Zn has been regarded as new kind of potential implant biomaterials due to the desirable biodegradability and good biocompatibility,but the low strength and ductility limit its application in bone repairs.In the presen...Zn has been regarded as new kind of potential implant biomaterials due to the desirable biodegradability and good biocompatibility,but the low strength and ductility limit its application in bone repairs.In the present study,nano-SiC was incorporated into Zn matrix via laser melting,aiming to improve the mechanical performance.The microstructure analysis showed that nano-SiC distributed along Zn grain boundaries.During the laser rapid solidification,nano-SiC particles acted as the sites for heterogeneous nucleation,which resulted in the reduction of Zn grain size from 250μm to 15μm with 2 wt%SiC(Zn-2 SiC).Meanwhile,nano-SiC acted as a reinforcer by virtue of Orowan strengthening and dispersion strengthening.As a consequence,the nanocomposites showed maximal compressive yield strength(121.8±5.3 MPa)and high microhardness(72.24±3.01 HV),which were increased by 441%and 78%,respectively,compared with pure Zn.Moreover,fracture analysis indicated a more ductile fracture of the nanocomposites after the incorporation of nano-SiC In addition,the nanocomposites presented favorable biocompatibility and accelerated degradation caused by intergranular corrosion.These findings suggested that the nano-SiC reinforced Zn biocomposites may be the potential candidates for orthopedic implants.展开更多
The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite it...The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite its significance,the precise regulatory mechanisms underlying its function remain elusive.In the present study,we unveil that the ORF9b protein of SARS-CoV-2,including emerging mutant strains like Delta and Omicron,can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway,despite certain mutations present among these strains.Moreover,our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70(TOM70)as a substrate receptor,bridging ORF9b with heat shock protein 90 alpha(HSP90α)and Cullin 5(CUL5)to form a complex.Within this complex,CUL5 triggers the ubiquitination and degradation of ORF9b,acting as a host antiviral factor,while HSP90αfunctions to stabilize it.Notably,treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b,leading to a pronounced inhibition of SARS-CoV-2 replication.Single-cell sequencing data revealed an up-regulation of HSP90αin lung epithelial cells from COVID-19 patients,suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90αto evade the host immunity.Our study identifies the CUL5-TOM70-HSP90αcomplex as a critical regulator of ORF9b protein stability,shedding light on the intricate host–virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.展开更多
基金supported financially by the National Natural Science Foundation of China (Nos.51705540,81871494 and 81871498)the Hunan Provincial Natural Science Foundation of China (Nos.2018JJ3671 and 2019JJ50588)+6 种基金the GuangdongProvince Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2018)the Open Sharing Fund for the Largescale Instruments and Equipments of Central South Universitythe Project of Hunan Provincial Science and Technology Plan (No.2017RS3008)the Shenzhen Science and Technology Plan Project (No.JCYJ20170817112445033)the National Postdoctoral Program for Innovative Talents (No.BX201700291)the Hunan Science and Technology Innovation Plan (Nos.2018SK2105 and kq1606001)the China Postdoctoral Science Foundation (No. 2018M632983)
文摘Zn has been regarded as new kind of potential implant biomaterials due to the desirable biodegradability and good biocompatibility,but the low strength and ductility limit its application in bone repairs.In the present study,nano-SiC was incorporated into Zn matrix via laser melting,aiming to improve the mechanical performance.The microstructure analysis showed that nano-SiC distributed along Zn grain boundaries.During the laser rapid solidification,nano-SiC particles acted as the sites for heterogeneous nucleation,which resulted in the reduction of Zn grain size from 250μm to 15μm with 2 wt%SiC(Zn-2 SiC).Meanwhile,nano-SiC acted as a reinforcer by virtue of Orowan strengthening and dispersion strengthening.As a consequence,the nanocomposites showed maximal compressive yield strength(121.8±5.3 MPa)and high microhardness(72.24±3.01 HV),which were increased by 441%and 78%,respectively,compared with pure Zn.Moreover,fracture analysis indicated a more ductile fracture of the nanocomposites after the incorporation of nano-SiC In addition,the nanocomposites presented favorable biocompatibility and accelerated degradation caused by intergranular corrosion.These findings suggested that the nano-SiC reinforced Zn biocomposites may be the potential candidates for orthopedic implants.
基金supported by the National Key Research and Development Program of China(2021YFC2300103)the National Natural Science Foundation of China(U21A20384 and 82072293)+1 种基金the Natural Science Foundation of Hunan Province,China(2022JJ30692)the China Postdoctoral Science Foundation(2023M731520).
文摘The ORF9b protein,derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2,serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response.Despite its significance,the precise regulatory mechanisms underlying its function remain elusive.In the present study,we unveil that the ORF9b protein of SARS-CoV-2,including emerging mutant strains like Delta and Omicron,can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway,despite certain mutations present among these strains.Moreover,our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70(TOM70)as a substrate receptor,bridging ORF9b with heat shock protein 90 alpha(HSP90α)and Cullin 5(CUL5)to form a complex.Within this complex,CUL5 triggers the ubiquitination and degradation of ORF9b,acting as a host antiviral factor,while HSP90αfunctions to stabilize it.Notably,treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b,leading to a pronounced inhibition of SARS-CoV-2 replication.Single-cell sequencing data revealed an up-regulation of HSP90αin lung epithelial cells from COVID-19 patients,suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90αto evade the host immunity.Our study identifies the CUL5-TOM70-HSP90αcomplex as a critical regulator of ORF9b protein stability,shedding light on the intricate host–virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.