2021
DOI: 10.1101/2021.01.26.428266
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Emergent signal execution modes in biochemical reaction networks calibrated to experimental data

Abstract: Mathematical models of biomolecular networks are commonly used to study mechanisms of cellular processes, but their usefulness is often questioned due to parameter uncertainty. Here, we employ Bayesian parameter inference and dynamic network analysis to study dominant reaction fluxes in models of extrinsic apoptosis. Although a simplified model yields thousands of parameter vectors with equally good fits to data, execution modes based on reaction fluxes clusters to three dominant execution modes. A larger mode… Show more

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Cited by 7 publications
(24 citation statements)
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References 88 publications
(190 reference statements)
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“…The rationale is that while different parameterizations of the model achieve cell death at approximately equal times, they may arrive there via significantly different sequences of molecular events. We utilized a computational tool 50 that identifies subnetworks of reactions that dominate the production or consumption of a target species, pMLKL in this case, at user-specified times along a time course. Each subnetwork is given an integer label and each time point is associated with a subnetwork.…”
Section: Resultsmentioning
confidence: 99%
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“…The rationale is that while different parameterizations of the model achieve cell death at approximately equal times, they may arrive there via significantly different sequences of molecular events. We utilized a computational tool 50 that identifies subnetworks of reactions that dominate the production or consumption of a target species, pMLKL in this case, at user-specified times along a time course. Each subnetwork is given an integer label and each time point is associated with a subnetwork.…”
Section: Resultsmentioning
confidence: 99%
“…53 It is of interest, therefore, to determine if modulating factors exist that are common across all modes of execution, which could represent novel therapeutic targets. Towards this end, we performed sensitivity analyses based on “representative” parameter sets for each mode (automatically generated by our dynamical systems analysis tool; 50 see Materials and Methods for details) over the 14 non-zero initial protein concentrations (Fig. 4A) and 40 rate constants (Fig.…”
Section: Resultsmentioning
confidence: 99%
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“…These pathways trigger apoptosis by activating effector caspases 19 . We built an abridged Extrinsic Apoptosis Reaction Model (aEARM) 20 , which represents these extrinsic apoptosis execution mechanisms as biomolecular reactions (Figure 2A).…”
Section: Contributions and Biases From Different Data Types To Mechanistic Modelsmentioning
confidence: 99%