The impact of Y content on the microstructure,mechanical properties,and electromagnetic interference shielding effectiveness(EMI SE)of the Mg-6Zn-xY-1La-0.5Zr alloy was investigated.After the extrusion treatment of Mg...The impact of Y content on the microstructure,mechanical properties,and electromagnetic interference shielding effectiveness(EMI SE)of the Mg-6Zn-xY-1La-0.5Zr alloy was investigated.After the extrusion treatment of Mg-6Zn-xY-1La-0.5Zr alloy,the large grains that did not experience dynamic recrystallization were elongated along the extrusion direction,and the small-sized dynamic recrystallized grains were distributed around the large grains.The Mg-6Zn-1Y-1La-0.5Zr alloy demonstrated a favorable balance between strength and plasticity,exhibiting ultimate tensile strength,yield strength,and elongation values of 332.3 MPa,267.3 MPa,and 16.2%,respectively.Moreover,the EMI SE within the frequency range of 30-1500 MHz changes from 79 to 110 dB,aligning with the electromagnetic shielding requirements of many high-strength applications.展开更多
采用真型试验与数值模拟相结合的方法研究了输电线路防风偏问题。根据500 k V聊长Ⅱ线防风偏治理实际工程,运用有限元分析软件SAP 2000建立输电塔-线耦合体系的三维有限元模型。提出"边相阻挡、中相牵制"的柔性防范措施,开展...采用真型试验与数值模拟相结合的方法研究了输电线路防风偏问题。根据500 k V聊长Ⅱ线防风偏治理实际工程,运用有限元分析软件SAP 2000建立输电塔-线耦合体系的三维有限元模型。提出"边相阻挡、中相牵制"的柔性防范措施,开展输电线路风偏真型试验,并结合有限元数值模拟,研究柔性防范装置的动力响应特点,验证该装置的合理性及有效性。展开更多
Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we ...Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.展开更多
Background Dairy cows’lactation performance is the outcome of the crosstalk between ruminal microbial metabo-lism and host metabolism.However,it is still unclear to what extent the rumen microbiome and its metabolite...Background Dairy cows’lactation performance is the outcome of the crosstalk between ruminal microbial metabo-lism and host metabolism.However,it is still unclear to what extent the rumen microbiome and its metabolites,as well as the host metabolism,contribute to regulating the milk protein yield(MPY).Methods The rumen fluid,serum and milk of 12 Holstein cows with the same diet(45%coarseness ratio),parity(2–3 fetuses)and lactation days(120–150 d)were used for the microbiome and metabolome analysis.Rumen metabolism(rumen metabolome)and host metabolism(blood and milk metabolome)were connected using a weighted gene co-expression network(WGCNA)and the structural equation model(SEM)analyses.Results Two different ruminal enterotypes,with abundant Prevotella and Ruminococcus,were identified as type1 and type2.Of these,a higher MPY was found in cows with ruminal type2.Interestingly,[Ruminococcus]gauvreauii group and norank_f_Ruminococcaceae(the differential bacteria)were the hub genera of the network.In addition,differential ruminal,serum and milk metabolome between enterotypes were identified,where the cows with type2 had higher L-tyrosine of rumen,ornithine and L-tryptophan of serum,and tetrahydroneopterin,palmitoyl-L-carnitine,S-lactoylglutathione of milk,which could provide more energy and substrate for MPY.Further,based on the identi-fied modules of ruminal microbiome,as well as ruminal serum and milk metabolome using WGCNA,the SEM analysis indicated that the key ruminal microbial module1,which contains the hub genera of the network([Ruminococcus]gauvreauii group and norank_f_Ruminococcaceae)and high abundance of bacteria(Prevotella and Ruminococcus),could regulate the MPY by module7 of rumen,module2 of blood,and module7 of milk,which contained L-tyrosine and L-tryptophan.Therefore,in order to more clearly reveal the process of rumen bacterial regulation of MPY,we established the path of SEM based on the L-tyrosine,L-tryptophan and related components.The SEM based on the metabolites suggested that[Ruminococcus]gauvreauii group could inhibit the energy supply of serum tryptophan to MPY by milk S-lactoylglutathione,which could enhance pyruvate metabolism.Norank_f_Ruminococcaceae could increase the ruminal L-tyrosine,which could provide the substrate for MPY.Conclusion Our results indicated that the represented enterotype genera of Prevotella and Ruminococcus,and the hub genera of[Ruminococcus]gauvreauii group and norank_f_Ruminococcaceae could regulate milk protein synthesis by affecting the ruminal L-tyrosine and L-tryptophan.Moreover,the combined analysis of enterotype,WGCNA and SEM could be used to connect rumen microbial metabolism with host metabolism,which provides a fundamental understanding of the crosstalk between host and microorganisms in regulating the synthesis of milk composition.展开更多
BA_(2)(MA)_(n-1)Pb_nI_(3n+1)series low-dimensional(2D)perovskites have been widely investigated for their re markable environmental stability,but still suffer the poor light absorption and disordered phase distri buti...BA_(2)(MA)_(n-1)Pb_nI_(3n+1)series low-dimensional(2D)perovskites have been widely investigated for their re markable environmental stability,but still suffer the poor light absorption and disordered phase distri bution,hindering their practical applications.In this work,we combine the introduction of FA and the addition of PbCl_(2)to optimize the film quality,strengthen the light absorption,regulate internal phase distribution,and promote carrier transport inside 2D perovskite films.The incorporation of FA promote sufficient light absorption and improve the film crystallinity.Furthermore,the addition of Pb Cl_(2)elimi nates the low n phase(n=1)and suppresses the forming of the low n phase of n=2,enhancing the film conductivity and diminishing carrier recombination.The synergistic of A-site cation engineering and phase manipulation achieves a high efficiency of 16.48%.Importantly,the synergistic prepared perovskite film does not show any changes after 60 days in the air with an average humidity of 57%±3%,and the corresponding solar cell maintains 85%of the original efficiency after more than 800 h,demonstrating remarkable environmental stability.The results indicate that the synergistic of A-site cation engineering and phase manipulation is promising for producing superior efficiency,along with satisfying humidity stability.展开更多
Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand.Substantial evidence points to cattle and non-ruminant animals being characterized by ph...Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand.Substantial evidence points to cattle and non-ruminant animals being characterized by phylogenetic features in terms of their differing capacity for hepatic gluconeogenesis,a process that is highly efficient in cattle yet the underlying mechanism remains unclear.Here we used a variety of transcriptome data,as well as tissue and cell-based methods to uncover the mechanisms of high-efficiency hepatic gluconeogenesis in cattle.We showed that cattle can efficiently convert propionate into pyruvate,at least partly,via high expression of acyl-CoA synthetase short-chain family member 1(ACSS1),propionyl-CoA carboxylase alpha chain(PCCA),methylmalonyl-CoA epimerase(MCEE),methylmalonyl-CoA mutase(MMUT),and succinate-CoA ligase(SUCLG2)genes in the liver(P<0.01).Moreover,higher expression of the rate-limiting enzymes of gluconeogenesis,such as phosphoenolpyruvate carboxykinase(PCK)and fructose 1,6-bisphosphatase(FBP),ensures the efficient operation of hepatic gluconeogenesis in cattle(P<0.01).Mechanistically,we found that cattle liver exhibits highly active mechanistic target of rapamycin complex 1(mTORC1),and the expressions of PCCA,MMUT,SUCLG2,PCK,and FBP genes are regulated by the activation of mTORC1(P<0.001).Finally,our results showed that mTORC1 promotes hepatic gluconeogenesis in a peroxisome proliferator-activated receptor γ coactivator 1a(PGC-1a)dependent manner.Collectively,our results not only revealed an important mechanism responsible for the quantitative differences in the efficiency of hepatic gluconeogenesis in cattle versus non-ruminant animals,but also established that mTORC1 is indeed involved in the regulation of hepatic gluconeogenesis through PGC-1a.These results provide a novel potential insight into promoting hepatic gluconeogenesis through activated mTORC1 in both ruminants and mammals.展开更多
Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expre...Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expression of the main genes involved in gluconeogenesis in calf hepatocytes and elucidate the associated mechanisms.Calf hepatocytes were obtained from 5 healthy calves(1 d old;30to 40 kg)and exposed to 0-,1-,2.5-,or 5-mM sodium propionate(NaP),which is known to promote the expression of genes involved in the gluconeogenesis pathway,including fructose 1,6-bisphosphatase,phosphoenolpyruvate carboxykinase,and glucose-6-phosphatase.With regard to the underlying mechanism,propionate promoted the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha,hepatocyte nuclear factor 4,and forkhead box O1(transcription factors that regulate the expression of hepatic gluconeogenic genes)by promoting mammalian target of rapamycin complex 1(mTORC1),but inhibiting mTORC2 activity(P<0.01).We also established a model of palmitic acid(PA)-induced hepatic injury in calf hepatocytes and found that PA could inhibit the gluconeogenic capacity of calf hepatocytes by suppressing the expression of gluconeogenic genes,inhibiting m TORC1,and promoting the activity of m TORC2(P<0.01).In contrast,NaP provided protection to calf hepatocytes by counteracting the inhibitory effect of PA on the gluconeogenic capacity of calf hepatocytes(P<0.05).Collectively,these findings indicate that NaP enhances the gluconeogenic capacity of calf hepatocytes by regulating the mTOR pathway activity.Thus,in addition to improving the glucose production potential,propionate may have therapeutic potential for the treatment of hepatic injury in dairy cows.展开更多
Steel and steel-concrete composite girders are two types of girders commonly used for long-span bridges. However, practice has shown that the two types of girders have some drawbacks. For steel girders, the orthotropi...Steel and steel-concrete composite girders are two types of girders commonly used for long-span bridges. However, practice has shown that the two types of girders have some drawbacks. For steel girders, the orthotropic steel deck (OSD) is vulnerable to fatigue cracking and the asphalt overlay is susceptible to damage such as rutting and pot holes. While for steel-concrete composite girders, the concrete deck is generally thick and heavy, and the deck is prone to cracking because of its low tensile strength and high creep. Thus, to improve the serviceability and durability of girders for long-span bridges, three new types of steel-UHPC lightweight composite bridge girders are proposed, where UHPC denotes ultra-high performance concrete. The first two types consist of an OSD and a thin UHPC layer while the third type consists of a steel beam and a UHPC waffle deck. Due to excellent mechanical behaviors and impressive durability of UHPC, the steel-UHPC composite girders have the advantages of light weight, high strength, low creep coefficient, low risk of cracking, and excellent durability, making them competitive alternatives for long-span bridges. To date, the proposed steel-UHPC composite girders have been applied to 14 real bridges in China. It is expected that the application of the new steel-UHPC composite girders on long-span bridges will have a promising future.展开更多
Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serv...Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME modulation and CSC stemness maintenance.Moreover,potential therapeutic targets for cancer are reviewed,as are the therapeutic effects of targeted drugs.展开更多
基金supported from the National Key R&D Program of China(No.2021YFB3701100)the National Natural Science Foundation of China(No.52225101)+1 种基金the Fundamental Research Funds for the Central Universities of China(Nos.2023CDJYXTD-002,2020CDJDPT001)the Graduate Research and Innovation Foundation of Chongqing,China(No.CYB23037).
文摘The impact of Y content on the microstructure,mechanical properties,and electromagnetic interference shielding effectiveness(EMI SE)of the Mg-6Zn-xY-1La-0.5Zr alloy was investigated.After the extrusion treatment of Mg-6Zn-xY-1La-0.5Zr alloy,the large grains that did not experience dynamic recrystallization were elongated along the extrusion direction,and the small-sized dynamic recrystallized grains were distributed around the large grains.The Mg-6Zn-1Y-1La-0.5Zr alloy demonstrated a favorable balance between strength and plasticity,exhibiting ultimate tensile strength,yield strength,and elongation values of 332.3 MPa,267.3 MPa,and 16.2%,respectively.Moreover,the EMI SE within the frequency range of 30-1500 MHz changes from 79 to 110 dB,aligning with the electromagnetic shielding requirements of many high-strength applications.
文摘采用真型试验与数值模拟相结合的方法研究了输电线路防风偏问题。根据500 k V聊长Ⅱ线防风偏治理实际工程,运用有限元分析软件SAP 2000建立输电塔-线耦合体系的三维有限元模型。提出"边相阻挡、中相牵制"的柔性防范措施,开展输电线路风偏真型试验,并结合有限元数值模拟,研究柔性防范装置的动力响应特点,验证该装置的合理性及有效性。
基金supported by the National Natural Science Foundation of China,No.81971425the Natural Science Foundation of Zhejiang Province,No.LY20H040002(both to XQF).
文摘Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.
基金the National Natural Science Foundation of China(32272829,32072761,31902184)Shaanxi Provincial Science and Technology Association Young Talents Lifting Program Project(20220203).
文摘Background Dairy cows’lactation performance is the outcome of the crosstalk between ruminal microbial metabo-lism and host metabolism.However,it is still unclear to what extent the rumen microbiome and its metabolites,as well as the host metabolism,contribute to regulating the milk protein yield(MPY).Methods The rumen fluid,serum and milk of 12 Holstein cows with the same diet(45%coarseness ratio),parity(2–3 fetuses)and lactation days(120–150 d)were used for the microbiome and metabolome analysis.Rumen metabolism(rumen metabolome)and host metabolism(blood and milk metabolome)were connected using a weighted gene co-expression network(WGCNA)and the structural equation model(SEM)analyses.Results Two different ruminal enterotypes,with abundant Prevotella and Ruminococcus,were identified as type1 and type2.Of these,a higher MPY was found in cows with ruminal type2.Interestingly,[Ruminococcus]gauvreauii group and norank_f_Ruminococcaceae(the differential bacteria)were the hub genera of the network.In addition,differential ruminal,serum and milk metabolome between enterotypes were identified,where the cows with type2 had higher L-tyrosine of rumen,ornithine and L-tryptophan of serum,and tetrahydroneopterin,palmitoyl-L-carnitine,S-lactoylglutathione of milk,which could provide more energy and substrate for MPY.Further,based on the identi-fied modules of ruminal microbiome,as well as ruminal serum and milk metabolome using WGCNA,the SEM analysis indicated that the key ruminal microbial module1,which contains the hub genera of the network([Ruminococcus]gauvreauii group and norank_f_Ruminococcaceae)and high abundance of bacteria(Prevotella and Ruminococcus),could regulate the MPY by module7 of rumen,module2 of blood,and module7 of milk,which contained L-tyrosine and L-tryptophan.Therefore,in order to more clearly reveal the process of rumen bacterial regulation of MPY,we established the path of SEM based on the L-tyrosine,L-tryptophan and related components.The SEM based on the metabolites suggested that[Ruminococcus]gauvreauii group could inhibit the energy supply of serum tryptophan to MPY by milk S-lactoylglutathione,which could enhance pyruvate metabolism.Norank_f_Ruminococcaceae could increase the ruminal L-tyrosine,which could provide the substrate for MPY.Conclusion Our results indicated that the represented enterotype genera of Prevotella and Ruminococcus,and the hub genera of[Ruminococcus]gauvreauii group and norank_f_Ruminococcaceae could regulate milk protein synthesis by affecting the ruminal L-tyrosine and L-tryptophan.Moreover,the combined analysis of enterotype,WGCNA and SEM could be used to connect rumen microbial metabolism with host metabolism,which provides a fundamental understanding of the crosstalk between host and microorganisms in regulating the synthesis of milk composition.
基金supported by the Chengdu Science and Technology Program(No.2021GH0200032HZ)Sichuan Engineering Technology Research Center of Basalt Fiber Composites Development and Application(No.2022SCXWYXWFC006)Natural Science Foundation of Sichuan Province(No.2022NSFSC0356)。
文摘BA_(2)(MA)_(n-1)Pb_nI_(3n+1)series low-dimensional(2D)perovskites have been widely investigated for their re markable environmental stability,but still suffer the poor light absorption and disordered phase distri bution,hindering their practical applications.In this work,we combine the introduction of FA and the addition of PbCl_(2)to optimize the film quality,strengthen the light absorption,regulate internal phase distribution,and promote carrier transport inside 2D perovskite films.The incorporation of FA promote sufficient light absorption and improve the film crystallinity.Furthermore,the addition of Pb Cl_(2)elimi nates the low n phase(n=1)and suppresses the forming of the low n phase of n=2,enhancing the film conductivity and diminishing carrier recombination.The synergistic of A-site cation engineering and phase manipulation achieves a high efficiency of 16.48%.Importantly,the synergistic prepared perovskite film does not show any changes after 60 days in the air with an average humidity of 57%±3%,and the corresponding solar cell maintains 85%of the original efficiency after more than 800 h,demonstrating remarkable environmental stability.The results indicate that the synergistic of A-site cation engineering and phase manipulation is promising for producing superior efficiency,along with satisfying humidity stability.
基金National Natural Science Foundation of China,China(grant numbers 32070782,32072761)。
文摘Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand.Substantial evidence points to cattle and non-ruminant animals being characterized by phylogenetic features in terms of their differing capacity for hepatic gluconeogenesis,a process that is highly efficient in cattle yet the underlying mechanism remains unclear.Here we used a variety of transcriptome data,as well as tissue and cell-based methods to uncover the mechanisms of high-efficiency hepatic gluconeogenesis in cattle.We showed that cattle can efficiently convert propionate into pyruvate,at least partly,via high expression of acyl-CoA synthetase short-chain family member 1(ACSS1),propionyl-CoA carboxylase alpha chain(PCCA),methylmalonyl-CoA epimerase(MCEE),methylmalonyl-CoA mutase(MMUT),and succinate-CoA ligase(SUCLG2)genes in the liver(P<0.01).Moreover,higher expression of the rate-limiting enzymes of gluconeogenesis,such as phosphoenolpyruvate carboxykinase(PCK)and fructose 1,6-bisphosphatase(FBP),ensures the efficient operation of hepatic gluconeogenesis in cattle(P<0.01).Mechanistically,we found that cattle liver exhibits highly active mechanistic target of rapamycin complex 1(mTORC1),and the expressions of PCCA,MMUT,SUCLG2,PCK,and FBP genes are regulated by the activation of mTORC1(P<0.001).Finally,our results showed that mTORC1 promotes hepatic gluconeogenesis in a peroxisome proliferator-activated receptor γ coactivator 1a(PGC-1a)dependent manner.Collectively,our results not only revealed an important mechanism responsible for the quantitative differences in the efficiency of hepatic gluconeogenesis in cattle versus non-ruminant animals,but also established that mTORC1 is indeed involved in the regulation of hepatic gluconeogenesis through PGC-1a.These results provide a novel potential insight into promoting hepatic gluconeogenesis through activated mTORC1 in both ruminants and mammals.
基金supported by the National Natural Science Foundation of China(grant numbers 32070782,32072761,32100578)the Guangdong Basic and Applied Basic Research Foundation(grant number 2021A1515220036).
文摘Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expression of the main genes involved in gluconeogenesis in calf hepatocytes and elucidate the associated mechanisms.Calf hepatocytes were obtained from 5 healthy calves(1 d old;30to 40 kg)and exposed to 0-,1-,2.5-,or 5-mM sodium propionate(NaP),which is known to promote the expression of genes involved in the gluconeogenesis pathway,including fructose 1,6-bisphosphatase,phosphoenolpyruvate carboxykinase,and glucose-6-phosphatase.With regard to the underlying mechanism,propionate promoted the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha,hepatocyte nuclear factor 4,and forkhead box O1(transcription factors that regulate the expression of hepatic gluconeogenic genes)by promoting mammalian target of rapamycin complex 1(mTORC1),but inhibiting mTORC2 activity(P<0.01).We also established a model of palmitic acid(PA)-induced hepatic injury in calf hepatocytes and found that PA could inhibit the gluconeogenic capacity of calf hepatocytes by suppressing the expression of gluconeogenic genes,inhibiting m TORC1,and promoting the activity of m TORC2(P<0.01).In contrast,NaP provided protection to calf hepatocytes by counteracting the inhibitory effect of PA on the gluconeogenic capacity of calf hepatocytes(P<0.05).Collectively,these findings indicate that NaP enhances the gluconeogenic capacity of calf hepatocytes by regulating the mTOR pathway activity.Thus,in addition to improving the glucose production potential,propionate may have therapeutic potential for the treatment of hepatic injury in dairy cows.
基金The authors would like to thank the following funders for providing support to this research: the National Key Research and Development Program of China (No. 2018YFC0705400)the National Natural Science Foundation of China (Grant Nos. 51778223 and 51708200)the Major Program of Science and Technology of Hunan Province (No. 2017SK1010).
文摘Steel and steel-concrete composite girders are two types of girders commonly used for long-span bridges. However, practice has shown that the two types of girders have some drawbacks. For steel girders, the orthotropic steel deck (OSD) is vulnerable to fatigue cracking and the asphalt overlay is susceptible to damage such as rutting and pot holes. While for steel-concrete composite girders, the concrete deck is generally thick and heavy, and the deck is prone to cracking because of its low tensile strength and high creep. Thus, to improve the serviceability and durability of girders for long-span bridges, three new types of steel-UHPC lightweight composite bridge girders are proposed, where UHPC denotes ultra-high performance concrete. The first two types consist of an OSD and a thin UHPC layer while the third type consists of a steel beam and a UHPC waffle deck. Due to excellent mechanical behaviors and impressive durability of UHPC, the steel-UHPC composite girders have the advantages of light weight, high strength, low creep coefficient, low risk of cracking, and excellent durability, making them competitive alternatives for long-span bridges. To date, the proposed steel-UHPC composite girders have been applied to 14 real bridges in China. It is expected that the application of the new steel-UHPC composite girders on long-span bridges will have a promising future.
基金supported by grants from the National Natural Science Foundation of China(Nos.31801177,81702659,31830053,31920103007,81625019)the Science Technology Commission of Shanghai Municipality(No.18410722000)+1 种基金the Shanghai Sailing Program(No.18YF1419500)the Fundamental Research Funds for the Central Universities(No.22120180043).
文摘Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME modulation and CSC stemness maintenance.Moreover,potential therapeutic targets for cancer are reviewed,as are the therapeutic effects of targeted drugs.
