Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.Th...Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.展开更多
The effect of multiphase microstructure in the center segregation zones(CSZ)of high-strength steel thick plates on work hardening characteristics and crack initiation/propagation were studied.Microstructure was correl...The effect of multiphase microstructure in the center segregation zones(CSZ)of high-strength steel thick plates on work hardening characteristics and crack initiation/propagation were studied.Microstructure was correlated with deformation damage behavior by using Taylor factor(TF)gradients,kernel average misorientation(KAM),and geometric necessary dislocation(GND)density.The results show that the segregation leads to a mixed structure of ferrite(soft phase)and martensite/bainite(hard phase)in the center of the thick plate.Compared to the 1/4 thickness(1/4 T)region,grain refinement occurred in the CSZ,with KAM values increasing from 0.24 to 0.49 and a decrease in the proportion of high-angle grain boundaries(>15°)from 77.4 to 51.8%.In the process of deformation,due to the influence of grain refinement and adjacent martensite/bainite,ferrite grains were divided into structural units with different TF values.The higher KAM value and GND density at the interface between soft/hard phases resulted in severe work hardening.In addition,the presence of micron-sized inclusions in the CSZ caused local strain concentration and non-continuous deformation of the matrix,which induced crack initiation.The fracture surface showed a mixed mode of brittle cleavage fracture and ductile fracture.展开更多
基金supported by grants from the National Key Research and Development Program of China (No.2021YFC2301404)the National Natural Science Foundation of China (Nos.81991491,82272305,and 32170942)+4 种基金Fujian Natural Science Foundation (No.2020J06007)the Industry-University-Research Project of Xiamen (No.2022CXY0106)the Fundamental Research Funds for the Central Universities (Nos.20720220006 and 20720220004)National Postdoctoral Science Foundation of China (No.2021M712659)CAMS Innovation Fund for Medical Sciences (No.2019RU022).
文摘Continual evolution of the severe acute respiratory syndrome coronavirus(SARS-CoV-2)virus has allowed for its gradual evasion of neutralizing antibodies(nAbs)produced in response to natural infection or vaccination.The rapid nature of these changes has incited a need for the development of superior broad nAbs(bnAbs)and/or the rational design of an antibody cocktail that can protect against the mutated virus strain.Here,we report two angiotensin-converting enzyme 2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants.Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing.Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5.Together,these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.
基金The authors are grateful for the financial support from the National Natural Science Foundation of China(No.U20A20279)the technical support provided by Analysis and Test Center of Wuhan University of Science and Technology,China.
文摘The effect of multiphase microstructure in the center segregation zones(CSZ)of high-strength steel thick plates on work hardening characteristics and crack initiation/propagation were studied.Microstructure was correlated with deformation damage behavior by using Taylor factor(TF)gradients,kernel average misorientation(KAM),and geometric necessary dislocation(GND)density.The results show that the segregation leads to a mixed structure of ferrite(soft phase)and martensite/bainite(hard phase)in the center of the thick plate.Compared to the 1/4 thickness(1/4 T)region,grain refinement occurred in the CSZ,with KAM values increasing from 0.24 to 0.49 and a decrease in the proportion of high-angle grain boundaries(>15°)from 77.4 to 51.8%.In the process of deformation,due to the influence of grain refinement and adjacent martensite/bainite,ferrite grains were divided into structural units with different TF values.The higher KAM value and GND density at the interface between soft/hard phases resulted in severe work hardening.In addition,the presence of micron-sized inclusions in the CSZ caused local strain concentration and non-continuous deformation of the matrix,which induced crack initiation.The fracture surface showed a mixed mode of brittle cleavage fracture and ductile fracture.
