A series of rare-earth (RE) metal complexes (Y, Sm, Nd, and La) stabilized by polydentate N-methylethylenediamine-bridged tris­(phenolato) ligands was synthesized and characterized. Lanthanum complexes showed good activity in catalyzing the cycloaddition reaction of terminal epoxides with CO2 under ambient conditions (i.e., room temperature, 1 bar CO2), giving rise to cyclic carbonates in 49–99% yields. More importantly, generally challenging internal epoxides were also transformed into cyclic carbonates in 70–99% yields in the presence of 1 bar CO2 at 60 °C. This is the first RE-based catalyst for efficient cycloaddition of CO2 and epoxides under ambient conditions and is among the most active catalysts for this important transformation. The lanthanum complex was also recycled six times. Kinetic study of the cycloaddition of cyclohexene oxide and CO2 was conducted, and the kinetic equation was determined as follows: rate = k[epoxide]1[CO2]0[cat.]1.26[TBAI]0.4. The Gibbs activation energy (333 K) was determined to be 29.8 kcal/mol.

Accumulated evidence demonstrates that Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, the precise role of PERK in JEV-induced apoptosis and encephalitis remains unknown. Here, we report that JEV infection activates the PERK-ATF4-CHOP apoptosis pathway both in vitro and in vivo. PERK activation also promotes the formation of stress granule, which in turn represses JEV-induced apoptosis. However, PERK inhibitor reduces apoptosis, indicating that JEV-activated PERK predominantly induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway. Among JEV proteins that have been reported to induce ER stress, only JEV NS4B can induce PERK activation. PERK has been reported to form an active molecule by dimerization. The coimmunoprecipitation assay shows that NS4B interacts with PERK. Moreover, glycerol gradient centrifugation shows that NS4B induces PERK dimerization. Both the LIG-FHA and the LIG-WD40 domains within NS4B are required to induce PERK dimerization, suggesting that JEV NS4B pulls two PERK molecules together by simultaneously interacting with them via different motifs. PERK deactivation reduces brain cell damage and encephalitis during JEV infection. Furthermore, expression of JEV NS4B is sufficient to induce encephalitis via PERK in mice, indicating that JEV activates PERK primarily via its NS4B to cause encephalitis. Taken together, our findings provide a novel insight into JEV-caused encephalitis. IMPORTANCE Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, whether the PERK pathway of ER stress response plays important roles in JEV-induced apoptosis and encephalitis remains unknown. Here, we found that JEV infection activates ER stress sensor PERK in neuronal cells and mouse brains. PERK activation induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway upon JEV infection. Among the JEV proteins prM, E, NS1, NS2A, NS2B, and NS4B, only NS4B activates PERK. Moreover, activated PERK participates in apoptosis and encephalitis induced by JEV and NS4B. These findings provide a novel therapeutic approach for JEV-caused encephalitis.

An efficient protocol for the selective synthesis of α-mono or α,α′-dihalo ketones via a water-controlled chemodivergent and regiospecific cascade reaction has been developed.