Objective: To develop a dual-branch deep learning framework for accurate multi-label classification of fundus diseases, addressing the key limitations of insufficient complementary feature extraction and inadequate cross-modal feature fusion in existing automated diagnostic methods. Methods: The fundus multi-label classification dataset with 12 disease categories (FMLC-12) dataset was constructed by integrating complementary samples from Ocular Disease Intelligent Recognition (ODIR) and Retinal Fundus Multi-Disease Image Dataset (RFMiD), yielding 6 936 fundus images across 12 retinal pathology categories, and the framework was validated on both FMLC-12 and ODIR. Inspired by the holistic multi-regional assessment principle of the Five Wheels theory in traditional Chinese medicine (TCM) ophthalmology, the dual-branch multi-label network (DBMNet) was developed as a novel framework integrating complementary visual feature extraction with pathological correlation modeling. The architecture employed a TransNeXt backbone within a dual-branch design: one branch processed red-green-blue (RGB) images to capture color-dependent features, such as vascular patterns and lesion morphology, while the other processed grayscale-converted images to enhance subtle textural details and contrast variations. A feature interaction module (FIM) effectively integrated the multi-scale features from both branches. Comprehensive ablation studies were conducted to evaluate the contributions of the dual-branch architecture and the FIM. The performance of DBMNet was compared against four state-of-the-art methods, including EfficientNet Ensemble, transfer learning-based convolutional neural network (CNN), BFENet, and EyeDeep-Net, using mean average precision (mAP), F1-score, and Cohen's kappa coefficient. Results: The dual-branch architecture improved mAP by 15.44 percentage points over the single-branch TransNeXt baseline, increasing from 34.41% to 44.24%, and the addition of FIM further boosted mAP to 49.85%. On FMLC-12, DBMNet achieved an mAP of 49.85%, a Cohen’s kappa coefficient of 62.14%, and an F1-score of 70.21%. Compared with BFENet (mAP: 45.42%, kappa: 46.64%, F1-score: 71.34%), DBMNet outperformed it by 4.43 percentage points in mAP and 15.50 percentage points in kappa, while BFENet achieved a marginally higher F1-score. On ODIR, DBMNet achieved an F1-score of 85.50%, comparable to state-of-the-art methods. Conclusion DBMNet effectively integrates RGB and grayscale visual modalities through a dual-branch architecture, significantly improving multi-label fundus disease classification. The framework not only addresses the issue of insufficient feature fusion in existing methods but also demonstrates outstanding performance in balancing detection across both common and rare diseases, providing a promising and clinically applicable pathway for standardized, intelligent fundus disease classification.

BACKGROUND:Preliminary research by our group suggests that targeting fibroblast growth factor receptor 1(FGFR1)may be an effective strategy for treating RA. OBJECTIVE:To investigate the effects of an FGFR1 inhibitor(PD173074)on bone destruction in rats with collagen-induced arthritis. METHODS:Twenty-five female Sprague-Dawley rats were randomly divided into five groups:normal control group,model group,methotrexate group,low-dose PD173074 group,and high-dose PD173074 group.Except for the normal control group,rat models of type Ⅱ collagen-induced arthritis were made in each group.After successful modeling,rats were injected intraperitoneally with sterile PBS in the normal and model groups,1.04 mg/kg methotrexate in the methotrexate group,and 5 and 20 mg/kg in the low-dose group and high-dose PD173074 groups,once a week.After 4 weeks of drug administration,clinical symptoms and joint swelling in rats were observed.Micro-CT was used for three-dimensional reconstruction and analysis of the ankle joints.Pathological changes in the ankle joints were observed.Periarticular angiogenesis and the expression of receptor activator of nuclear factor-Κb ligand were detected.The expression levels of p-FGFR1,vascular endothelial growth factor A,and tartrate-resistant acid phosphatase in the synovial membrane were measured.Pathological changes in the liver,spleen,and kidney were observed and liver,spleen,and kidney indices were calculated. RESULTS AND CONCLUSION:PD173074 could alleviate clinical symptoms and joint swelling,delay bone loss,improve bone structure,reduce synovial invasion and cartilage bone erosion,reduce the number of periarticular osteoclasts,inhibit angiogenesis in synovial tissues,reduce the expression of receptor activator of nuclear factor-Κb ligand,and inhibit the expression of FGFR1 phosphorylated protein,tartrate-resistant acid phosphatase and vascular endothelial growth factor A.Pathologic observation of the liver,spleen and kidney in rats showed no obvious toxic side effects after PD173074 treatment.To conclude,the FGFR1 inhibitor can delay the progression of joint inflammation and bone destruction and inhibit angiogenesis in the rat model of type Ⅱ collagen-induced arthritis.The therapeutic effect of PD173074 has been preliminarily validated in the type Ⅱ collagen-induced arthritis model and may act by inhibiting FGFR1 phosphorylation,which provides a direction for the search of new therapeutic targets for rheumatoid arthritis.

ObjectiveThis study aimed to investigate the intervention effect of Renqing Mangjue on the malignant transformation of gastric mucosal epithelial cells induced by N-methyl-N′-nitro-N-nitrosoguanidine （MNNG） and to explore its molecular mechanism in preventing precancerous lesions of gastric cancer based on the cyclic guanosine monophosphate （cGMP）/protein kinase G （PKG）/mitogen-activated protein kinase （MEK）/extracellular signal-regulated kinase （ERK） signaling pathway. MethodsHuman gastric mucosal epithelial cells （GES-1） were initially induced by MNNG to establish a precancerous cell model （MC cells）. The effective concentration of MNNG for inducing malignant transformation in GES-1 cells was screened using the cell proliferation activity decection （CCK-8） assay， and the effective concentration of Renqing Mangjue for inhibiting the proliferation of transformed GES-1 cells was also determined. GES-1 cells were divided into a blank control group， a model group， and treatment groups with Renqing Mangjue at concentrations of 1， 3， 10， and 30 mg·L^-1. Furthermore， the effects of Renqing Mangjue on the migratory ability and epithelial-mesenchymal transition （EMT） characteristics of GES-1 malignant transformed cells were evaluated using Transwell migration assays， wound healing assays， and real-time quantitative reverse transcription polymerase chain reaction （Real-time PCR）. Additionally， candidate chemical components and target sites of Renqing Mangjue were obtained from the TCMIP v2.0 database， and disease targets at various stages of gastric cancer precursors were sourced from the Gene Expression Omnibus （GEO） database. Pathway enrichment analysis was performed using the Metascape database to predict the potential mechanisms of action of Renqing Mangjue. Finally， the protective mechanism of Renqing Mangjue against gastric cancer precursors was validated through Western blot analysis. ResultsAt a concentration of 20 μmol·L^-1， MNNG exhibited an inhibition rate of approximately 50% on GES-1 cells （P<0.01）， and at this concentration， the GES-1 cells displayed biological characteristics indicative of malignant transformation. In contrast， Renqing Mangjue had no significant effect on the proliferation of normal GES-1 cells， but significantly inhibited the proliferation of MC cells （P<0.01） and markedly reduced their migratory capacity （P<0.01）. Moreover， it also increased the mRNA expression level of E-cadherin during the EMT process （P<0.05）， while inhibiting the expression of both N-cadherin and the transcription factor Snail mRNA （P<0.05， P<0.01）. Network predictions suggested that Renqing Mangjue may prevent gastric cancer precursors through modulating the cGMP/PKG and MAPK/ERK signaling pathways. Furthermore， Western blot results indicated that Renqing Mangjue upregulated the expression of PKG and NPRB （B-type natriuretic peptide receptor） proteins in the cGMP/PKG pathway （P<0.01）， while downregulating the expression of the downstream proteins MEK and ERK （P<0.05， P<0.01）. ConclusionIn summary， Renqing Mangjue can prevent gastric cancer precursors by inhibiting the proliferation and migration of malignant transformed GES-1 cells， thereby delaying the EMT process. The underlying mechanisms may be related to the activation of the cGMP/PKG pathway and the inhibition of the MEK/ERK signaling pathway.

BACKGROUND:Although researchers have noted that fibroblast growth factor receptor 1 shows great potential in rheumatoid arthritis bone destruction,there is a lack of reviews related to the potential mechanisms of fibroblast growth factor receptor 1 in rheumatoid arthritis bone destruction. OBJECTIVE:To comprehensively analyze the mechanism of fibroblast growth factor receptor 1 in bone destruction in rheumatoid arthritis by reviewing the relevant literature at both home and abroad. METHODS:We searched the CNKI database using the Chinese search terms"fibroblast growth factor receptor 1,rheumatoid arthritis,bone destruction,bone cells,osteoblasts,osteoclasts,chondrocytes,macrophages,synovial fibroblasts,T cells,vascular endothelial cells."PubMed database was searched using the English search terms"fibroblast growth factor receptor 1,rheumatoid arthritis,bone destruction,osteocytes,osteoblasts,osteoclasts,chondrocytes,macrophages,synovial fibroblasts,T cells,endothelial cells."The search period focused on April 1992 to January 2024.After screening the literature by reading titles,abstracts,and full texts,a total of 82 articles were finally included for review according to inclusion and exclusion criteria. RESULTS AND CONCLUSION:Fibroblast growth factor receptor 1 was found to be widely expressed in bone tissue-associated cells,including osteoblasts,osteoclasts,and osteoclasts.Fibroblast growth factor receptor 1 affects bone remodeling and homeostasis by regulating the function of these cells,as well as promoting the onset and progression of bone destruction in rheumatoid arthritis.Fibroblast growth factor receptor 1 is involved in the inflammatory response of synovial fibroblasts and macrophages and regulates angiogenesis of endothelial cells in synovial tissues.Fibroblast growth factor receptor 1 promotes bone destruction in several ways.Fibroblast growth factor receptor 1 may be a potential causative agent of bone destruction in rheumatoid arthritis and provides a reference for further research on its therapeutic targets.

BACKGROUND: Lung cancer has the highest mortality rate among all malignant tumors, and non-small cell lung cancer (NSCLC) accounts for about 80%-85% of all lung cancers. Lobectomy and lymph node dissection are one of the most important treatment methods, and lymph node dissection, as an important part, has attracted much attention. And its mode and scope of dissection may affect postoperative complications, particularly the occurrence of chronic cough. The aim of this study is to investigate the effect of lymph node dissection on postoperative chronic cough in patients with NSCLC undergoing lobectomy, and to provide clinical evidence for optimizing surgical strategy and reducing postoperative chronic cough. METHODS: A retrospective analysis was conducted on the clinical data of 365 NSCLC patients who underwent lobectomy at the First Affiliated Hospital of University of Science and Technology of China from December 2020 to December 2023. The relationship between clinical characteristics and postoperative chronic cough was analyzed. The Chinese version of the Leicester Cough Questionnaire (LCQ-MC) scores were collected from the patients at 2 time points: 1 day before surgery and 8 weeks after surgery. Patients were divided according to lymph node dissection methods, to explore the relationship between lymph node dissection and chronic cough after lobectomy. Additionally, patients were divided into chronic cough and non-chronic cough groups based on the presence of postoperative chronic cough, to investigate whether perioperative data, lymph node dissection methods, and lymph node dissection regions were influencing factors. RESULTS: Patients undergoing lobectomy were more likely to have chronic cough after surgery in the systematic lymph node dissection group than in the lymph node sampling group (P<0.05). LCQ-MC scale evaluation showed that the psychological, physiological, social and total score of the patients in systematic lymph node dissection group were significantly lower than those in lymph node sampling group (P<0.05). Multivariate analysis showed that anesthesia time, operation site, lymph node dissection method, whether to perform upper mediastinal lymph node dissection, number of upper mediastinal lymph node dissection, whether to perform lower mediastinal lymph node dissection and total number of lymph node dissection were independent risk factors for postoperative chronic cough in NSCLC patients (P<0.05). CONCLUSIONS When NSCLC patients underwent lobectomy, lymph node sampling was associated with a significantly lower risk of chronic cough than systematic lymph node dissection. Dissecting lymph nodes in the upper and lower mediastinal regions and the number of lymph nodes dissected may increase the risk of postoperative cough and reduce the quality of life of patients after surgery.
Humans ; Carcinoma, Non-Small-Cell Lung/surgery* ; Male ; Female ; Lung Neoplasms/surgery* ; Middle Aged ; Cough/etiology* ; Retrospective Studies ; Lymph Node Excision/methods* ; Aged ; Chronic Disease ; Postoperative Complications/etiology* ; Adult ; Lymph Nodes/surgery* ; Pneumonectomy/adverse effects* ; Chronic Cough

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB⁺ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg ^-/- Rag2 ^-/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

BACKGROUND:Platelet-rich fibrin(PRF)is a second generation platelet concentrate with the advantages of simple operation,no anticoagulant,and high bioactivity,which has been applied in the fields of trauma repair,bone defect repair,and tendon soft tissue repair,and has been proved to have a certain tissue repair-promoting effect. OBJECTIVE:To study the repair effect of PRF on articular cartilage tissue in rats with knee osteoarthritis. METHODS:Thirty-six Sprague-Dawley rats were randomly divided into normal group,model group,and PRF group,with 12 rats in each group.Rats in the normal group did not undergo any treatment.In the model group,animal models of knee osteoarthritis were prepared and rat models were then given physiological saline into the joint cavity once a week after surgery.Rat models of knee osteoarthritis were also prepared in the PRF group,and autologous PRF was injected into the joint cavity once a week after surgery.After 5 weeks of continuous treatment,tissue samples were taken.Hematoxylin-eosin staining was used to observe the morphology of cartilage tissue.Tunel staining was used to detect chondrocyte apoptosis,ELISA was used to detect inflammatory factor levels.Western blot and RT-PCR were used to detect Bcl-2,Bax,and Caspase-3 expression in protein and mRNA levels,respectively. RESULTS AND CONCLUSION:The model group had severe cartilage tissue damage,while the PRF group had significantly improved cartilage tissue morphology compared with the model group.The model group had more apoptotic chondrocytes.Compared with the model group,the mean absorbance of Tunel positive staining in the PRF group significantly decreased(P<0.01).The levels of interleukin-1β,interleukin-6 and tumor necrosis factor-α were significantly increased in the model group and PRF group compared with the normal group(P<0.01)and were significantly decreased in the PRF group compared with the model group(P<0.01).The relative expressions of Bax and Caspase-3 at protein and mRNA levels were significantly increased in the model group and PRF group compared with the normal group(P<0.01),while the relative expressions of Bcl-2 at protein and mRNA were significantly decreased(P<0.01).Compared with the model group,the relative expression of Bax and Caspase-3 at protein and mRNA levels were significantly decreased in the PRF group(P<0.01),while the relative expressions of Bcl-2 at protein and mRNA levels were significantly increased(P<0.01).To conclude,PRF can inhibit chondrocyte apoptosis by inhibiting the expression of pro-inflammatory factors,thereby promoting cartilage tissue repair in knee osteoarthritis rats.