scholarly journals HillTau: A fast, compact abstraction for model reduction in biochemical signaling networks

2021 ◽  
Vol 17 (11) ◽  
pp. e1009621
Author(s):  
Upinder S. Bhalla
Keyword(s):  
Model Reduction ◽  
Time Course ◽  
Feedback Inhibition ◽  
Experimental Tests ◽  
Mass Action ◽  
Signaling Networks ◽  
Direct Mapping ◽  
Biological Entities ◽  
The Hill ◽  
State Concentration

Signaling networks mediate many aspects of cellular function. The conventional, mechanistically motivated approach to modeling such networks is through mass-action chemistry, which maps directly to biological entities and facilitates experimental tests and predictions. However such models are complex, need many parameters, and are computationally costly. Here we introduce the HillTau form for signaling models. HillTau retains the direct mapping to biological observables, but it uses far fewer parameters, and is 100 to over 1000 times faster than ODE-based methods. In the HillTau formalism, the steady-state concentration of signaling molecules is approximated by the Hill equation, and the dynamics by a time-course tau. We demonstrate its use in implementing several biochemical motifs, including association, inhibition, feedforward and feedback inhibition, bistability, oscillations, and a synaptic switch obeying the BCM rule. The major use-cases for HillTau are system abstraction, model reduction, scaffolds for data-driven optimization, and fast approximations to complex cellular signaling.

scholarly journals HillTau: A fast, compact abstraction for model reduction in biochemical signaling networks

2020 ◽  
Author(s):  
Upinder S. Bhalla
Keyword(s):  
Model Reduction ◽  
Time Course ◽  
Feedback Inhibition ◽  
Experimental Tests ◽  
Mass Action ◽  
Signaling Networks ◽  
Reaction Products ◽  
Biological Entities ◽  
The Hill ◽  
State Concentration

AbstractSignaling networks mediate many aspects of cellular function, yet their complexity and experimental inaccessibility limit the completeness and precision with which we can specify them. The conventional, mechanistically motivated approach to modeling such networks is through mass-action chemistry, which maps directly to biological entities, facilitating experimental tests and predictions. However such models are complex, need many parameters, and are computationally costly. Here we introduce the HillTau form for signaling models. HillTau retains the direct mapping to biological observables, but in contrast it is sparse, uses far fewer parameters, and is extremely efficient to compute. In the HillTau formalism, the steady-state concentration of all reaction products is approximated by the Hill equation, and the dynamics by a time-course tau. We demonstrate its use in implementing several biochemical motifs, including association, inhibition, feedforward and feedback inhibition, bistability, oscillations, and a synaptic switch obeying the BCM rule. We show how HillTau models closely fit existing mass-action models 10 times their size, and run 100 times faster even with a Python implementation. The same data-fitting approach serves for model construction from experimental data. The major use-cases for HillTau are system abstraction, model reduction, scaffolds for data-driven optimization, and fast approximations to complex cellular signaling.

Divergent effects of intravenous GSH and cysteine on renal and hepatic GSH

1992 ◽  
Vol 263 (2) ◽  
pp. R348-R352 ◽  
Author(s):  
S. Aebi ◽  
B. H. Lauterburg
Keyword(s):  
Steady State ◽  
De Novo ◽  
Feedback Inhibition ◽  
Therapeutic Use ◽  
Steady State Concentration ◽  
De Novo Synthesis ◽  
State Concentration ◽  
Cellular Thiol

There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutathione (GSH) and cysteine on the cellular thiol status, thiols were administered intravenously to rats in doses ranging from 1.67 to 8.35 mmol/kg with and without pretreatment with 4 mmol/kg buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis. One hour after administration of 1.67 mmol/kg GSH, the concentration of GSH rose from 5.2 +/- 1.0 to 8.4 +/- 0.9 mumol/g and from 2.5 +/- 0.5 to 3.7 +/- 0.7 mumol/g in liver and kidneys, respectively. After 8.35 mmol/kg, hepatic GSH did not increase further, but renal GSH rose to 6.7 +/- 1.8 mumol/g. Infusion of cysteine increased hepatic GSH to the same extent as intravenous GSH, but renal GSH did not increase after 1.67 mmol/kg and even significantly decreased to 0.6 +/- 0.2 mumol/g after 8.35 mmol/kg. In the presence of BSO, GSH resulted in a significant increase in renal but not hepatic GSH, suggesting that the kidneys take up intact GSH and indicating that the increment in hepatic GSH was due to de novo synthesis. The present data show that hepatic GSH can be markedly increased in vivo by increasing the supply of cysteine. Measurements of hepatic cysteine indicate that up to a concentration of approximately 0.5 mumol/g cysteine is a key determinant of hepatic GSH, such that the physiological steady-state concentration of GSH in the liver appears to be mainly determined by the availability of cysteine. At higher concentrations GSH does not increase further, possibly due to feedback inhibition of GSH synthesis or increased efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

GABAA-Mediated IPSCs in Piriform Cortex Have Fast and Slow Components With Different Properties and Locations on Pyramidal Cells

1997 ◽  
Vol 78 (5) ◽  
pp. 2531-2545 ◽  
Author(s):  
A. Kapur ◽  
R. A. Pearce ◽  
W. W. Lytton ◽  
L. B. Haberly
Keyword(s):  
Time Course ◽  
Feedback Inhibition ◽  
Slow Component ◽  
Piriform Cortex ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Companion Paper ◽  
Protective Role ◽  
Functional Roles ◽  
Term Potentiation

Kapur, A., R. A. Pearce, W. W. Lytton, and L. B. Haberly.GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells. J. Neurophysiol. 78: 2531–2545, 1997. A recent study in piriform (olfactory) cortex provided evidence that, as in hippocampus and neocortex, γ-aminobutyric acid-A (GABAA)-mediated inhibition is generated in dendrites of pyramidal cells, not just in the somatic region as previously believed. This study examines selected properties of GABAA inhibitory postsynaptic currents (IPSCs) in dendritic and somatic regions that could provide insight into their functional roles. Pharmacologically isolated GABAA-mediated IPSCs were studied by whole cell patch recording in slices. To compare properties of IPSCs in distal dendritic and somatic regions, local stimulation was carried out with tungsten microelectrodes, and spatially restricted blockade of GABAA-mediated inhibition was achieved by pressure-ejection of bicuculline from micropipettes. The results revealed that largely independent circuits generate GABAA inhibition in distal apical dendritic and somatic regions. With such independence, a selective decrease in dendritic-region inhibition could enhance integrative or plastic processes in dendrites while allowing feedback inhibition in the somatic region to restrain system excitability. This could allow modulatory fiber systems from the basal forebrain or brain stem, for example, to change the functional state of the cortex by altering the excitability of interneurons that mediate dendritic inhibition without increasing the propensity for regenerative bursting in this highly epileptogenic system. As in hippocampus, GABAA-mediated IPSCs were found to have fast and slow components with time constants of decay on the order of 10 and 40 ms, respectively, at 29°C. Modeling analysis supported physiological evidence that the slow time constant represents a true IPSC component rather than an artifactual slowing of the fast component from voltage clamp of a dendritic current. The results indicated that, whereas both dendritic and somatic-region IPSCs have both fast and slow GABAA components, there is a greater proportion of the slow component in dendrites. In a companion paper, the hypothesis is explored that the resulting slower time course of the dendritic IPSC increases its capacity to regulate the N-methyl-d-aspartate component of EPSPs. Finally, evidence is presented that the slow GABAA-mediated IPSC component is regulated by presynaptic GABAB inhibition whereas the fast is not. Based on the requirement for presynaptic GABAB-mediated block of inhibition for expression of long-term potentiation, this finding is consistent with participation of the slow GABAA component in regulation of synaptic plasticity. The lack of susceptibility of the fast GABAA component to the long-lasting, activity-induced suppression mediated by presynaptic GABAB receptors is consistent with a protective role for this process in preventing seizure activity.

scholarly journals A dominant role for the beta 4 nicotinic receptor subunit in nicotinic modulation of glomerular microcircuits in the mouse olfactory bulb

2018 ◽  
Vol 120 (4) ◽  
pp. 2036-2048 ◽  
Author(s):  
Michael S. Spindle ◽  
Pirooz V. Parsa ◽  
Spencer G. Bowles ◽  
Rinaldo D. D’Souza ◽  
Sukumar Vijayaraghavan
Keyword(s):  
Olfactory Bulb ◽  
Nicotinic Acetylcholine Receptors ◽  
Information Transfer ◽  
Time Course ◽  
Feedback Inhibition ◽  
Dominant Role ◽  
Receptor Gene ◽  
Gaba Release ◽  
Cell Types ◽  
Receptor Activation

Nicotinic acetylcholine receptors (nAChRs) regulate information transfer across the main olfactory bulb by instituting a high-pass intensity filter allowing for the filtering out of weak inputs. Excitation-driven inhibition of the glomerular microcircuit via GABA release from periglomerular cells appears to underlie this effect of nAChR activation. The multiplicity of nAChR subtypes and cellular locations raises questions about their respective roles in mediating their effects on the glomerular output. In this study, we address this issue by targeting heteromeric nAChRs using receptor knockouts (KOs) for the two dominant nAChR β-subunit genes known to be expressed in the central nervous system. KOs of the β2-nAChR subunit did not affect nAChR currents from mitral cells (MCs) but attenuated those from the external tufted (ET) cells. In slices from these animals, activation of nAChRs still effectively inhibited excitatory postsynaptic currents (EPSCs) and firing on MCs evoked by the olfactory nerve (ON) stimulation, thereby indicating that the filter mechanism was intact. On the other hand, recordings from β4-KOs showed that nAChR responses from MCs were abolished and those from ET cells were attenuated. Excitation-driven feedback was abolished as was the effect of nAChR activation on ON-evoked EPSCs. Experiments using calcium imaging showed that one possible consequence of the β2-subunit activation might be to alter the time course of calcium transients in juxtaglomerular neurons suggesting a role for these receptors in calcium signaling. Our results indicate that nAChRs containing the β4-subunit are critical in the filtering of odor inputs and play a determinant role in the cholinergic modulation of glomerular output. NEW & NOTEWORTHY In this study, using receptor gene knockouts we examine the relative contributions of heteromeric nAChR subtypes located on different cell types to this effect of receptor activation. Our results demonstrate that nAChRs containing the β4-subunit activate MCs resulting in feedback inhibition from glomerular interneurons. This period of inhibition results in the selective filtering of weak odor inputs providing one mechanism by which nAChRs can enhance discrimination between two closely related odors.

scholarly journals A structural property for reduction of biochemical networks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anika Küken ◽  
Philipp Wendering ◽  
Damoun Langary ◽  
Zoran Nikoloski
Keyword(s):  
Steady State ◽  
Model Reduction ◽  
Structural Property ◽  
Large Scale ◽  
Biochemical Networks ◽  
Mass Action ◽  
Mass Action Kinetics ◽  
Reduced Models ◽  
Metabolic Phenotypes ◽  
Genome Scale

AbstractLarge-scale biochemical models are of increasing sizes due to the consideration of interacting organisms and tissues. Model reduction approaches that preserve the flux phenotypes can simplify the analysis and predictions of steady-state metabolic phenotypes. However, existing approaches either restrict functionality of reduced models or do not lead to significant decreases in the number of modelled metabolites. Here, we introduce an approach for model reduction based on the structural property of balancing of complexes that preserves the steady-state fluxes supported by the network and can be efficiently determined at genome scale. Using two large-scale mass-action kinetic models of Escherichia coli, we show that our approach results in a substantial reduction of 99% of metabolites. Applications to genome-scale metabolic models across kingdoms of life result in up to 55% and 85% reduction in the number of metabolites when arbitrary and mass-action kinetics is assumed, respectively. We also show that predictions of the specific growth rate from the reduced models match those based on the original models. Since steady-state flux phenotypes from the original model are preserved in the reduced, the approach paves the way for analysing other metabolic phenotypes in large-scale biochemical networks.

Succinate aggravates NAFLD progression to liver cancer on the onset of obesity: An in silico model

2018 ◽  
Vol 16 (04) ◽  
pp. 1850008 ◽  
Author(s):  
Indrani Ray ◽  
Abhijit Dasgupta ◽  
Rajat K. De
Keyword(s):  
Liver Disease ◽  
Liver Cancer ◽  
Feedback Inhibition ◽  
State Space Model ◽  
Mass Action ◽  
Nonalcoholic Fatty Liver ◽  
Mass Action Law ◽  
Poor Outcomes ◽  
Classical Control ◽  
Induced Proteins

The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) have been increasing to epidemic proportions around the world. NAFLD, a chronic liver disease that affects the nondrinkers, is mainly associated with steatohepatitis and cirrhosis. The progression of NAFLD associated with obesity increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. In order to investigate the underlying cellular dynamics leading to NAFLD progression towards cancer on the onset of obesity, we have integrated human hepatocyte pathway with hypoxia-inducible factor1-[Formula: see text] (HIF1-[Formula: see text]) signaling pathway using state space model based on classical control theory. Modified Michaelis–Menten equation and mass action law have been used to define flux vectors of the proposed model. We have incorporated feedback inhibition/activation and allosteric effects into the simulink-based model. The values of kinetic constants have been taken from the literature. It is found that on the onset of obesity, HIF1-[Formula: see text]-induced proteins stabilize approximately 62 times that in the case of a normal cell. Consequently, the HIF1-[Formula: see text]-induced proteins enhance the enzymatic activities of hexokinase (HK), phosphofructo kinase (PFK), lactate dehydrogenase (LDH), and pyruvate dehydrogenase (PDH), which induce Warburg effect promoting an environment suitable for cancer cells.

scholarly journals The arginine regulon of Escherichia coli: whole-system transcriptome analysis discovers new genes and provides an integrated view of arginine regulation

Microbiology ◽  
2006 ◽  
Vol 152 (11) ◽  
pp. 3343-3354 ◽  
Author(s):  
Marina Caldara ◽  
Daniel Charlier ◽  
Raymond Cunin
Keyword(s):  
Escherichia Coli ◽  
Transcriptional Repression ◽  
Time Course ◽  
Feedback Inhibition ◽  
Uptake System ◽  
Mobility Shift ◽  
Real Time Quantitative Pcr ◽  
New Genes ◽  
Genes Encoding ◽  
K 12

Analysis of the response to arginine of the Escherichia coli K-12 transcriptome by microarray hybridization and real-time quantitative PCR provides the first coherent quantitative picture of the ArgR-mediated repression of arginine biosynthesis and uptake genes. Transcriptional repression was shown to be the major control mechanism of the biosynthetic genes, leaving only limited room for additional transcriptional or post-transcriptional regulation. The art genes, encoding the specific arginine uptake system, are subject to ArgR-mediated repression, with strong repression of artJ, encoding the periplasmic binding protein of the system. The hisJQMP genes of the histidine transporter (part of the lysine-arginine-ornithine uptake system) were discovered to be a part of the arginine regulon. Analysis of their control region with reporter gene fusions and electrophoretic mobility shift in the presence of pure ArgR repressor showed the involvement in repression of the ArgR protein and an ARG box 120 bp upstream of hisJ. No repression of the genes of the third uptake system, arginine-ornithine, was observed. Finally, comparison of the time course of arginine repression of gene transcription with the evolution of the specific activities of the cognate enzymes showed that while full genetic repression was achieved 2 min after arginine addition, enzyme concentrations were diluted at the rate of cell division. This emphasizes the importance of feedback inhibition of the first enzymic step in the pathway in controlling the metabolic flow through biosynthesis in the period following the onset of repression.

scholarly journals Model Reduction Tools For Phenomenological Modeling of Input-Controlled Biological Circuits

2020 ◽  
Author(s):  
Ayush Pandey ◽  
Richard M. Murray
Keyword(s):  
Phenomenological Models ◽  
Model Reduction ◽  
Chemical Reaction ◽  
Species Abundance ◽  
Reaction Model ◽  
Mass Action ◽  
Mass Action Kinetics ◽  
Time Scale Separation ◽  
Effective Relationships ◽  
Biological Circuits

AbstractWe present a Python-based software package to automatically obtain phenomenological models of input-controlled synthetic biological circuits that guide the design using chemical reaction-level descriptive models. From the parts and mechanism description of a synthetic biological circuit, it is easy to obtain a chemical reaction model of the circuit under the assumptions of mass-action kinetics using various existing tools. However, using these models to guide design decisions during an experiment is difficult due to a large number of reaction rate parameters and species in the model. Hence, phenomenological models are often developed that describe the effective relationships among the circuit inputs, outputs, and only the key states and parameters. In this paper, we present an algorithm to obtain these phenomenological models in an automated manner using a Python package for circuits with inputs that control the desired outputs. This model reduction approach combines the common assumptions of time-scale separation, conservation laws, and species’ abundance to obtain the reduced models that can be used for design of synthetic biological circuits. We consider an example of a simple gene expression circuit and another example of a layered genetic feedback control circuit to demonstrate the use of the model reduction procedure.

scholarly journals On the estimation errors of KM and V from time-course experiments using the Michaelis–Menten equation

2016 ◽  
Author(s):  
Wylie Stroberg ◽  
Santiago Schnell
Keyword(s):  
Time Course ◽  
Enzyme Concentration ◽  
Mass Action ◽  
Accurate Estimation ◽  
Estimation Errors ◽  
Experimental Conditions ◽  
Progress Curve ◽  
Steady State Kinetics ◽  
Initial Substrate ◽  
Order Of Magnitude

AbstractThe conditions under which the Michaelis–Menten equation accurately captures the steady-state kinetics of a simple enzyme-catalyzed reaction is contrasted with the conditions under which the same equation can be used to estimate parameters, KM and V, from progress curve data. Validity of the underlying assumptions leading to the Michaelis–Menten equation are shown to be necessary, but not sufficient to guarantee accurate estimation of KM and V. Detailed error analysis and numerical “experiments” show the required experimental conditions for the independent estimation of both KM and V from progress curves. A timescale, tQ, measuring the portion of the time course over which the progress curve exhibits substantial curvature provides a novel criterion for accurate estimation of KM and V from a progress curve experiment. It is found that, if the initial substrate concentration is of the same order of magnitude as KM, the estimated values of the KM and V will correspond to their true values calculated from the microscopic rate constants of the corresponding mass-action system, only so long as the initial enzyme concentration is less than KM.

scholarly journals Relation between the content of acetyl-coenzyme A and acetylcholine in brain slices

1980 ◽  
Vol 188 (3) ◽  
pp. 683-688 ◽  
Author(s):  
J Rícný ◽  
S Tucek
Keyword(s):  
Incubation Medium ◽  
Brain Slices ◽  
Mass Action ◽  
Direct Relation ◽  
Law Of Mass Action ◽  
Acetyl Coa ◽  
Caudate Nuclei ◽  
High K ◽  
State Concentration

Slices of rat caudate nuclei were incubated in vitro in media containing, among other constituents, three different concentrations of glucose (0.5, 2 and 10 mM), 0.2 mM-choline, paraoxon as an inhibitor of cholinesterase, and 5 mM- or 30 mM-K+. After 30 and 60 min of incubation, the concentrations of acetyl-CoA, acetylcholine and choline in the tissue and of acetylcholine in the incubation medium were measured. The content of acetyl-CoA in the sliced varied in direct relation to the concentration of glucose in the incubation medium. The content of acetylcholine in the slices and, in experiments with high K+, also the amount of acetylcholine released into the incubation medium varied in direct relation to the concentration of glucose in the incubation medium and to the concentration of acetyl-CoA in the slices; the relation between the concentrations of acetyl-CoA and of acetylcholine in the slices was linear. It was concluded that the availability of acetyl-CoA had a decisive influence on both the rate of synthesis of acetylcholine and its steady-state concentration. The observations accord with the view that, at the ultimate level, the synthesis of acetylcholine is controlled by the Law of Mass Action.

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