Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generati...Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosorbent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey sera.These assays were successfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit linkers.The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias%ranged from -12.2% to -5.2%,precision ranged from -12.4% to -1.4%,and the relative standard deviation(RSD)was less than 6.6% and 8.7%,respectively.The total error was less than 20.4%.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK studies.Furthermore,these assays can be easily adopted for development of other similar immunoassays.展开更多
Through the analysis of the impact of changes in the cotton planting industry on cotton production structure and benefit in Shandong under the national cotton production pattern in past ten years,based on the guarante...Through the analysis of the impact of changes in the cotton planting industry on cotton production structure and benefit in Shandong under the national cotton production pattern in past ten years,based on the guarantee of food security and the overall ecological regional layout of Shandong s agricultural characteristic and advantageous industries,we proposed that through the development of high-quality short-season cotton and the industrial application of high-efficiency technologies,a green and high-efficiency farming system should be established to comprehensively reduce cotton planting costs,improve comparative benefits,and realize green and efficient optimization technologies that unify the stable production of cotton and high-quality cotton supply and the industrial path supported by the new industrial model.It is aimed to speed up the upgrading and transformation of the existing traditional cotton cropping system,reconstruct a ternary structure of grains,economic crops and fodder in the ecological suitable cotton areas and sub-suitable cotton areas in Shandong,and maintain a series of new green and ecological cotton rotation industrial models including the“double security”of the grain and cotton industries,the ecological“double superiority”of "cotton and fodder",and the high-efficiency"double increase"of cotton and garlic,providing a certain foundation for the research on technological integration innovation and industrial structure optimization of the green,efficient and high-quality development and transformation of the cotton industry in Shandong during the"14 th Five-Year Plan"period.展开更多
Due to low efficiency resulted from the unduly high cost,intractable climatic and market risk of cotton production,the development of cotton industry suffers a setback in Shandong Province. Based on analyzing the impo...Due to low efficiency resulted from the unduly high cost,intractable climatic and market risk of cotton production,the development of cotton industry suffers a setback in Shandong Province. Based on analyzing the importance of Shandong cotton industry for the economic and social development under the new situation,we put forward the basic idea and effective way for stable and continuous development of Shandong cotton production from the perspective of supply side structural reform.展开更多
At present,the comparative benefits and comparative labor productivity of cotton production are relatively low,and cotton production and industrial development of cotton get seriously frustrated. The fundamental reaso...At present,the comparative benefits and comparative labor productivity of cotton production are relatively low,and cotton production and industrial development of cotton get seriously frustrated. The fundamental reason is that the quality of cotton production development and the development mode are not suitable for the market demands. In this situation,the cotton production and development must take the road of green development concept as the guidance,and improve the quality and benefits of cotton development. Finally,it came up with the basic idea,technical approach and industrial mode of taking simplified cultivation technique as the support,to promote green and efficient cotton production in Shandong Province.展开更多
Plasma membrane-associated abscisic acid(ABA)signal transduction is an integral part of ABA signaling.The C2-domain ABA-related(CAR)proteins play important roles in the recruitment of ABA receptors to the plasma membr...Plasma membrane-associated abscisic acid(ABA)signal transduction is an integral part of ABA signaling.The C2-domain ABA-related(CAR)proteins play important roles in the recruitment of ABA receptors to the plasma membrane to facilitate ABA signaling.However,how CAR proteins are regulated remains unclear.In this study,we conducted a genetic screen for mutants with altered leaf transpiration and identified an uncharacterized protein,LOWER TEMPERATURE 1(LOT1),which regulates the dynamic localization and stability of CAR proteins.The lotimutant had a lower leaf temperature as compared with the wild type due to higher transpiration.We found that LOT1 physically interacts with CAR9,and ABA reduces LOT1-CAR9 interaction in the nucleus,likely via Ca^2+,resulting in increased localization of CAR9 to the plasma membrane.We further found that the stability of CAR9 is affected by LOT1 less CAR9 proteins were accumulated and more were ubiquitinated in lot1.While the lot1 car9 and/of f car9 mutants were hyposerisitive to ABA,the hyposensitive phenotype of loticould be rescued by CAR9 overexpression.Collectively,our study reveals that LOT1 regulates plant tolerance to drought stress by affecting ABA signaling through regulating the stability and dynamic localization of CAR9.展开更多
The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting mo...The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting monoclonal antibody,3E8,blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2,SARS-CoV-2 mutant variants(SARS-CoV-2-D614G,B.1.1.7,B.1.351,B.1.617.1,and P.1).展开更多
During adaptive radiation,mitochondria have co-evolved with their hosts,leading to gain or loss of subunits and assembly factors of respiratory complexes.Plant mitochondrial complex Ⅰ harbors40 nuclearand 9 mitochond...During adaptive radiation,mitochondria have co-evolved with their hosts,leading to gain or loss of subunits and assembly factors of respiratory complexes.Plant mitochondrial complex Ⅰ harbors40 nuclearand 9 mitochondrial-encoded subunits,and is formed by stepwise assembly during which different intermediates are integrated via various assembly factors.In mammals,the mitochondrial complex Ⅰ intermediate assembly(MCIA)complex is required for building the membrane arm module.However,plants have lost almost all of the MCIA complex components,giving rise to the hypothesis that plants follow an ancestral pathway to assemble the membrane arm subunits.Here,we characterize a maize crumpled seed mutant,crk1,and reveal by map-based cloning that CRK1 encodes an ortholog of human complex Ⅰ assembly factor 1,zNDUFAF1,the only evolutionarily conserved MCIA subunit in plants.zNDUFAF1 is localized in the mitochondria and accumulates in two intermediate complexes that contain complex Ⅰ membrane arm subunits.Disruption of zNDUFAF1 results in severe defects in complex Ⅰ assembly and activity,a cellular bioenergetic shift to aerobic glycolysis,and mitochondrial vacuolation.Moreover,we found that zNDUFAF1,the putative mitochondrial import inner membrane translocase ZmTIM17-1,and the isovaleryl-coenzyme A dehydrogenase ZmIVD1 interact each other,and could be co-precipitated from the mitochondria and co-migrate in the same assembly intermediates.Knockout of either ZmTIM17-1 or ZmIVD1 could lead to the significantly reduced complex Ⅰ stability and activity as well as defective seeds.These results suggest that zNDUFAF1,ZmTIM17-1 and ZmIVD1 probably form an MCIA-like complex that is essential for the biogenesis of mitochondrial complex Ⅰ and seed development in maize.Our findings also imply that plants and mammals recruit MCIA subunits independently for mitochondrial complex Ⅰ assembly,highlighting the importance of parallel evolution in mitochondria adaptation to their hosts.展开更多
Dear Editor,The pandemic of COVID-19 continues worldwide with many variants arising,especially SARS-CoV-2 Delta(B.1.617.2)and Omicron(B.1.1.529)variants of concern(VOCs).According to WHO,Omicron has spread in almost a...Dear Editor,The pandemic of COVID-19 continues worldwide with many variants arising,especially SARS-CoV-2 Delta(B.1.617.2)and Omicron(B.1.1.529)variants of concern(VOCs).According to WHO,Omicron has spread in almost all the countries with a doubling time less than Delta VOC.展开更多
Preventing urban regions from seismic wave destruction is of paramount significance because it is closely related to urban lifeline and prosperity of cities.Almost all conventional seismic resistance approaches rely o...Preventing urban regions from seismic wave destruction is of paramount significance because it is closely related to urban lifeline and prosperity of cities.Almost all conventional seismic resistance approaches rely on the stiffness and strength of buildings,which require excessive structural components with additional self-weights.In this study,we propose a pine-like seismic metamaterial for efficient attenuation of surface Rayleigh waves.The pine arrays in suburban regions demonstrate an ability to convert Rayleigh waves to shear bulk waves or attenuate waves on the surface via local resonation.This property originates from a gradient design of pine arrays,where a scale ratio is defined to tune the geometric properties of each pine unit.Specifically,a gradient pine array with a scale ratio smaller than one can interact with the Rayleigh waves and convert them to shear waves that propagate deep to underground.The transmission ratio of the entire system indicates a broadband wave attenuation at subwavelength scale.It reveals that the pine is able to couple with a certain elastic Rayleigh wave whose wavelength is much larger than the lattice constant,which is rarely achieved in any conventional civil engineering structures such as open trench barriers and filled trench barriers.Additionally,a numerical model of an urban region and suburban pine array is established and analyzed.Infrastructures and structures in a city that suffer direct Rayleigh wave interference run into a high risk of structural destruction as compared to urban structures protected with suburban metamaterial pine arrays.Finally,two real earthquake wave signals are used to validate the efficiency of the pine arrays in dissipating earthquake energy.The approach in this paper can be extended to deal with more complex naturally available structures for examining the elastic wave attenuation abilities of these novel structures.展开更多
基金supported by the China National Major Scientific and Technological Special Project for“Significant New Drugs Innovation and Development”(Grant No.:2019ZX09732002-006)the National New Drug Creation Program of China(Grant No.:2018ZX09201017-004)+5 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant Nos.:XDA12020223,XDA12020330,XDA12020360,and XDA12050305)the National Natural Science Foundation of China(Grant Nos.:81872785 and 81673347)the Science and Technology Planning Projects of Department of Science and Technology Province(Grant No.:20190202)Shanghai Municipal Commission of Science and Technology of China(Grant Nos.:17431904400,19YF1457400,and 21S11904500)Institutes for Drug Discovery and Development,the Chinese Academy of Sciences(Grant Nos.:CASIMM0120202007 and CASIMM0120202008)Major Scientific and Technological Special Project of Zhongshan City(Grant Nos.:191022172638719 and 210205143867019).
文摘Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosorbent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey sera.These assays were successfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit linkers.The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias%ranged from -12.2% to -5.2%,precision ranged from -12.4% to -1.4%,and the relative standard deviation(RSD)was less than 6.6% and 8.7%,respectively.The total error was less than 20.4%.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK studies.Furthermore,these assays can be easily adopted for development of other similar immunoassays.
基金Shandong Provincial Cotton Green,High-yield and Efficient Creation Project(LNMZ[2017]5).
文摘Through the analysis of the impact of changes in the cotton planting industry on cotton production structure and benefit in Shandong under the national cotton production pattern in past ten years,based on the guarantee of food security and the overall ecological regional layout of Shandong s agricultural characteristic and advantageous industries,we proposed that through the development of high-quality short-season cotton and the industrial application of high-efficiency technologies,a green and high-efficiency farming system should be established to comprehensively reduce cotton planting costs,improve comparative benefits,and realize green and efficient optimization technologies that unify the stable production of cotton and high-quality cotton supply and the industrial path supported by the new industrial model.It is aimed to speed up the upgrading and transformation of the existing traditional cotton cropping system,reconstruct a ternary structure of grains,economic crops and fodder in the ecological suitable cotton areas and sub-suitable cotton areas in Shandong,and maintain a series of new green and ecological cotton rotation industrial models including the“double security”of the grain and cotton industries,the ecological“double superiority”of "cotton and fodder",and the high-efficiency"double increase"of cotton and garlic,providing a certain foundation for the research on technological integration innovation and industrial structure optimization of the green,efficient and high-quality development and transformation of the cotton industry in Shandong during the"14 th Five-Year Plan"period.
基金Supported by Cotton Green High-yield Establishment ProjectCotton Farming System Innovation Demonstration Project in Shandong Province
文摘Due to low efficiency resulted from the unduly high cost,intractable climatic and market risk of cotton production,the development of cotton industry suffers a setback in Shandong Province. Based on analyzing the importance of Shandong cotton industry for the economic and social development under the new situation,we put forward the basic idea and effective way for stable and continuous development of Shandong cotton production from the perspective of supply side structural reform.
基金Supported by Cotton Green High yield Establishment ProjectCotton Farming System Innovation Demonstration Project in Shandong Province
文摘At present,the comparative benefits and comparative labor productivity of cotton production are relatively low,and cotton production and industrial development of cotton get seriously frustrated. The fundamental reason is that the quality of cotton production development and the development mode are not suitable for the market demands. In this situation,the cotton production and development must take the road of green development concept as the guidance,and improve the quality and benefits of cotton development. Finally,it came up with the basic idea,technical approach and industrial mode of taking simplified cultivation technique as the support,to promote green and efficient cotton production in Shandong Province.
文摘Plasma membrane-associated abscisic acid(ABA)signal transduction is an integral part of ABA signaling.The C2-domain ABA-related(CAR)proteins play important roles in the recruitment of ABA receptors to the plasma membrane to facilitate ABA signaling.However,how CAR proteins are regulated remains unclear.In this study,we conducted a genetic screen for mutants with altered leaf transpiration and identified an uncharacterized protein,LOWER TEMPERATURE 1(LOT1),which regulates the dynamic localization and stability of CAR proteins.The lotimutant had a lower leaf temperature as compared with the wild type due to higher transpiration.We found that LOT1 physically interacts with CAR9,and ABA reduces LOT1-CAR9 interaction in the nucleus,likely via Ca^2+,resulting in increased localization of CAR9 to the plasma membrane.We further found that the stability of CAR9 is affected by LOT1 less CAR9 proteins were accumulated and more were ubiquitinated in lot1.While the lot1 car9 and/of f car9 mutants were hyposerisitive to ABA,the hyposensitive phenotype of loticould be rescued by CAR9 overexpression.Collectively,our study reveals that LOT1 regulates plant tolerance to drought stress by affecting ABA signaling through regulating the stability and dynamic localization of CAR9.
基金This work was supported by the China National Major Scientific and Technological Special Project for"Significant New Drugs Innovation and Development"(2019ZX09732002-006)the Strategic Priority Research Program of the Chinese Academy of Sciences(CAS)(XDA12020223 and XDA12020330)+7 种基金the National Natural Science Foundation of China(81872785,81673347,31971123,32022037,81920108015,and 31930059)Shanghai Municipal Commission of Science and Technology of China(17431904400 and 19YF1457400)Institutes for Drug Discovery and Development,Chinese Academy of Sciences(CASIMM0120202008 and CASIMM0120202007)the National Key R&D Program(2020YFA0509303)Major Scientific and Technological Special Project of Zhongshan City(191022172638719 and 210205143867019)the Key R&D Program of Zhejiang Province(2020C04001)the SARS-CoV-2 emergency project of the Science and Technology Department of Zhejiang Province(2020C03129)the Leading Innovative and Entrepreneur Team Introduction Program of Hangzhou,Westlake Education Foundation and Tencent Foundation.
文摘The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting monoclonal antibody,3E8,blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2,SARS-CoV-2 mutant variants(SARS-CoV-2-D614G,B.1.1.7,B.1.351,B.1.617.1,and P.1).
基金supported by a grant from the Ministry of Science and Technology of the People’s Republic of China 2021YFF1000303(to Guifeng Wang)grants from the National Natural Science Foundation of China(U1804235 to Guifeng Wang,32001562 to Q.S.).
文摘During adaptive radiation,mitochondria have co-evolved with their hosts,leading to gain or loss of subunits and assembly factors of respiratory complexes.Plant mitochondrial complex Ⅰ harbors40 nuclearand 9 mitochondrial-encoded subunits,and is formed by stepwise assembly during which different intermediates are integrated via various assembly factors.In mammals,the mitochondrial complex Ⅰ intermediate assembly(MCIA)complex is required for building the membrane arm module.However,plants have lost almost all of the MCIA complex components,giving rise to the hypothesis that plants follow an ancestral pathway to assemble the membrane arm subunits.Here,we characterize a maize crumpled seed mutant,crk1,and reveal by map-based cloning that CRK1 encodes an ortholog of human complex Ⅰ assembly factor 1,zNDUFAF1,the only evolutionarily conserved MCIA subunit in plants.zNDUFAF1 is localized in the mitochondria and accumulates in two intermediate complexes that contain complex Ⅰ membrane arm subunits.Disruption of zNDUFAF1 results in severe defects in complex Ⅰ assembly and activity,a cellular bioenergetic shift to aerobic glycolysis,and mitochondrial vacuolation.Moreover,we found that zNDUFAF1,the putative mitochondrial import inner membrane translocase ZmTIM17-1,and the isovaleryl-coenzyme A dehydrogenase ZmIVD1 interact each other,and could be co-precipitated from the mitochondria and co-migrate in the same assembly intermediates.Knockout of either ZmTIM17-1 or ZmIVD1 could lead to the significantly reduced complex Ⅰ stability and activity as well as defective seeds.These results suggest that zNDUFAF1,ZmTIM17-1 and ZmIVD1 probably form an MCIA-like complex that is essential for the biogenesis of mitochondrial complex Ⅰ and seed development in maize.Our findings also imply that plants and mammals recruit MCIA subunits independently for mitochondrial complex Ⅰ assembly,highlighting the importance of parallel evolution in mitochondria adaptation to their hosts.
基金This work was supported by Institutes for Drug Research and Development of New Outbreak of Viral Infectious Diseases(SIMM020101),"One-Three-Five"Strategic Programs,Wuhan Institute of Virology,Chinese Academy of Sciences,China.
文摘Dear Editor,The pandemic of COVID-19 continues worldwide with many variants arising,especially SARS-CoV-2 Delta(B.1.617.2)and Omicron(B.1.1.529)variants of concern(VOCs).According to WHO,Omicron has spread in almost all the countries with a doubling time less than Delta VOC.
基金supported by City University of Hong Kong(Project No.ARG 9667253)Fundamental Research Funds for the Central Universities(Grant Number RF1028623346).
文摘Preventing urban regions from seismic wave destruction is of paramount significance because it is closely related to urban lifeline and prosperity of cities.Almost all conventional seismic resistance approaches rely on the stiffness and strength of buildings,which require excessive structural components with additional self-weights.In this study,we propose a pine-like seismic metamaterial for efficient attenuation of surface Rayleigh waves.The pine arrays in suburban regions demonstrate an ability to convert Rayleigh waves to shear bulk waves or attenuate waves on the surface via local resonation.This property originates from a gradient design of pine arrays,where a scale ratio is defined to tune the geometric properties of each pine unit.Specifically,a gradient pine array with a scale ratio smaller than one can interact with the Rayleigh waves and convert them to shear waves that propagate deep to underground.The transmission ratio of the entire system indicates a broadband wave attenuation at subwavelength scale.It reveals that the pine is able to couple with a certain elastic Rayleigh wave whose wavelength is much larger than the lattice constant,which is rarely achieved in any conventional civil engineering structures such as open trench barriers and filled trench barriers.Additionally,a numerical model of an urban region and suburban pine array is established and analyzed.Infrastructures and structures in a city that suffer direct Rayleigh wave interference run into a high risk of structural destruction as compared to urban structures protected with suburban metamaterial pine arrays.Finally,two real earthquake wave signals are used to validate the efficiency of the pine arrays in dissipating earthquake energy.The approach in this paper can be extended to deal with more complex naturally available structures for examining the elastic wave attenuation abilities of these novel structures.
