Objective To initially explore the possibility of applying the fluorescence micro-optical sectioning tomography(fMOST)high-resolution 3D reconstruction system to the morphological study of the intestinal nervous system and to preliminarily establish a method for studying the morphology of the intestinal nervous system using this system.Methods fMOST high-resolution 3D reconstruction system was used to study the intestinal nervous system of C57BL/6 mice in detail.Based on this method,a new morphological method of the visceral nervous system of small animal models was explored at the single-cell level.Results Compared with the large intestine,the small intestine lacked the typical myenteric plexus(Auerbach),deep mucosal plexus(Henley),and submucosal superficial plexus(Meissner).Conclusion The result of this paper provide a clearer and systematic display of the anatomical structure of the enteric nervous system in C57BL/6 mice,and further clarify the similarities and differences between the enteric nervous system of mice and human,and provide a theoretical basis for its rational application in the study of digestive system diseases.The morphological study of fMOST high-resolution 3D reconstruction system is not limited to the central nervous system,but can be extended to the morphological study of multiple visceral nervous systems.

Clathrin-mediated endocytosis (CME) is a critical process by which cells internalize macromolecular substances and initiate vesicle trafficking, serving as the foundation for many cellular activities. Central to this process are clathrin-coated structures (CCSs), which consist of clathrin-coated pits (CCPs) and clathrin plaques. While clathrin-coated pits are well-established in the study of endocytosis, clathrin plaques represent a more recently discovered but equally important component of this system. These plaques are large, flat, and extended clathrin-coated assemblies found on the cytoplasmic membrane. They are distinct from the more typical clathrin-coated pits in terms of their morphology, larger surface area, and longer lifespan. Recent research has revealed that clathrin plaques play roles that go far beyond endocytosis, contributing to diverse cellular processes such as cellular adhesion, mechanosensing, migration, and pathogen invasion. Unlike traditional clathrin-coated pits, which are transient and dynamic structures involved primarily in the internalization of molecules, clathrin plaques are more stable and extensive, often persisting for extended periods. Their extended lifespan suggests that they serve functions beyond the typical endocytic role, making them integral to various cellular processes. For instance, clathrin plaques are involved in the regulation of intercellular adhesion, allowing cells to better adhere to one another or to the extracellular matrix, which is crucial for tissue formation and maintenance. Furthermore, clathrin plaques act as mechanosensitive hubs, enabling the cell to sense and respond to mechanical stress, a feature that is essential for processes like migration, tissue remodeling, and even cancer progression. Recent discoveries have also highlighted the role of clathrin plaques in cellular signaling. These plaques can serve as scaffolds for signaling molecules, orchestrating the activation of various pathways that govern cellular behavior. For example, the recruitment of actin-binding proteins such as F-actin and vinculin to clathrin plaques can influence cytoskeletal dynamics, helping cells adapt to mechanical changes in their environment. This recruitment also plays a pivotal role in regulating cellular migration, which is crucial for developmental processes. Additionally, clathrin plaques influence receptor-mediated signal transduction by acting as platforms for the assembly of signaling complexes, thereby affecting processes such as growth factor signaling and cellular responses to extracellular stimuli. Despite the growing body of evidence that supports the involvement of clathrin plaques in a wide array of cellular functions, much remains unknown about the precise molecular mechanisms that govern their formation, maintenance, and turnover. For example, the factors that regulate the recruitment of clathrin and other coat proteins to form plaques, as well as the signaling molecules that coordinate plaque dynamics, remain areas of active research. Furthermore, the complex interplay between clathrin plaques and other cellular systems, such as the actin cytoskeleton and integrin-based adhesion complexes, needs further exploration. Studies have shown that clathrin plaques can respond to mechanical forces, with recent findings indicating that they act as mechanosensitive structures that help the cell adapt to changing mechanical environments. This ability underscores the multifunctional nature of clathrin plaques, which, in addition to their role in endocytosis, are involved in cellular processes such as mechanotransduction and adhesion signaling. In summary, clathrin plaques represent a dynamic and versatile component of clathrin-mediated endocytosis. They play an integral role not only in the internalization of macromolecular cargo but also in regulating cellular adhesion, migration, and signal transduction. While much has been learned about their structural and functional properties, significant questions remain regarding the molecular mechanisms that regulate their formation and their broader role in cellular physiology. This review highlights the evolving understanding of clathrin plaques, emphasizing their importance in both endocytosis and a wide range of other cellular functions. Future research is needed to fully elucidate the mechanisms by which clathrin plaques contribute to cellular processes and to better understand their implications for diseases, including cancer and tissue remodeling. Ultimately, clathrin plaques are emerging as crucial hubs that integrate mechanical, biochemical, and signaling inputs, providing new insights into cellular function and the regulation of complex cellular behaviors.

OBJECTIVE: The results of limited studies on the relationship between environmental pollution and dementia have been contradictory. We analyzed the combined effects of PM _2.5 and smoking on the prevalence of dementia and cognitive impairment in an elderly community-dwelling Chinese population. METHODS: We assessed 24,117 individuals along with the annual average PM _2.5 concentrations from 2012 to 2016. Dementia was confirmed in the baseline survey at a qualified clinical facility, and newly suspected dementia was assessed in 2017, after excluding cases of suspected dementia in 2015. National census data were used to weight the sample data to reflect the entire population in China, with multiple logistic regression performed to analyze the combined effects of PM _2.5 and smoking frequency on dementia and cognitive impairment. RESULTS: Individuals exposed to the highest PM _2.5 concentration and smoked daily were at higher risk of dementia than those in the lowest PM _2.5 concentration group ( OR, 1.603; 95% CI [1.626-1.635], P < 0.0001) and in the nonsmoking group ( OR, 1.248; 95% CI [1.244-1.252]; P < 0.0001). Moderate PM _2.5 exposure and occasional smoking together increased the short-term risk of cognitive impairment. High-level PM _2.5 exposure and smoking were associated with an increased risk of dementia, so more efforts are needed to reduce this risk through environmental protection and antismoking campaigns. CONCLUSION High-level PM _2.5 exposure and smoking were associated with an increased risk of dementia. Lowering the ambient PM _2.5, and smoking cessation are recommended to promote health.
Humans ; Dementia/etiology* ; Male ; Aged ; Female ; Cognitive Dysfunction/etiology* ; China/epidemiology* ; Particulate Matter/analysis* ; Smoking/epidemiology* ; Air Pollutants/analysis* ; Aged, 80 and over ; Environmental Exposure/adverse effects* ; Prevalence ; Middle Aged

BACKGROUND: PANoptosis has the features of pyroptosis, apoptosis, and necroptosis. Numerous studies have confirmed the diverse roles of various types of cell death in acute liver failure (ALF), but limited attention has been given to the crosstalk among them. In this study, we aimed to explore the role of PANoptosis in ALF and uncover new targets for its prevention or treatment. METHODS: Three ALF-related datasets (GSE14668, GSE62029, and GSE74000) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Hub genes were identified through intersecting DEGs, genes obtained from weighted gene co-expression network analysis (WGCNA), and genes related to PANoptosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein‍‒‍protein interaction (PPI) analyses and gene set enrichment analysis (GSEA) were performed to determine functional roles. Verification was performed using an ALF mouse model. RESULTS: Our results showed that expression of seven hub genes (B-cell lymphoma-2-modifying factor (BMF), B-cell lymphoma-2-interacting protein 3-like (BNIP3L), Caspase-1 (CASP1), receptor-interacting protein kinase 3 (RIPK3), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA), uncoordinated-5 homolog B receptor (UNC5B), and Z-DNA-binding protein 1 (ZBP1)) was up-regulated in liver samples of patients. However, in the ALF mouse model, the expression of BNIP3L, RIPK3, phosphorylated RIPK3 (P-RIPK3), UACA, and cleaved caspase-1 was up-regulated, while the expression of CASP1 and UNC5B was down-regulated. The expression of ZBP1 and BMF increased only during the development of ALF, and there was no significant change in the end stage. Immunofluorescence of mouse liver tissue showed that macrophages expressed all seven markers. Western blot results showed that pyroptosis, apoptosis, and necroptosis were always involved in lipopolysaccharide (LPS)/ d-galactosamine (d-gal)‍-induced ALF mice. The ALF cell model showed that bone marrow-derived macrophages (BMDMs) form PANoptosomes after LPS stimulation. CONCLUSIONS: Our results suggest that PANoptosis of macrophages promotes the development of ALF. The seven new ALF biomarkers identified and validated in this study may contribute to further investigation of diagnostic markers or novel therapeutic targets of ALF.
Animals ; Liver Failure, Acute/genetics* ; Computational Biology ; Mice ; Pyroptosis/genetics* ; Humans ; Protein Interaction Maps ; Apoptosis/genetics* ; Necroptosis/genetics* ; Gene Regulatory Networks ; Gene Ontology ; Gene Expression Profiling ; Disease Models, Animal

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Intentional tooth replantation (ITR) is an advanced treatment modality and the procedure of last resort for preserving teeth with inaccessible endodontic or resorptive lesions. ITR is defined as the deliberate extraction of a tooth; evaluation of the root surface, endodontic manipulation, and repair; and placement of the tooth back into its original socket. Case reports, case series, cohort studies, and randomized controlled trials have demonstrated the efficacy of ITR in the retention of natural teeth that are untreatable or difficult to manage with root canal treatment or endodontic microsurgery. However, variations in clinical protocols for ITR exist due to the empirical nature of the original protocols and rapid advancements in the field of oral biology and dental materials. This heterogeneity in protocols may cause confusion among dental practitioners; therefore, guidelines and considerations for ITR should be explicated. This expert consensus discusses the biological foundation of ITR, the available clinical protocols and current status of ITR in treating teeth with refractory apical periodontitis or anatomical aberration, and the main complications of this treatment, aiming to refine the clinical management of ITR in accordance with the progress of basic research and clinical studies; the findings suggest that ITR may become a more consistent evidence-based option in dental treatment.
Humans ; Tooth Replantation/methods* ; Consensus ; Periapical Periodontitis/surgery*

Objective:To investigate the predictive value of thromboelastogram(TEG)combined with blood D-dimer in patients with diffuse large B-cell lymphoma(DLBCL)complicated with venous thromboembolism(VTE)of lower extremities.Methods:A total of 155 patients diagnosed with DLBCL in our hospital from August 2022 to August 2024 were collected as the research objects.Among them,73 patients received lower extremity arteriovenous color Doppler ultrasound,and 14 patients with lower extremity venous thrombosis were detected,59 cases were not detected,which were included in the VTE group and non-VTE group,respectively.The TEG parameters including coagulation angle(Angle),comprehensive coagulation index(CI),clotting time(K),maximum amplitude(MA),coagulation reaction time(R),together with blood D-dimer level,international prognostic index and whether it was relapsed or refractory were compared between the two groups.Multivariate Logistic regression analysis was used to explore the independent influencing factors of VTE formation in all patients.The area under the curve(AUC)of the receiver operating characteristic(ROC)curve was used to evaluate the predictive value of each parameter for VTE.Results:There was no significant difference in gender and age between the VTE group and the non-VET group(all P＞0.05).The number of high-risk and relapse/refractory patients in the VTE group was significantly higher than that in the non-VTE group(all P＜0.05).Angle and CI in VTE group were significantly higher than those in non-VTE group(all P＜0.05),K value and R value were significantly lower than those in non-VTE group(all P＜0.05),and blood D-dimer level was significantly higher than that in non-VTE group(all P＜0.05).Multivariate logistic regression analysis showed that R value was an independent protective factor for VTE in patients with DLBCL(OR=0.256,P＜0.05),however,Ann Arbor stage(OR=3.885,P＜0.05)was independent risk factors for VTE in patients with DLBCL.The results of ROC curve analysis showed that there was no significant difference in the sensitivity of TEG(TEG group)prediction and TEG combined with blood D-dimer level(combined group)in predicting VTE in patients with DLBCL(92.86％,85.71％)and the sensitivity of blood D-dimer level(D-dimer group)prediction(71.43％)(P＞0.05).There was no significant difference in the specificity between TEG group prediction(74.58％)and combined group prediction(81.36％),TEG group prediction and D-dimer group prediction(64.41％)(P＞0.05).However,the specificity of the combined group was higher than that of the D-dimer group(x2=4.288,P＜0.05).The AUC of the TEG group(0.901)and the combined group(0.915)was higher than that of the D-dimer group(0.692)(Z=2.647,P＜0.05;Z=3.106,P＜0.05),but there was no significant difference in AUC between TEG group prediction and combined group prediction(P＞0.05).Conclusion:TEG and blood D-dimer levels have certain predictive efficacy for VTE in DLBCL patients,but TEG combined with blood D-dimer level has higher clinical value for VTE in DLBCL patients,which is worthy of clinical promotion.

Objective:To investigate the predictive value of thromboelastogram(TEG)combined with blood D-dimer in patients with diffuse large B-cell lymphoma(DLBCL)complicated with venous thromboembolism(VTE)of lower extremities.Methods:A total of 155 patients diagnosed with DLBCL in our hospital from August 2022 to August 2024 were collected as the research objects.Among them,73 patients received lower extremity arteriovenous color Doppler ultrasound,and 14 patients with lower extremity venous thrombosis were detected,59 cases were not detected,which were included in the VTE group and non-VTE group,respectively.The TEG parameters including coagulation angle(Angle),comprehensive coagulation index(CI),clotting time(K),maximum amplitude(MA),coagulation reaction time(R),together with blood D-dimer level,international prognostic index and whether it was relapsed or refractory were compared between the two groups.Multivariate Logistic regression analysis was used to explore the independent influencing factors of VTE formation in all patients.The area under the curve(AUC)of the receiver operating characteristic(ROC)curve was used to evaluate the predictive value of each parameter for VTE.Results:There was no significant difference in gender and age between the VTE group and the non-VET group(all P＞0.05).The number of high-risk and relapse/refractory patients in the VTE group was significantly higher than that in the non-VTE group(all P＜0.05).Angle and CI in VTE group were significantly higher than those in non-VTE group(all P＜0.05),K value and R value were significantly lower than those in non-VTE group(all P＜0.05),and blood D-dimer level was significantly higher than that in non-VTE group(all P＜0.05).Multivariate logistic regression analysis showed that R value was an independent protective factor for VTE in patients with DLBCL(OR=0.256,P＜0.05),however,Ann Arbor stage(OR=3.885,P＜0.05)was independent risk factors for VTE in patients with DLBCL.The results of ROC curve analysis showed that there was no significant difference in the sensitivity of TEG(TEG group)prediction and TEG combined with blood D-dimer level(combined group)in predicting VTE in patients with DLBCL(92.86％,85.71％)and the sensitivity of blood D-dimer level(D-dimer group)prediction(71.43％)(P＞0.05).There was no significant difference in the specificity between TEG group prediction(74.58％)and combined group prediction(81.36％),TEG group prediction and D-dimer group prediction(64.41％)(P＞0.05).However,the specificity of the combined group was higher than that of the D-dimer group(x2=4.288,P＜0.05).The AUC of the TEG group(0.901)and the combined group(0.915)was higher than that of the D-dimer group(0.692)(Z=2.647,P＜0.05;Z=3.106,P＜0.05),but there was no significant difference in AUC between TEG group prediction and combined group prediction(P＞0.05).Conclusion:TEG and blood D-dimer levels have certain predictive efficacy for VTE in DLBCL patients,but TEG combined with blood D-dimer level has higher clinical value for VTE in DLBCL patients,which is worthy of clinical promotion.

Objective To explore causal relationship between atopic diseases(asthma and atopic dermatitis)and os-teoarthritis(OA)by using mendelian randomization(MR).Methods Asthma and atopic dermatitis as instrumental variables were selected,searched them through IEU database,and selected the latest data with a large number of cases and single nu-cleotide polymorphism(SNP).Data were collected and processed using R language,inverse varianceweighted(IVW)method was adopted as main MR Evaluation method.Single linear regression was performed to estimate causality based on pooled knee and hip data from genome-wide association studies(GWAS).The forest map was drawn to visualize the results,and gene pleiotropy and sensitivity were analyzed by scatter plot and funnel plot.At the same time,asthma,atopic dermatitis,body mass index(BMI),osteoporosis and OA were selected for multivariate MR Analysis to exclude the effect of horizontal pleiotropy on the results in GWAS data.Results Analysis of MR-IVW results showed asthma was positively correlated with causal effect of OA[OR=1.41,95％CI(1.07,1.85),P=0.02],multivariate Mendelian randomization(MVMR)adjusted for BMI and osteo-porosis and a direct causal effect on OA was observed[OR=1.57,95％CI(1.03,2.39),P=0.03)].MR Results of two samples of atopic dermatitis and OA were[OR=1.01,95％CI(0.97,1.04),P=0.76],and MVMR results were[OR=1.02,95％CI(0.99,1.05),P=0.25],indicating no clear causal relationship between two samples.Conclusion Asthma could increase risk of OA,atopic dermatitis has no obvious relationship with OA,and the relationship between atopic diseases and OA still needs to be discussed.

Objective To evaluate and compare the success rate and short-term clinical prognosis of transfemoral transcatheter aortic valve replacement(TF-TAVR)for patients with pure aortic regurgitation(PAR)of different annulus sizes.Methods This study is a single center retrospective study,selecting symptomatic PAR patients who received TF-TAVR treatment at Zhongshan Hospital Fudan University from September 2019 to September 2023.Based on preoperative CT results,all patients were divided into three groups:Group A(aortic annulus circumference＜80 mm),Group B(80 mm≤aortic annulus circumference＜85 mm),and Group C(aortic annulus circumference&ge; 85 mm).The primary endpoint was success rate and 30d all-cause mortality,while the secondary endpoint was TAVR related complications.Results A total of 61 PAR patients were included in this study,including 27 in Group A,21 in Group B,and 13 in Group C.The overall success rate is 82.0％,and the 30 d all-cause mortality rate is 3.3％.The success rate of Group C patients was significantly lower(P=0.012),with higher rates of conversion to surgery and valve-in-valve implantation(P=0.022 and P=0.040).In terms of secondary endpoint events,there were no significant differences among the three groups in major bleeding events,major vascular complications,stroke,myocardial infarction,newly developed atrial fibrillation,implantation of new pacemakers,coronary artery occlusion,and postoperative moderate to severe perivalvular leakage(all P＞0.05).Conclusions The circumference of the aortic valve annulus is a key factor affecting the success rate of TF-TAVR in PAR,and PAR patients with an aortic valve annulus circumference less than 85mm may be more suitable for TF-TAVR.