Algorithms for the derivation of Flux and Concentration Control Coefficients.
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ABSTRACT:
SUBMITTER: Schulz AR
PROVIDER: S-EPMC1151482 | biostudies-other | 1991 Aug
REPOSITORIES: biostudies-other
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Project description:1. Equations for control coefficients are derived by using a method that generates all the control coefficients for a system in a single procedure. This requires solving fewer simultaneous equations than an equivalent method based on 'control theorems'. 2. The interpretation of control coefficients is discussed: in particular, it is shown that these functions are unsatisfactory as measures of 'control' and are perhaps best used as a means of testing control theories (models).
| S-EPMC1148377 | biostudies-other
Project description:Flux Control Coefficients have been used in the analysis of metabolic regulation for quantifying the effect of an enzyme on the overall steady-state flux. However, the experimental determination of these coefficients is very time-consuming, involving either determining the individual enzyme kinetics or perturbing the enzyme activity by genetic or other means. We developed a methodology that enables the determination of the Flux Control Coefficients from transient metabolite concentrations without knowing kinetic parameters. The transient states can be generated by changing the incubation conditions or adding the initial substrate. This approach is suitable for investigating metabolic regulation in vivo or multiple enzyme systems in vitro. It is particularly helpful if used in conjunction with n.m.r. measurements. The approach is based on a relationship between transient metabolite concentrations and the Flux Control Coefficients. The methodology has been improved from our previous results, and it is illustrated by three examples with simple pathway topologies.
| S-EPMC1130875 | biostudies-other
Project description:The methodology previously developed for determining the Flux Control Coefficients [Delgado & Liao (1992) Biochem. J. 282, 919-927] is extended to the calculation of metabolite Concentration Control Coefficients. It is shown that the transient metabolite concentrations are related by a few algebraic equations, attributed to mass balance, stoichiometric constraints, quasi-equilibrium or quasi-steady states, and kinetic regulations. The coefficients in these relations can be estimated using linear regression, and can be used to calculate the Control Coefficients. The theoretical basis and two examples are discussed. Although the methodology is derived based on the linear approximation of enzyme kinetics, it yields reasonably good estimates of the Control Coefficients for systems with non-linear kinetics.
| S-EPMC1132889 | biostudies-other
Project description:Within the premises of the flux-oriented theory of Crabtree & Newsholme [(1987) Biochem. J. 247, 113-120], I have used a graph-theoretic approach for calculating the Control Coefficients of metabolic pathways. It is shown that a directed graph representing the control structure of a metabolic pathway can be constructed in a heuristic manner directly from the reaction diagram of the pathway, without the necessity of writing down the governing equations for the Control Coefficients. The Control Coefficients are derived from an analysis of the topology of the directed graph. The graph-theoretic approach also provides a visual framework for analysing the functional relationships of the individual enzymes. The control structures of the following pathways are examined here: (a) a simple unbranched pathway with four enzymes, (b) a simple branched pathway with three enzymes, and (c) a branched pathway with both carbon and energy (ATP) fluxes.
| S-EPMC1151546 | biostudies-other
Project description:The influence of experimental errors on the determination of flux control coefficients from transient metabolite concentrations with the method proposed by Delgado and Liao [(1992) Biochem. J. 282, 919-927] has been investigated by using Monte Carlo simulations. The method requires least-squares fitting of the transient metabolite concentrations. Three different fitting methods have been evaluated. Simulated metabolite concentrations of a fictive metabolic pathway were scattered randomly, emulating experimental errors, before performing the fits. This was repeated a large number of times; the mean values and standard deviations of the resulting control coefficients are reported. The results show that the proposed method for determining control coefficients is too sensitive to experimental errors to be practicable, with theoretically justified fitting methods. This is in particular due to the high degree of correlation between the concentrations. An alternative ad hoc fitting method produced biased mean values of the estimates of the control coefficients, but with remarkably low standard deviations.
| S-EPMC1216970 | biostudies-other
Project description:This paper is a study into the effects of experimental error on the estimated values of flux control coefficients obtained using specific inhibitors. Two possible techniques for analysing the experimental data are compared: a simple extrapolation method (the so-called graph method) and a non-linear function fitting method. For these techniques, the sources of systematic errors are identified and the effects of systematic and random errors are quantified, using both statistical analysis and numerical computation. It is shown that the graph method is very sensitive to random errors and, under all conditions studied, that the fitting method, even under conditions where the assumptions underlying the fitted function do not hold, outperformed the graph method. Possible ways of designing experiments to minimize the effects of experimental errors are analysed and discussed.
| S-EPMC1137713 | biostudies-other
Project description:This work provides the first quantitative measure of in situ flux of semi-volatile contaminants on artificial turf fields. Passive samplers were used to identify gas-phase PAHs and OPAHs not previously reported associated with artificial turf. Utilizing a broad and targeted screen, we assess both artificial turf and from crumb rubber for 1,529 chemicals, including several with known health effects including benzo[c]fluorene. We also report the presence of 25 chemicals that have not yet been reported in artificial turf literature, including some with known effects on human health. This is the first report of bioavailable gas-phase PAH and OPAH concentrations on an outdoor field, to date gas-phase concentrations have only been reported from indoor facilities. Turf air and air were highly correlated at all three sites, and particularly at the recently-installed indoor site. Finally, thermal extraction and silicone passive samplers are highly suitable for larger-scale sampling campaigns that aim for less solvent and sample processing. We demonstrate for the first time that silicone passive samplers can be used to quantify volatile and semi-volatile organic chemicals from artificial turf. Co-deploying silicone passive samplers and conventional low density polyethylene, we develop partitioning coefficients that can be used for silicone passive air sampling environmental assessment.
| S-EPMC7083577 | biostudies-literature
Project description:We have used control analysis to quantify the distribution of control in the gluconeogenic pathway in liver cells from starved rats. Lactate and pyruvate were used as gluconeogenic substrates. The flux control coefficients of the various enzymes in the gluconeogenic pathway were calculated from the elasticity coefficients of the enzymes towards their substrates and products and the fluxes through the different branches in the pathway. The elasticity coefficients were either calculated from gamma/Keq. ratios (where gamma is the mass-action ratio and Keq. is the equilibrium constant) and enzyme-kinetic data or measured experimentally. It is concluded that the gluconeogenic enzyme pyruvate carboxylase and the glycolytic enzyme pyruvate kinase play a central role in control of gluconeogenesis. If pyruvate kinase is inactive, gluconeogenic flux from lactate is largely controlled by pyruvate carboxylase. The low elasticity coefficient of pyruvate carboxylase towards its product oxaloacetate minimizes control by steps in the gluconeogenic pathway located after pyruvate carboxylase. This situation occurs when maximal gluconeogenic flux is required, i.e. in the presence of glucagon. In the absence of the hormone, when pyruvate kinase is active, control of gluconeogenesis is distributed among many steps, including pyruvate carboxylase, pyruvate kinase, fructose-1,6-bisphosphatase and also steps outside the classic gluconeogenic pathway such as the adenine-nucleotide translocator.
| S-EPMC1146997 | biostudies-other
Project description:BACKGROUND:Flux analyses, such as Metabolic Flux Analysis (MFA), Flux Balance Analysis (FBA), Flux Variability Analysis (FVA) or similar methods, can provide insights into the cellular metabolism, especially in combination with experimental data. The most common integration of extracellular concentration data requires the estimation of the specific fluxes (/rates) from the measured concentrations. This is a time-consuming, mathematically ill-conditioned inverse problem, raising high requirements for the quality and quantity of data. METHOD:In this contribution, a time integrated flux analysis approach is proposed which avoids the error-prone estimation of specific flux values. The approach is adopted for a Metabolic time integrated Flux Analysis and (sparse) time integrated Flux Balance/Variability Analysis. The proposed approach is applied to three case studies: (1) a simulated bioprocess case studying the impact of the number of samples (experimental points) and measurements' noise on the performance; (2) a simulation case to understand the impact of network redundancies and reaction irreversibility; and (3) an experimental bioprocess case study, showing its relevance for practical applications. RESULTS:It is observed that this method can successfully estimate the time integrated flux values, even with relatively low numbers of samples and significant noise levels. In addition, the method allows the integration of additional constraints (e.g., bounds on the estimated concentrations) and since it eliminates the need for estimating fluxes from measured concentrations, it significantly reduces the workload while providing about the same level of insight into the metabolism as classic flux analysis methods.
| S-EPMC6955888 | biostudies-literature
Project description:The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator.The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not require a priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen.The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current modulation) without increasing peak variance. The 15-element piecewise-linear dynamic attenuator reduces dose by an average of 42%, and the perfect attenuator reduces dose by an average of 50%. Improvements in peak variance are several times larger than improvements in mean variance. Heuristic control eliminates the need for a prescan. For the piecewise-linear attenuator, the cost of heuristic control is an increase in dose of 9%. The proposed iterated WMV minimization produces results that are within a few percent of the true solution.Dynamic attenuators show potential for significant dose reduction. A wide class of dynamic attenuators can be accurately controlled using the described methods.
| S-EPMC4032442 | biostudies-other