Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

Bio-mineralization has emerged as a promising strategy to enhance vaccine immunogenicity. This study optimized the calcium phosphate (CaP) mineralization process of foot-and-mouth disease virus-like particles (FMD VLPs) to achieve high mineralization efficiency and scalability. Key parameters, including concentrations of Ca²⁺, HPO₄^2-, NaCl, and VLPs, as well as stirring speed, were systematically optimized. Stability of the scaled-up reaction system and immunogenicity of the mineralized vaccine were evaluated. Optimal conditions [25.50 mmol/L Ca(NO₃)₂, 15 mmol/L Na₂HPO₄, 300 mmol/L NaCl, 0.75 mg/mL VLPs, and 1 500 r/min] yielded CaP-mineralized VLPs (VLPs-CaP) with high mineralization efficiency, uniform morphology, and a favorable particle size. Scaling up the reaction by 25 folds maintained consistent mineralization efficiency and particle characteristics. Immunization in mice demonstrated that VLPs-CaP induced higher titers of specific antibodies and neutralizing antibodies than unmineralized VLPs (P < 0.05). Higher IgG2a/IgG1 ratio and enhanced IFN-γ secretion (P < 0.05) further indicated robust cellular immune responses. We establish a stable and scalable protocol for VLPs-CaP, providing a theoretical and technical foundation for developing high-efficacy VLPs-CaP vaccines.
Vaccines, Virus-Like Particle/immunology* ; Immunogenicity, Vaccine ; Calcium Phosphates/chemistry* ; Foot-and-Mouth Disease Virus ; Biomineralization ; Particle Size ; Animals ; Mice ; Antibodies, Neutralizing/blood* ; Antibodies, Viral/blood* ; Immunity, Cellular

Vaccination is a crucial strategy for the prevention and control of infectious diseases. Virus-like particles (VLPs), composed of structural proteins, have garnered significant attention as a novel type of vaccine due to their excellent safety and immunogenicity. However, similar to most vaccine antigens, VLPs exhibit insufficient thermal stability, which not only restricts the widespread application of vaccines but also increases the risk of vaccine inactivation. This study aims to enhance the stability and shelf life of VLPs derived from type A foot-and-mouth disease virus (FMDV) by employing vacuum freeze-drying technology. The optimal lyoprotectant formulation was determined through single-factor and combinatorial screening. Subsequently, the correlation between the immunogenicity of the freeze-dried vaccine and the content of FMDV VLPs was evaluated via a mouse model. The stability of FMDV VLPs before and after freeze-drying was further assessed by storing them at 4, 25, and 37 ℃ for varying time periods. Results indicated that the lyoprotectant formulation No.1, composed of 7.5% trehalose, 0.1% Tween 80, 50 mmol/L glycine, 1% sodium glutamate, and 3% polyvinylpyrrolidone (PVP), effectively preserved the content of FMDV VLPs during the vacuum freeze-drying process. The immunization trial in mice revealed that the levels of specific antibodies, immunoglobulin G1 (IgG1), interleukin-4 (IL-4), and neutralizing antibodies induced by freeze-dried FMDV VLPs were comparable to those induced by non-freeze-dried FMDV VLPs. The heat treatment results showed that the storage periods of freeze-dried FMDV VLPs at 4, 25, and 37 ℃ were significantly longer than those of non-freeze-dried FMDV VLPs. In conclusion, the selected lyoprotectant formulation effectively improved the stability of FMDV VLPs vaccines. This study provides valuable insights for enhancing the stability of novel subunit vaccines.
Freeze Drying/methods* ; Animals ; Foot-and-Mouth Disease Virus/immunology* ; Mice ; Vaccines, Virus-Like Particle/chemistry* ; Foot-and-Mouth Disease/immunology* ; Vacuum ; Drug Stability ; Mice, Inbred BALB C ; Viral Vaccines/immunology*

OBJECTIVE To analyze the effects of biapenem on the blood concentration of sodium valproate （VPA） in patients with severe infections. METHODS A retrospective collection of patient data was conducted， encompassing individuals admitted to our hospital from January 2021 to May 2024 who were treated with biapenem for severe infections and concurrently or sequentially administered VPA for the prevention or treatment of epilepsy. The effects of various factors on the blood concentration of VPA， including the combination of biapenem， the sequence of biapenem administration， the number of days of biapenem combination， the dosage of biapenem， and the time after biapenem discontinuation. RESULTS A total of 70 patients with 117 VPA blood concentration results were included in this study. When VPA was used alone， no statistically significant difference was observed in the steady-state blood concentrations of VPA between patients who received biapenem first and those who received it later （P＞ 0.05）. There was no statistically significant difference between the steady-state concentration of VPA in patients who received biapenem in combination for 1 to 3 days and those who did not receive the combination therapy （P＞0.05）. The steady-state concentration of VPA in patients not receiving biapenem combination therapy was significantly higher than that of the patients who received combination therapy for 4 to 7 days and more than 7 days （P＜0.001）. With the prolonged duration of combination therapy， the blood concentration of VPA gradually decreased （P＜0.001）. However， no statistically significant difference was observed between the group receiving combination therapy for more than 7 days and the group receiving it for 4 to 7 days （P＞ 0.05）. After 1 to 3 days of combination therapy， no statistically significant differences in VPA blood concentrations were observed among patients with different discontinuation times of biapenem （P＞0.05）. The blood concentration of VPA in patients who received combination therapy for more than 3 days was significantly lower than those who discontinued biapenem 4 to 7 days or more than 7 days after more than 3 days of combination therapy（P＜0.001）. There was no statistically significant difference in VPA blood concentrations between patients receiving a daily biapenem dose ＞1.0 g and those receiving a daily dose ＜1.0 g （P＞0.05）. CONCLUSIONS The concomitant administration of biapenem for 1-3 days has a minimal impact on the blood concentration of VPA. In patients receiving combination therapy for longer than 3 days， VPA blood concentrations return to baseline levels chouxiaoh@163.com within 4-7 days after biapenem discontinuation.

Objective:To summarize the clinical features associated with respiratory syncytial virus (RSV) infection in patients following the hematopoietic stem cell transplant (HSCT) and exploring the risk factors for death.Methods:Patients who had RSV infection after undergoing HSCT from October 2023 to January 2024 in the hematology department of Peking University People’s Hospital were enrolled in the study. The clinical characteristics of the participating patients were summarized. The clinical characteristics of the surviving and the dying patients were compared, and the risk factors of death were analyzed by binary logistic regression.Results:Among the 43 RSV-positive HSCT patients, 20 (46.5%) were hypoxemic, six (14.0%) were admitted to the ICU for further treatment, four (9.3%) required tracheal intubation assisted ventilation, and seven patients (16.3%) died. A comparison of the clinical features of the surviving patients and the deceased patients demonstrated that the deceased patients had a lower PLT when infected with RSV [74.5 (8.0-348.0) ×10 9/L vs 15.0 (10.0-62.0) ×10 9/L, P=0.003], a higher incidence of simultaneous bacterial infections (85.7% vs 41.7%, P=0.046), and a higher rate of hematological recurrence (71.4% vs 13.9%, P=0.004). Hematological recurrence ( OR=15.500, 95% CI 2.336-102.848, P=0.005), influenza A viral infection ( OR=14.000, 95% CI 1.064-184.182, P=0.045), and low PLT at the time of RSV infection ( OR=0.945, 95% CI 0.894-0.999, P=0.048) were the factors associated with death following HSCT. Conclusion:Patients infected with RSV after undergoing HSCT have a poor prognosis, and active prevention and treatment of RSV in the autumn and winter requires urgent attention.

Objective:To analyze the distribution and drug resistance of pathogens of bacterial bloodstream infection in patients with hematological diseases in the Department of Hematology of Tianjin Medical University General Hospital, and to provide etiological data for clinical empirical anti-infection treatment.Methods:A retrospective analysis was conducted on the general clinical information, pathogenic bacteria and drug susceptibility test results of patients with hematological diseases diagnosed with bacterial bloodstream infection by menstrual blood culture in our center from January 2016 to December 2022.Results:Patients included 498 inpatients, with a total of 639 bacterial strains. Among the patients, 86.9% patients had malignancies, and 76.7% had agranulocytosis. Symptoms of concurrent infections, including those of the respiratory tract, oral mucosa, skin and soft tissues, and abdominal sources were observed in 68.3% patients. Gram-negative bacteria (G -) accounted for 79.0% of the isolated bacteria, and gram-positive bacteria (G +) accounted for 21.0%. The top five isolated pathogens were Klebsiella pneumoniae (22.5%), Escherichia coli (20.8%), Pseudomonas aeruginosa (15.0%), Enterococcus faecium (5.5%), and Stenotrophomonas maltophilum (5.0%). Escherichia coli exhibited a decreasing trend of resistance to quinolones, cephalosporins, and carbapenems. Klebsiella pneumoniae exhibited increasing rates of resistance to quinolones and cephalosporins between 2016 and 2018, but the rated decreased after 2019. The resistance rate to carbapenems exhibited by Pseudomonas aeruginosa was approximately 20%. Carbapenem-resistant strains of Pseudomonas aeruginosa strains were first detected in 2017, with a peak resistance rate of 35.7%, detected in 2019. A 60.0% resistance rate to methicillin was observed in methicillin-resistant coagulase-negative staphylococci (MRCNS), and one case of linezolid-resistant MRCNS was detected. Conclusions:Pathogenic bacteria of bacterial bloodstream infections were widely distributed in our center, and precautions are warranted against carbapenem resistant P. aeruginosa and Klebsiella pneumoniae.

Objective To explore the relationship between basic motor skills and social interaction ability in school-age children with moderate autism,and the mediating role of executive function and the realization path.Methods A cross-sectional design was used to investigate 117 school-age children with autism from Sep.to Dec.2020.The level of basic motor skills was assessed by the test of gross motor development(TGMD),the impairment of executive function was assessed by the behavior rating inventory of executive function(BRIEF),and the social disorder was assessed by the social responsive scale-second edition(SRS-2).Pearson correlation analysis was used to explore the interrelationship,and structural equation modeling was applied to explore the path relationship.Results There was a significant negative correlation between the level of basic motor skills and SRS-2 scores(r=-0.312,P＜0.001).There were significant negative correlations between the level of basic motor skills and the BRIEF scores of inhibition(r=-0.336,P＜0.001),switching(r=-0.325,P＜0.001),affective control(r=-0.338,P＜0.001),task initiation(r=-0.240,P=0.009),working memory(r=-0.278,P=0.002),and planning(r=-0.224,P=0.015).The SRS-2 score was positively correlated with the BRIEF scores of inhibition(r=0.378,P＜0.001),switching(r=0.299,P=0.001),affective control(r=0.417,P＜0.001),task initiation(r=0.246,P=0.007),working memory(r=0.409,P＜0.001),and monitoring(r=0.258,P=0.005).Executive function played a complete intermediary role between basic motor skills and social interaction ability(B=-1.912,95％confidence interval:-3.116 to-1.069).Conclusion In school-age children with moderate autism,executive function and social interaction ability change positively with the level of basic motor skills.Basic motor skills can affect social interaction ability through the mediating role of executive function,and inhibition and affective control are important pathways to achieve this.

Chinese materia medica has a wide range of clinical applications， but it has many active ingredients with different physicochemical properties， and the target organs， action pathways and mechanisms for different ingredients to exert their efficacy are not the same. Therefore， it is difficult to design and develop a co-delivery system loading multiple components of Chinese materia medica to maximize the synergistic therapeutic efficiency. Based on the characteristics of effectiveness and functionality of active ingredients， the strategies for multi-component co-delivery of Chinese materia medica can be categorized into two types：firstly， based on the effectiveness of active ingredients， new carriers such as liposomes， nanoparticles can be constructed to load multi-components of Chinese materia medica. secondly， based on the functionality of some active ingredients of Chinese materia medica， they are employed in the construction of co-delivery system， which can give play to the dual characteristics of their own efficacy and preparation functions. In this paper， we summarized the relevant research progress of the above two types of multi-component co-delivery strategies， and mainly discussed the pharmaceutical functions of the active ingredients in co-delivery systems， in order to find a more suitable multi-component co-delivery strategy， promoting the design and development of new delivery systems of Chinese materia medica.

Objective     To construct a radiomics model for identifying clinical high-risk carotid plaques. Methods     A retrospective analysis was conducted on patients with carotid artery stenosis in China-Japan Friendship Hospital from December 2016 to June 2022. The patients were classified as a clinical high-risk carotid plaque group and a clinical low-risk carotid plaque group according to the occurrence of stroke, transient ischemic attack and other cerebrovascular clinical symptoms within six months. Six machine learning models including eXtreme Gradient Boosting, support vector machine, Gaussian Naive Bayesian, logical regression, K-nearest neighbors and artificial neural network were established. We also constructed a joint predictive model combined with logistic regression analysis of clinical risk factors. Results    Finally 652 patients were collected, including 427 males and 225 females, with an average age of 68.2 years. The results showed that the prediction ability of eXtreme Gradient Boosting was the best among the six machine learning models, and the area under the curve (AUC) in validation dataset was 0.751. At the same time, the AUC of eXtreme Gradient Boosting joint prediction model established by clinical data and carotid artery imaging data validation dataset was 0.823. Conclusion     Radiomics features combined with clinical feature model can effectively identify clinical high-risk carotid plaques.