2200 - Mathematical Sciences

Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies (2024)
Journal Article
Grandits, T., Augustin, C. M., Haase, G., Jost, N., Mirams, G. R., Niederer, S. A., …Jung, A. (2024). Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies. eLife, 12, Article RP91911. https://doi.org/10.7554/elife.91911.3

Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimen... Read More about Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies.

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation (2024)
Journal Article
Ayagama, T., Charles, P. D., Bose, S. J., Boland, B., Priestman, D. A., Aston, D., …Burton, R. A. (2024). Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation. iScience, 27(6), Article 109609. https://doi.org/10.1016/j.isci.2024.109609

Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signalling.... Read More about Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation.

Understanding the impact of numerical solvers on inference for differential equation models (2024)
Journal Article
Creswell, R., Shepherd, K. M., Lambert, B., Mirams, G. R., Lei, C. L., Tavener, S., …Gavaghan, D. J. (2024). Understanding the impact of numerical solvers on inference for differential equation models. Journal of the Royal Society, Interface, 21(212), Article 20230369. https://doi.org/10.1098/rsif.2023.0369

Most ordinary differential equation (ODE) models used to describe biological or physical systems must be solved approximately using numerical methods. Perniciously, even those solvers that seem sufficiently accurate for the forward problem, i.e. for... Read More about Understanding the impact of numerical solvers on inference for differential equation models.

Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics (2023)
Journal Article
Shuttleworth, J. G., Lei, C. L., Whittaker, D. G., Windley, M. J., Hill, A. P., Preston, S. P., & Mirams, G. R. (2024). Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics. Bulletin of Mathematical Biology, 86(1), Article 2. https://doi.org/10.1007/s11538-023-01224-6

When using mathematical models to make quantitative predictions for clinical or industrial use, it is important that predictions come with a reliable estimate of their accuracy (uncertainty quantification). Because models of complex biological system... Read More about Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics.

The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk (2023)
Journal Article
Lei, C. L., Whittaker, D. G., & Mirams, G. R. (2024). The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk. British Journal of Pharmacology, 181(7), 987-1004. https://doi.org/10.1111/bph.16250

Background and Purpose Drug-induced reduction of the rapid delayed rectifier potassium current carried by the human Ether-à-go-go-Related Gene (hERG) channel is associated with increased risk of arrhythmias. Recent updates to drug safety regulatory... Read More about The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk.

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings (2023)
Journal Article
Clark, A. P., Clerx, M., Wei, S., Lei, C. L., de Boer, T. P., Mirams, G. R., …Krogh-Madsen, T. (2023). Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. EP-Europace, 25(9), Article euad243. https://doi.org/10.1093/europace/euad243

Aims Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data,... Read More about Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.

Model-driven optimal experimental design for calibrating cardiac electrophysiology models (2023)
Journal Article
Lei, C. L., Clerx, M., Gavaghan, D. J., & Mirams, G. R. (2023). Model-driven optimal experimental design for calibrating cardiac electrophysiology models. Computer Methods and Programs in Biomedicine, 240, Article 107690. https://doi.org/10.1016/j.cmpb.2023.107690

Background and Objective: Models of the cardiomyocyte action potential have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, action potential models are highly nonlin... Read More about Model-driven optimal experimental design for calibrating cardiac electrophysiology models.

Computational Cardiac Safety Testing (2023)
Book Chapter
Mirams, G. R. (2023). Computational Cardiac Safety Testing. In F. J. Hock, M. R. Gralinski, & M. K. Pugsley (Eds.), Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays (1-33). Springer. https://doi.org/10.1007/978-3-030-73317-9_137-1

In recent years, computational cardiac electrophysiology simulations using mathematical models have begun to be used in industrial and regulatory assessment of the proarrhythmic risk of candidate drug compounds. The aim of this chapter is to equip th... Read More about Computational Cardiac Safety Testing.

Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development (2022)
Conference Proceeding
Barral, Y. S. H., Polonchuk, L., R. Mirams, G., Clerx, M., Page, G., Sweat, K., …Gavaghan, D. J. (2022). Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development. In Computing in Cardiology 2022. https://doi.org/10.22489/cinc.2022.356

In silico models of cardiomyocyte electrophysiology describe the various ionic currents and fluxes that lead to the formation of action potentials (APs). Experimental data used to create such models can be recorded in adult human cardiac trabeculae u... Read More about Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development.

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