General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有...General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有关键的调节作用,与肿瘤、心肌损伤、肺纤维化等的发生发展有一定的相关性。综述GCN2的生物学功能、结构特征、作用机制和疾病关联性,并总结分析GCN2抑制剂或激动剂的研发现状,重点阐述GCN2抑制剂或激动剂在抗肿瘤方向的临床应用潜力,为靶向GCN2激酶的新药开发提供参考。展开更多
在哺乳动物中有4个真核翻译起始因子2α(Eu⁃karyotic initiation factor 2α,eIF2α)激酶,即一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)、蛋白激酶R样内质网激酶(PKR-like ER ki⁃nase,PERK)、双链RNA依赖性蛋...在哺乳动物中有4个真核翻译起始因子2α(Eu⁃karyotic initiation factor 2α,eIF2α)激酶,即一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)、蛋白激酶R样内质网激酶(PKR-like ER ki⁃nase,PERK)、双链RNA依赖性蛋白激酶(Doublestranded RNA-dependent protein kinase,PKR)和血红素调节抑制剂激酶(Heme-regulated inhibitor,HRI)[1],这4个激酶会在不同胁迫条件下磷酸化eIF2α亚基第51位的丝氨酸/苏氨酸,从而削弱了eIF2在翻译过程中结合GTP的能力,进一步抑制细胞总体蛋白翻译以缓解细胞应激,恢复细胞蛋白稳态,这种细胞反应被称为整合应激反应(Integrated stress response,ISR)[2]。展开更多
本文结合了Node2vec和GCN这两种方法,先利用Node2vec方法得到初步的图嵌入,之后将其作为输入利用GCN进一步更新图嵌入矩阵。本文选择在维基数据集上进行节点分类任务,比较了结合前后方法的表现,验证了其有效性。In this paper, we integ...本文结合了Node2vec和GCN这两种方法,先利用Node2vec方法得到初步的图嵌入,之后将其作为输入利用GCN进一步更新图嵌入矩阵。本文选择在维基数据集上进行节点分类任务,比较了结合前后方法的表现,验证了其有效性。In this paper, we integrate the Node2vec and GCN methods. Initially, the Node2vec method is employed to obtain preliminary graph embeddings, which are then used as input to further update the graph embedding matrix through GCN. The study selects the Wikipedia dataset for node classification tasks, comparing the performance of the methods before and after integration to validate their effectiveness.展开更多
Photocatalysis holds great promise for the conversion of plastic waste into valuable chemicals.However,the conversion efficiency is constrained by the poor carriers’separation efficiency over the single component pho...Photocatalysis holds great promise for the conversion of plastic waste into valuable chemicals.However,the conversion efficiency is constrained by the poor carriers’separation efficiency over the single component photocatalyst.Herein,we synthesized a novel typeⅡNb_(2)O_(5)/GCN heterojunction to investigate its efficiency in the photocatalytic upcycling of polybutylene adipate/terephthalate(PBAT)microplastics(MPs)into acids and alcohols under visible light irradiation(100mW/cm^(2)).The findings indicate that the charge transfer within the typeⅡNb_(2)O_(5)/GCN occurs from the conduction band of GCN to the conduction band of Nb_(2)O_(5),thereby enhancing the separation efficiency of carriers Notably,the rates of ethanol and acetic acid generation from 1.5mg/mL PBAT MPs treated with the 60%Nb_(2)O_(5)/GCN photocatalyst were 21.8-fold and 1.8-fold higher,respectively,compared to those by Nb_(2)O_(5) alone.Density functional theory calculations demonstrate that the hydroxyl radicals(·OH)produced by the Nb_(2)O_(5)/GCN heterojunction cleaves the ester bond(O-C=O)of PBAT MP into the monomer.These monomers are subsequently converted into acids and alcohols through various reactions,including C-C bond cleavage,hydrodeoxygenation,and C-C bond coupling.This study highlights the effectiveness of heterojunction photocatalyst in converting PBAT MPs into valuable chemicals,thus significantly promoting advancements in bioplastics recycling.展开更多
Nitrogen(N),phosphorus(P)or potassium(K)deficiency in plants can lead to a decrease in amino acid and protein synthesis.However,it is unknown how protein translation gets repressed during macronutrient deficiencies.Pr...Nitrogen(N),phosphorus(P)or potassium(K)deficiency in plants can lead to a decrease in amino acid and protein synthesis.However,it is unknown how protein translation gets repressed during macronutrient deficiencies.Previous research has shown that general control non-depressible 1(GCN1)cooperate with GCN2 to phosphorylate the alpha subunit of eukaryotic translation initiation factor(eIF2α).In this study,we observed phosphorylation of eIF2αunder N,P,and K deficiencies,which was found to be lost in gcn1.Mutant gcn1 displayed higher sensitivity to macronutrient deficiencies compared to the wild-type(WT).The evidence of in situ reactive oxygen species(ROS)accumulation in leaves indicated that macronutrient starvation triggers ROS production.Treatment with Dimethylthiourea(DMTU),a ROS scavenger,eliminated ROS and reversed eIF2αphosphorylation induced by nutrient deficiency.Moreover,it was discovered that protein translation was reduced under N or K deficiency in the WT but not in gcn1,whereas under P deprivation,protein translation was reduced in both the WT and gcn1.We additionally found that DMTU can partially recover translation inhibition under N or K deprivation.Taken together,it is concluded that GCN1-GCN2-eIF2αpathway is regulated by ROS and is essential for plant survival under macronutrient starvation conditions.展开更多
Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that...Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.展开更多
Gln, one of the most abundant amino acids(AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters,protein synthes...Gln, one of the most abundant amino acids(AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters,protein synthesis, and underlying mechanisms in vivo is scarce. The present study aimed to explore the effects of low-crude protein diet inclusion with differential doses of L-Gln on intestinal AA levels,transporters, protein synthesis, and potential mechanisms in weaned piglets. A total of 128 healthy weaned piglets(Landrace × Yorkshire) were randomly allocated into four treatments with four replicates. Pigs in the four groups were fed a low-crude protein diet containing 0%, 1%, 2%, or 3% L-Gln for28 d. L-Gln administration markedly(linear, P < 0.05) increased Ala, Arg, Asn, Asp, Glu, Gln, His, Ile, Lys,Met, Orn, Phe, Ser, Thr, Tyr, and Val levels and promoted trypsin activity in the jejunal content of piglets.Moreover, L-Gln treatment significantly enhanced concentrations of colonic Gln and Trp, and serum Thr(linear, P < 0.01), and quadratically increased serum Lys and Phe levels(P < 0.05), and decreased plasma Glu, Ile, and Leu levels(linear, P < 0.05). Further investigation revealed that L-Gln administration significantly upregulated Atp1a1, Slc1a5, Slc3a2, Slc6a14, Slc7a5, Slc7a7, and Slc38a1 relative expressions in the jejunum(linear, P < 0.05). Additionally, dietary supplementation with L-Gln enhanced protein abundance of general control nonderepressible 2(GCN2, P = 0.010), phosphorylated eukaryotic initiation factor 2 subunit alpha(eIF2α, P < 0.001), and activating transcription factor 4(ATF4) in the jejunum of piglets(P = 0.008). These results demonstrated for the first time that a low crude protein diet with highlevel L-Gln inclusion exhibited side effects on piglets. Specifically, 2% and 3% L-Gln administration exceeded the intestinal utilization capacity and compromised the jejunal AA utilization efficiency, which is independent of digestive enzyme activities. A high level of L-Gln supplementation would inhibit protein synthesis by GCN2/eIF2α/ATF4 signaling in piglets fed low-protein diets, which, in turn, upregulates certain AA transporters to maintain AA homeostasis.展开更多
文摘General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有关键的调节作用,与肿瘤、心肌损伤、肺纤维化等的发生发展有一定的相关性。综述GCN2的生物学功能、结构特征、作用机制和疾病关联性,并总结分析GCN2抑制剂或激动剂的研发现状,重点阐述GCN2抑制剂或激动剂在抗肿瘤方向的临床应用潜力,为靶向GCN2激酶的新药开发提供参考。
文摘在哺乳动物中有4个真核翻译起始因子2α(Eu⁃karyotic initiation factor 2α,eIF2α)激酶,即一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)、蛋白激酶R样内质网激酶(PKR-like ER ki⁃nase,PERK)、双链RNA依赖性蛋白激酶(Doublestranded RNA-dependent protein kinase,PKR)和血红素调节抑制剂激酶(Heme-regulated inhibitor,HRI)[1],这4个激酶会在不同胁迫条件下磷酸化eIF2α亚基第51位的丝氨酸/苏氨酸,从而削弱了eIF2在翻译过程中结合GTP的能力,进一步抑制细胞总体蛋白翻译以缓解细胞应激,恢复细胞蛋白稳态,这种细胞反应被称为整合应激反应(Integrated stress response,ISR)[2]。
文摘本文结合了Node2vec和GCN这两种方法,先利用Node2vec方法得到初步的图嵌入,之后将其作为输入利用GCN进一步更新图嵌入矩阵。本文选择在维基数据集上进行节点分类任务,比较了结合前后方法的表现,验证了其有效性。In this paper, we integrate the Node2vec and GCN methods. Initially, the Node2vec method is employed to obtain preliminary graph embeddings, which are then used as input to further update the graph embedding matrix through GCN. The study selects the Wikipedia dataset for node classification tasks, comparing the performance of the methods before and after integration to validate their effectiveness.
基金financially supported by the National Natural Science Foundation of China(Nos.52170024,T2421005,and 22006031).
文摘Photocatalysis holds great promise for the conversion of plastic waste into valuable chemicals.However,the conversion efficiency is constrained by the poor carriers’separation efficiency over the single component photocatalyst.Herein,we synthesized a novel typeⅡNb_(2)O_(5)/GCN heterojunction to investigate its efficiency in the photocatalytic upcycling of polybutylene adipate/terephthalate(PBAT)microplastics(MPs)into acids and alcohols under visible light irradiation(100mW/cm^(2)).The findings indicate that the charge transfer within the typeⅡNb_(2)O_(5)/GCN occurs from the conduction band of GCN to the conduction band of Nb_(2)O_(5),thereby enhancing the separation efficiency of carriers Notably,the rates of ethanol and acetic acid generation from 1.5mg/mL PBAT MPs treated with the 60%Nb_(2)O_(5)/GCN photocatalyst were 21.8-fold and 1.8-fold higher,respectively,compared to those by Nb_(2)O_(5) alone.Density functional theory calculations demonstrate that the hydroxyl radicals(·OH)produced by the Nb_(2)O_(5)/GCN heterojunction cleaves the ester bond(O-C=O)of PBAT MP into the monomer.These monomers are subsequently converted into acids and alcohols through various reactions,including C-C bond cleavage,hydrodeoxygenation,and C-C bond coupling.This study highlights the effectiveness of heterojunction photocatalyst in converting PBAT MPs into valuable chemicals,thus significantly promoting advancements in bioplastics recycling.
基金Science and Technology Innovation Funding of Henan Agricultural University to Hairong Zhang(30500715).
文摘Nitrogen(N),phosphorus(P)or potassium(K)deficiency in plants can lead to a decrease in amino acid and protein synthesis.However,it is unknown how protein translation gets repressed during macronutrient deficiencies.Previous research has shown that general control non-depressible 1(GCN1)cooperate with GCN2 to phosphorylate the alpha subunit of eukaryotic translation initiation factor(eIF2α).In this study,we observed phosphorylation of eIF2αunder N,P,and K deficiencies,which was found to be lost in gcn1.Mutant gcn1 displayed higher sensitivity to macronutrient deficiencies compared to the wild-type(WT).The evidence of in situ reactive oxygen species(ROS)accumulation in leaves indicated that macronutrient starvation triggers ROS production.Treatment with Dimethylthiourea(DMTU),a ROS scavenger,eliminated ROS and reversed eIF2αphosphorylation induced by nutrient deficiency.Moreover,it was discovered that protein translation was reduced under N or K deficiency in the WT but not in gcn1,whereas under P deprivation,protein translation was reduced in both the WT and gcn1.We additionally found that DMTU can partially recover translation inhibition under N or K deprivation.Taken together,it is concluded that GCN1-GCN2-eIF2αpathway is regulated by ROS and is essential for plant survival under macronutrient starvation conditions.
基金This work was supported by the National Natural Science Foundation of China(31830044,91957207,81870592,82270905,81970742,82000764,82170868,and 81970731)The National Key R&D Program of China(grant 2018YFA0800600).
文摘Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.
基金supported by grants from the National Key R&D Program of China(2022YFF1100102,2022YFF1100104,2022YFC2105005)the National Natural Science Foundation of China(No.32172749,31625025).
文摘Gln, one of the most abundant amino acids(AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters,protein synthesis, and underlying mechanisms in vivo is scarce. The present study aimed to explore the effects of low-crude protein diet inclusion with differential doses of L-Gln on intestinal AA levels,transporters, protein synthesis, and potential mechanisms in weaned piglets. A total of 128 healthy weaned piglets(Landrace × Yorkshire) were randomly allocated into four treatments with four replicates. Pigs in the four groups were fed a low-crude protein diet containing 0%, 1%, 2%, or 3% L-Gln for28 d. L-Gln administration markedly(linear, P < 0.05) increased Ala, Arg, Asn, Asp, Glu, Gln, His, Ile, Lys,Met, Orn, Phe, Ser, Thr, Tyr, and Val levels and promoted trypsin activity in the jejunal content of piglets.Moreover, L-Gln treatment significantly enhanced concentrations of colonic Gln and Trp, and serum Thr(linear, P < 0.01), and quadratically increased serum Lys and Phe levels(P < 0.05), and decreased plasma Glu, Ile, and Leu levels(linear, P < 0.05). Further investigation revealed that L-Gln administration significantly upregulated Atp1a1, Slc1a5, Slc3a2, Slc6a14, Slc7a5, Slc7a7, and Slc38a1 relative expressions in the jejunum(linear, P < 0.05). Additionally, dietary supplementation with L-Gln enhanced protein abundance of general control nonderepressible 2(GCN2, P = 0.010), phosphorylated eukaryotic initiation factor 2 subunit alpha(eIF2α, P < 0.001), and activating transcription factor 4(ATF4) in the jejunum of piglets(P = 0.008). These results demonstrated for the first time that a low crude protein diet with highlevel L-Gln inclusion exhibited side effects on piglets. Specifically, 2% and 3% L-Gln administration exceeded the intestinal utilization capacity and compromised the jejunal AA utilization efficiency, which is independent of digestive enzyme activities. A high level of L-Gln supplementation would inhibit protein synthesis by GCN2/eIF2α/ATF4 signaling in piglets fed low-protein diets, which, in turn, upregulates certain AA transporters to maintain AA homeostasis.
