The Experts below are selected from a list of 3894 Experts worldwide ranked by ideXlab platform
Arif Sasongko - One of the best experts on this subject based on the ideXlab platform.
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energy management of fuel cell Battery supercapacitor hybrid power sources using model predictive control
IEEE Transactions on Industrial Informatics, 2014Co-Authors: Riyanto T Bambang, Arief Syaichu Rohman, Cees Jan Dronkers, Romeo Ortega, Arif SasongkoAbstract:Well known as an efficient and eco-friendly power source, fuel cell, unfortunately, offers slow dynamics. When attached as primary energy source in a vehicle, fuel cell would not be able to respond to abrupt load variations. Supplementing Battery and/or supercapacitor to the system will provide a solution to this shortcoming. On the other hand, a current regulation that is vital for lengthening time span of the energy storage system is needed. This can be accomplished by keeping fuel cell's and batteries' current slope in reference to certain values, as well as attaining a stable dc output voltage. For that purpose, a feedback control system for regulating the hybrid of fuel cell, batteries, and supercapacitor was constructed for this study. Output voltage of the studied hybrid power sources (HPS) was administered by assembling three dc-dc converters comprising two bidirectional converters and one boost converter. Current/voltage output of fuel cell was regulated by boost converter, whereas the bidirectional converters regulated Battery and supercapacitor. Reference current for each converter was produced using Model Predictive Control (MPC) and subsequently tracked using hysteresis control. These functions were done on a controller board of a dSPACE DS1104. Subsequently, on a test bench made up from 6 V, 4.5 Ah Battery and 7.5 V, 120 F supercapacitor together with a fuel cell of 50 W, 10 A, experiment was conducted. Results show that constructing a control system to restrict fuel cell's and batteries' current slope and maintaining dc bus voltage in accordance with the reference values using MPC was feasible and effectively done.
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energy management of fuel cell Battery supercapacitor hybrid power sources using model predictive control
IEEE Transactions on Industrial Informatics, 2014Co-Authors: Riyanto T Bambang, Arief Syaichu Rohman, Cees Jan Dronkers, Romeo Ortega, Arif SasongkoAbstract:Well known as an efficient and eco-friendly power source, fuel cell, unfortunately, offers slow dynamics. When attached as primary energy source in a vehicle, fuel cell would not be able to respond to abrupt load variations. Supplementing Battery and/or supercapacitor to the system will provide a solution to this shortcoming. On the other hand, a current regulation that is vital for lengthening time span of the energy storage system is needed. This can be accomplished by keeping fuel cell's and batteries' current slope in reference to certain values, as well as attaining a stable dc output voltage. For that purpose, a feedback control system for regulating the hybrid of fuel cell, batteries, and supercapacitor was constructed for this study. Output voltage of the studied hybrid power sources (HPS) was administered by assembling three dc-dc converters comprising two bidirectional converters and one boost converter. Current/voltage output of fuel cell was regulated by boost converter, whereas the bidirectional converters regulated Battery and supercapacitor. Reference current for each converter was produced using Model Predictive Control (MPC) and subsequently tracked using hysteresis control. These functions were done on a controller board of a dSPACE DS1104. Subsequently, on a test bench made up from 6 V, 4.5 Ah Battery and 7.5 V, 120 F supercapacitor together with a fuel cell of 50 W, 10 A, experiment was conducted. Results show that constructing a control system to restrict fuel cell's and batteries' current slope and maintaining dc bus voltage in accordance with the reference values using MPC was feasible and effectively done.
Timothy P Dalton - One of the best experts on this subject based on the ideXlab platform.
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targeted knockout of cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse Ah Battery
Biochemical and Biophysical Research Communications, 2000Co-Authors: Timothy P Dalton, Matthew Z Dieter, Howard G Shertzer, Robin S Matlib, Nicole L Childs, Mary Beth Genter, Daniel W. NebertAbstract:Using the Cre-lox system, we have generated a cytochrome P450 1A1 Cyp1a1(-/-) knockout mouse by deletion of the translated portions of the Cyp1a1 gene. These mice are viable and demonstrate no obvious phenotype, compared with wild-type littermates. As a first step toward characterizing genes that might be expected to compensate for loss of CYP1A1, constitutive expression of [Ah] gene Battery members was examined. In a cultured hepatoma CYP1A1 metabolism-deficient mutant line that does not express Cyp1a2, we have previously shown that constitutive transcriptional up-regulation of other [Ah] gene Battery members occurs; these results are consistent with the elevation of a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1. The [Ah] Battery includes Cyp1a2, NAD(P)H:quinone oxidoreductase (Nqo1), and three other Phase II genes. Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1. We postulate that CYP1A1 and CYP1A2 might have overlapping substrate specificity for metabolism of the EL, such that basal CYP1A2 in the liver can compensate for the loss of CYP1A1.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Matthew Z Dieter, Willy A Solis, Yi Yang, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes—P450 1A1 and 1A2 (Cyp1a1, Cyp1a2)—and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, β-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYP1A1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell’s decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of “metabolic potentiation” and “detoxification” of various foreign chemicals.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Daniel W. Nebert, Matthew Z Dieter, Willy A Solis, Yi Yang, Amy L Roe, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes-P450 1A1 and 1A2 (Cypla1, Cypla2-and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYPA1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell's decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of "metabolic potentiation" and "detoxification" of various foreign chemicals.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Matthew Z Dieter, Willy A Solis, Yi Yang, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes—P450 1A1 and 1A2 (Cyp1a1, Cyp1a2)—and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, β-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYP1A1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell’s decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of “metabolic potentiation” and “detoxification” of various foreign chemicals.
Daniel W. Nebert - One of the best experts on this subject based on the ideXlab platform.
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targeted knockout of cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse Ah Battery
Biochemical and Biophysical Research Communications, 2000Co-Authors: Timothy P Dalton, Matthew Z Dieter, Howard G Shertzer, Robin S Matlib, Nicole L Childs, Mary Beth Genter, Daniel W. NebertAbstract:Using the Cre-lox system, we have generated a cytochrome P450 1A1 Cyp1a1(-/-) knockout mouse by deletion of the translated portions of the Cyp1a1 gene. These mice are viable and demonstrate no obvious phenotype, compared with wild-type littermates. As a first step toward characterizing genes that might be expected to compensate for loss of CYP1A1, constitutive expression of [Ah] gene Battery members was examined. In a cultured hepatoma CYP1A1 metabolism-deficient mutant line that does not express Cyp1a2, we have previously shown that constitutive transcriptional up-regulation of other [Ah] gene Battery members occurs; these results are consistent with the elevation of a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1. The [Ah] Battery includes Cyp1a2, NAD(P)H:quinone oxidoreductase (Nqo1), and three other Phase II genes. Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1. We postulate that CYP1A1 and CYP1A2 might have overlapping substrate specificity for metabolism of the EL, such that basal CYP1A2 in the liver can compensate for the loss of CYP1A1.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Daniel W. Nebert, Matthew Z Dieter, Willy A Solis, Yi Yang, Amy L Roe, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes-P450 1A1 and 1A2 (Cypla1, Cypla2-and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYPA1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell's decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of "metabolic potentiation" and "detoxification" of various foreign chemicals.
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interaction between the Ah receptor and proteins binding to the ap 1 like electrophile response element epre during murine phase ii Ah Battery gene expression
Biochemical Pharmacology, 1995Co-Authors: Vasilis Vasiliou, Alvaro Puga, Chingyi Chang, Wilson M Tabor, Daniel W. NebertAbstract:We have studied three Phase II genes in the mouse dioxin-inducible [Ah] Battery: Nmol [encoding NAD(P)H:menadione oxidoreductase], Ahd4 (encoding the cytosolic aldehyde dehydrogenase ALDH3c), and Ugtl∗06 (a UDP glucuronosyltransferase). Oxidant-induced Nmol gene expression in the 14CoS14Cos mouse appears likely to be caused by homozygous loss of the fumarylacetoacetate hydrolase (FAh) gene on Chr 7 and absence of the enzyme (FAh), which leads to increased levels of endogenous tyrosine oxidative metabolites. We show here that increases in [Ah] Phase II gene expression in the 14CoS14CoS mouse are correlated with an AP-1-like DNA motif called the electrophile response element (EpRE), which has been found in the 5′ flanking regulatory regions of all murine [Ah] Phase II genes. Aromatic hydrocarbon response element (AhREs) are responsible for dioxin-mediated upregulation of all six [Ah] Battery genes, and one or more AhREs have been found in the 5′ flanking regulatory regions of all of these [Ah] genes. Gel mobility shift assays, with a synthetic oligonucleotide probe corresponding to the EpRE, show that EpRE-binding proteins are more than twice as abundant in 14CoS14CoS than in the wild-type chch nuclear extracts. Competition studies of EpRE-specific binding with an excess of EpRE, mutated EpRE, AP-1, AhRE3, mutated AhRE3, and C/EBPα oligonucleotides suggest that several common transcriptional factors bind to the EpRE and AhRE3 motifs. Two monospecific antibodies to the Ah receptor (AhR) protein block formation of an EpRE-specific complex on gel mobility electrophoresis. These data suggest that AhR (or AhR-related protein) might be an integral part of the EpRE-binding transcriptional complex associated with the oxidative stress response. To our knowledge, this is among the first reports of the same transcription factor operating at two different response elements upstream of a single gene.
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response of Ah Battery genes to compounds that protect against menadione toxicity
Biochemical Pharmacology, 1995Co-Authors: Vasilis Vasiliou, Howard G Shertzer, Ruiming Liu, Malcolm Sainsbury, Daniel W. NebertAbstract:We have studied the response of genes in the dioxin-inducible [Ah] Battery to three compounds that protect mouse hepatoma cells (Hepa-1c7c7 wild-type, wt) against menadione toxicity. Pretreatment of wt cells with 25 μM 5,10-dihydroindeno[1,2-b]indole (DHII), 25 μM tert-butylhydroquinone (tBHQ), or 10 μM menadione itself, generated substantial protection against toxicity produced by subsequent menadione exposure. The gene response was examined in wt cells, and three mutant lines: CYP1A1 metabolism-deficient (c37 or P−1); nuclear translocation-impaired (c4 or nt−); and AhR-deficient (c2 or r−, containing < 10% of normal functional receptor levels). DHII treatment of wt cells for 12 hr markedly elevated the enzyme activities and mRNA levels of genes in the [Ah] Battery: aryl hydrocarbon hydroxylase (Cyplal), NAD(P)H: menadione oxidoreductase (Nmol), cytosolic aldehyde dehydrogenase class 3 (Ahd4), and UDP-glucuronosyltransferase form 1∗06 (Ugtl∗06). Treatment of the c4 and c2 cells with DHII failed to induce mRNA levels of the genes, indicating that induction of the [Ah] gene Battery by DHII is aromatic hydrocarbon receptor (AhR)-mediated. On the other hand, neither tBHQ nor menadione caused increases in CYP1A1 mRNA, but tBHQ significantly enhanced the NMO1, AhD4, and UGT1∗06 mRNA levels in all three mutant cell lines. In conclusion, we expect one or more putative electrophile response elements (EpRE), previously found in the regulatory regions of the murine Nmol, Ahd4, and Ugtl∗06 genes, to be functional in responding to phenolic antioxidants.
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role of the Ah receptor and the dioxin inducible Ah gene Battery in toxicity cancer and signal transduction
Annals of the New York Academy of Sciences, 1993Co-Authors: Daniel W. Nebert, Alvaro Puga, Vasilis VasiliouAbstract:1. On the basis of our current knowledge about the evolution of drug-metabolizing enzymes, it appears to be extremely likely that these enzymes play a critical role in maintaining steady-state levels of the ligands involved in ligand-modulated transcription of genes effecting growth, differentiation, homeostasis, and neuroendocrine functions. 2. The original observations about genetic differences in CYP1A1 (cytochrome P1-450) induction by TCDD or benzo[a]pyrene in the mouse have led to an appreciation for a similar polymorphism in the human and the recent cloning of the murine Ah receptor (Ahr) and human Ah receptor nuclear translocator (ARNT) genes. It is most likely that the correlation between genetic differences in human or murine CYP1A1 inducibility by polycyclic hydrocarbons or TCDD and increased risk of cancer will be explained by differences in the AhR gene, leading to enhanced tumor promotion (rather than in the CYP1A1 structural gene). Perhaps the same will be found for birth defects, immunotoxicity, and other forms of toxic damage caused by these environmental chemicals. 3. In a manner similar to that of the phorbol ester tumor promoter, TCDD induces intracellular Ca2+ changes, accumulation of FOS and JUN mRNAs, and large increases in AP-1 transcription factor activity. Interestingly, these early effects of TCDD, and also of benzo[a]pyrene, appear not to require the Ah receptor. 4. Many genes are induced by TCDD, and many others are induced by electrophilic metabolites such as quinones and H2O2; using several mouse experimental systems, we have defined a subset of six of these genes as constituting the [Ah] Battery by the sole criterion that a functional CYP1A1 or CYP1A2 enzyme is able to repress the expression of genes that are members of this gene Battery.
Riyanto T Bambang - One of the best experts on this subject based on the ideXlab platform.
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energy management of fuel cell Battery supercapacitor hybrid power sources using model predictive control
IEEE Transactions on Industrial Informatics, 2014Co-Authors: Riyanto T Bambang, Arief Syaichu Rohman, Cees Jan Dronkers, Romeo Ortega, Arif SasongkoAbstract:Well known as an efficient and eco-friendly power source, fuel cell, unfortunately, offers slow dynamics. When attached as primary energy source in a vehicle, fuel cell would not be able to respond to abrupt load variations. Supplementing Battery and/or supercapacitor to the system will provide a solution to this shortcoming. On the other hand, a current regulation that is vital for lengthening time span of the energy storage system is needed. This can be accomplished by keeping fuel cell's and batteries' current slope in reference to certain values, as well as attaining a stable dc output voltage. For that purpose, a feedback control system for regulating the hybrid of fuel cell, batteries, and supercapacitor was constructed for this study. Output voltage of the studied hybrid power sources (HPS) was administered by assembling three dc-dc converters comprising two bidirectional converters and one boost converter. Current/voltage output of fuel cell was regulated by boost converter, whereas the bidirectional converters regulated Battery and supercapacitor. Reference current for each converter was produced using Model Predictive Control (MPC) and subsequently tracked using hysteresis control. These functions were done on a controller board of a dSPACE DS1104. Subsequently, on a test bench made up from 6 V, 4.5 Ah Battery and 7.5 V, 120 F supercapacitor together with a fuel cell of 50 W, 10 A, experiment was conducted. Results show that constructing a control system to restrict fuel cell's and batteries' current slope and maintaining dc bus voltage in accordance with the reference values using MPC was feasible and effectively done.
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energy management of fuel cell Battery supercapacitor hybrid power sources using model predictive control
IEEE Transactions on Industrial Informatics, 2014Co-Authors: Riyanto T Bambang, Arief Syaichu Rohman, Cees Jan Dronkers, Romeo Ortega, Arif SasongkoAbstract:Well known as an efficient and eco-friendly power source, fuel cell, unfortunately, offers slow dynamics. When attached as primary energy source in a vehicle, fuel cell would not be able to respond to abrupt load variations. Supplementing Battery and/or supercapacitor to the system will provide a solution to this shortcoming. On the other hand, a current regulation that is vital for lengthening time span of the energy storage system is needed. This can be accomplished by keeping fuel cell's and batteries' current slope in reference to certain values, as well as attaining a stable dc output voltage. For that purpose, a feedback control system for regulating the hybrid of fuel cell, batteries, and supercapacitor was constructed for this study. Output voltage of the studied hybrid power sources (HPS) was administered by assembling three dc-dc converters comprising two bidirectional converters and one boost converter. Current/voltage output of fuel cell was regulated by boost converter, whereas the bidirectional converters regulated Battery and supercapacitor. Reference current for each converter was produced using Model Predictive Control (MPC) and subsequently tracked using hysteresis control. These functions were done on a controller board of a dSPACE DS1104. Subsequently, on a test bench made up from 6 V, 4.5 Ah Battery and 7.5 V, 120 F supercapacitor together with a fuel cell of 50 W, 10 A, experiment was conducted. Results show that constructing a control system to restrict fuel cell's and batteries' current slope and maintaining dc bus voltage in accordance with the reference values using MPC was feasible and effectively done.
Matthew Z Dieter - One of the best experts on this subject based on the ideXlab platform.
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targeted knockout of cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse Ah Battery
Biochemical and Biophysical Research Communications, 2000Co-Authors: Timothy P Dalton, Matthew Z Dieter, Howard G Shertzer, Robin S Matlib, Nicole L Childs, Mary Beth Genter, Daniel W. NebertAbstract:Using the Cre-lox system, we have generated a cytochrome P450 1A1 Cyp1a1(-/-) knockout mouse by deletion of the translated portions of the Cyp1a1 gene. These mice are viable and demonstrate no obvious phenotype, compared with wild-type littermates. As a first step toward characterizing genes that might be expected to compensate for loss of CYP1A1, constitutive expression of [Ah] gene Battery members was examined. In a cultured hepatoma CYP1A1 metabolism-deficient mutant line that does not express Cyp1a2, we have previously shown that constitutive transcriptional up-regulation of other [Ah] gene Battery members occurs; these results are consistent with the elevation of a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1. The [Ah] Battery includes Cyp1a2, NAD(P)H:quinone oxidoreductase (Nqo1), and three other Phase II genes. Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1. We postulate that CYP1A1 and CYP1A2 might have overlapping substrate specificity for metabolism of the EL, such that basal CYP1A2 in the liver can compensate for the loss of CYP1A1.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Matthew Z Dieter, Willy A Solis, Yi Yang, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes—P450 1A1 and 1A2 (Cyp1a1, Cyp1a2)—and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, β-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYP1A1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell’s decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of “metabolic potentiation” and “detoxification” of various foreign chemicals.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Daniel W. Nebert, Matthew Z Dieter, Willy A Solis, Yi Yang, Amy L Roe, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes-P450 1A1 and 1A2 (Cypla1, Cypla2-and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYPA1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell's decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of "metabolic potentiation" and "detoxification" of various foreign chemicals.
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role of the aromatic hydrocarbon receptor and Ah gene Battery in the oxidative stress response cell cycle control and apoptosis
Biochemical Pharmacology, 2000Co-Authors: Matthew Z Dieter, Willy A Solis, Yi Yang, Timothy P DaltonAbstract:The chronology and history of characterizing the aromatic hydrocarbon [Ah] Battery is reviewed. This Battery represents the Ah receptor (AhR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes—P450 1A1 and 1A2 (Cyp1a1, Cyp1a2)—and four non-P450 genes, have experimentally been documented to be members of this Battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AhR-mediated aromatic hydrocarbon response element (AhRE) DNA motif. In contrast to dioxin, AhR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, β-naphthoflavone) activate genes via both AhREs and the EPRE. The importance of the AhR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AhR, but that CYP1A1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] Battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell’s decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AhR and the [Ah] Battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AhR and [Ah] enzymes are, of course, in addition to the frequently described functions of “metabolic potentiation” and “detoxification” of various foreign chemicals.