3-Hydroxy-3-methylglutaryl coenzyme A （HMG CoA） reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant...3-Hydroxy-3-methylglutaryl coenzyme A （HMG CoA） reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant amount of feedback control through multiple mechanisms that are mediated by sterol and nonsterol end-products of mevalonate metabolism. Here, I will discuss recent advances that shed light on one mechanism for control of reductase, which involves rapid degradation of the enzyme. Accumulation of certain sterols triggers binding of reductase to endoplasmic reticulum （ER） membrane proteins called Insig-1 and Insig-2. Reductase-Insig binding results in recruitment of a membrane-associated ubiquitin ligase called gp78, which initiates ubiquitination of reductase. This ubiquitination is an obligatory reaction for recognition and degradation of reductase from ER membranes by cytosolic 26S proteasomes. Thus, sterol-accelerated degradation of reductase represents an example of how a general cellular process （ER-associated degradation） is used to control an important metabolic pathway （cholesterol synthesis）.展开更多
Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppres...Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppress oxidative stress and inflammation in endothelial cells, and this concept was examined in human coronary artery endothelial cells （HCAECs）. Methods Human coronary artery endothelial cells were cultured and treated with oxidized-low density lipoprotein （ox-LDL, 60 ug/ml for 24 hours） alone, or pre-treated with aspirin （1, 2 or 5 mmol/L）, pravastatin （1, 5 or 10 umol/L） or their combination （1 mmol/L aspirin and 5umol/L pravastatin）, followed by ox-LDL treatment. After respective treatment, superoxide anion production, p38 mitogen activated protein kinase and transcription factor NF-KB activation, protein expression of lectin-like ox-LDL receptor-1 （LOX-1） and adhesion molecules, and monocyte adhesion were measured. Results Ox-LDL treatment greatly elicited its receptor LOX-1 expression, superoxide anion production and inflammatory response, which were minimally affected by low concentration of aspirin （1 mmol/L） or pravastatin （5umol/L）, but were markedly decreased by their combination. Activation of p38 mitogen activated protein kinase and NF-KB, the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-I, which were only mildly affected by aspirin or pravastatin alone, were significantly attenuated by their combination. As a consequence, monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents. Well-known anti-oxidants a-tocopherol and y-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin. Conclusions These studies point to a positive interaction between aspirin and pravastatin with regard to endothelial bioloqy. Anti-oxidant and subsequent anti-inflammatory effect may be on展开更多
Cinnamoyl CoA reductase （CCR） and cinnamyl alcohol dehydrogenase （CAD） catalyze the last steps of mono- lignol biosynthesis. In Arabidopsis, one CCR gene （CCR1, Atlg15950） and two CAD genes （CAD C At3g19450 and...Cinnamoyl CoA reductase （CCR） and cinnamyl alcohol dehydrogenase （CAD） catalyze the last steps of mono- lignol biosynthesis. In Arabidopsis, one CCR gene （CCR1, Atlg15950） and two CAD genes （CAD C At3g19450 and CAD D At4g34230） are involved in this pathway. A triple cad c cad d ccrl mutant, named ccc, was obtained. This mutant displays a severe dwarf phenotype and male sterility. The lignin content in ccc mature stems is reduced to 50% of the wild-type level. In addition, stem lignin structure is severely affected, as shown by the dramatic enrichment in resistant inter-unit bonds and incorporation into the polymer of monolignol precursors such as coniferaldehyde, sinapaldehyde, and ferulic acid. Male sterility is due to the lack of lignification in the anther endothecium, which causes the failure of anther de- hiscence and of pollen release. The cc~ hypolignified stems accumulate higher amounts of flavonol glycosides, sinapoyl malate and feruloyl malate, which suggests a redirection of the phenolic pathway. Therefore, the absence of CAD and CCR, key enzymes of the monolignol pathway, has more severe consequences on the phenotype than the individual absence of each of them. Induction of another CCR （CCR2, Atlg80820） and another CAD （CAD1, At4g39330） does not compensate the absence of the main CCR and CAD activities. This lack of CCR and CAD activities not only impacts lignification, but also severely affects the development of the plants. These consequences must be carefully considered when trying to reduce the lignin content of plants in order to facilitate the lignocellulose-to-bioethanol conversion process.展开更多
Coal pillar design has historically assigned a factor of safety(Fo S) or stability factor(SF) according to their estimated strength and the assumed overburden load acting on them. Acceptable Fo S values have been assi...Coal pillar design has historically assigned a factor of safety(Fo S) or stability factor(SF) according to their estimated strength and the assumed overburden load acting on them. Acceptable Fo S values have been assigned based on past mining experience or a statistical link between Fo S and probability of failure(Po F). Pillar width-to-height(w/h) ratio has long been established as having a material influence on both pillar strength and its potential failure mode. However, there has been significant disagreement on using both factor of safety(Fo S) and w/h as part of pillar system stability criterion, as compared to using Fo S in isolation. This paper will argue that there are valid technical reasons to bring w/h ratio into system stability criteria(other than its influence on pillar strength), as it is related to the post-failure stiffness of the pillar, as measured in situ, and its interaction with overburden stiffness. When overburden stiffness is also brought into pillar system stability considerations, two issues emerge. The first is the width-todepth(W/D) ratio of the panel and whether it is sub-critical or super-critical from a surface subsidence perspective. The second relates to a re-evaluation of pillar Fo S based on whether the pillar is in an elastic or non-elastic(i.e., post-yield) state in its as-designed condition, as this is relevant to maintaining overburden stiffness at the highest possible level. The significance of the model is the potential to maximise both reserve recovery and mining efficiencies without any discernible increase in geotechnical risk, particularly in thick seams and higher depth of cover mining situations. At a time when mining economics are, at best, marginal, removing potentially unnecessary design conservatism is of interest to all mine operators and is an important topic for discussion amongst the geotechnical community.展开更多
In this article, some methods are proposed for enhancing the converging velocity of the COA (chaos optimization algorithm) based on using carrier wave two times, which can greatly increase the speed and efficiency of ...In this article, some methods are proposed for enhancing the converging velocity of the COA (chaos optimization algorithm) based on using carrier wave two times, which can greatly increase the speed and efficiency of the first carrier wave’s search for the optimal point in implementing the sophisticated searching during the second carrier wave is faster and more accurate. In addition, the concept of using the carrier wave three times is proposed and put into practice to tackle the multi-variables opti- mization problems, where the searching for the optimal point of the last several variables is frequently worse than the first several ones.展开更多
According to synthetic pathway of plant chlorogenic acid （CGA）, the expression patterns of genes encoding enzymes that are associated with CGA synthesis were studied in normally developed Xuehua pear fruit. The stud...According to synthetic pathway of plant chlorogenic acid （CGA）, the expression patterns of genes encoding enzymes that are associated with CGA synthesis were studied in normally developed Xuehua pear fruit. The study demonstrated that CGA content in peel and flesh of Xuehua pear decreased as fruit development progressed, with a higher level in peel. The expression levels of PbPAL 1, PbPAL2, PbC3H, PbC4H, Pb4CL 1, Pb4CL2, Pb4CL6, PbHC T1 and PbHC T3 genes decreased in fruit, which was consistent with the pattern of variation in CGA content. That indicated that these genes might be key genes for influencing fruit CGA synthesis in Xuehua pear. However, Pb4CL7 gene expression profile is not consistent with variation of CGA content, hence, it may not be a key gene involved in CGA synthesis.展开更多
Bitter acids, known for their use as beer flavoring and for their diverse biological activities, are predominantly formed in hop （Humulus lupulus） glandular trichomes. Branched short-chain acyI-CoAs （e.g. isobutyry...Bitter acids, known for their use as beer flavoring and for their diverse biological activities, are predominantly formed in hop （Humulus lupulus） glandular trichomes. Branched short-chain acyI-CoAs （e.g. isobutyryI-CoA, isovaleryl- CoA and 2-methylbutyryI-CoA）, derived from the degradation of branched-chain amino acids （BCAAs）, are essential building blocks for the biosynthesis of bitter acids in hops. However, little is known regarding what components are needed to produce and maintain the pool of branched short-chain acyI-CoAs in hop trichomes. Here, we present several lines of evidence that both CoA ligases and thioesterases are likely involved in bitter acid biosynthesis. Recombinant HICCL2 （carboxyl CoA ligase） protein had high specific activity for isovaleric acid as a substrate （Kcat/Km = 4100 s-~ M-l）, whereas recombinant HICCL4 specifically utilized isobutyric acid （Kcat/Km = 1800 s-1 M-1） and 2-methylbutyric acid （Kcat/ Km = 6900 s-1 M-~） as substrates. Both HICCLs, like hop valerophenone synthase （HIVPS）, were expressed strongly in glandular trichomes and localized to the cytoplasm. Co-expression of HICCL2 and HICCL4 with HIVPS in yeast led to significant production of acylphloroglucinols （the direct precursors for bitter acid biosynthesis）, which further confirmed the biochemical function of these two HICCLs in vivo. Functional identification of a thioesterase that catalyzed the reverse reaction of CCLs in mitochondria, together with the comprehensive analysis of genes involved BCAA catabolism, supported the idea that cytosolic CoA ligases are required for linking BCAA degradation and bitter acid biosynthesis in glandular trichomes. The evolution and other possible physiological roles of branched short-chain fatty acid：CoA ligases in planta are also discussed.展开更多
This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and ...This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and FAO datasets were used to identify these key genes.Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain(ACADM)between KIRC and non cancer samples.The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features.The diagnostic performance of ACADM for KIRC was asessed using a diagnostic receiver operating ch aracteristic(ROC)curve.The co-expressed genes of ACADM were identifed in LinkedOmics database,and their function and pathway enrichment were analyzed.The correlation between ACADM expression level and immune infitration was analyzed by Gene Set Variation Analysis(GSVA)method Additionally,the proliferation,migration,and invasion abilities of KIRC cells were assessed after overexpressing ACADM.Following differential analysis and intersection,we identifed six hub genes,induding ACADM.We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic efect(AUC=0.916).Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis.According to correlation analysis,a variety of dinical features were associated with the expression level of ACADML By analyzing the infiltration level of immune cells,we found that ACADM may be related to the enrichment of immune cells.Finally,ACADM overexpression inhibited proliferation,migration,and invasion of KIRC cells.In conclusion,our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis.These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC,offering a reference for dinicians in diagnosis and treatment.展开更多
文摘3-Hydroxy-3-methylglutaryl coenzyme A （HMG CoA） reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant amount of feedback control through multiple mechanisms that are mediated by sterol and nonsterol end-products of mevalonate metabolism. Here, I will discuss recent advances that shed light on one mechanism for control of reductase, which involves rapid degradation of the enzyme. Accumulation of certain sterols triggers binding of reductase to endoplasmic reticulum （ER） membrane proteins called Insig-1 and Insig-2. Reductase-Insig binding results in recruitment of a membrane-associated ubiquitin ligase called gp78, which initiates ubiquitination of reductase. This ubiquitination is an obligatory reaction for recognition and degradation of reductase from ER membranes by cytosolic 26S proteasomes. Thus, sterol-accelerated degradation of reductase represents an example of how a general cellular process （ER-associated degradation） is used to control an important metabolic pathway （cholesterol synthesis）.
文摘Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppress oxidative stress and inflammation in endothelial cells, and this concept was examined in human coronary artery endothelial cells （HCAECs）. Methods Human coronary artery endothelial cells were cultured and treated with oxidized-low density lipoprotein （ox-LDL, 60 ug/ml for 24 hours） alone, or pre-treated with aspirin （1, 2 or 5 mmol/L）, pravastatin （1, 5 or 10 umol/L） or their combination （1 mmol/L aspirin and 5umol/L pravastatin）, followed by ox-LDL treatment. After respective treatment, superoxide anion production, p38 mitogen activated protein kinase and transcription factor NF-KB activation, protein expression of lectin-like ox-LDL receptor-1 （LOX-1） and adhesion molecules, and monocyte adhesion were measured. Results Ox-LDL treatment greatly elicited its receptor LOX-1 expression, superoxide anion production and inflammatory response, which were minimally affected by low concentration of aspirin （1 mmol/L） or pravastatin （5umol/L）, but were markedly decreased by their combination. Activation of p38 mitogen activated protein kinase and NF-KB, the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-I, which were only mildly affected by aspirin or pravastatin alone, were significantly attenuated by their combination. As a consequence, monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents. Well-known anti-oxidants a-tocopherol and y-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin. Conclusions These studies point to a positive interaction between aspirin and pravastatin with regard to endothelial bioloqy. Anti-oxidant and subsequent anti-inflammatory effect may be on
文摘Cinnamoyl CoA reductase （CCR） and cinnamyl alcohol dehydrogenase （CAD） catalyze the last steps of mono- lignol biosynthesis. In Arabidopsis, one CCR gene （CCR1, Atlg15950） and two CAD genes （CAD C At3g19450 and CAD D At4g34230） are involved in this pathway. A triple cad c cad d ccrl mutant, named ccc, was obtained. This mutant displays a severe dwarf phenotype and male sterility. The lignin content in ccc mature stems is reduced to 50% of the wild-type level. In addition, stem lignin structure is severely affected, as shown by the dramatic enrichment in resistant inter-unit bonds and incorporation into the polymer of monolignol precursors such as coniferaldehyde, sinapaldehyde, and ferulic acid. Male sterility is due to the lack of lignification in the anther endothecium, which causes the failure of anther de- hiscence and of pollen release. The cc~ hypolignified stems accumulate higher amounts of flavonol glycosides, sinapoyl malate and feruloyl malate, which suggests a redirection of the phenolic pathway. Therefore, the absence of CAD and CCR, key enzymes of the monolignol pathway, has more severe consequences on the phenotype than the individual absence of each of them. Induction of another CCR （CCR2, Atlg80820） and another CAD （CAD1, At4g39330） does not compensate the absence of the main CCR and CAD activities. This lack of CCR and CAD activities not only impacts lignification, but also severely affects the development of the plants. These consequences must be carefully considered when trying to reduce the lignin content of plants in order to facilitate the lignocellulose-to-bioethanol conversion process.
文摘Coal pillar design has historically assigned a factor of safety(Fo S) or stability factor(SF) according to their estimated strength and the assumed overburden load acting on them. Acceptable Fo S values have been assigned based on past mining experience or a statistical link between Fo S and probability of failure(Po F). Pillar width-to-height(w/h) ratio has long been established as having a material influence on both pillar strength and its potential failure mode. However, there has been significant disagreement on using both factor of safety(Fo S) and w/h as part of pillar system stability criterion, as compared to using Fo S in isolation. This paper will argue that there are valid technical reasons to bring w/h ratio into system stability criteria(other than its influence on pillar strength), as it is related to the post-failure stiffness of the pillar, as measured in situ, and its interaction with overburden stiffness. When overburden stiffness is also brought into pillar system stability considerations, two issues emerge. The first is the width-todepth(W/D) ratio of the panel and whether it is sub-critical or super-critical from a surface subsidence perspective. The second relates to a re-evaluation of pillar Fo S based on whether the pillar is in an elastic or non-elastic(i.e., post-yield) state in its as-designed condition, as this is relevant to maintaining overburden stiffness at the highest possible level. The significance of the model is the potential to maximise both reserve recovery and mining efficiencies without any discernible increase in geotechnical risk, particularly in thick seams and higher depth of cover mining situations. At a time when mining economics are, at best, marginal, removing potentially unnecessary design conservatism is of interest to all mine operators and is an important topic for discussion amongst the geotechnical community.
基金Project supported by the National Natural Science Foundation of China (No. 60474064), and the Natural Science Foundation of Zhejiang Province (No. Y105694), China
文摘In this article, some methods are proposed for enhancing the converging velocity of the COA (chaos optimization algorithm) based on using carrier wave two times, which can greatly increase the speed and efficiency of the first carrier wave’s search for the optimal point in implementing the sophisticated searching during the second carrier wave is faster and more accurate. In addition, the concept of using the carrier wave three times is proposed and put into practice to tackle the multi-variables opti- mization problems, where the searching for the optimal point of the last several variables is frequently worse than the first several ones.
基金supported by the Specific Financial Funds of Hebei Province,China (494-0502-JSN-7FB3)
文摘According to synthetic pathway of plant chlorogenic acid （CGA）, the expression patterns of genes encoding enzymes that are associated with CGA synthesis were studied in normally developed Xuehua pear fruit. The study demonstrated that CGA content in peel and flesh of Xuehua pear decreased as fruit development progressed, with a higher level in peel. The expression levels of PbPAL 1, PbPAL2, PbC3H, PbC4H, Pb4CL 1, Pb4CL2, Pb4CL6, PbHC T1 and PbHC T3 genes decreased in fruit, which was consistent with the pattern of variation in CGA content. That indicated that these genes might be key genes for influencing fruit CGA synthesis in Xuehua pear. However, Pb4CL7 gene expression profile is not consistent with variation of CGA content, hence, it may not be a key gene involved in CGA synthesis.
基金the National Program on Key Basic Research Projects，the 'One hundred talents' project of the Chinese Academy of Sciences，the National Natural Sciences Foundation of China，the National Science Foundation，the State Key Laboratory of Plant Genomics of China
文摘Bitter acids, known for their use as beer flavoring and for their diverse biological activities, are predominantly formed in hop （Humulus lupulus） glandular trichomes. Branched short-chain acyI-CoAs （e.g. isobutyryI-CoA, isovaleryl- CoA and 2-methylbutyryI-CoA）, derived from the degradation of branched-chain amino acids （BCAAs）, are essential building blocks for the biosynthesis of bitter acids in hops. However, little is known regarding what components are needed to produce and maintain the pool of branched short-chain acyI-CoAs in hop trichomes. Here, we present several lines of evidence that both CoA ligases and thioesterases are likely involved in bitter acid biosynthesis. Recombinant HICCL2 （carboxyl CoA ligase） protein had high specific activity for isovaleric acid as a substrate （Kcat/Km = 4100 s-~ M-l）, whereas recombinant HICCL4 specifically utilized isobutyric acid （Kcat/Km = 1800 s-1 M-1） and 2-methylbutyric acid （Kcat/ Km = 6900 s-1 M-~） as substrates. Both HICCLs, like hop valerophenone synthase （HIVPS）, were expressed strongly in glandular trichomes and localized to the cytoplasm. Co-expression of HICCL2 and HICCL4 with HIVPS in yeast led to significant production of acylphloroglucinols （the direct precursors for bitter acid biosynthesis）, which further confirmed the biochemical function of these two HICCLs in vivo. Functional identification of a thioesterase that catalyzed the reverse reaction of CCLs in mitochondria, together with the comprehensive analysis of genes involved BCAA catabolism, supported the idea that cytosolic CoA ligases are required for linking BCAA degradation and bitter acid biosynthesis in glandular trichomes. The evolution and other possible physiological roles of branched short-chain fatty acid：CoA ligases in planta are also discussed.
基金the National Natural Science Foundation of China(Grant Nos.82072816 and 81672553)the Natural Science Foundation of Shandong Province(Grant No.ZR2021LZY003).
文摘This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and FAO datasets were used to identify these key genes.Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain(ACADM)between KIRC and non cancer samples.The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features.The diagnostic performance of ACADM for KIRC was asessed using a diagnostic receiver operating ch aracteristic(ROC)curve.The co-expressed genes of ACADM were identifed in LinkedOmics database,and their function and pathway enrichment were analyzed.The correlation between ACADM expression level and immune infitration was analyzed by Gene Set Variation Analysis(GSVA)method Additionally,the proliferation,migration,and invasion abilities of KIRC cells were assessed after overexpressing ACADM.Following differential analysis and intersection,we identifed six hub genes,induding ACADM.We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic efect(AUC=0.916).Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis.According to correlation analysis,a variety of dinical features were associated with the expression level of ACADML By analyzing the infiltration level of immune cells,we found that ACADM may be related to the enrichment of immune cells.Finally,ACADM overexpression inhibited proliferation,migration,and invasion of KIRC cells.In conclusion,our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis.These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC,offering a reference for dinicians in diagnosis and treatment.
