Metabolic Control

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Metabolic Nutri Expert System: A Comprehensive Tool for Achieving Metabolic Control of Inborn Errors of Amino Acid Metabolism

Metabolic Nutri Expert System: A Comprehensive Tool for Achieving Metabolic Control of Inborn Errors of Amino Acid Metabolism

The main aim of this study was to develop a comprehensive nutritional planning expert system for inborn errors of amino acid metabolism (IEAAM). Metabolic Nutri-Expert System, integrated in the electronic nutritional history record, was designed to accelerate either dietitian or patient/parent knowledge acquisition and education about the particular disease and propose culturally appropriate low protein diet to improve metabolic control or maintain the present health status. The Genetic Metabolic Dietitians International (GMDI) nutritional guideline was used to estimate the recommended nutritional values in the proposed system. The recommended daily Intakes (RDIs) for patients ingesting amino acid mixture, the U.S. Department of agriculture (UDSA) nutrient list, and both Iranian and modern low protein recipes were applied to perform diet planning. The proposed system also allows the user to modify the diet as he/she likes, and to propose his/her own low protein cookery recipes as well. This comprehensive computer system, through the multidisciplinary viewpoint, aimed to at least partially replace some of the regular traditional metabolic dietitian visits and optimize the patient's metabolic control and adherence outcomes.
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(Im) Perfect robustness and adaptation of metabolic networks subject to metabolic and gene-expression regulation: marrying control engineering with metabolic control analysis

(Im) Perfect robustness and adaptation of metabolic networks subject to metabolic and gene-expression regulation: marrying control engineering with metabolic control analysis

With the development of quantitative functional genomics approaches, it has become possible to analyse the cellular adaptation of cell physiology to altered environmental conditions experimentally, by monitoring changes in fluxes, metabolites, proteins or mRNAs. Such adaptations tend to occur at multiple regulatory levels if not simultan- eously, then subsequently, depending on the time scales of observation [1-3]. In principle, an adaptive change in the rate of an enzyme (or flux) can be mediated by changes in (i) the concentration of metabolites (e.g. substrates, prod- ucts and effectors) with direct, cooperative and allosteric effects on the activity of the enzyme [4], (ii) changes in the concentration of the enzyme through gene-expression al- terations, and (iii) covalent modification via signal trans- duction. The first is termed metabolic (or enzymatic) regulation. The second is known as gene-expression (me- diated) regulation and the third as signal-transduction (mediated) regulation. Because of similar properties, the latter two types of regulation have been considered to- gether under the term ‘hierarchical regulation’ [2,5,6]. Al- though in this paper only the former two types of adaptive changes will be discussed explicitly, because of the above- mentioned similarities, the third type is addressed impli- citly. Until now, significant progress has been made on the modelling of genome-scale metabolic networks in micro- organisms integrating metabolic and gene-expression regulation [7,8]. The steady-state properties of a number of representative metabolic regulatory mechanisms, such as end-product inhibition, have been investigated substan- tially both in terms of metabolic control analysis (MCA) [9,10] and by the supply–demand theory championed by Hofmeyr and Cornish-Bowden [11-13]. In order to take gene-expression regulation into account, hierarchical con- trol analysis (HCA) [14,15] has been developed as an ex- tension to MCA, but it has not yet been linked up with the supply–demand theory. Developing such a link would seem useful as in quantitative experimental studies gene- expression regulation turned out to be as important as metabolic regulation [1,2,5,16].
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Metabolic control analysis: biological applications and insights

Metabolic control analysis: biological applications and insights

Metabolic control analysis provides a robust mathematical and theoretical framework for describing metabolic and sig- naling pathways and networks, and for quantifying the con- trols over these processes. It can deal with systems of any complexity or architecture and does not require all system components to be known a priori, making it a valuable post- genomic tool. It was developed in the 1970s by Kacser and Burns [18] and Heinrich and Rapoport [19]. Since then, ded- icated researchers have expanded and advanced metabolic control analysis theory and applications, carefully defined
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Dynamic metabolic control : towards precision engineering of metabolism

Dynamic metabolic control : towards precision engineering of metabolism

Advances in metabolic engineering have led to the synthesis of a wide variety of valuable chemicals in microorganisms. The key to commercializing these processes is the improvement of titer, productivity, yield, and robustness. Traditional approaches to enhancing production uses the “push-pull-block” strategy that modulates enzyme expression under static control. However, strains are often optimized for specific laboratory set-up and are sensitive to environmental fluctuations. Exposure to sub-optimal growth conditions during large-scale fermentation often reduces their production capacity. Moreover, static control of engineered pathways may imbalance cofactors or cause the accumulation of toxic intermediates, which imposes burden on the host and results in decreased production. To overcome these problems, the last decade has witnessed the emergence of a new technology that uses synthetic regulation to control heterologous pathways dynamically, in ways akin to regulatory networks found in nature. Here we review natural metabolic control strategies and recent developments in how they inspire the engineering of dynamically regulated pathways. We further discuss the challenges of designing and engineering dynamic control and highlight how model-based design can provide a powerful formalism to engineer dynamic control circuits, which together with the tools of synthetic biology, can work to enhance microbial production.
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Mutation-selection balance and metabolic control theory.

Mutation-selection balance and metabolic control theory.

Changes in activity of an enzyme will affect the immediately flanking metabolite pools more than pools more distant in the pathway (as is the case for the human inborn e[r]

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Biochemical studies of metabolic control changes in neoplasia

Biochemical studies of metabolic control changes in neoplasia

Intermediary Metabolism of Aminoazo Dyes Intermediary Metabolism of MDAB Effect of Diet on the Carcino­ genicity of MDAB 3 3 1.2 1.3 1.4 1 1 5 1.5 1.6 Tumour Carbohydrate Metabolism Rele[r]

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Metabolic control of circulation  Effects of iodoacetate and fluoroacetate

Metabolic control of circulation Effects of iodoacetate and fluoroacetate

administration of both inhibitors, but neither systemic hemodynamics nor myocardial contractility changed significantly. Coronary blood flow did not change after iodoacetate administration but increased four- to five-fold after fluoroacetate. Administration of normal saline had no effect on any of the parameters. The changes in pulmonary arterial blood pressure and coronary blood flow after fluoroacetate were not mediated via the autonomic nerves or adrenergic neurohumors because they still occurred after autonomic nervous system inhibition. Neither myocardial oxygen consumption nor left ventricular work changed. A selective increase in myocardial blood flow also occurred in conscious dogs after fluoroacetate administration; hepatic artery flow was reduced, but other organ flows did not change significantly. These results indicate that pulmonary pressor and coronary dilator effects may be produced in intact dogs by selective metabolic blockade, in the absence of reduced oxygen supply or impairment in the electron transport system. These results also suggest that the increases in pulmonary arterial blood pressure, coronary blood flow, and cardiac output that occur during hypoxia probably are related to separate metabolic events in the tissue.
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Metabolic Control of Spontaneous Glowing in Isolated Photophores of Porichthys

Metabolic Control of Spontaneous Glowing in Isolated Photophores of Porichthys

At 10~6mol P 1 glucose, the half-extinction rate was similar to the value measured on control photophores injected with glucose-free saline; the lowest concentration at which extinction [r]

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Metabolic Control of the Circulation: EFFECTS OF ACETATE AND PYRUVATE

Metabolic Control of the Circulation: EFFECTS OF ACETATE AND PYRUVATE

As in anesthetized dogs, acetate infusion increased cardiac output, left ventricular dPldt and dPIdtIP, but had no effect on mean aortic blood TABLE IV Concentrations of Adenosine, Inosi[r]

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Arginine metabolic control of airway inflammation

Arginine metabolic control of airway inflammation

This study shows that arginine metabolism is a critical modulator of severity of inflammation and remod- eling in eosinophilic and neutrophilic asthma. Early GWAS showed a strong association of asthma and ARG1 and ARG2 gene variants (8, 10, 38, 39). Increased serum arginase activity was also quantitatively related to airflow limitation, as measured by FEV 1 (40). Here, we show that arginase activity depends on specific ARG2 SNPs. Common ARG2 variants that were associated with lower arginase activity, combined with high levels of F E NO, identified a more severe asthma phenotype. We modeled this severe asthma phe- notype in the HDME ARG2 –/– mouse models to investigate the underlying arginine metabolic pathways.
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Differences in metabolic potential of skeletal muscle fibres and their significance for metabolic control

Differences in metabolic potential of skeletal muscle fibres and their significance for metabolic control

The relationship between ADP concentration and reaction velocity of mitochondria prepared from the skeletal muscle of endurance trained and sedentary rats with pyruvate-malate as substra[r]

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Involvement of the metabolic sensor GPR81 in cardiovascular control

Involvement of the metabolic sensor GPR81 in cardiovascular control

We hypothesize that GPR81-induced vasoconstriction is a physiological defense response to high sys- temic lactate levels for preserving systemic homeostasis in situations of extreme stress, e.g., intense exer- cise, hypoxia, or injury. Blood flow would be diverted away from the kidney (and other as yet undefined tissues) to bolster perfusion in critical tissues, including heart and skeletal muscle. This would augment classic systemic stress–induced sympathetic outflow responses leading to renal vasoconstriction (44) while minimizing conflict with ordinary metabolic control. Even the established antilipolytic effect of GPR81 agonism may represent an appropriate response in this situation, by limiting FFA availability and thereby optimizing the use of oxygen for ATP production (45). Such a novel whole-body homeostatic mechanism is perhaps not that surprising given recent evidence that lactate sensing by another GPCR, Olfr78, plays a critical role in the carotid body by sensing hypoxia and breathing regulation (46). Locally in the kidney, vasoconstriction in response to physiological or pathophysiological GPR81 agonism seems incompatible with blood flow autoregulation and tissue survival. Thus, an accumulation of lactate might worsen isch- emic damage, especially if glomerular filtration rate, the major determinant of kidney metabolic rate and oxygen demand (47), remains unchanged. In line with this, chronic hypoxia in the tubulointerstitium of the kidney is thought to be a driver of impaired glomerular function and fibrosis leading to the development of end-stage renal disease (48).
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Use of metformin and vildagliptin for treatment of type 2 diabetes in the elderly

Use of metformin and vildagliptin for treatment of type 2 diabetes in the elderly

Methods: We conducted a multicenter, retrospective, observational study that included patients aged $65 years treated with metformin who started a second oral antidiabetic therapy during the years 2008–2009. There were two groups of patients: a study group receiving metformin + vildagliptin and a reference group receiving metformin + other oral antidiabetics (sulfonylureas or glitazones). The main measures were comorbidity, compliance/persistence, metabolic control (glycosylated hemoglobin ,7%), complications (hypoglycemic, macrovascular), and total costs. The patients were followed for 2 years.
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Fluxes and Metabolic Pools as Model Traits for Quantitative Genetics. I. The L-Shaped Distribution of Gene Effects

Fluxes and Metabolic Pools as Model Traits for Quantitative Genetics. I. The L-Shaped Distribution of Gene Effects

The fluxes through metabolic pathways can be considered as model quantitative traits, whose QTL are the polymorphic loci controlling the activity or quantity of the enzymes. Relying on metabolic control theory, we investigated the relationships between the variations of enzyme activity along metabolic pathways and the variations of the flux in a population with biallelic QTL. Two kinds of variations were taken into account, the variation of the average enzyme activity across the loci, and the variation of the activity of each enzyme of the pathway among the individuals of the population. We proposed analytical approximations for the flux mean and variance in the population as well as for the additive and dominance variances of the individual QTL. Monte Carlo simulations based on these approximations showed that an L -shaped distribution of the contributions of individual QTL to the flux variance (R 2 ) is consistently expected in
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Economic Evaluation of Continuous Subcutaneous Insulin Infusion for Children with Diabetes—Part II

Economic Evaluation of Continuous Subcutaneous Insulin Infusion for Children with Diabetes—Part II

Continuous subcutaneous insulin infusion (CSII) systems are of a limited usage because they are not reimbursed by the Health Insurance Fund in Bulgaria. No official crite- ria for CSII usage in child populations have been estab- lished and only parents with sufficiently high income are able to afford such a therapeutic approach. In this sense, evaluation of the cost-effectiveness of CSII usage is in- fluenced by a number of factors, such as health insurance policy, parents’ preferences, income and therapeutic standards. This study shows that the usage of CSII with child populations is an efficient therapy and confirms similar findings reported in the literature on improve- ments in terms of better metabolic control, reduced rates of complications and better quality of life [2,13].
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Variation among extracted lines of Drosophila melanogaster in triacylglycerol and carbohydrate storage.

Variation among extracted lines of Drosophila melanogaster in triacylglycerol and carbohydrate storage.

significant correlations between storage compounds and biosynthetic enzymes, are discussed in light of metabolic control theory.. MATERIALS AND METHODS.[r]

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Signalling pathways that control development and antibiotic production in streptomyces

Signalling pathways that control development and antibiotic production in streptomyces

Key in the sensing system is probably that chitin is metabolized and internalized as (GlcNAc) 2 , which is imported via the ABC-transporter system DasABC-MsiK, while GlcNAc is imported via the PTS (Nothaft et al., 2003a; Saito et al., 2007; Saito et al., 2008; Nothaft et al., 2010). This GlcNAc disaccharide, (GlcNAc) 2 , hydrolysed from chitin, induces the expression of chitinase genes as well as DasABC transporter of chitobiose in S. coelicolor (Saito et al., 2007). In Streptomyces olivaceoviridis, the ngcEFG operon encodes an ABC transporter that imports N-acetylglucosamine and (GlcNAc) 2 with similar affinities (Xiao et al., 2002; Saito and Schrempf, 2004). A homologue of this system exists in S. coelicolor, which might also import monomers and/or dimers of GlcNAc under certain conditions. After uptake, (GlcNAc) 2 is cleaved by the N-acetyl-β-d-glucosaminidase DasD into monomers of GlcNAc (Saito et al., 2013) which are then phosphorylated by the NagK kinase and GlcNAc-6P is fed into the GlcNAc pathway described above (Fig. 2). The precise role of these transporters in nutrient sensing is not yet well understood, such as why deletion of either any of the pts genes or of dasA (but not dasBC) blocks development, even in the absence of the molecules they transport (Seo et al., 2002; Rigali et al., 2006; Colson et al., 2008). In addition to GlcN-6P and GlcNAc-6P, other metabolites also modulate the DasR response regulon, including high concentrations of phosphate (organic or inorganic) which enhance binding of DasR to its recognition site in vitro (Świątek-Połatyńska et al., 2015; Tenconi et al., 2015). This suggests that the metabolic status of the cell determines the selectivity of DasR for its recognition site and thus the expression of its regulon.
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<p>Mitochondrial Dynamic Dysfunction as a Main Triggering Factor for Inflammation Associated Chronic Non-Communicable Diseases</p>

<p>Mitochondrial Dynamic Dysfunction as a Main Triggering Factor for Inflammation Associated Chronic Non-Communicable Diseases</p>

Mitochondria are central to the regulation of energy metabo- lism and cellular homeostasis due to their principal role in bioenergetics, ROS production, ion homeostasis, apoptosis and signal transduction. This organelle is highly dynamic and can re-program itself depending on various environmental and intracellular signals important for multiple mitochondrial functions, including mtDNA stability, respiratory function, apoptosis, response to cellular stress, and mitochondrial degradation. The dynamic process of mitochondria may not be balanced as a result of proteins required for fusion and fi ssion that decreases the crucial role of mitochondria bioe- nergetics and the accumulation of damaged mitochondria producing ROS.ROS generated by dysfunctional mitochon- dria further damage mitochondrial of different organs and tissues that cannot function properly to result in chronic and age-related disorders. Non-communicable diseases that are increasing worldwide in recent years are the consequences of unhealthy diets and physical inactivity, which shares basic mechanisms of mitochondrial defects, systemic in fl amma- tion, and oxidative stress. Consequent oxidative stress caus- ing endoplasmic reticulum (ER) and mitochondrial stress leads to excess accumulation of food energy favoring obesity and the development of other metabolic syndrome and related complications. Maintaining the health of mitochon- dria is very valuable and could aid in the prevention of age- related disorders.
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Metabolic flux control of mitochondrial dynamics in cancer cells

Metabolic flux control of mitochondrial dynamics in cancer cells

Mutations that affect the expression of mtDNA have been reported in a number of studies. They have been found to be involved in a variety of cancers such as increased breast cancer risk in African American women with a variant in the CI, subunit ND3 gene. Single nucleotide polymorphisms (SNPs) in the cytochrome c oxidase subunit 1 (T6777C) have been linked with epithelial ovarian cancer, along with variants in several nuclear deoxyribonucleic acid (nDNA) mitochondrial genes. mtDNA control region variant C150 has been associated with an increased risk of human papilloma virus (HPV) infection and cervical cancer in Chinese woman (Wallace 2012). Yet the requirement of mtDNA is essential for cancer cells to function, confirmed by the elimination of mtDNA from various cancers. Culturing cells in ethidium bromide removes mtDNA. Cancer cells lacking mtDNA showed reduced growth rates, decreased colony formation and reduced colony formation in nude mice (Desjardins, Frost et al. 1985, Morais, Zinkewich-Peotti et al. 1994, Cavalli, Varella-Garcia et al. 1997). mtDNA mutation alone is not sufficient to explain the shift from OXPHOS to glycolysis. Therefore, cancer cells still require mtDNA and need to sustain an adequate balance between fusion and fission for maintenance and sharing of mtDNA.
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Thermal control of metabolic cold defence in pigeons columba livia

Thermal control of metabolic cold defence in pigeons columba livia

Experimentally induced temperature displacements do not necessarily reflect naturally occurring body temperature changes. In this connection, it is interesting to note that any attempt to demonstrate a correlation between normal fluctuations in CNS temperature and thermoregulatory effector activity have failed both in mammals (Abrams and Hammel, 1965; Rawson et al. 1965) and in birds (Graf and Necker, 1979). Furthermore, several studies have noted a lack of cold signal inputs from the body core during exposure of homeotherms to low ambient temperatures (Graf and Necker, 1979; Mercer and Hammel, 1989; Hammel, 1990; Østnes and Bech, 1997). Thus, it is still unknown to what extent thermosensors situated inside the body core contribute to the combined error signal that controls metabolic cold defence when homeothermic animals are subjected to an external cold challenge. Information about the actual regional body temperature changes which occur during exposure to low ambient temperatures is therefore needed for an evaluation of the importance of the different thermosensory areas in mediating metabolic cold responses.
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