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
Dynamic nonlinearities of C70/toluene solution are measured and analysed by an improved picosecond timeresolved pump-probe system based on a nonlinear imaging technique with phase object. The photophysical parameters ...Dynamic nonlinearities of C70/toluene solution are measured and analysed by an improved picosecond timeresolved pump-probe system based on a nonlinear imaging technique with phase object. The photophysical parameters are determined by the five-level model, which is adopted to interpret the experimental data. The change of refraction index per unit density of the excited state obtained by a numerically simulation is a critical factor to determine the nonlinear behaviour of C70 in picosecond time regime.展开更多
In this paper the absorption spectra of Nd-SXO-CPC complex by 4f electron transitions have been studied by zero-order and fourth-order derivative spectrophotome-try. The molar absorptivity is 2.6×10~3 1.mol^(-1)....In this paper the absorption spectra of Nd-SXO-CPC complex by 4f electron transitions have been studied by zero-order and fourth-order derivative spectrophotome-try. The molar absorptivity is 2.6×10~3 1.mol^(-1).cm^(-1) at 585 nm, the fourth-order derivative molar absorptivity is 1.4×10~4 1.mol^(-1).cm^(-1) at 584.5(-) and 587(+) nm. They are 300 times and 1600 times greater than those of the chloride, respectively.展开更多
Hearing relies on the structural and functional integrity of cochlear hair cells,particularly their apical F-actin-filled stereocilia.Phospholipid scramblases are important for maintaining membrane asymmetry,but their...Hearing relies on the structural and functional integrity of cochlear hair cells,particularly their apical F-actin-filled stereocilia.Phospholipid scramblases are important for maintaining membrane asymmetry,but their roles in the stereocilia and auditory functions are not fully understood.Here,we identify Plscr5 as a downstream target of the transcription factor POU4F3 essential for hair cell function,whose mutation causes human DFNA15 deafness.Plscr5 knockout mice exhibit progressive hearing loss due to stereocilia degeneration and hair cell loss.Functional analyses reveal that PLSCR5 contributes to phosphatidylserine externalization in hair cell apical membranes,particularly in inner hair cells,and is important for outer hair cell and stereocilia maintenance.Our findings highlight PLSCR5 as an important downstream effector of POU4F3 and regulator of phosphatidylserine externalization and membrane dynamics required for auditory functions.展开更多
本文从分析目前研学实践活动开展所存在的问题出发,提出将4F教学模式融入研学实践活动方案设计的优势,并以内蒙古集宁区霸王河国家湿地公园为例,确立基于地理学科核心素养的研学目标,依据4F教学模式的四个阶段设计研学活动实施过程,同...本文从分析目前研学实践活动开展所存在的问题出发,提出将4F教学模式融入研学实践活动方案设计的优势,并以内蒙古集宁区霸王河国家湿地公园为例,确立基于地理学科核心素养的研学目标,依据4F教学模式的四个阶段设计研学活动实施过程,同时制定了基于4F模式的评价量表,对学生的研学过程与研学结果进行全方位多角度评价,以期提高研学效果,为相关研究者和一线地理教师更好地设计基于4F模式的研学实践活动方案提供参考。Based on the analysis of the existing problems in the development of current research practice activities, this paper proposes the advantages of integrating 4F teaching mode into the design of research practice activities. Taking Bawanghe National Wetland Park in Jining District, Inner Mongolia as an example, this paper establishes research objectives based on the core accomplishment of geography, and designs the implementation process of research activities according to the four stages of 4F teaching mode. At the same time, an evaluation scale based on 4F model is developed to evaluate students’ research process and research results from a comprehensive and multi-angle, in order to improve the research effect and provide references for relevant researchers and front-line geography teachers to better design research practice activities based on 4F model.展开更多
研学旅行可以让学生在真实的自然和社会情境中,通过亲身体验和观察,开阔视野、增长能力和培养素养。4F教学模式作为一种符合学生认知规律的教学模式,与地理研学旅行具有一定的适切性,本文以包头钢铁集团的研学资源为依托,依据4F教学模...研学旅行可以让学生在真实的自然和社会情境中,通过亲身体验和观察,开阔视野、增长能力和培养素养。4F教学模式作为一种符合学生认知规律的教学模式,与地理研学旅行具有一定的适切性,本文以包头钢铁集团的研学资源为依托,依据4F教学模式的四个环节Fact (事实)、Feel (感受)、Find (发现)、Future (未来)设计了以工业为主题的研学活动,激发学生的学习兴趣,培养学生的探究精神和地理学科核心素养,此外,还设计了基于4F教学模式的评价量表对学生的研学过程和研学成果进行评价。Research travel allows students to broaden their horizons, develop their abilities and cultivate their literacy through personal experience and observation in real natural and social situations. 4F teaching mode, as a teaching mode that conforms to the cognitive law of students, is of certain relevance to geographical research travel. This paper relies on the research resources of Baotou Iron and Steel Group. According to the four links of 4F teaching mode, namely Fact, Feel, Find and Future, research activities with industry as the theme are designed to stimulate students’ interest in learning, cultivate students’ spirit of inquiry and the core quality of geography. In addition, the evaluation scale based on 4F teaching model is also designed to evaluate students’ research process and research results.展开更多
SF_6因具有良好的绝缘效果而被广泛地应用于电力系统中。但同时,SF_6也是一种温室气体,随着环境问题日益恶化,人们迫切需要找到替代SF_6的绝缘气体。为此,通过实验研究了环境友好气体c-C_4F_8及c-C_4F_8/N_2混合气体替代SF_6的可行性。...SF_6因具有良好的绝缘效果而被广泛地应用于电力系统中。但同时,SF_6也是一种温室气体,随着环境问题日益恶化,人们迫切需要找到替代SF_6的绝缘气体。为此,通过实验研究了环境友好气体c-C_4F_8及c-C_4F_8/N_2混合气体替代SF_6的可行性。通过调节电极间隙(1~6 mm)和气压(150~350 k Pa),测量了气体在不同条件下的击穿电压及击穿电流波形,得到了气体的绝缘特性并与SF_6气体进行了对比分析。实验结果表明:纯净的c-C_4F_8气体的绝缘强度约为SF_6的1.3倍,体积比为1:1的c-C_4F_8/N_2混合气体的绝缘强度约为与SF_6的0.9倍。通过计算,c-C_4F_8/N_2混合气体的液化温度可以达到电力系统使用要求。考虑到c-C_4F_8气体对于环境的影响较小,使用c-C_4F_8/N_2混合气体作为替代SF_6的绝缘气体,有着良好的应用前景。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.
基金Project supported by the National Natural Science Fundation of China(Grant No.90922007)
文摘Dynamic nonlinearities of C70/toluene solution are measured and analysed by an improved picosecond timeresolved pump-probe system based on a nonlinear imaging technique with phase object. The photophysical parameters are determined by the five-level model, which is adopted to interpret the experimental data. The change of refraction index per unit density of the excited state obtained by a numerically simulation is a critical factor to determine the nonlinear behaviour of C70 in picosecond time regime.
文摘In this paper the absorption spectra of Nd-SXO-CPC complex by 4f electron transitions have been studied by zero-order and fourth-order derivative spectrophotome-try. The molar absorptivity is 2.6×10~3 1.mol^(-1).cm^(-1) at 585 nm, the fourth-order derivative molar absorptivity is 1.4×10~4 1.mol^(-1).cm^(-1) at 584.5(-) and 587(+) nm. They are 300 times and 1600 times greater than those of the chloride, respectively.
基金supported by the National Natural Science Foundation of China(82171136 and 92368110 to G.W.,82201291 to G.-J.Z.,82192861 to Z.X.,81970884 and 82192862 to X.G.)the Natural Science Foundation of Jiangsu Province(BK20220188 to Q.L.,BK20220189 to G.-J.Z.)the Fundamental Research Funds for the Central Universities(021414380533 to G.W.).
文摘Hearing relies on the structural and functional integrity of cochlear hair cells,particularly their apical F-actin-filled stereocilia.Phospholipid scramblases are important for maintaining membrane asymmetry,but their roles in the stereocilia and auditory functions are not fully understood.Here,we identify Plscr5 as a downstream target of the transcription factor POU4F3 essential for hair cell function,whose mutation causes human DFNA15 deafness.Plscr5 knockout mice exhibit progressive hearing loss due to stereocilia degeneration and hair cell loss.Functional analyses reveal that PLSCR5 contributes to phosphatidylserine externalization in hair cell apical membranes,particularly in inner hair cells,and is important for outer hair cell and stereocilia maintenance.Our findings highlight PLSCR5 as an important downstream effector of POU4F3 and regulator of phosphatidylserine externalization and membrane dynamics required for auditory functions.
文摘本文从分析目前研学实践活动开展所存在的问题出发,提出将4F教学模式融入研学实践活动方案设计的优势,并以内蒙古集宁区霸王河国家湿地公园为例,确立基于地理学科核心素养的研学目标,依据4F教学模式的四个阶段设计研学活动实施过程,同时制定了基于4F模式的评价量表,对学生的研学过程与研学结果进行全方位多角度评价,以期提高研学效果,为相关研究者和一线地理教师更好地设计基于4F模式的研学实践活动方案提供参考。Based on the analysis of the existing problems in the development of current research practice activities, this paper proposes the advantages of integrating 4F teaching mode into the design of research practice activities. Taking Bawanghe National Wetland Park in Jining District, Inner Mongolia as an example, this paper establishes research objectives based on the core accomplishment of geography, and designs the implementation process of research activities according to the four stages of 4F teaching mode. At the same time, an evaluation scale based on 4F model is developed to evaluate students’ research process and research results from a comprehensive and multi-angle, in order to improve the research effect and provide references for relevant researchers and front-line geography teachers to better design research practice activities based on 4F model.
文摘研学旅行可以让学生在真实的自然和社会情境中,通过亲身体验和观察,开阔视野、增长能力和培养素养。4F教学模式作为一种符合学生认知规律的教学模式,与地理研学旅行具有一定的适切性,本文以包头钢铁集团的研学资源为依托,依据4F教学模式的四个环节Fact (事实)、Feel (感受)、Find (发现)、Future (未来)设计了以工业为主题的研学活动,激发学生的学习兴趣,培养学生的探究精神和地理学科核心素养,此外,还设计了基于4F教学模式的评价量表对学生的研学过程和研学成果进行评价。Research travel allows students to broaden their horizons, develop their abilities and cultivate their literacy through personal experience and observation in real natural and social situations. 4F teaching mode, as a teaching mode that conforms to the cognitive law of students, is of certain relevance to geographical research travel. This paper relies on the research resources of Baotou Iron and Steel Group. According to the four links of 4F teaching mode, namely Fact, Feel, Find and Future, research activities with industry as the theme are designed to stimulate students’ interest in learning, cultivate students’ spirit of inquiry and the core quality of geography. In addition, the evaluation scale based on 4F teaching model is also designed to evaluate students’ research process and research results.
文摘SF_6因具有良好的绝缘效果而被广泛地应用于电力系统中。但同时,SF_6也是一种温室气体,随着环境问题日益恶化,人们迫切需要找到替代SF_6的绝缘气体。为此,通过实验研究了环境友好气体c-C_4F_8及c-C_4F_8/N_2混合气体替代SF_6的可行性。通过调节电极间隙(1~6 mm)和气压(150~350 k Pa),测量了气体在不同条件下的击穿电压及击穿电流波形,得到了气体的绝缘特性并与SF_6气体进行了对比分析。实验结果表明:纯净的c-C_4F_8气体的绝缘强度约为SF_6的1.3倍,体积比为1:1的c-C_4F_8/N_2混合气体的绝缘强度约为与SF_6的0.9倍。通过计算,c-C_4F_8/N_2混合气体的液化温度可以达到电力系统使用要求。考虑到c-C_4F_8气体对于环境的影响较小,使用c-C_4F_8/N_2混合气体作为替代SF_6的绝缘气体,有着良好的应用前景。
