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 investigate the effect of sanguinarine(SAN)on proliferation and ferroptosis of colorectal cancer cells.Methods SW620 and HCT-116 cells treated with different concentrations of SAN were examined for cell viability changes using CCK8 assay to determine the IC50 of SAN in the two cells.The inhibitory effects of SAN on proliferation,invasion and migration of the cells were evaluated using colony-forming assay and Transwell assays.ROS production in the treated cells was analyzed with flow cytometry,and lipid peroxide production was assessed by detecting malondialdehyde(MDA)level.Glutathione(GSH)levels in the cells were detected,and Western blotting was used to detect the expressions of ferroptosis-related proteins STUB1 and GPX4.Results SAN significantly inhibited the proliferation,invasion and migration of SW620 and HCT-116 cells.SAN treatment significantly promoted ROS production,increased intracellular MDA level,and lowered GSH level in the two cells(P<0.05).Western blotting showed that SAN significantly upregulated the expression of STUB1 and down-regulated the expression of its downstream protein GPX4(P<0.05).Conclusion SAN induces ferroptosis in colorectal cancer cells by regulating STUB1/GPX4,which may serve as a new therapeutic target for colorectal cancer.

Objective To investigate the effect of sanguinarine(SAN)on proliferation and ferroptosis of colorectal cancer cells.Methods SW620 and HCT-116 cells treated with different concentrations of SAN were examined for cell viability changes using CCK8 assay to determine the IC50 of SAN in the two cells.The inhibitory effects of SAN on proliferation,invasion and migration of the cells were evaluated using colony-forming assay and Transwell assays.ROS production in the treated cells was analyzed with flow cytometry,and lipid peroxide production was assessed by detecting malondialdehyde(MDA)level.Glutathione(GSH)levels in the cells were detected,and Western blotting was used to detect the expressions of ferroptosis-related proteins STUB1 and GPX4.Results SAN significantly inhibited the proliferation,invasion and migration of SW620 and HCT-116 cells.SAN treatment significantly promoted ROS production,increased intracellular MDA level,and lowered GSH level in the two cells(P<0.05).Western blotting showed that SAN significantly upregulated the expression of STUB1 and down-regulated the expression of its downstream protein GPX4(P<0.05).Conclusion SAN induces ferroptosis in colorectal cancer cells by regulating STUB1/GPX4,which may serve as a new therapeutic target for colorectal cancer.

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.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Objective To investigate the distribution and antimicrobial resistance profiles of the common pathogens isolated from urine from 2015 to 2021 in the CHINET Antimicrobial Resistance Surveillance Program.Methods The bacterial strains were isolated from urine and identified routinely in 51 hospitals across China in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Antimicrobial susceptibility was determined by Kirby-Bauer method,automatic microbiological analysis system and E-test according to the unified protocol.Results A total of 261 893 nonduplicate strains were isolated from urine specimen from 2015 to 2021,of which gram-positive bacteria accounted for 23.8％(62 219/261 893),and gram-negative bacteria 76.2％(199 674/261 893).The most common species were E.coli(46.7％),E.faecium(10.4％),K.pneumoniae(9.8％),E.faecalis(8.7％),P.mirabilis(3.5％),P.aeruginosa(3.4％),SS.agalactiae(2.6％),and E.cloacae(2.1％).The strains were more frequently isolated from inpatients versus outpatients and emergency patients,from females versus males,and from adults versus children.The prevalence of ESBLs-producing strains in E.coli,K.pneumoniae and P.mirabilis was 53.2％,52.8％and 37.0％,respectively.The prevalence of carbapenem-resistant strains in E.coli,K.pneumoniae,P.aeruginosa and A.baumannii was 1.7％,18.5％,16.4％,and 40.3％,respectively.Lower than 10％of the E.faecalis isolates were resistant to ampicillin,nitrofurantoin,linezolid,vancomycin,teicoplanin and fosfomycin.More than 90％of the E.faecium isolates were ressitant to ampicillin,levofloxacin and erythromycin.The percentage of strains resistant to vancomycin,linezolid or teicoplanin was＜2％.The E.coli,K.pneumoniae,P.aeruginosa and A.baumannii strains isolated from ICU inpatients showed significantly higher resistance rates than the corresponding strains isolated from outpatients and non-ICU inpatients.Conclusions E.coli,Enterococcus and K.pneumoniae are the most common pathogens in urinary tract infection.The bacterial species and antimicrobial resistance of urinary isolates vary with different populations.More attention should be paid to antimicrobial resistance surveillance and reduce the irrational use of antimicrobial agents.