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Christoph R Meier - One of the best experts on this subject based on the ideXlab platform.

  • proton pump inhibitor use and risk of developing alzheimer s disease or vascular dementia a case Control Analysis
    Drug Safety, 2018
    Co-Authors: Patrick Imfeld, Michael Bodmer, Susan S Jick, Christoph R Meier
    Abstract:

    Long-term use of proton pump inhibitors (PPIs) has been associated with an increased risk of Alzheimer’s disease (AD) in observational studies. The role of exposure duration, and whether this applies to other dementia subtypes, has not been explored in these studies. The aim was to study the association between long-term use of PPIs (or of histamine-2 receptor antagonists [H2RAs], as a negative Control) and the risk of developing AD or vascular dementia (VaD). We conducted a case–Control Analysis on the UK-based Clinical Practice Research Datalink (CPRD). We identified 41,029 patients aged ≥ 65 years with newly diagnosed AD or VaD between 1998 and 2015 and matched them 1:1 to dementia-free Controls on age, sex, calendar time, general practice, and number of years of recorded history. We applied conditional logistic regression analyses to calculate adjusted odds ratios (aORs), with 95% confidence intervals (CIs), of developing AD or VaD in relation to previous use of PPIs or H2RAs, categorized by exposure duration. As compared to non-use, long-term PPI use (≥ 100 prescriptions) was not associated with an increased risk of developing AD (aOR 0.88, 95% CI 0.80–0.97) or VaD (aOR 1.18, 95% CI 1.04–1.33). Neither was long-term use of H2RAs (≥ 20 prescriptions) associated with an increased risk of developing AD (aOR 0.94, 95% CI 0.87–1.02) or VaD (aOR 0.99, 95% CI 0.89–1.10). In this large, case-Control Analysis, we did not find any evidence for an increased risk of either AD or VaD related to PPI or H2RA use.

  • benzodiazepine use and risk of developing alzheimer s disease or vascular dementia a case Control Analysis
    Drug Safety, 2015
    Co-Authors: Michael Bodmer, Susan S Jick, Christoph R Meier, Patrick Imfeld
    Abstract:

    Previous observational studies have associated benzodiazepine use with an increased risk of dementia. However, limitations in the study methods leave questions unanswered regarding the interpretation of the findings. A case–Control Analysis was conducted using data from the UK-based Clinical Practice Research Datalink (CPRD). A total of 26,459 patients aged ≥65 years with newly diagnosed Alzheimer’s disease (AD) or vascular dementia (VaD) between 1998 and 2013 were identified and matched 1:1 to dementia-free Controls on age, sex, calendar time, general practice, and number of years of recorded history. Adjusted odds ratios (aORs) were calculated with 95 % confidence intervals (CIs) of developing AD or VaD in relation to previous benzodiazepine use, stratified by duration and benzodiazepine type. The aOR (95 % CI) of developing AD for those who started benzodiazepines <1 year before diagnosis was 2.20 (1.91–2.53), and fell to the null for those who started between 2 and <3 years before [aOR 0.99 (0.84–1.17)]. The aOR (95 % CI) of developing VaD for those who started benzodiazepines <1 year before diagnosis was 3.30 (2.78–3.92), and fell close to the null for those who started between 3 and <4 years before [aOR 1.16 (0.96–1.40)]. After accounting for benzodiazepine use initiated during this prodromal phase, long-term use of benzodiazepines was not associated with an increased risk of developing AD [aOR 0.69 (0.57–0.85)] or VaD [aOR 1.11 (0.85–1.45)]. After taking a prodromal phase into consideration, benzodiazepine use was not associated with an increased risk of developing AD or VaD.

  • seizures in patients with alzheimer s disease or vascular dementia a population based nested case Control Analysis
    Epilepsia, 2013
    Co-Authors: Patrick Imfeld, Michael Bodmer, Susan S Jick, Christoph R Meier, Markus Schuerch
    Abstract:

    Purpose:  Patients with Alzheimer's disease (AD) have an increased risk of developing seizures or epilepsy. Little is known about the role of risk factors and about the risk of developing seizures/epilepsy in patients with vascular dementia (VD). The aim of this study was to assess incidence rates (IRs) of seizures/epilepsy in patients with AD, VD, or without dementia, and to identify potential risk factors of seizures or epilepsy. Methods:  We conducted a follow-up study with a nested case-Control Analysis using the United Kingdom-based General Practice Research Database (GPRD). We identified patients aged ≥65 years with an incident diagnosis of AD or VD between 1998 and 2008 and a matched comparison group of dementia-free patients. Conditional logistic regression was used to estimate the odds ratio (OR) with a 95% confidence interval (CI) of developing seizures/epilepsy in patients with AD or VD, stratified by age at onset and duration of dementia as well as by use of antidementia drugs. Key Findings:  Among 7,086 cases with AD, 4,438 with VD, and 11,524 matched dementia-free patients, we identified 180 cases with an incident diagnosis of seizures/epilepsy. The IRs of epilepsy/seizures for patients with AD or VD were 5.6/1,000 person-years (py) (95% CI 4.6-6.9) and 7.5/1,000 py (95% CI 5.7-9.7), respectively, and 0.8/1,000 py (95% CI 0.6-1.1) in the dementia-free group. In the nested case-Control Analysis, patients with longer standing (≥3 years) AD had a slightly higher risk of developing seizures or epilepsy than those with a shorter disease duration, whereas in patients with VD the contrary was observed. Significance:  Seizures or epilepsy were substantially more common in patients with AD and VD than in dementia-free patients. The role of disease duration as a risk factor for seizures/epilepsy seems to differ between AD and VD.

  • psoriasis and risk of incident myocardial infarction stroke or transient ischaemic attack an inception cohort study with a nested case Control Analysis
    British Journal of Dermatology, 2009
    Co-Authors: Yolanda B Brauchli, Susan S Jick, M Miret, Christoph R Meier
    Abstract:

    BACKGROUND: Systemic inflammation may increase the risk for cardiovascular diseases in patients with psoriasis, but data on this risk in patients with early psoriasis are scarce. OBJECTIVES: To assess and compare the risk of developing incident myocardial infarction (MI), stroke or transient ischaemic attack (TIA) between an inception cohort of patients with psoriasis and a psoriasis-free population. METHODS: We conducted an inception cohort study with a nested case-Control Analysis within the U.K.-based General Practice Research Database. The study population encompassed 36,702 patients with a first-time recorded diagnosis of psoriasis 1994-2005, matched 1 : 1 to psoriasis-free patients. We assessed crude incidence rates (IRs) and applied conditional logistic regression to obtain odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Overall, the IRs of MI (n = 449), stroke (n = 535) and TIA (n = 402) were similar among patients with or without psoriasis. However, the adjusted OR of developing MI for patients with psoriasis aged > 60 years was 1.66 (95% CI 1.03-2.66) compared with patients without psoriasis, while the OR for patients aged 60 years, mainly with severe disease.

  • metformin sulfonylureas or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia a nested case Control Analysis
    Diabetes Care, 2008
    Co-Authors: Michael Bodmer, Christian Meier, Stephan Krahenbuhl, Susan S Jick, Christoph R Meier
    Abstract:

    OBJECTIVE — Lactic acidosis has been associated with use of metformin. Hypoglycemia is a major concern using sulfonylureas. The aim of this study was to compare the risk of lactic acidosis and hypoglycemia among patients with type 2 diabetes using oral antidiabetes drugs. RESEARCH DESIGN AND METHODS — This study is a nested case-Control Analysis using the U.K.-based General Practice Research Database to identify patients with type 2 diabetes who used oral antidiabetes drugs. Within the study population, all incident cases of lactic acidosis and hypoglycemia were identified, and hypoglycemia case subjects were matched to up to four Control patients based on age, sex, practice, and calendar time. RESULTS — Among the study population of 50,048 type 2 diabetic subjects, six cases of lactic acidosis during current use of oral antidiabetes drugs were identified, yielding a crude incidence rate of 3.3 cases per 100,000 person-years among metformin users and 4.8 cases per 100,000 person-years among users of sulfonylureas. Relevant comorbidities known as risk factors for lactic acidosis could be identified in all case subjects. A total of 2,025 case subjects with hypoglycemia and 7,278 matched Control subjects were identified. Use of sulfonylureas was associated with a materially elevated risk of hypoglycemia. The adjusted odds ratio for current use of sulfonylureas was 2.79 (95% CI 2.23–3.50) compared with current metformin use. CONCLUSIONS — Lactic acidosis during current use of oral antidiabetes drugs was very rare and was associated with concurrent comorbidity. Hypoglycemic episodes were substantially more common among sulfonylurea users than among users of metformin.

Patti A. Quant - One of the best experts on this subject based on the ideXlab platform.

  • studies on the regulation of lipid biosynthesis in plants application of Control Analysis to soybean
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Irina A. Guschina, Patti A. Quant, John D Everard, Anthony J Kinney, John L Harwood
    Abstract:

    Although there is much knowledge of the enzymology (and genes coding the proteins) of lipid biosynthesis in higher plants, relatively little attention has been paid to regulation. We have demonstrated the important role for cholinephosphate cytidylyltransferase in the biosynthesis of the major extra-plastidic membrane lipid, phosphatidylcholine. We followed this work by applying Control Analysis to light-induced fatty acid synthesis. This was the first such application to lipid synthesis in any organism. The data showed that acetyl-CoA carboxylase was very important, exerting about half of the total Control. We then applied metabolic Control Analysis to lipid accumulation in important oil crops - oilpalm, olive, and rapeseed. Recent data with soybean show that the block of fatty acid biosynthesis reactions exerts somewhat more Control (63%) than lipid assembly although both are clearly very important. These results suggest that gene stacks, targeting both parts of the overall lipid synthesis pathway will be needed to increase significantly oil yields in soybean. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

  • informed metabolic engineering of oil crops using Control Analysis
    Biocatalysis and agricultural biotechnology, 2014
    Co-Authors: Umi S Ramli, Mingguo Tang, Irina A. Guschina, Tony Fawcett, Patti A. Quant, John L Harwood
    Abstract:

    Oil crops are a very important agricultural commodity. Demand for such oils is rising steadily (at more than 5% per year over the last half century). Although the majority of plant oils are used for food or animal feed, there is increasing interest in their use as renewable chemicals for industry. Because of the demonstrated demand for oils and finite agricultural land, attention is focussing on improving productivity. Genetic manipulation of crop plants needs a knowledge of the biosynthetic pathways concerned and how they are regulated. Although there are different ways to acquire much information, metabolic flux and metabolic Control analyses are ways to provide quantitative assessments. In this review we describe our experiments using metabolic Control Analysis on important crops – oil palm, oilseed rape, olive and soybean. Such research provides information for future informed genetic manipulations and we give a successful example of this in oilseed rape (Brassica napus L.).

  • regulation and enhancement of lipid accumulation in oil crops the use of metabolic Control Analysis for informed genetic manipulation
    European Journal of Lipid Science and Technology, 2013
    Co-Authors: John L Harwood, Mingguo Tang, Tony Fawcett, Patti A. Quant, Umi S Ramli, Randall J Weselake, Irina A. Guschina
    Abstract:

    Plant oils are a very valuable agricultural commodity. They are currently mainly used (>80%) for food and animal feed but, increasingly, they have utility as renewable sources of industrial feedstocks or biofuel. Because of finite agricultural land, the best way to increase availability (in order to match demand) is by improving productivity. To do this requires a knowledge of metabolism and its regulation. Various methods have been used to provide information but only systems biology can yield quantitative data about complete metabolic pathways. We have used metabolic Control Analysis to provide information about major oil crops such as oilseed rape, oil palm, olive, and soybean. Such knowledge has then been used to inform genetic manipulation for crop improvement.

  • Metabolic Control Analysis of developing oilseed rape (brassica napus cv Westar) embryos shows that lipid assembly exerts significant Control over oil accumulation
    New Phytologist, 2012
    Co-Authors: Mingguo Tang, Paul O'hara, Irina A. Guschina, Tony Fawcett, Patti A. Quant, Antoni R Slabas, John L Harwood
    Abstract:

    Summary\r\n•\r\nMetabolic Control Analysis allows the study of metabolic regulation. We applied both single- and double-manipulation top-down Control Analysis to examine the Control of lipid accumulation in developing oilseed rape (Brassica napus) embryos.\r\n•\r\nThe biosynthetic pathway was conceptually divided into two blocks of reactions (fatty acid biosynthesis (Block A), lipid assembly (Block B)) connected by a single system intermediate, the acyl-coenzyme A (acyl-CoA) pool. Single manipulation used exogenous oleate. Triclosan was used to inhibit specifically Block A, whereas diazepam selectively manipulated flux through Block B.\r\n•\r\nExogenous oleate inhibited the radiolabelling of fatty acids from [1-14C]acetate, but stimulated that from [U-14C]glycerol into acyl lipids. The calculation of group flux Control coefficients showed that c. 70% of the metabolic Control was in the lipid assembly block of reactions. Monte Carlo simulations gave an estimation of the error of the resulting group flux Control coefficients as 0.27 ± 0.06 for Block A and 0.73 ± 0.06 for Block B.\r\n•\r\nThe two methods of Control Analysis gave very similar results and showed that Block B reactions were more important under our conditions. This contrasts notably with data from oil palm or olive fruit cultures and is important for efforts to increase oilseed rape lipid yields.

  • Use of metabolic Control Analysis to give quantitative information on Control of lipid biosynthesis in the important oil crop, Elaeis guineensis (oilpalm)
    The New phytologist, 2009
    Co-Authors: Umi S Ramli, Patti A. Quant, Joaquín J. Salas, John L Harwood
    Abstract:

    * Oil crops are a very important commodity. Although many genes and enzymes involved in lipid accumulation have been identified, much less is known of regulation of the overall process. To address the latter we have applied metabolic Control Analysis to lipid synthesis in the important crop, oilpalm (Elaeis guineensis). * Top-down metabolic Control Analysis (TDCA) was applied to callus cultures capable of accumulating appreciable triacylglycerol. The biosynthetic pathway was divided into two blocks, connected by the intermediate acyl-CoAs. Block A comprised enzymes for fatty acid synthesis and Block B comprised enzymes of lipid assembly. * Double manipulation TDCA used diflufenican and bromooctanoate to inhibit Block A and Block B, respectively, giving Block flux Control coefficients of 0.61 and 0.39. Monte Carlo simulations provided extra information from previously-reported single manipulation TDCA data, giving Block flux Control coefficients of 0.65 and 0.35 for A and B. * These experiments are the first time that double manipulation TDCA has been applied to lipid biosynthesis in any organism. The data show that approaching two-thirds of the total Control of carbon flux to lipids in oilpalm cultures lies with the fatty acid synthesis block of reactions. This quantitative information will assist future, informed, genetic manipulation of oilpalm.

John L Harwood - One of the best experts on this subject based on the ideXlab platform.

  • studies on the regulation of lipid biosynthesis in plants application of Control Analysis to soybean
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Irina A. Guschina, Patti A. Quant, John D Everard, Anthony J Kinney, John L Harwood
    Abstract:

    Although there is much knowledge of the enzymology (and genes coding the proteins) of lipid biosynthesis in higher plants, relatively little attention has been paid to regulation. We have demonstrated the important role for cholinephosphate cytidylyltransferase in the biosynthesis of the major extra-plastidic membrane lipid, phosphatidylcholine. We followed this work by applying Control Analysis to light-induced fatty acid synthesis. This was the first such application to lipid synthesis in any organism. The data showed that acetyl-CoA carboxylase was very important, exerting about half of the total Control. We then applied metabolic Control Analysis to lipid accumulation in important oil crops - oilpalm, olive, and rapeseed. Recent data with soybean show that the block of fatty acid biosynthesis reactions exerts somewhat more Control (63%) than lipid assembly although both are clearly very important. These results suggest that gene stacks, targeting both parts of the overall lipid synthesis pathway will be needed to increase significantly oil yields in soybean. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

  • informed metabolic engineering of oil crops using Control Analysis
    Biocatalysis and agricultural biotechnology, 2014
    Co-Authors: Umi S Ramli, Mingguo Tang, Irina A. Guschina, Tony Fawcett, Patti A. Quant, John L Harwood
    Abstract:

    Oil crops are a very important agricultural commodity. Demand for such oils is rising steadily (at more than 5% per year over the last half century). Although the majority of plant oils are used for food or animal feed, there is increasing interest in their use as renewable chemicals for industry. Because of the demonstrated demand for oils and finite agricultural land, attention is focussing on improving productivity. Genetic manipulation of crop plants needs a knowledge of the biosynthetic pathways concerned and how they are regulated. Although there are different ways to acquire much information, metabolic flux and metabolic Control analyses are ways to provide quantitative assessments. In this review we describe our experiments using metabolic Control Analysis on important crops – oil palm, oilseed rape, olive and soybean. Such research provides information for future informed genetic manipulations and we give a successful example of this in oilseed rape (Brassica napus L.).

  • regulation and enhancement of lipid accumulation in oil crops the use of metabolic Control Analysis for informed genetic manipulation
    European Journal of Lipid Science and Technology, 2013
    Co-Authors: John L Harwood, Mingguo Tang, Tony Fawcett, Patti A. Quant, Umi S Ramli, Randall J Weselake, Irina A. Guschina
    Abstract:

    Plant oils are a very valuable agricultural commodity. They are currently mainly used (>80%) for food and animal feed but, increasingly, they have utility as renewable sources of industrial feedstocks or biofuel. Because of finite agricultural land, the best way to increase availability (in order to match demand) is by improving productivity. To do this requires a knowledge of metabolism and its regulation. Various methods have been used to provide information but only systems biology can yield quantitative data about complete metabolic pathways. We have used metabolic Control Analysis to provide information about major oil crops such as oilseed rape, oil palm, olive, and soybean. Such knowledge has then been used to inform genetic manipulation for crop improvement.

  • Metabolic Control Analysis of developing oilseed rape (brassica napus cv Westar) embryos shows that lipid assembly exerts significant Control over oil accumulation
    New Phytologist, 2012
    Co-Authors: Mingguo Tang, Paul O'hara, Irina A. Guschina, Tony Fawcett, Patti A. Quant, Antoni R Slabas, John L Harwood
    Abstract:

    Summary\r\n•\r\nMetabolic Control Analysis allows the study of metabolic regulation. We applied both single- and double-manipulation top-down Control Analysis to examine the Control of lipid accumulation in developing oilseed rape (Brassica napus) embryos.\r\n•\r\nThe biosynthetic pathway was conceptually divided into two blocks of reactions (fatty acid biosynthesis (Block A), lipid assembly (Block B)) connected by a single system intermediate, the acyl-coenzyme A (acyl-CoA) pool. Single manipulation used exogenous oleate. Triclosan was used to inhibit specifically Block A, whereas diazepam selectively manipulated flux through Block B.\r\n•\r\nExogenous oleate inhibited the radiolabelling of fatty acids from [1-14C]acetate, but stimulated that from [U-14C]glycerol into acyl lipids. The calculation of group flux Control coefficients showed that c. 70% of the metabolic Control was in the lipid assembly block of reactions. Monte Carlo simulations gave an estimation of the error of the resulting group flux Control coefficients as 0.27 ± 0.06 for Block A and 0.73 ± 0.06 for Block B.\r\n•\r\nThe two methods of Control Analysis gave very similar results and showed that Block B reactions were more important under our conditions. This contrasts notably with data from oil palm or olive fruit cultures and is important for efforts to increase oilseed rape lipid yields.

  • Use of metabolic Control Analysis to give quantitative information on Control of lipid biosynthesis in the important oil crop, Elaeis guineensis (oilpalm)
    The New phytologist, 2009
    Co-Authors: Umi S Ramli, Patti A. Quant, Joaquín J. Salas, John L Harwood
    Abstract:

    * Oil crops are a very important commodity. Although many genes and enzymes involved in lipid accumulation have been identified, much less is known of regulation of the overall process. To address the latter we have applied metabolic Control Analysis to lipid synthesis in the important crop, oilpalm (Elaeis guineensis). * Top-down metabolic Control Analysis (TDCA) was applied to callus cultures capable of accumulating appreciable triacylglycerol. The biosynthetic pathway was divided into two blocks, connected by the intermediate acyl-CoAs. Block A comprised enzymes for fatty acid synthesis and Block B comprised enzymes of lipid assembly. * Double manipulation TDCA used diflufenican and bromooctanoate to inhibit Block A and Block B, respectively, giving Block flux Control coefficients of 0.61 and 0.39. Monte Carlo simulations provided extra information from previously-reported single manipulation TDCA data, giving Block flux Control coefficients of 0.65 and 0.35 for A and B. * These experiments are the first time that double manipulation TDCA has been applied to lipid biosynthesis in any organism. The data show that approaching two-thirds of the total Control of carbon flux to lipids in oilpalm cultures lies with the fatty acid synthesis block of reactions. This quantitative information will assist future, informed, genetic manipulation of oilpalm.

Mary A Robinson - One of the best experts on this subject based on the ideXlab platform.

  • doping Control Analysis of four jwh 250 metabolites in equine urine by liquid chromatography tandem mass spectrometry
    Drug Testing and Analysis, 2019
    Co-Authors: Youwen You, Rachel M Proctor, Eric D Vasilko, Mary A Robinson
    Abstract:

    JWH-250 is a synthetic cannabinoid. Its use is prohibited in equine sport according to the Association of Racing Commissioners International (ARCI) and the Federation Equestre Internationale (FEI). A doping Control method to confirm the presence of four JWH-250 metabolites (JWH-250 4-OH-pentyl, JWH-250 5-OH-pentyl, JWH-250 5-OH-indole, and JWH-250 N-pentanoic acid) in equine urine was developed and validated. Urine samples were treated with acetonitrile and evaporated to concentrate the analytes prior to the Analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The chromatographic separation was carried out using a Phenomenex Lux® 3 μm AMP column (150 x 3.0 mm). A triple quadrupole mass spectrometer was used for detection of the analytes in positive mode electrospray ionization using multiple reaction monitoring (MRM). The limits of detection, quantification, and confirmation for these metabolites were 25, 50, and 50 pg/mL, respectively. The linear dynamic range of quantification was 50-10000 pg/mL. Enzymatic hydrolysis indicated that JWH-250 4-OH-pentyl, JWH-250 5-OH-pentyl, and JWH-250 5-OH indole are highly conjugated whereas JWH-250 N-pentanoic acid is not conjugated. Relative retention time and product ion intensity ratios were employed as the criteria to confirm the presence of these metabolites in equine urine. The method was successfully applied to post-race urine samples collected from horses suspected of being exposed to JWH-250. All four JWH-250 metabolites were confirmed in these samples, demonstrating the method applicability for equine doping Control Analysis.

  • high throughput doping Control Analysis of 28 amphetamine type stimulants in equine plasma using hydrophilic interaction liquid chromatography tandem mass spectrometry
    Drug Testing and Analysis, 2019
    Co-Authors: Youwen You, Fuyu Guan, Robert Dippolito, Lawrence R Soma, Mary A Robinson
    Abstract:

    A hydrophilic interaction liquid chromatography-tandem mass spectrometry method (HILIC-MS/MS) was developed for the simultaneous determination of 28 amphetamine-type stimulants (ATSs) in equine plasma for doping Control Analysis. In this method, stimulants were recovered from equine plasma by liquid-liquid extraction (LLE) at pH 9.5 using methyl tert-butyl ether and detected on a Thermo Finnigan triple quadrupole mass spectrometer operating in positive-ion mode electrospray ionization. All stimulants were eluted within 7 minutes and baseline separation was achieved for isomeric and isobaric compounds using HILIC chromatography. Extraction efficiency was greater than 80% and matrix effect was acceptable for most stimulants. The limit of detection (LOD) was in the range of 10-50 pg/mL and the lower limit of quantification (LLOQ) was in the range of 50-100 pg/mL. Quadratic regression was employed for quantification and the dynamic range of quantification was 50-10000 pg/mL. Confirmatory Analysis criteria were established using product ion ratios and retention time. The limit of confirmation (LOC) was in the range of 20-100 pg/mL. Stability study results indicated that some stimulants were unstable in equine plasma at room temperature and 4°C. However, all the stimulants studied were stable at -20°C and - 80°C for the 6 month study period.

Hans V Westerhoff - One of the best experts on this subject based on the ideXlab platform.

  • im perfect robustness and adaptation of metabolic networks subject to metabolic and gene expression regulation marrying Control engineering with metabolic Control Analysis
    BMC Systems Biology, 2013
    Co-Authors: Vincent Fromion, Hans V Westerhoff
    Abstract:

    Metabolic Control Analysis (MCA) and supply–demand theory have led to appreciable understanding of the systems properties of metabolic networks that are subject exclusively to metabolic regulation. Supply–demand theory has not yet considered gene-expression regulation explicitly whilst a variant of MCA, i.e. Hierarchical Control Analysis (HCA), has done so. Existing analyses based on Control engineering approaches have not been very explicit about whether metabolic or gene-expression regulation would be involved, but designed different ways in which regulation could be organized, with the potential of causing adaptation to be perfect. This study integrates Control engineering and classical MCA augmented with supply–demand theory and HCA. Because gene-expression regulation involves time integration, it is identified as a natural instantiation of the ‘integral Control’ (or near integral Control) known in Control engineering. This study then focuses on robustness against and adaptation to perturbations of process activities in the network, which could result from environmental perturbations, mutations or slow noise. It is shown however that this type of ‘integral Control’ should rarely be expected to lead to the ‘perfect adaptation’: although the gene-expression regulation increases the robustness of important metabolite concentrations, it rarely makes them infinitely robust. For perfect adaptation to occur, the protein degradation reactions should be zero order in the concentration of the protein, which may be rare biologically for cells growing steadily. A proposed new framework integrating the methodologies of Control engineering and metabolic and hierarchical Control Analysis, improves the understanding of biological systems that are regulated both metabolically and by gene expression. In particular, the new approach enables one to address the issue whether the intracellular biochemical networks that have been and are being identified by genomics and systems biology, correspond to the ‘perfect’ regulatory structures designed by Control engineering vis-a-vis optimal functions such as robustness. To the extent that they are not, the analyses suggest how they may become so and this in turn should facilitate synthetic biology and metabolic engineering.

  • metabolic Control Analysis indicates a change of strategy in the treatment of cancer
    Mitochondrion, 2010
    Co-Authors: Rafael Morenosanchez, Emma Saavedra, Sara Rodriguezenriquez, Hans V Westerhoff, Juan Carlos Gallardoperez, Hector Quezada
    Abstract:

    Much of the search for the "magic cancer bullet" or "block buster" has followed the expectation of a single gene or protein as "the rate-limiting step" for tumor persistence. Examples continue to abound: EGFR, VEGFR, Akt/PI3K, HIF-1α, PHD, PDK, or FAS continue to be targeted individually. However, many such attempts to block a metabolic or signal transduction pathway by targeting, specifically, a single rate-limiting molecule have proven to be unsuccessful. Metabolic Control Analysis (MCA) of cancer cells has generated a generic explanation for this phenomenon: several steps share the Control of energy metabolism (for glycolysis: glucose transporter, hexokinase, glycogen synthesis and ATP demand; for oxidative phosphorylation: respiratory complex I and ATP demand), i.e., there is no single "rate-limiting step". Targeting a type of step that does not exist is unlikely to be a successful paradigm for continued research into drug targeting of cancer. MCA establishes how to determine, quantitatively, the degrees of Control that the various enzymes in the intracellular network exert on vital flux (or function) and on the concentration of important metabolites, substituting for the intuitive, qualitative and most often erroneous concept of single rate-limiting step. Moreover, MCA helps to understand (i) the underlying mechanisms by which a given enzyme exerts high or low Control, (ii) why the Control of the pathway is shared by several pathway enzymes and transporters and (iii) what are the better sets of drug targets. Indeed, by applying MCA it should now be possible to identify the group of proteins (and genes) that should be modified to achieve a successful modulation of the intracellular networks of biotechnological or clinical relevance. The challenge is to move away from the design of drugs that specifically inhibit a single Controlling step, towards unspecific drugs or towards drug mixtures, which may have multiple target sites in the most exacerbated, unique and Controlling pathways in cancer cells. Successful nonspecific drugs should still be specific for the networks of cancer cells over those of normal cells and to establish such cell-type specificity within molecular non-specificity will continue to require sophisticated analyses. Clinical practice has anticipated the latter strategy of mixtures of drugs: combinations of anti-neoplastic drugs are already administered with encouraging results. Therefore, the most promising strategy for cancer treatment seems to be that of a multi-targeted, MCA-advised, therapy.

  • metabolic Control Analysis to identify optimal drug targets
    Progress in drug research, 2007
    Co-Authors: Jorrit J Hornberg, Hans V Westerhoff, Barbara M Bakker, Frank J Bruggeman
    Abstract:

    This chapter describes the basic principles of Metabolic Control Analysis (MCA) which is a quantitative methodology to evaluate the importance and relative contribution of individual metabolic steps in the overall functioning of a particular system. The Control on the flux through a metabolic pathway or subsystem can be quantified by the Control coefficients of the individual enzymes or components which reflects the extent to which the component is rate-limiting. The perturbation of an individual step is measured by its elasticity coefficient. The effect of perturbation of a single step on the entire pathway or subsystemis, in turn, measured by the response coefficient. Differential Control Analysis can be used to compare flux through a single metabolic pathway in a pathogen with the same pathway in its host to identify uniquely vulnerable steps with the greatest potential for specifically inhibiting flux through the pathogen metabolic pathway. The utility of this methodology is illustrated with the glycolysis in Trypanosomes and with oncogenic signaling.

  • metabolic Control Analysis as a tool in the elucidation of the function of novel genes
    Methods in Microbiology, 1998
    Co-Authors: Hans V Westerhoff, Bas Teusink, Frank Baganz, Stephen G Oliver
    Abstract:

    Publisher Summary This chapter discusses metabolic Control Analysis (MCA) as a tool in the elucidation of the function of novel genes. MCA is an attempt to understand quantitatively the global behavior of complex systems on the basis of the local properties of the components—the enzymes. In the past decade, substantial progress has been made to extend the MCA theory to more and more complex systems, such as large systems, group transfer pathways, channeling, and many more. The chapter explains the basic concepts and theorems of MCA because they may be applied to the functional Analysis of novel genes. It explains MCA with respect to its implications for the elucidation of the functions of novel genes. All the experiments demonstrated in the chapter are done in silico using a simple kinetic model that mimics functional Analysis experiments. A simple example is used in the chapter to illustrate the principles of MCA: the regulation of phosphofructokinase (PFK) by fructose, 2,6-bisphosphate (F26bP). The definitions and concepts of metabolic Control Analysis are also discussed in the chapter.