In the present study,a large set of data related to well killing is considered.Through a complete exploration of the whole process leading to well-killing,various factors affecting such a process are screened and sort...In the present study,a large set of data related to well killing is considered.Through a complete exploration of the whole process leading to well-killing,various factors affecting such a process are screened and sorted,and a correlation model is built accordingly in order to introduce an auxiliary method for well-killing monitoring based on statistical information.The available data show obvious differences due to the diverse control parameters related to different well-killing methods.Nevertheless,it is shown that a precise three-fold relationship exists between the reservoir parameters,the elapsed time and the effectiveness of the considered well-killing strategy.The proposed monitoring auxiliary method is intended to support risk assessment and optimization in the context of typical well-killing applications.展开更多
Identification of a suitable nonhuman primate(NHP)model of COVID-19 remains challenging.Here,we characterized severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in three NHP species:Old World monkeys...Identification of a suitable nonhuman primate(NHP)model of COVID-19 remains challenging.Here,we characterized severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in three NHP species:Old World monkeys Macaca mulatta(M.mulatta)and Macaca fascicularis(M.fascicularis)and New World monkey Callithrix jacchus(C.jacchus).Infected M.mulatta and M.fascicularis showed abnormal chest radiographs,an increased body temperature and a decreased body weight.Viral genomes were detected in swab and blood samples from all animals.Viral load was detected in the pulmonary tissues of M.mulatta and M.fascicularis but not C.jacchus.Furthermore,among the three animal species,M.mulatta showed the strongest response to SARS-CoV-2,including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.Collectively,these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M.mulatta as the most suitable for modeling COVID-19.展开更多
Neurological manifestations are frequently reported in the COVID-19 patients.Neuromechanism of SARS-CoV-2 remains to be elucidated.In this study,we explored the mechanisms of SARS-CoV-2 neurotropism via our establishe...Neurological manifestations are frequently reported in the COVID-19 patients.Neuromechanism of SARS-CoV-2 remains to be elucidated.In this study,we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19.In rhesus monkey,SARS-CoV-2 invades the CNS primarily via the olfactory bulb.Thereafter,viruses rapidly spread to functional areas of the central nervous system,such as hippocampus,thalamus,and medulla oblongata.The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons,microglia,and astrocytes in the CNS.Consistently,SARS-CoV-2 infects neuro-derived SK-N-SH,glial-derived U251,and brain microvascular endothelial cells in vitro.To our knowledge,this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model,which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and ...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.展开更多
Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development o...Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development of vaccines with broad protective effects.In this study,we selected hotspot mutations in the receptor-binding domain(RBD)that contribute to immune escape properties and integrated them into the original RBD protein to obtain a complex RBD protein(cRBD),and we found cRBDs have broad protective effects against SARS-CoV-2 variants.Three cRBDs were designed in our study.Compared with the BA.1 RBD protein,the cRBDs induced the production of higher levels of broader-spectrum neutralizing antibodies,suggesting stronger and broader protective efficacy.In viral challenge experiments,cRBDs were more effective than BA.1 RBD in attenuating lung pathologic injury.Among the three constructs,cRBD3 showed optimal broad-spectrum and protective effects and is a promising candidate for a broad-spectrum SARS-CoV-2 vaccine.In conclusion,immunization with cRBDs triggered immunity against a wide range of variants,including those that emerged after we had completed designing the cRBDs.This study preliminarily explores and validates the feasibility of incorporating hotspot mutations that contribute to immune evasion into the RBD to expand the activity spectrum of antigen-induced antibodies.展开更多
基金supported by research on key equipment and supporting technology for Onshore Well Control Emergency,CNPC(2021ZZ03-2).
文摘In the present study,a large set of data related to well killing is considered.Through a complete exploration of the whole process leading to well-killing,various factors affecting such a process are screened and sorted,and a correlation model is built accordingly in order to introduce an auxiliary method for well-killing monitoring based on statistical information.The available data show obvious differences due to the diverse control parameters related to different well-killing methods.Nevertheless,it is shown that a precise three-fold relationship exists between the reservoir parameters,the elapsed time and the effectiveness of the considered well-killing strategy.The proposed monitoring auxiliary method is intended to support risk assessment and optimization in the context of typical well-killing applications.
基金supported by the National Research and Development Project of China(2020YFC0841100,2020YFC0846400,and 2020YFA0707600)CAMS Innovation Fund for Medical Sciences(2016-I2M-2-006 and 2020-I2M-CoV19-012)+1 种基金the Talents Project of Yunnan Province(2017HB068)the Special Funds for High-level Health and Family Planning Technical Personnel training of Yunnan Province(D-201653).
文摘Identification of a suitable nonhuman primate(NHP)model of COVID-19 remains challenging.Here,we characterized severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in three NHP species:Old World monkeys Macaca mulatta(M.mulatta)and Macaca fascicularis(M.fascicularis)and New World monkey Callithrix jacchus(C.jacchus).Infected M.mulatta and M.fascicularis showed abnormal chest radiographs,an increased body temperature and a decreased body weight.Viral genomes were detected in swab and blood samples from all animals.Viral load was detected in the pulmonary tissues of M.mulatta and M.fascicularis but not C.jacchus.Furthermore,among the three animal species,M.mulatta showed the strongest response to SARS-CoV-2,including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.Collectively,these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M.mulatta as the most suitable for modeling COVID-19.
基金This study was supported by the National Key R&D Project of China(2020YFA0707602,2020YFC0846400,2020YFC0841100)CAMS Innovation Fund for Medical Sciences(2016-I2M-2-001,2016-I2M-2-006,and 2020-I2M-COV19-012)+1 种基金Yunnan Key R&D Project(202003AC100003)The Talents Project of Yunnan Province(2017HB068).
文摘Neurological manifestations are frequently reported in the COVID-19 patients.Neuromechanism of SARS-CoV-2 remains to be elucidated.In this study,we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19.In rhesus monkey,SARS-CoV-2 invades the CNS primarily via the olfactory bulb.Thereafter,viruses rapidly spread to functional areas of the central nervous system,such as hippocampus,thalamus,and medulla oblongata.The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons,microglia,and astrocytes in the CNS.Consistently,SARS-CoV-2 infects neuro-derived SK-N-SH,glial-derived U251,and brain microvascular endothelial cells in vitro.To our knowledge,this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model,which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.
基金supported by the National Key R&D Program of China(Grant No.2021YFC0863300)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB0490000)+6 种基金the CAMS Innovation Fund for Medical Sciences(Grant No.2021-I2M-1-024)the STI2030-Major Projects(Grant No.2021ZD0200900)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(Grant No.82221004)the National Natural Science Foundation of China(Grant Nos.32121001,32200460,and 32200460)the K.C.Wong Education Foundation(Grant No.GJTD-2019-08)the Shanghai Municipal Science and Technology Major Project,China(Grant No.2017SHZDZX01)the China National Postdoctoral Program for Innovative Talents(Grant No.BX2021291).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.
基金supported by the Key Project of applied basic research in Yunnan Province(202401AS070049)CAMS Innovation Fund for Medical Sciences(2021-I2M-1-038,2022-I2M-CoV19-002)+1 种基金National Key R&D Program of China(2021YFC230170402)Yunnan Key R&D Project(202103AQ100001).
文摘Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development of vaccines with broad protective effects.In this study,we selected hotspot mutations in the receptor-binding domain(RBD)that contribute to immune escape properties and integrated them into the original RBD protein to obtain a complex RBD protein(cRBD),and we found cRBDs have broad protective effects against SARS-CoV-2 variants.Three cRBDs were designed in our study.Compared with the BA.1 RBD protein,the cRBDs induced the production of higher levels of broader-spectrum neutralizing antibodies,suggesting stronger and broader protective efficacy.In viral challenge experiments,cRBDs were more effective than BA.1 RBD in attenuating lung pathologic injury.Among the three constructs,cRBD3 showed optimal broad-spectrum and protective effects and is a promising candidate for a broad-spectrum SARS-CoV-2 vaccine.In conclusion,immunization with cRBDs triggered immunity against a wide range of variants,including those that emerged after we had completed designing the cRBDs.This study preliminarily explores and validates the feasibility of incorporating hotspot mutations that contribute to immune evasion into the RBD to expand the activity spectrum of antigen-induced antibodies.
