Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to ...Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.展开更多
Crystallized lithium fluoride(LiF)melts at 848℃ upon heating,and evaporates subsequently at a remarkably high temperature of 1673℃,characterizing its excellent thermally stability as one of the most representative m...Crystallized lithium fluoride(LiF)melts at 848℃ upon heating,and evaporates subsequently at a remarkably high temperature of 1673℃,characterizing its excellent thermally stability as one of the most representative metal halides.The marriage between Li F and rechargeable batteries dates back to early activities related to the electrochemical properties of lithium metal(Li°)negative electrodes,in which the nonaqueous electrolytes containing fluorinated salts were generally employed,e.g.,lithium tetrafluoroborate(LiBF_(4)),lithium hexafluoroarsenate(LiAsF_(6)),lithium trifluoromethanesulfonate(CF_(3)SO_(3)Li)[1].展开更多
The soft actuator is characterized by high safety,flexibility,and adaptability.It is capable of both active and passive defor-mations.This paper presents a discrete degree of freedom(DOF)method for soft actuators to r...The soft actuator is characterized by high safety,flexibility,and adaptability.It is capable of both active and passive defor-mations.This paper presents a discrete degree of freedom(DOF)method for soft actuators to reveal DOF characteristics.The method draws on the superposition mechanism of the deformation characteristics of the sarcomere in the skeletal muscles of living organisms.Firstly,the multi-DOF deformation characteristics of the soft actuator are discretized into superimposed combinations of single-DOF micro-units.Then,the soft actuator was determined to contain deformation characteristics such as extension-contraction,bending,and twisting.Eighteen types of micro-units with basic deforma-tion characteristics were obtained depending on the axis and orientation.Further,the mapping relationship between the combination of micro-units and the motion characteristics of the soft actuator based on the GF set theory was established.Finally,an active-passive DOF co-structured soft actuator(APCSA)was developed.The graphical approach analyzes the experimental results,and it can be concluded that active and passive DOFs can coexist in the composite deformation of the soft actuator.展开更多
In this paper,we first give a sufficient condition for a graph being fractional ID-[a,b]-factor-critical covered in terms of its independence number and minimum degree,which partially answers the problem posed by Sizh...In this paper,we first give a sufficient condition for a graph being fractional ID-[a,b]-factor-critical covered in terms of its independence number and minimum degree,which partially answers the problem posed by Sizhong Zhou,Hongxia Liu and Yang Xu(2022).Then,an A_(α)-spectral condition is given to ensure that G is a fractional ID-[a,b]-factor-critical covered graph and an(a,b,k)-factor-critical graph,respectively.In fact,(a,b,k)-factor-critical graph is a graph which has an[a,b]-factor for k=0.Thus,these above results extend the results of Jia Wei and Shenggui Zhang(2023)and Ao Fan,Ruifang Liu and Guoyan Ao(2023)in some sense.展开更多
文摘Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.
文摘Crystallized lithium fluoride(LiF)melts at 848℃ upon heating,and evaporates subsequently at a remarkably high temperature of 1673℃,characterizing its excellent thermally stability as one of the most representative metal halides.The marriage between Li F and rechargeable batteries dates back to early activities related to the electrochemical properties of lithium metal(Li°)negative electrodes,in which the nonaqueous electrolytes containing fluorinated salts were generally employed,e.g.,lithium tetrafluoroborate(LiBF_(4)),lithium hexafluoroarsenate(LiAsF_(6)),lithium trifluoromethanesulfonate(CF_(3)SO_(3)Li)[1].
基金The Central Government Guides Local Foundation for Science and Technology Development(Grant No.YDZJSX2024B004).
文摘The soft actuator is characterized by high safety,flexibility,and adaptability.It is capable of both active and passive defor-mations.This paper presents a discrete degree of freedom(DOF)method for soft actuators to reveal DOF characteristics.The method draws on the superposition mechanism of the deformation characteristics of the sarcomere in the skeletal muscles of living organisms.Firstly,the multi-DOF deformation characteristics of the soft actuator are discretized into superimposed combinations of single-DOF micro-units.Then,the soft actuator was determined to contain deformation characteristics such as extension-contraction,bending,and twisting.Eighteen types of micro-units with basic deforma-tion characteristics were obtained depending on the axis and orientation.Further,the mapping relationship between the combination of micro-units and the motion characteristics of the soft actuator based on the GF set theory was established.Finally,an active-passive DOF co-structured soft actuator(APCSA)was developed.The graphical approach analyzes the experimental results,and it can be concluded that active and passive DOFs can coexist in the composite deformation of the soft actuator.
基金Supported by the National Natural Science Foundation of China(Grant Nos.11961041,12261055)the Key Project of Natural Science Foundation of Gansu Province(Grant No.24JRRA222)the Foundation for Innovative Fundamental Research Group Project of Gansu Province(Grant No.25JRRA805).
文摘In this paper,we first give a sufficient condition for a graph being fractional ID-[a,b]-factor-critical covered in terms of its independence number and minimum degree,which partially answers the problem posed by Sizhong Zhou,Hongxia Liu and Yang Xu(2022).Then,an A_(α)-spectral condition is given to ensure that G is a fractional ID-[a,b]-factor-critical covered graph and an(a,b,k)-factor-critical graph,respectively.In fact,(a,b,k)-factor-critical graph is a graph which has an[a,b]-factor for k=0.Thus,these above results extend the results of Jia Wei and Shenggui Zhang(2023)and Ao Fan,Ruifang Liu and Guoyan Ao(2023)in some sense.
