RESULTS: Most of the tested compounds showed insecticidal activity compared to fluralaner as positive control and commercially available insecticide. Especially, the isoxazoline-secondary sulfonamides containing halogens (Br and Cl) on the phenyl group attached to the isoxazoline, 6g (LC50 = 0.31 mg/mL), 6j (LC50 = 0.38 mg/mL), 6k (LC50 = 0.18 mg/mL), 6L (LC50 = 0.49 mg/mL), 6m (LC50 = 0.24 mg/mL), 6q (LC50 = 0.46 mg/mL), exhibited much higher larvicidal activity than fluralaner (LC50 = 0.99 mg/mL).
CONCLUSION: Novel isoxazolines containing sulfonamide moieties were designed, synthesized and confirmed by two single-crystal structures of 4e and 6q. Their bioassay results showed significant larvicidal activity with significant morphological changes in vivo. These results will lay the foundation for the further discovery and development of isoxazoline-sulfonamide derivatives as novel crop protection larvicides of cork oak. © 2023 Society of Chemical Industry.
METHODS: Using a Usp7K444R point mutation knock-in mouse strain, we performed immunohistochemistry and standard molecular biological methods to examine the organ defects of liver and kidney in this knock-in mouse strain. Mechanistic studies were performed by using deubiquitination, immunoprecipitation, and quantitative immunoprecipitations (qChIP) assays.
RESULTS: We observed multiple organ defects, including decreased liver and muscle weight, decreased tibia/fibula length, liver glycogen storage defect, and polycystic kidneys. The underlying mechanisms include the regulation of protein stability and/or modulation of transcriptional activation of several key factors, leading to decreased protein levels of Prr5l, Hnf4α, Cebpα, and Hnf1β. Repression of these crucial factors leads to the organ defects described above.
CONCLUSIONS: K63-polyubiquitinated Usp7 plays an essential role in the development of multiple organs and illustrates the importance of the process of K63-linked polyubiquitination in regulating critical protein functions.