The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

The perioperative shivering, as one of the adverse reactions during cesarean sections, has many bad influences on the parturients and the neonates. Several studies have already explored in the evaluation methods, risk factors, possible mechanisms, and effective prevention measures for the occurrence of perioperative shivering during cesarean sections. This article will make a review on the basis of literature, hoping to provide a reference for the prevention and treatment of shivering during the perioperative period of cesarean section.

【Objective】 To investigate the application of 5W+ 1H combined with ECRS analysis principle in reducing the under-reporting rate of adverse reactions to blood transfusion (ARBT). 【Methods】 The causes of under-reporting rate of ARBT were analyzed using 5W+ 1H combined with ECRS analysis principle in Department of Hematology, and the countermeasures and intervention measures were carried out. The under-reporting rate of ARBTs before(January 2018 to December 2019, control) and after(January 2016 to December 2017, test) the interventions was compared. 【Results】 After the application of 5W+ 1H combined ECRS analysis principle, the under-reporting rate of ARBTs decreased significantly(17.39% test vs 37.67% control) (P<0.05). 【Conclusion】 The application of 5W+ 1H combined ECRS analysis principle can effectively reduce the under-reporting rate of ARBT, improve the report management of it, and improve the safety of the blood products.

This study was to develop a quantitative immunoassay for hyaluronic acid(HA). We firstly prepared a monoclonal antibody(MAb)against it. HA, activated by 1-cyano-4-dimethyl-aminopyridinium tetrafluoroborate(CDAP), was coupled to bovine serum albumin(BSA). BALB/c mice were immunized with purified complete antigen BSA-HA and the monoclonal antibody was prepared by hybridoma technique. To characterize the specificity of the antibody, inhibition enzyme-linked immunosorbent assay(ELISA)was conducted and the cross reactivity along with affinity constant was determined. The results showed that the substitution degree of BSA-HA(mBSA/wHA)was about 9. Also, a hybridoma cell line named 8B6 was obtained by hybridoma technology. The indirect ELISA titer of the ascetic fluid was 1 ∶256 000; the isotype of MAb 8B6 was IgG1 and the affinity constant was Ka=6. 71×109 mol-1. To establish the indirect competitive ELISA method, polystyrene microwell plates were coated with 10. 0 ng/mL HA and blocked with 1. 0% BSA. The linear range of indirect competitive ELISA was between 10. 0 ng/mL to 10. 0 μg/mL which confirmed that the method was specific and sensitive.