scholarly journals Delving deeper: Relating the behaviour of a metabolic system to the properties of its components using symbolic metabolic control analysis

2018 ◽  
Author(s):  
Carl D. Christensen ◽  
Jan-Hendrik S. Hofmeyr ◽  
Johann M. Rohwer
Keyword(s):  
Reaction Rates ◽  
Mass Action ◽  
Control Analysis ◽  
Metabolic System ◽  
Flux Control ◽  
Symbolic Control ◽  
Mechanistic Understanding ◽  
The Individual ◽  
High Level ◽  
Molecular Components

AbstractHigh-level behaviour of metabolic systems results from the properties of, and interactions between, numerous molecular components. Reaching a complete understanding of metabolic behaviour based on the system’s components is therefore a difficult task. This problem can be tackled by constructing and subsequently analysing kinetic models of metabolic pathways since such models aim to capture all the relevant properties of the system components and their interactions.Symbolic control analysis is a framework for analysing pathway models in order to reach a mechanistic understanding of their behaviour. By providing algebraic expressions for the sensitivities of system properties, such as metabolic fluxor steady-state concentrations, in terms of the properties of individual reactions it allows one to trace the high level behaviour back to these low level components. Here we apply this method to a model of pyruvate branch metabolism inLactococcus lactisin order to explain a previously observed negative flux response towards an increase in substrate concentration. With this method we are able to show, first, that the sensitivity of flux towards changes in reaction rates (represented by flux control coefficients) is determined by the individual metabolic branches of the pathway, and second, how the sensitivities of individual reaction rates towards their substrates (represented by elasticity coefficients) contribute to this flux control. We also quantify the contributions of enzyme binding and mass-action to enzyme elasticity separately, which allows for an even finer-grained understanding of flux control.These analytical tools allow us to analyse the control properties of a metabolic model and to arrive at a mechanistic understanding of the quantitative contributions of each of the enzymes to this control. Our analysis provides an example of the descriptive power of the general principles of symbolic control analysis.Author summaryMetabolic networks are complex systems consisting of numerous individual molecular components. The properties of these components, together with their non-linear interactions, give rise to high-level observed behaviour of the system in which they reside. Therefore, in order to fully understand the behaviour of a metabolic system, one has to consider the properties of all of its components. The analysis of computer models that capture and represent these systems and their components simplifies this task by allowing for an easy way to isolate the effects of each individual component. In this paper we use the framework of symbolic control analysis to investigate the sensitivity of the rate of flow of matter through one of the branches in a particular metabolic pathway towards changes in the rates of individual reactions. Here we are able to quantify how certain chains of reactions, individual reactions, and even thermodynamic and kinetic aspects of individual reactions contribute to the overall sensitivity of the rate of matter-flow. Thus, we are able to trace the behaviour of the system as a whole in a mechanistic way to the properties of the individual molecular components.

scholarly journals Metabolic control analysis of biochemical pathways based on a thermokinetic description of reaction rates

1997 ◽  
Vol 321 (1) ◽  
pp. 133-138 ◽  
Author(s):  
Jens NIELSEN
Keyword(s):  
Metabolic Control ◽  
Reaction Rate ◽  
Reaction Rates ◽  
Rate Function ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Flux Control ◽  
Biochemical Pathways ◽  
Flux Control Coefficients

Metabolic control analysis is a powerful technique for the evaluation of flux control within biochemical pathways. Its foundation is the elasticity coefficients and the flux control coefficients (FCCs). On the basis of a thermokinetic description of reaction rates it is here shown that the elasticity coefficients can be calculated directly from the pool levels of metabolites at steady state. The only requirement is that one thermodynamic parameter be known, namely the reaction affinity at the intercept of the tangent in the inflection point of the curve of reaction rate against reaction affinity. This parameter can often be determined from experiments in vitro. The methodology is applicable only to the analysis of simple two-step pathways, but in many cases larger pathways can be lumped into two overall conversions. In cases where this cannot be done it is necessary to apply an extension of the thermokinetic description of reaction rates to include the influence of effectors. Here the reaction rate is written as a linear function of the logarithm of the metabolite concentrations. With this type of rate function it is shown that the approach of Delgado and Liao [Biochem. J. (1992) 282, 919–927] can be much more widely applied, although it was originally based on linearized kinetics. The methodology of determining elasticity coefficients directly from pool levels is illustrated with an analysis of the first two steps of the biosynthetic pathway of penicillin. The results compare well with previous findings based on a kinetic analysis.

scholarly journals Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon

1986 ◽  
Vol 237 (2) ◽  
pp. 379-389 ◽  
Author(s):  
A K Groen ◽  
C W van Roermund ◽  
R C Vervoorn ◽  
J M Tager
Keyword(s):  
Pyruvate Kinase ◽  
Pyruvate Carboxylase ◽  
Adenine Nucleotide ◽  
Liver Cells ◽  
Glycolytic Enzyme ◽  
Mass Action ◽  
Control Analysis ◽  
Flux Control ◽  
Flux Control Coefficients ◽  
Control Coefficients

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.

scholarly journals Quantitative determination of the steady-state kinetics of multienzyme reactions using the algebraic rate equations for the component single-enzyme reactions

1993 ◽  
Vol 291 (2) ◽  
pp. 585-593 ◽  
Author(s):  
C D Stoner
Keyword(s):  
Steady State ◽  
Direct Calculation ◽  
Rate Equations ◽  
Maximum Efficiency ◽  
Control Analysis ◽  
Flux Control ◽  
Enzyme Reactions ◽  
Dependent Variables ◽  
The Individual ◽  
Single Enzyme

Methods are given whereby the steady-state kinetic characteristics of multienzyme reactions consisting of individual single-enzyme reactions linked by freely diffusible intermediates can be determined quantitatively from the experimentally determined complete algebraic rate equations for the individual reactions. The approach is based on the fact that a valid steady-state rate equation for such a multienzyme reaction, in terms of the rate equations for the individual reactions, can be obtained simply from knowledge of the relative rates of the individual reactions when the multienzyme reaction is in the steady state. A number of model multienzyme reactions, which differ as to structural arrangement of the individual reactions, are examined by this approach. Simple mathematical methods which are applicable to most of these models are given for direct calculation of dependent variables. It is either pointed out or demonstrated with Mathematica that the rate equations for all of these models can be handled very easily with the aid of a personal computer equipped with appropriate equation-solving software. Since the approach permits evaluation of all dependent variables for any specific combination of values for the kinetic parameters and independent variables, numerical values for the flux control coefficients of the individual enzymes can be obtained by direct calculation for a wide variety of conditions and can be compared with those obtained according to the methods of Metabolic Control Analysis. Several such comparisons have been made and in all cases identical results were obtained. The intuitive notion that the individual enzymes of a multienzyme reaction would be equally rate limiting if the total amount of enzyme were being used with maximum efficiency is tested and shown to be incorrect. In the course of this test the flux control coefficient for the individual enzymes were found to be appropriate indicators of relative rate limitation or control by the enzymes and to account properly for differences in specific activity among the enzymes.

scholarly journals Kinetics methods for clinical epidemiology problems

2015 ◽  
Vol 112 (46) ◽  
pp. 14150-14155 ◽  
Author(s):  
Alexandru Dan Corlan ◽  
John Ross
Keyword(s):  
Clinical Epidemiology ◽  
Meta Analysis ◽  
Reaction Rates ◽  
Mass Action ◽  
Reaction Systems ◽  
Disease Epidemiology ◽  
Mass Action Law ◽  
The Individual ◽  
Kinetics Of ◽  
Stochastic Kinetics

Calculating the probability of each possible outcome for a patient at any time in the future is currently possible only in the simplest cases: short-term prediction in acute diseases of otherwise healthy persons. This problem is to some extent analogous to predicting the concentrations of species in a reactor when knowing initial concentrations and after examining reaction rates at the individual molecule level. The existing theoretical framework behind predicting contagion and the immediate outcome of acute diseases in previously healthy individuals is largely analogous to deterministic kinetics of chemical systems consisting of one or a few reactions. We show that current statistical models commonly used in chronic disease epidemiology correspond to simple stochastic treatment of single reaction systems. The general problem corresponds to stochastic kinetics of complex reaction systems. We attempt to formulate epidemiologic problems related to chronic diseases in chemical kinetics terms. We review methods that may be adapted for use in epidemiology. We show that some reactions cannot fit into the mass-action law paradigm and solutions to these systems would frequently exhibit an antiportfolio effect. We provide a complete example application of stochastic kinetics modeling for a deductive meta-analysis of two papers on atrial fibrillation incidence, prevalence, and mortality.

Territorial Distribution of Alcohol and Drug Addictions Mortality Concerning Regional Disparities in the Slovak Republic from Year 1996 to Year 2015

2020 ◽  
Keyword(s):  
Mortality Rate ◽  
Slovak Republic ◽  
Regional Disparities ◽  
Point Of View ◽  
Extreme Position ◽  
Data Set ◽  
Female Sex ◽  
Male Sex ◽  
The Individual ◽  
High Level

BACKGROUND: This paper deals with territorial distribution of the alcohol and drug addictions mortality at a level of the districts of the Slovak Republic. AIM: The aim of the paper is to explore the relations within the administrative territorial division of the Slovak Republic, that is, between the individual districts and hence, to reveal possibly hidden relation in alcohol and drug mortality. METHODS: The analysis is divided and executed into the two fragments – one belongs to the female sex, the other one belongs to the male sex. The standardised mortality rate is computed according to a sequence of the mathematical relations. The Euclidean distance is employed to compute the similarity within each pair of a whole data set. The cluster analysis examines is performed. The clusters are created by means of the mutual distances of the districts. The data is collected from the database of the Statistical Office of the Slovak Republic for all the districts of the Slovak Republic. The covered time span begins in the year 1996 and ends in the year 2015. RESULTS: The most substantial point is that the Slovak Republic possesses the regional disparities in a field of mortality expressed by the standardised mortality rate computed particularly for the diagnoses assigned to the alcohol and drug addictions at a considerably high level. However, the female sex and the male sex have the different outcome. The Bratislava III District keeps absolutely the most extreme position. It forms an own cluster for the both sexes too. The Topoľčany District bears a similar extreme position from a point of view of the male sex. All the Bratislava districts keep their mutual notable dissimilarity. Contrariwise, evaluation of a development of the regional disparities among the districts looks like notably heterogeneously. CONCLUSIONS: There are considerable regional discrepancies throughout the districts of the Slovak Republic. Hence, it is necessary to create a common platform how to proceed with the solution of this issue.

Quantitative indicators of air traffic controllers’ attitude to the danger of errors

2020 ◽  
pp. 68-78
Author(s):  
O. M. Reva ◽  
V. V. Kamyshin ◽  
S. P. Borsuk ◽  
V. A. Shulhin ◽  
A. V. Nevynitsyn
Keyword(s):  
Human Factor ◽  
Differential Method ◽  
Air Traffic ◽  
Professional Activity ◽  
Aviation Accidents ◽  
Air Traffic Controllers ◽  
The Difference ◽  
Level Of Significance ◽  
The Individual ◽  
High Level

The negative and persistent impact of the human factor on the statistics of aviation accidents and serious incidents makes proactive studies of the attitude of “front line” aviation operators (air traffic controllers, flight crewmembers) to dangerous actions or professional conditions as a key component of the current paradigm of ICAO safety concept. This “attitude” is determined through the indicators of the influence of the human factor on decision-making, which also include the systems of preferences of air traffic controllers on the indicators and characteristics of professional activity, illustrating both the individual perception of potential risks and dangers, and the peculiarities of generalized group thinking that have developed in a particular society. Preference systems are an ordered (ranked) series of n = 21 errors: from the most dangerous to the least dangerous and characterize only the danger preference of one error over another. The degree of this preference is determined only by the difference in the ranks of the errors and does not answer the question of how much time one error is more dangerous in relation to another. The differential method for identifying the comparative danger of errors, as well as the multistep technology for identifying and filtering out marginal opinions were applied. From the initial sample of m = 37 professional air traffic controllers, two subgroups mB=20 and mG=7 people were identified with statisti-cally significant at a high level of significance within the group consistency of opinions a = 1%. Nonpara-metric optimization of the corresponding group preference systems resulted in Kemeny’s medians, in which the related (middle) ranks were missing. Based on these medians, weighted coefficients of error hazards were determined by the mathematical prioritization method. It is substantiated that with the ac-cepted accuracy of calculations, the results obtained at the second iteration of this method are more ac-ceptable. The values of the error hazard coefficients, together with their ranks established in the preference systems, allow a more complete quantitative and qualitative analysis of the attitude of both individual air traffic controllers and their professional groups to hazardous actions or conditions.

Kinetics of esterification of monoisopropylphenols with phosphoryl trichloride

1989 ◽  
Vol 54 (5) ◽  
pp. 1311-1317
Author(s):  
Miroslav Magura ◽  
Ján Vojtko ◽  
Ján Ilavský
Keyword(s):  
Liquid Phase ◽  
Rate Constants ◽  
Reaction Rates ◽  
Activation Energies ◽  
The Individual ◽  
Kinetics Of

The kinetics of liquid-phase isothermal esterification of POCl3 with 2-isopropylphenol and 4-isopropylphenol have been studied within the temperature intervals of 110 to 130 and 90 to 110 °C, respectively. The rate constants and activation energies of the individual steps of this three-step reaction have been calculated from the values measured. The reaction rates of the two isomers markedly differ: at 110 °C 4-isopropylphenol reacts faster by the factors of about 7 and 20 for k1 and k3, respectively. This finding can be utilized in preparation of mixed triaryl phosphates, since the alkylation mixture after reaction of phenol with propene contains an excess of 2-isopropylphenol over 4-isopropylphenol.

scholarly journals Automatic Labeled Dialogue Generation for Nursing Record Systems

2020 ◽  
Vol 10 (3) ◽  
pp. 62
Author(s):  
Tittaya Mairittha ◽  
Nattaya Mairittha ◽  
Sozo Inoue
Keyword(s):  
Data Augmentation ◽  
Short Term Memory ◽  
Generative Models ◽  
Abstract Knowledge ◽  
Augmentation Techniques ◽  
Nursing Record ◽  
Long Short Term Memory ◽  
The Individual ◽  
High Level ◽  
Embedding Methods

The integration of digital voice assistants in nursing residences is becoming increasingly important to facilitate nursing productivity with documentation. A key idea behind this system is training natural language understanding (NLU) modules that enable the machine to classify the purpose of the user utterance (intent) and extract pieces of valuable information present in the utterance (entity). One of the main obstacles when creating robust NLU is the lack of sufficient labeled data, which generally relies on human labeling. This process is cost-intensive and time-consuming, particularly in the high-level nursing care domain, which requires abstract knowledge. In this paper, we propose an automatic dialogue labeling framework of NLU tasks, specifically for nursing record systems. First, we apply data augmentation techniques to create a collection of variant sample utterances. The individual evaluation result strongly shows a stratification rate, with regard to both fluency and accuracy in utterances. We also investigate the possibility of applying deep generative models for our augmented dataset. The preliminary character-based model based on long short-term memory (LSTM) obtains an accuracy of 90% and generates various reasonable texts with BLEU scores of 0.76. Secondly, we introduce an idea for intent and entity labeling by using feature embeddings and semantic similarity-based clustering. We also empirically evaluate different embedding methods for learning good representations that are most suitable to use with our data and clustering tasks. Experimental results show that fastText embeddings produce strong performances both for intent labeling and on entity labeling, which achieves an accuracy level of 0.79 and 0.78 f1-scores and 0.67 and 0.61 silhouette scores, respectively.

scholarly journals Opportunities and Challenges of Green-Lean: An Integrated System for Sustainable Construction

2020 ◽  
Vol 12 (11) ◽  
pp. 4460 ◽  
Author(s):  
Mohammadsoroush Tafazzoli ◽  
Ehsan Mousavi ◽  
Sharareh Kermanshachi
Keyword(s):  
Cost Savings ◽  
Integrated Approach ◽  
Integrated System ◽  
Waste Minimization ◽  
Sustainable Construction ◽  
Future Research ◽  
Safety Improvement ◽  
The Individual ◽  
High Level ◽  
Industry Professionals

Although the two concepts of lean and sustainable construction have been developed due to different incentives, and they do not pursue the same exact goals, there exists considerable commonality between them. This paper discusses the potentials for integrating the two approaches and their practices and how the resulting synergy from combining the two methods can potentially lead to higher levels of fulfilling the individual goals of each of them. Some limitations and challenges to implementing the integrated approach are also discussed. Based on a comprehensive review of existing papers related to sustainable and lean construction topics, the commonality between the two approaches is discussed and grouped in five categories of (1) cost savings, (2) waste minimization, (3) Jobsite safety improvement, (4) reduced energy consumption, and (5) customers’ satisfaction improvement. The challenges of this integration are similarly identified and discussed in the four main categories of (1) additional initial costs to the project, (2) difficulty of providing specialized expertise, (3) contractors’ unwillingness to adopt the additional requirements, and (4) challenges to establish a high level of teamwork. Industry professionals were then interviewed to rank the elements in each of the two categories of opportunities and challenges. The results of the study highlight how future research can pursue the development of a new Green-Lean approach by investing in the communalities and meeting the challenges of this integration.

scholarly journals Analysis of Results of Specific IgE in 100 Atopic Dermatitis Patients with the Use of Multiplex Examination ALEX2—Allergy Explorer

2021 ◽  
Vol 22 (10) ◽  
pp. 5286
Author(s):  
Jarmila Čelakovská ◽  
Josef Bukač ◽  
Eva Cermákova ◽  
Radka Vaňková ◽  
Hana Skalská ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Arginine Kinase ◽  
Specific Ige ◽  
Protein Domain ◽  
Storage Mites ◽  
Fel D 1 ◽  
Analysis Of Results ◽  
Can F 1 ◽  
High Level ◽  
Molecular Components

Background and aim: Progress in laboratory diagnostics of IgE-mediated allergy is the use of component-resolved diagnosis. Our study analyses the results of specific IgE to 295 allergen reagents (117 allergenic extracts and 178 molecular components) in patients suffering from atopic dermatitis (AD) with the use of ALEX2 Allergy Explorer. Method: The complete dermatological and allergological examination, including the examination of the sensitization to molecular components with ALEX2 Allergy Explorer testing, was performed. The statistical analysis of results was performed with these methods: TURF (total unduplicated reach and frequency), best reach and frequency by group size, two-sided tests, Fisher’s exact test, and chi-square test (at an expected minimum frequency of at least 5). Results: Altogether, 100 atopic dermatitis patients were examined: 48 men, 52 women, the average age 40.9 years, min. age 14 years, max. age 67 years. The high and very high level of specific IgE was reached in 75.0% of patients to 18 molecular components: from PR-10 proteins (Aln g 1, Bet v 1, Cor a1.0103, Cor a1.0401, Fag s 1), lipocalin (Can f 1), NPC2 family (Der f 2, Der p 2), uteroglobin (Fel d 1), from Alternaria alternata (Alt a 1), Beta expansin (Lol p 1, Phl p 1), molecular components from Timothy, cultivated rye (Secc pollen) and peritrophin-like protein domain Der p 23. The high and very high level of specific IgE to other lipocalins (Fel d 7, Can f 4), to arginine kinase (Bla g 9, German cockroach), and to allergen extracts Art v (mugwort), and Cyn d (Bermuda grass) reached 52.0% of patients. The severity of AD is in significant relation to the sensitization to molecular components of storage mites (Gly d 2, Lep d 2—NPC2 family), lipocalins (Can f 1, Can f 2, Can f 4, and Can f 6), arginine kinase (Asp f 6, Bla g 9, Der p 20, Pen m 2), uteroglobin (Fel d 1, Ory c 3), Mn superoxide dismutase (Mala s 11), PR-10 proteins (Fag s 1, Mal d 1, Cor a 1.0401, Cor a 1.0103), molecular components of the peritrophin-like domain (Der p 21, Der p 23), and to Secc pollen. In the subgroup of patients suffering from bronchial asthma, the significant role play molecular components from house dust mites and storage mites (Lep d 2, Der p 2, Der f 2—NPC2 family), cysteine protease (Der p 1), peritrophin-like protein domain (Der p 21, Der p 23), enolase from Alternaria alternata (Alt a 6), and Beta expansin Phl p 1. Conclusion: The results of our study demonstrate the detailed profile of sensitization to allergens reagents (allergen extract and molecular components) in patients with atopic dermatitis. We show the significance of disturbed epidermal barrier, resulting in increased penetration of allergens. We confirmed the significant relationship between the severity of AD, the occurrence of bronchial asthma and allergic rhinitis, and high levels of specific IgE to allergen reagents. Our results may be important for regime measures and immunotherapy; Der p 23 shall be considered as an essential component for the diagnosis and specific immunotherapy of house dust mite allergy.

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