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
In an environment where demand for housing is growing and the supply from public authorities is virtually non-existent,several mechanisms for housing production are emerging in the formal,semi-informal and informal co...In an environment where demand for housing is growing and the supply from public authorities is virtually non-existent,several mechanisms for housing production are emerging in the formal,semi-informal and informal construction sectors.The project owner wonders how much it costs to construct a building to an acceptable standard.Cost forecasting in general faces a number of difficulties,including a lack of available information during the preliminary phase of the project.As such,estimation becomes a crucial task involving great responsibility,which can lead to either more convincing results or chaotic situations.This study proposes a quick and effective method for estimating the cost of a single-storey F4 residential building.The modelling is done using multiple linear regression based on a statistical approach applied to twenty(20)projects that have already been completed.The project data are collected from design offices in the city of Brazzaville.The method expresses the cost of an F4 construction by certain project tasks,representing five(5)variables,three(3)of which are related to structural work and two(2)to finishing work,which are easy to determine.This approach,known as MECSO(Cost Estimation Model by Sub-structure),gives good results in all statistical tests carried out with reasonable confidence intervals.This method is very practical for engineering professionals working on the evaluation and control of construction costs.展开更多
UGT(UDP-dependent glycosyltransferase)family members are mainly involved in the modification of secondary metabolites,as well as plant stress responses.Previously,we identified the UGT gene MdUGT88F4 from Malus spp.In...UGT(UDP-dependent glycosyltransferase)family members are mainly involved in the modification of secondary metabolites,as well as plant stress responses.Previously,we identified the UGT gene MdUGT88F4 from Malus spp.In order to verify whether it had biological function in apple plants,we generated transgenic apple plants overexpressed MdUGT88F4 and treated them with salt stress.The results showed that it conferred enhanced salt stress tolerance in transgenic‘GL-3’apple(Malus domestica)plants.The expression of MdUGT88F4 was induced by salt stress,and overexpression of this gene alleviated the inhibitory effects of salt stress on the growth of apple plants.After 15 days of salt stress treatment(100 mmol·L^(-1)NaCl),necrotic spots were present on the leaves of wild-type(WT)plants,and none were observed on the leaves of transgenic plants overexpressing MdUGT88F4(OX).The relative electrolyte leakage and malondialdehyde content were lower and the total chlorophyll content and the relative water content were higher in OX plants than in WT plants.The photosynthetic efficiency was higher in OX plants than in WT plants under salt stress,which was consistent with their larger stomatal aperture;this might stem from a reduction in the content of abscisic acid.The production of reactive oxygen species was lower and the activities of antioxidant enzymes were higher in OX plants than in WT plants.In addition,OX plants accumulated less Na^(+)but more K^(+)than WT plants,and the expression of several genes involved in Na^(+)transport was upregulated in OX plants.MdUGT88F4 failed to promote the accumulation of isosalipurposide in vivo,and it was involved in isosalipurposide synthesis.Most of the flavonoid metabolites accumulated to a greater degree in OX plants than in WT plants.In summary,our results show that MdUGT88F4 positively regulates the salt stress response in apple plants,possibly by affecting stomatal movement,as well as the accumulation of ions and flavonoids.Our findings enhance our understanding of the metabolic mechanisms by which UGT proteins ameliorate the effects of salt stress in plants.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In an environment where demand for housing is growing and the supply from public authorities is virtually non-existent,several mechanisms for housing production are emerging in the formal,semi-informal and informal construction sectors.The project owner wonders how much it costs to construct a building to an acceptable standard.Cost forecasting in general faces a number of difficulties,including a lack of available information during the preliminary phase of the project.As such,estimation becomes a crucial task involving great responsibility,which can lead to either more convincing results or chaotic situations.This study proposes a quick and effective method for estimating the cost of a single-storey F4 residential building.The modelling is done using multiple linear regression based on a statistical approach applied to twenty(20)projects that have already been completed.The project data are collected from design offices in the city of Brazzaville.The method expresses the cost of an F4 construction by certain project tasks,representing five(5)variables,three(3)of which are related to structural work and two(2)to finishing work,which are easy to determine.This approach,known as MECSO(Cost Estimation Model by Sub-structure),gives good results in all statistical tests carried out with reasonable confidence intervals.This method is very practical for engineering professionals working on the evaluation and control of construction costs.
基金supported by the Natural Science Basic Research Program of Shaanxi(Grant No.2023-JC-YB-170)the earmarked fund for the China Agricultural Research System(Grant No.CARS-27)the Key S&T Special Projects of Shannxi Province(Grant No.2020zdzx03-01-02)。
文摘UGT(UDP-dependent glycosyltransferase)family members are mainly involved in the modification of secondary metabolites,as well as plant stress responses.Previously,we identified the UGT gene MdUGT88F4 from Malus spp.In order to verify whether it had biological function in apple plants,we generated transgenic apple plants overexpressed MdUGT88F4 and treated them with salt stress.The results showed that it conferred enhanced salt stress tolerance in transgenic‘GL-3’apple(Malus domestica)plants.The expression of MdUGT88F4 was induced by salt stress,and overexpression of this gene alleviated the inhibitory effects of salt stress on the growth of apple plants.After 15 days of salt stress treatment(100 mmol·L^(-1)NaCl),necrotic spots were present on the leaves of wild-type(WT)plants,and none were observed on the leaves of transgenic plants overexpressing MdUGT88F4(OX).The relative electrolyte leakage and malondialdehyde content were lower and the total chlorophyll content and the relative water content were higher in OX plants than in WT plants.The photosynthetic efficiency was higher in OX plants than in WT plants under salt stress,which was consistent with their larger stomatal aperture;this might stem from a reduction in the content of abscisic acid.The production of reactive oxygen species was lower and the activities of antioxidant enzymes were higher in OX plants than in WT plants.In addition,OX plants accumulated less Na^(+)but more K^(+)than WT plants,and the expression of several genes involved in Na^(+)transport was upregulated in OX plants.MdUGT88F4 failed to promote the accumulation of isosalipurposide in vivo,and it was involved in isosalipurposide synthesis.Most of the flavonoid metabolites accumulated to a greater degree in OX plants than in WT plants.In summary,our results show that MdUGT88F4 positively regulates the salt stress response in apple plants,possibly by affecting stomatal movement,as well as the accumulation of ions and flavonoids.Our findings enhance our understanding of the metabolic mechanisms by which UGT proteins ameliorate the effects of salt stress in plants.
