Natural evidence of coronaviral 2′-O-methyltransferase activity affecting viral pathogenesis via improved substrate RNA binding

Previous studies through targeted mutagenesis of K-D-K-E motif have demonstrated that 2′-O-MTase activity is essential for efficient viral replication and immune evasion.However,the K-D-K-E catalytic motif of 2′-O-MTase is highly conserved across numerous viruses,including flaviviruses,vaccinia viruses,coronaviruses,and extends even to mammals.Here,we observed a stronger 2′-O-MTase activity in SARS-CoV-2 compared to SARS-CoV,despite the presence of a consistently active catalytic center.We further identified critical residues(Leu-36,Asn-138 and Ile-153)which served as determinants of discrepancy in 2′-O-MTase activity between SARS-CoV-2 and SARS-CoV.These residues significantly enhanced the RNA binding affinity of 2′-O-MTase and boosted its versatility toward RNA substrates.Of interest,a triple substitution(Leu^(36)→Ile^(36),Asn^(138)→His^(138),Ile^(153)→Leu^(153),from SARS-CoV-2 to SARS-CoV)within nsp16 resulted in a proportional reduction in viral 2′-O-methylation and impaired viral replication.Furthermore,it led to a significant upregulation of type I interferon(IFN-I)and proinflammatory cytokines both in vitro and vivo,relying on the cooperative sensing of melanoma differentiation-associated protein 5(MDA5)and laboratory of genetics and physiology 2(LGP2).In conclusion,our findings demonstrated that alterations in residues other than K-D-K-E of 2′-O-MTase may affect viral replication and subsequently influence pathogenesis.Monitoring changes in nsp16 residues is crucial as it may aid in identifying and assessing future alteration in viral pathogenicity resulting from natural mutations occurring in nsp16.

Recent status and advanced progress of tip effect induced by micro-nanostructure

The unique structural features represented by micro-nanoneedle tip structure reflect wonderful physical and chemical properties.The tip effect includes the concentration of energy such as electrons,photons and magnetism in the tip region,which has promising applications in the fields of energy conversion,water capture,environmental restoration and so on.In this review,a comprehensive and systematic summary of the latest advances in the application of the tip effect in different fields is provided.Utilizing advanced Finite Difference Time Domain simulation,we further propose our understanding of the fundamental mechanism of the tip effect induced by micro-nanostructure.However,we need to forge the present study to further reveal the essential law of the tip effect from the perspective of theoretical calculations.This review would provide a solid foundation for further development and application of the tip effect.