Oxide pegging is a widely accepted mechanistic model explaining the reactive element effect on the improved adherence of scale.However,previous models for the oxide peg formation process have not considered the effect...Oxide pegging is a widely accepted mechanistic model explaining the reactive element effect on the improved adherence of scale.However,previous models for the oxide peg formation process have not considered the effects of more than one active element added into the alloy during the peg formation.This study proposes a new model of oxide peg formation and growth for the doping of two reactive elements in an alloy(the precipitated Y and solid solute Ti).Different amounts of Ti and Y were added to a Co Ni Cr Al alloy,and the characteristics of the resulting oxide pegs,such as their linear density,size,and forming process,are obtained by examining alloy samples subjected to an isothermal oxidation operation at a temperature of 1150℃.It is found that the amount of Y determines the density of the oxide pegs,and Ti does not form a Ti-rich oxide core if a Y-rich oxide exists in the sample.In samples with the same Y content,the oxide pegs primarily grow in length,and with increased Ti content,they grow along the b-phase boundary and into the alloy.Based on these results,a three-step model for oxide peg formation and growth is conceived.展开更多
Objective To study mechanism of various effects of HLA antigen camouflaged by differentmPEGs. Methods Effects of the modification of HLA antigen camouflaged by various mPEGs were detected by microlymphocytotoxicity te...Objective To study mechanism of various effects of HLA antigen camouflaged by differentmPEGs. Methods Effects of the modification of HLA antigen camouflaged by various mPEGs were detected by microlymphocytotoxicity test. The ability of modification was detected by SDS-PAGE. The mechanism of the modification was depicted by the three-dimensional structure of HLA antigen. Results The specific reaction between HLA-A2 antigen and its antibody were completely blocked by mPEG-BTC and mPEG-SPA. mPEG-MAL did not camouflage HLA antigen. The diversity of the modification of HLA antigen camouflaged by varied mPEGs was closely associated with the amides displayed on the surface of HLA antigen. Conclusion Only the amides which were exposed to the surface of HLA antigen can be camouflaged by mPEG. The amides on the surface of three-dimensional structure of HLA-A2 antigen determine the effect of the modification by various mPEGs.展开更多
Polyethylene glycols(PEGs)in general use are polydisperse molecules with molecular weight(MW)distributed around an average value applied in their designation e.g.,PEG 4000.Previous research has shown that PEGs can act...Polyethylene glycols(PEGs)in general use are polydisperse molecules with molecular weight(MW)distributed around an average value applied in their designation e.g.,PEG 4000.Previous research has shown that PEGs can act as P-glycoprotein(P-gp)inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs.However,questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed.In this study,we examined the mechanism of uptake of PEGs by MDCK-mock cells,in particular,the effect of MW and interaction with P-gp by MDCK-hMDRl and A549 cells.The results show that:(a)the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors;(b)PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil;and(c)uptake of PEGs of low MW(<2000 Da)occurs by passive diffusion whereas uptake of PEGs of hish MW(>5000 Da)occurs by a combination of passive diffusion and caveolae-mediated endocytosis.These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.展开更多
PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PE-Gylated small-molecule...PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PE-Gylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatographytriple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase Ⅲ clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles-through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis-positions this workflow as an attractive tool for accelerating the development of PE-Gylated small-molecule therapeutics.展开更多
目的比较硫酸镁钠钾口服液(OSS)与复方聚乙二醇电解质散(PEG)在结肠镜检查前肠道准备中的安全性和有效性。方法回顾性分析2023月9月-2024年9月该院采用OSS与PEG在肠镜检查行前肠道准备的患者2000例。根据不同肠道准备药物,将患者分为OSS...目的比较硫酸镁钠钾口服液(OSS)与复方聚乙二醇电解质散(PEG)在结肠镜检查前肠道准备中的安全性和有效性。方法回顾性分析2023月9月-2024年9月该院采用OSS与PEG在肠镜检查行前肠道准备的患者2000例。根据不同肠道准备药物,将患者分为OSS组(1000例,口服OSS)和PEG组(1000例,口服4 L PEG)。比较两组患者肠道清洁度、清洁效果、肠腔气泡、结肠镜检查阳性率和不良反应发生率。结果OSS组肠道准备成功率为92.5%(925/1000),PEG组肠道准备成功率为91.7%(917/1000),两组患者比较,差异无统计学意义(P>0.05);两组患者左侧结肠波士顿肠道准备量表(BBPS)评分比较,差异无统计学意义(P>0.05),OSS组BBPS总分,以及中段和右侧结肠BBPS评分明显高于PEG组,差异均有统计学意义(P<0.05);OSS组气泡评估满意率为96.2%,高于PEG组的90.3%,差异有统计学意义(P<0.05);两组患者结肠镜检查阳性率和不良反应发生率比较,差异均无统计学意义(P>0.05)。结论OSS在肠道准备方面具有较好的去泡效果,清洁效果与PEG相当,且有较高的安全性。展开更多
DNA结合单锌指蛋白(DNA binding with one finger,Dof)是植物中特有的一类转录因子,参与调控植物组织分化、种子萌发、植物抗逆及代谢等生理生化过程。为鉴定并分析高粱Dof转录因子家族成员,利用生物信息学方法从全基因组水平对高粱Dof...DNA结合单锌指蛋白(DNA binding with one finger,Dof)是植物中特有的一类转录因子,参与调控植物组织分化、种子萌发、植物抗逆及代谢等生理生化过程。为鉴定并分析高粱Dof转录因子家族成员,利用生物信息学方法从全基因组水平对高粱Dof转录因子家族成员的基本基因结构、理化性质、保守基序、启动子顺式作用元件、组织特异性表达及干旱胁迫表达等进行分析。20%PEG6000模拟干旱胁迫处理豫粱10号的幼苗后,利用qPCR技术分析Dof基因家族成员响应不同时间段干旱胁迫的表达情况。结果共鉴定了30个高粱Dof基因,分布在9条染色体上,基因保守性分析结果显示,Motif1(即锌指结构)是高粱Dof基因家族中保守的蛋白质序列;其中29个基因中都含有CX2CX21CX2C保守基序,而SbDof15基因保守序列为CX20CX2C;启动子结构分析表明,Dof基因的启动子区域中含有ABA、MYB、MeJA、低温等逆境胁迫响应元件;进化树分析结果表明,高粱Dof蛋白与玉米的同源性更高,热图分析表明Dof家族成员在高粱的不同部位都有表达。qRT-PCR结果表明,高粱Dof基因家族成员可能参与高粱应对干旱胁迫的响应,不同的Dof基因成员在应对干旱胁迫时的调控机制可能不一样。展开更多
基金financially supported by Tsinghua University Initiative Scientific Research Program and the National Magnetic Confinement Fusion Energy Research Project of China(No.2015GB118001)。
文摘Oxide pegging is a widely accepted mechanistic model explaining the reactive element effect on the improved adherence of scale.However,previous models for the oxide peg formation process have not considered the effects of more than one active element added into the alloy during the peg formation.This study proposes a new model of oxide peg formation and growth for the doping of two reactive elements in an alloy(the precipitated Y and solid solute Ti).Different amounts of Ti and Y were added to a Co Ni Cr Al alloy,and the characteristics of the resulting oxide pegs,such as their linear density,size,and forming process,are obtained by examining alloy samples subjected to an isothermal oxidation operation at a temperature of 1150℃.It is found that the amount of Y determines the density of the oxide pegs,and Ti does not form a Ti-rich oxide core if a Y-rich oxide exists in the sample.In samples with the same Y content,the oxide pegs primarily grow in length,and with increased Ti content,they grow along the b-phase boundary and into the alloy.Based on these results,a three-step model for oxide peg formation and growth is conceived.
基金Supported by the National High Technology Research and Development Program(2001AA261161) of China(863 Program).
文摘Objective To study mechanism of various effects of HLA antigen camouflaged by differentmPEGs. Methods Effects of the modification of HLA antigen camouflaged by various mPEGs were detected by microlymphocytotoxicity test. The ability of modification was detected by SDS-PAGE. The mechanism of the modification was depicted by the three-dimensional structure of HLA antigen. Results The specific reaction between HLA-A2 antigen and its antibody were completely blocked by mPEG-BTC and mPEG-SPA. mPEG-MAL did not camouflage HLA antigen. The diversity of the modification of HLA antigen camouflaged by varied mPEGs was closely associated with the amides displayed on the surface of HLA antigen. Conclusion Only the amides which were exposed to the surface of HLA antigen can be camouflaged by mPEG. The amides on the surface of three-dimensional structure of HLA-A2 antigen determine the effect of the modification by various mPEGs.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81430087,81673396,81872831 and 81603182)the National Science and Technology Major Projects for‘significant new drugs creation’of the 13th five-year plan(2017ZX09101001 and 2018ZX09721002007,China)
文摘Polyethylene glycols(PEGs)in general use are polydisperse molecules with molecular weight(MW)distributed around an average value applied in their designation e.g.,PEG 4000.Previous research has shown that PEGs can act as P-glycoprotein(P-gp)inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs.However,questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed.In this study,we examined the mechanism of uptake of PEGs by MDCK-mock cells,in particular,the effect of MW and interaction with P-gp by MDCK-hMDRl and A549 cells.The results show that:(a)the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors;(b)PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil;and(c)uptake of PEGs of low MW(<2000 Da)occurs by passive diffusion whereas uptake of PEGs of hish MW(>5000 Da)occurs by a combination of passive diffusion and caveolae-mediated endocytosis.These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.
基金support from the National Natural Science Foundation of China(Nos.82030107,82304443,82373944)the Hainan Provincial Natural Science Foundation of China(No.825QN288).
文摘PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PE-Gylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatographytriple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase Ⅲ clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles-through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis-positions this workflow as an attractive tool for accelerating the development of PE-Gylated small-molecule therapeutics.
文摘目的比较硫酸镁钠钾口服液(OSS)与复方聚乙二醇电解质散(PEG)在结肠镜检查前肠道准备中的安全性和有效性。方法回顾性分析2023月9月-2024年9月该院采用OSS与PEG在肠镜检查行前肠道准备的患者2000例。根据不同肠道准备药物,将患者分为OSS组(1000例,口服OSS)和PEG组(1000例,口服4 L PEG)。比较两组患者肠道清洁度、清洁效果、肠腔气泡、结肠镜检查阳性率和不良反应发生率。结果OSS组肠道准备成功率为92.5%(925/1000),PEG组肠道准备成功率为91.7%(917/1000),两组患者比较,差异无统计学意义(P>0.05);两组患者左侧结肠波士顿肠道准备量表(BBPS)评分比较,差异无统计学意义(P>0.05),OSS组BBPS总分,以及中段和右侧结肠BBPS评分明显高于PEG组,差异均有统计学意义(P<0.05);OSS组气泡评估满意率为96.2%,高于PEG组的90.3%,差异有统计学意义(P<0.05);两组患者结肠镜检查阳性率和不良反应发生率比较,差异均无统计学意义(P>0.05)。结论OSS在肠道准备方面具有较好的去泡效果,清洁效果与PEG相当,且有较高的安全性。
文摘DNA结合单锌指蛋白(DNA binding with one finger,Dof)是植物中特有的一类转录因子,参与调控植物组织分化、种子萌发、植物抗逆及代谢等生理生化过程。为鉴定并分析高粱Dof转录因子家族成员,利用生物信息学方法从全基因组水平对高粱Dof转录因子家族成员的基本基因结构、理化性质、保守基序、启动子顺式作用元件、组织特异性表达及干旱胁迫表达等进行分析。20%PEG6000模拟干旱胁迫处理豫粱10号的幼苗后,利用qPCR技术分析Dof基因家族成员响应不同时间段干旱胁迫的表达情况。结果共鉴定了30个高粱Dof基因,分布在9条染色体上,基因保守性分析结果显示,Motif1(即锌指结构)是高粱Dof基因家族中保守的蛋白质序列;其中29个基因中都含有CX2CX21CX2C保守基序,而SbDof15基因保守序列为CX20CX2C;启动子结构分析表明,Dof基因的启动子区域中含有ABA、MYB、MeJA、低温等逆境胁迫响应元件;进化树分析结果表明,高粱Dof蛋白与玉米的同源性更高,热图分析表明Dof家族成员在高粱的不同部位都有表达。qRT-PCR结果表明,高粱Dof基因家族成员可能参与高粱应对干旱胁迫的响应,不同的Dof基因成员在应对干旱胁迫时的调控机制可能不一样。
