireless Communication Antenna Based on High-Conductivity Graphene-Assembled Film.

Millimeter-wave and short-range wireless communication is an important part of the Internet of Things due to its advantages of high transmission speed and large data capacity. In this paper, two antenna arrays operating at typical millimeter-wave bands (45 and 60 GHz) based on graphene-assembled films (GAF) are proposed for short-range wireless communication application. The 45 GHz graphene-assembled film antenna array is in the form of a magnetoelectric dipole antenna with a strip slot coupling to achieve bidirectional radiation, which offers an operating bandwidth of 40-49.5 GHz with a realized gain of 11.8 dBi. The 60 GHz graphene-assembled film antenna utilizes a microstrip discontinuous radiation array to achieve radiation with an operating bandwidth of 59-64 GHz, reaching the peak realized gain of 14.92 dBi over the working frequency. Finally, we proposed an experimental validation to verify the transmission performance of both antenna arrays in an actual conference room. The results show that the signal drops slowly in the room with drop rates of 0.064 dB/cm (at 45 GHz) and 0.071 dB/cm (at 60 GHz), while it steeply dropped through the wall with the drop rates of 2.3 and 3.13 dB/cm, more than 35-fold difference in signal drop rates in the room and through the wall. It has been confirmed that the proposed antenna arrays can successfully realize fast indoor short-range wireless communication while also preventing signal leakage through walls, thereby enhancing the security of information. In summary, this is the first time that we have applied graphene-based materials to millimeter-wave and short-range wireless communications, revealing the significant potential of carbon-based materials in high-frequency communication systems.

Metabolomic profiles, polygenic risk scores and risk of rheumatoid arthritis: a population-based cohort study in the UK Biobank.

OBJECTIVE: To investigate the relationship between metabolomic profiles, genome-wide polygenic risk scores (PRSs) and risk of rheumatoid arthritis (RA). METHODS: 143 nuclear magnetic resonance-based plasma metabolic biomarkers were measured among 93 800 participants in the UK Biobank. The Cox regression model was used to assess the associations between these metabolic biomarkers and RA risk, and genetic correlation and Mendelian randomisation analyses were performed to reveal their causal relationships. Subsequently, a metabolic risk score (MRS) comprised of the weighted sum of 17 clinically validated metabolic markers was constructed. A PRS was derived by assigning weights to genetic variants that exhibited significant associations with RA at a genome-wide level. RESULTS: A total of 620 incident RA cases were recorded during a median follow-up time of 8.2 years. We determined that 30 metabolic biomarkers were potentially associated with RA, while no further significant causal associations were found. Individuals in the top decile of MRS had an increased risk of RA (HR 3.52, 95% CI: 2.80 to 4.43) compared with those below the median of MRS. Further, significant gradient associations between MRS and RA risk were observed across genetic risk strata. Specifically, compared with the low genetic risk and favourable MRS group, the risk of incident RA in the high genetic risk and unfavourable MRS group has almost elevated by fivefold (HR 6.10, 95% CI: 4.06 to 9.14). CONCLUSION: Our findings suggested the metabolic profiles comprising multiple metabolic biomarkers contribute to capturing an elevated risk of RA, and the integration of genome-wide PRSs further improved risk stratification.

Identification and validation of a novel signature based on T cell marker genes to predict prognosis, immunotherapy response and chemotherapy sensitivity in head and neck squamous carcinoma by integrated analysis of single-cell and bulk RNA-sequencing.

T cells are among the most potent anti-tumor cells that are found in humans. Our study sought to develop a reliable signature incorporating T cell marker genes (TMGs) for predicting the prognosis and therapy responsiveness of head and neck squamous cell carcinoma (HNSCC) patients. We downloaded scRNA-seq data from the GSE181919 to identify TMGs. Subsequently, we devised a 12 TMG signature in the TCGA HNSCC cohort by using LASSO analysis. Patients with high-risk scores were shown to experience unfavorable progression-free survival, disease-specific survival, and overall survival, which was validated in the GSE65858 cohort. Additionally, the nomogram integrated risk score and clinical features are more suitable for clinical application. The enrichment analyses of both pathways and functions showed that high- and low-risk patients had functionally related distinctions. Furthermore, analysis of the immunological landscape confirmed that the low-risk patients had a larger percentage of infiltrating immune cells as well as a higher incidence rate of immune-related events. In the meantime, a greater IPS score and expression of immune checkpoint genes suggested significantly favorable responsiveness to immunotherapy in low-risk patients. On the other hand, the high-risk patients had a greater degree of sensitivity to the chemotherapy agents, which included paclitaxel, gemcitabine, docetaxel, and cisplatin. Our finding revealed that this TMG signature independently functioned as a prognostic marker and guided individualized immunotherapy and chemotherapy selection for patients with HNSCC.

Mechanism and treatment of olfactory dysfunction caused by coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the start of the pandemic, olfactory dysfunction (OD) has been reported as a common symptom of COVID-19. In some asymptomatic carriers, OD is often the first and even the only symptom. At the same time, persistent OD is also a long-term sequela seen after COVID-19 that can have a serious impact on the quality of life of patients. However, the pathogenesis of post-COVID-19 OD is still unclear, and there is no specific treatment for its patients. The aim of this paper was to review the research on OD caused by SARS-CoV-2 infection and to summarize the mechanism of action, the pathogenesis, and current treatments.

Young people exposure to antibiotics: Implication for health risk and the impact from eating habits of takeaway food.

Exposure to antibiotics, mainly from animal food ingestion, may have adverse effects on human health. Takeaway food is the preferred choice for the dietary of most Chinese young people nowadays, but the relationship between takeaway eating and antibiotic exposure is not yet adequately understood. In the present study, 297 young people were recruited to collect urine samples and questionnaires with an emphasis on their takeaway eating habits. The internal exposure to 16 antibiotics and three metabolites was measured in urine samples by high-performance liquid chromatography-tandem mass spectrometry, as well as a DNA oxidative damage marker, 8-hydroxydeoxyguanosine (8-OHdG). At least one kind of antibiotic was found in over 90 % of urine samples, with total concentrations from 0.667 to 3.02 × 104 ng/mL. High exposure levels of antibiotics were more likely to be found in individuals with a larger body mass index. The concentrations of six antibiotics were significantly different among people with different overall weekly eating frequencies, usually an upward trend. The estimated daily intakes of antibiotics were on the levels of 0.001-1.0 µg/kg/day, mainly contributed by clarithromycin, ciprofloxacin and oxytetracycline, indicating a potential health risk based on the microbiological effect. A significantly positive correlation was found between DNA oxidative damage and exposure for four categories of antibiotics, conformed by both Spearman correlation and multiple linear regression analysis. The levels of 8-OHdG were 355 %, 239 %, 234 %, and 334 % higher with elevated levels of phenicols, macrolides, tetracyclines and sulfonamides from quartiles 2 to 4. Our results suggest that high-frequency consumption of takeaways may exacerbate oxidative stress trends through human exposure to antibiotics.

Deep learning classification of deep ultraviolet fluorescence images toward intra-operative margin assessment in breast cancer.

Background: Breast-conserving surgery is aimed at removing all cancerous cells while minimizing the loss of healthy tissue. To ensure a balance between complete resection of cancer and preservation of healthy tissue, it is necessary to assess themargins of the removed specimen during the operation. Deep ultraviolet (DUV) fluorescence scanning microscopy provides rapid whole-surface imaging (WSI) of resected tissues with significant contrast between malignant and normal/benign tissue. Intra-operative margin assessment with DUV images would benefit from an automated breast cancer classification method. Methods: Deep learning has shown promising results in breast cancer classification, but the limited DUV image dataset presents the challenge of overfitting to train a robust network. To overcome this challenge, the DUV-WSI images are split into small patches, and features are extracted using a pre-trained convolutional neural network-afterward, a gradient-boosting tree trains on these features for patch-level classification. An ensemble learning approach merges patch-level classification results and regional importance to determine the margin status. An explainable artificial intelligence method calculates the regional importance values. Results: The proposed method's ability to determine the DUV WSI was high with 95% accuracy. The 100% sensitivity shows that the method can detect malignant cases efficiently. The method could also accurately localize areas that contain malignant or normal/benign tissue. Conclusion: The proposed method outperforms the standard deep learning classification methods on the DUV breast surgical samples. The results suggest that it can be used to improve classification performance and identify cancerous regions more effectively.

N6-methyladenosine-modified circIRF2, identified by YTHDF2, suppresses liver fibrosis via facilitating FOXO3 nuclear translocation.

Circular RNA (circRNA) has been implicated in liver fibrosis and modulated by multiple elusive molecular mechanisms, while the effects of N6-methyladenosine (m6A) modification on circRNA are still elusive. Herein, we identify circIRF2 from our circRNA sequencing data, which decreased in liver fibrogenesis stage and restored in resolution stage, indicating that dysregulated circIRF2 may be closely associated with liver fibrosis. Gain/loss-of-function analysis was performed to evaluate the effects of circIRF2 on liver fibrosis at both the fibrogenesis and resolution in vivo. Ectopic expression of circIRF2 attenuated liver fibrogenesis and HSCs activation at the fibrogenesis stage, whereas downregulation of circIRF2 impaired mouse liver injury repair and inflammation resolution. Mechanistically, YTHDF2 recognized m6A-modified circIRF2 and diminished circIRF2 stability, partly accounting for the decreased circIRF2 in liver fibrosis. Microarray was applied to investigate miRNAs regulated by circIRF2, our data elucidate cytoplasmic circIRF2 may directly harbor miR-29b-1-5p and competitively relieve its inhibitory effect on FOXO3, inducing FOXO3 nuclear translocation and accumulation. Clinically, circIRF2 downregulation was prevalent in liver fibrosis patients compared with healthy individuals. In summary, our findings offer a novel insight into m6A modification-mediated regulation of circRNA and suggest that circIRF2 may be an exploitable prognostic marker and/or therapeutic target for liver fibrosis.