ABSTRACT
Nerve agents are used in civil wars and terrorist attacks, posing a threat to public safety. Acute exposure to nerve agents such as soman (GD) causes serious brain damage, leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation. However, data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited. Here, we evaluated the potential effects of transient receptor vanilloid 4 (TRPV4) in the treatment of soman-induced status epilepticus (SE) and secondary brain injury. We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures. Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity. TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure. Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity. The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1β and IL-18 increased in soman-exposed rat hippocampus. However, TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway. In conclusion, our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation. To our knowledge, this is the first study regarding the “dual-switch” function of TRPV4 in the treatment of soman intoxication.
ABSTRACT
Although human antibodies elicited by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-directed antibodies. Herein, we isolated and profiled a panel of 32 N protein-specific monoclonal antibodies (mAb) from a quick recovery coronavirus disease-19 (COVID-19) convalescent, who had dominant antibody responses to SARS-CoV-2 N protein rather than to Spike protein. The complex structure of N protein RNA binding domain with the highest binding affinity mAb nCoV396 reveals the epitopes and antigens allosteric changes. Functionally, a virus-free complement hyper-activation analysis demonstrates that nCoV396 specifically compromises N protein-induced complement hyper-activation, a risk factor for morbidity and mortality in COVID-19, thus paving the way for functional anti-N mAbs identification. One Sentence SummaryB cell profiling, structural determination, and protease activity assays identify a functional antibody to N protein.
ABSTRACT
OBJECTIVE:To study influential factors for retail chain drugstore undertaking the pharmacy function of community health center based on the perspective of retail chain drugstore pharmacist. METHODS:The stratified sampling method was used to conduct questionnaire survey among pharmacists in retail chain drugstores from Pearl River Delta(Guangzhou,Foshan, Dongguan),eastern Guangdong,western Guangdong and northern Guangdong. Multivariate analysis of variance was performed to study main effects of independent variables,pairwise comparison and interaction,with social demographic characteristics(gender, age,educational level,major,profession at title,working life,location)as independent variables,using fear of workload increase,inadequate pharmaceutical care,lower wages,inadequate electronic prescription acceptance and change in the work model as dependent variable. RESULTS:A total of 242 questionnaires were sent out,involving 239 valid questionnaires with effective recovery rate of 98.8%. The results of multivariate analysis of variance showed that majors of main effect and the interaction between major and professional title affected the fear of increase in the workload;age,education and working years of main effect,and the interaction between age and location affected the fear of inadequate pharmaceutical care;professional title of main effect affected the fear of electronic prescription acceptance;age and location of main effect,and the interactions between age and professional title influenced the fear of change in work model. CONCLUSIONS:It is suggested to strengthen pharmaceutical care and electronic prescription acceptance of pharmaceutical staff in retail chain drugstore,increase the number of professional pharmaceutical staff,allocate pharmaceutical staff reasonably and consider about regional differences.
