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The main protease (Mpro) of SARS‐CoV‐2 is a well‐characterized target for antiviral drug discovery. To date, most antiviral drug discovery efforts have focused on the S4–S1′ pocket of Mpro; however, it is still unclear whether the S1′–S3′ pocket per se can serve as a new site for drug discovery. In this study, the S1′–S3′ pocket of Mpro was found to differentially recognize viral peptidyl substrates. For instance, S3′ in Mpro strongly favors Phe or Trp, and S1′ favors Ala. The peptidyl inhibitor D‐4–77, which possesses an α‐bromoacetamide warhead, was discovered to be a promising inhibitor of Mpro, with an IC50 of 0.95 μM and an antiviral EC50 of 0.49 μM. The Mpro/inhibitor co‐crystal structure confirmed the binding mode of the inhibitor to the S1′–S3′ pocket and revealed a covalent mechanism. In addition, D‐4–77 functions as an immune protectant and suppresses SARS‐CoV‐2 Mpro‐induced antagonism of the host NF‐κB innate immune response. These findings indicate that the S1′–S3′ pocket of SARS‐CoV‐2 Mpro is druggable, and that inhibiting SARS‐CoV‐2 Mpro can simultaneously protect human innate immunity and inhibit virion assembly. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to evaluate the effectiveness of home-based exercise interventions on pain, physical function and quality of life in individuals with knee osteoarthritis (KOA). Methods: Five databases (PubMed, Embase, Cochrane Library, CINAHL, Web of Science Core Collection) were searched for relevant randomized controlled trials (RCTs) published from database inception to 2 August 2022. The Cochrane Collaboration's standards were followed for study selection, eligibility criteria, data extraction and statistics, using the Cochrane Collaboration Risk of Bias Tool and PEDro for quality assessment. A meta-analysis and subgroup analyses, stratified by control condition and intervention duration, were conducted using RevMan 5.4. The study was reported in compliance with the PRISMA statement. Results: A total of 12 independent RCTs with 1442 participants were included. The meta-analysis showed that the home-based exercise interventions significantly reduced pain in individuals with KOA (SMD = − 0.32, 95% CI [− 0.41, − 0.22], p <.01) and improved physical function (SMD = − 0.25, 95% CI [− 0.47, − 0.02], p =.03) and quality of life (SMD = 0.63, 95% CI [0.41, 0.85], p <.001). Subgroup analysis revealed that home-based exercise interventions were superior to health education and no treatment, in terms of pain and physical function, and similar to clinic-based exercise and pharmacologic treatment. Conclusions: The effect of home-based exercise intervention is significantly better than health education and no treatment for reducing knee pain and improving physical function, and was able to achieve the effects of clinic-based exercise treatment and pharmacologic treatment. With regard to quality of life, the unsupervised home strength exercise intervention showed a significant effect compared with the health education control and combined with cognitive behavioural therapies may produce better results. Although home-based intervention provides effective treatment options for individuals with clinical treatment limitations, individual disease complications and the dosimetry of exercise need to be considered in practice. Furthermore, growing evidence supports the effectiveness of Tai Chi in the rehabilitation of KOA. [ABSTRACT FROM AUTHOR]

The residue of simazine herbicide in the environment is known as one of pollutant stress for lizards by crippling its fitness on direct toxic effects and indirect food shortage via the food chain effects. Both stressors were considered in our experiment in the simazine exposure and food availability to lizards (Eremias argus). The results revealed that starvation significantly reduced the lizard's energy reserve and native immune function, while the accumulation of simazine in the liver was significantly increased. Simazine caused oxidative stress in the liver of lizards, but oxidative damage only occurred in the starved lizards. Simazine also changed the energy reserves, native immune function and detoxification of well-fed lizards, while the starved lizards showed different sensitivity to simazine. Simazine or starvation treatment independently activated the lizard HPA axis, but co-treatment caused the HPA axis inhibition. Besides, according to the variations on amino acid neurotransmitters, corticosterone hormone and thermoregulatory behavior, we inferred that lizards in threatens take the appropriate strategy on energy investment and allocation through neural, endocrine and behavioral pathways to maximize benefits in dilemma. Energy allocation was necessary, while suppression on any physiological process comes at a cost that is detrimental to long-term individual fitness. Image 1 • Starvation increased the accumulation of simazine in the liver of lizards. • Simazine changed the antioxidant, immunity and detoxification of well-fed lizards. • Starved lizards showed different sensitivity to simazine on those processes. • HPA axis is related to the starvation and simazine stressors. • Lizards maximize benefits through neural, endocrine and behavioral pathways. Lizards could change the energy allocation of several physiological processes under simazine and starvation stresses, and maximize benefits through neural, endocrine and behavioral pathways. [ABSTRACT FROM AUTHOR]