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Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development (2022)
Presentation / Conference Contribution
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.

Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation (2022)
Journal Article
Lin, Y.-P., Scappini, E., Landaverde, C., Parekh-Glitsch, F., Tucker, C. J., Mirams, G. R., & Parekh, A. B. (2022). Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation. Molecular and Cellular Biology, 42(11), Article e00175-22. https://doi.org/10.1128/mcb.00175-22

A-kinase anchoring protein 79 (AKAP79) is a human scaffolding protein that organizes Ca2+/calmodulin-dependent protein phosphatase calcineurin, calmodulin, cAMP-dependent protein kinase, protein kinase C, and the transcription factor nuclear factor o... Read More about Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation.

A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models (2022)
Journal Article
Barral, Y. H. M., Shuttleworth, J., Clerx, M., Whittaker, D. G., Wang, K., Polonchuk, L., …Mirams, G. R. (2022). A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models. Frontiers in Physiology, 13, Article 879035. https://doi.org/10.3389/fphys.2022.879035

Computational models of the electrical potential across a cell membrane are longstanding and vital tools in electrophysiology research and applications. These models describe how ionic currents, internal fluxes, and buffering interact to determine me... Read More about A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability (2022)
Journal Article
Sher, A., Niederer, S. A., Mirams, G. R., Kirpichnikova, A., Allen, R., Pathmanathan, P., …Noble, D. (2022). A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability. Bulletin of Mathematical Biology, 84(3), Article 39. https://doi.org/10.1007/s11538-021-00982-5

There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models.... Read More about A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability.

A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer (2021)
Journal Article
Lei, C. L., Fabbri, A., Whittaker, D. G., Clerx, M., Windley, M. J., Hill, A. P., Mirams, G. R., & de Boer, T. P. (2021). A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer. Wellcome Open Research, 5, 1-34. https://doi.org/10.12688/wellcomeopenres.15968.2

Automated patch-clamp platforms are widely used and vital tools in both academia and industry to enable high-throughput studies such as drug screening. A leak current to ground occurs whenever the seal between a pipette and cell (or internal solution... Read More about A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer.

Neural Network Differential Equations For Ion Channel Modelling (2021)
Journal Article
Lei, C. L., & Mirams, G. R. (2021). Neural Network Differential Equations For Ion Channel Modelling. Frontiers in Physiology, 12, Article 708944. https://doi.org/10.3389/fphys.2021.708944

Mathematical models of cardiac ion channels have been widely used to study and predict the behaviour of ion currents. Typically models are built using biophysically-based mechanistic principles such as Hodgkin-Huxley or Markov state transitions. Thes... Read More about Neural Network Differential Equations For Ion Channel Modelling.

Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia (2021)
Journal Article
Clerx, M., Mirams, G. R., Rogers, A. J., Narayan, S. M., & Giles, W. R. (2021). Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia. Frontiers in Physiology, 12, Article 651162. https://doi.org/10.3389/fphys.2021.651162

Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K+, Na+, Ca2+, and/or Mg2+ can significantly alter physiological responses in the heart, blood vessels, and... Read More about Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia.

Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment (2020)
Presentation / Conference Contribution
Camporesi, M., Bartolucci, C., Lei, C. L., Mirams, G. R., De Boer, T. P., & Severi, S. (2020). Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment. . https://doi.org/10.22489/CinC.2020.416

© 2020 Creative Commons; the authors hold their copyright. As drugs can be multichannel blockers it is important to assess their cardiac safety taking into account multiple currents. In silico action potential (AP) models have been proposed for being... Read More about Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment.

Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk (2020)
Journal Article
Davies, M. R., Martinec, M., Walls, R., Schwarz, R., Mirams, G. R., Wang, K., …Polonchuk, L. (2020). Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk. Cell Reports Medicine, 1(5), Article 100076. https://doi.org/10.1016/j.xcrm.2020.100076

There is an increasing expectation that computational approaches may supplement existing human decision-making. Frontloading of models for cardiac safety prediction is no exception to this trend, and ongoing regulatory initiatives propose use of high... Read More about Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk.

A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer [version 1; peer review: 2 approved with reservations] (2020)
Journal Article
Lei, C. L., Fabbri, A., Whittaker, D. G., Clerx, M., Windley, M. J., Hill, A. P., …de Boer, T. P. (2020). A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer [version 1; peer review: 2 approved with reservations]. Wellcome Open Research, 5, Article 152. https://doi.org/10.12688/wellcomeopenres.15968.1

Automated patch-clamp platforms are widely used and vital tools in both academia and industry to enable high-throughput studies such as drug screening. A leak current to ground occurs whenever the seal between a pipette and cell (or internal solution... Read More about A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer [version 1; peer review: 2 approved with reservations].

Considering discrepancy when calibrating a mechanistic electrophysiology model (2020)
Journal Article
Wilkinson, R. D., Worden, K., Walmsley, J., Dos Santos, R. W., Riabiz, M., Pathmanathan, P., …Whittaker, D. G. (2020). Considering discrepancy when calibrating a mechanistic electrophysiology model. Philosophical Transactions A: Mathematical, Physical and Engineering Sciences, 378(2173), 20190349. https://doi.org/10.1098/rsta.2019.0349

Uncertainty quantification (UQ) is a vital step in using mathematical models and simulations to take decisions. The field of cardiac simulation has begun to explore and adopt UQ methods to characterize uncertainty in model inputs and how that propaga... Read More about Considering discrepancy when calibrating a mechanistic electrophysiology model.

Corrigendum to “A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm” [Toxicology and Applied Pharmacology volume 394C (2020) 114961] (2020)
Journal Article
Ridder, B. J., Leishman, D. J., Bridgland-Taylor, M., Samieegohar, M., Han, X., Wu, W. W., …Li, Z. (2020). Corrigendum to “A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm” [Toxicology and Applied Pharmacology volume 394C (2020) 114961]. Toxicology and Applied Pharmacology, 395, Article 114983. https://doi.org/10.1016/j.taap.2020.114983

© 2020 The Author(s) The authors regret that one affiliation address is mistaken in the published paper. Matthew Bridgland-Taylor's affiliation was incorrectly listed as Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, United Kin... Read More about Corrigendum to “A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm” [Toxicology and Applied Pharmacology volume 394C (2020) 114961].

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm (2020)
Journal Article
Bardenet, R., Ridder, B. J., Leishman, D. J., Bridgland-Taylor, M., Samieegohar, M., Han, X., …Li, Z. (2020). A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm. Toxicology and Applied Pharmacology, 394, Article 114961. https://doi.org/10.1016/j.taap.2020.114961

© 2020 Introduction: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quant... Read More about A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

Rapid characterisation of hERG channel kinetics II: temperature dependence (2019)
Journal Article
Lei, C. L., Clerx, M., Beattie, K. A., Melgari, D., Hancox, J. C., Gavaghan, D. J., …Mirams, G. R. (2019). Rapid characterisation of hERG channel kinetics II: temperature dependence. Biophysical Journal, 117(12), 2455-2470. https://doi.org/10.1101/609719

Ion channel behavior can depend strongly on temperature, with faster kinetics at physiological temperatures leading to considerable changes in currents relative to room temperature. These temperature-dependent changes in voltage-dependent ion channel... Read More about Rapid characterisation of hERG channel kinetics II: temperature dependence.

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy (2019)
Journal Article
Li, Z., Mirams, G. R., Yoshinaga, T., Ridder, B. J., Han, X., Chen, J. E., …Strauss, D. G. (2020). General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy. Clinical Pharmacology and Therapeutics, 107(1), 102-111. https://doi.org/10.1002/cpt.1647

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and... Read More about General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy.

Four Ways to Fit an Ion Channel Model (2019)
Journal Article
Clerx, M., Beattie, K., Gavaghan, D., & Mirams, G. (2019). Four Ways to Fit an Ion Channel Model. Biophysical Journal, 117(12), 2420-2437. https://doi.org/10.1016/j.bpj.2019.08.001

© 2019 Biophysical Society Mathematical models of ionic currents are used to study the electrophysiology of the heart, brain, gut, and several other organs. Increasingly, these models are being used predictively in the clinic, for example, to predict... Read More about Four Ways to Fit an Ion Channel Model.

Rapid Characterization of hERG Channel Kinetics II: Temperature Dependence (2019)
Journal Article
Lei, C. L., Clerx, M., Beattie, K. A., Melgari, D., Hancox, J. C., Gavaghan, D. J., …Mirams, G. R. (2019). Rapid Characterization of hERG Channel Kinetics II: Temperature Dependence. Biophysical Journal, 117(12), 2455-2470. https://doi.org/10.1016/j.bpj.2019.07.030

© 2019 Biophysical Society Ion channel behavior can depend strongly on temperature, with faster kinetics at physiological temperatures leading to considerable changes in currents relative to room temperature. These temperature-dependent changes in vo... Read More about Rapid Characterization of hERG Channel Kinetics II: Temperature Dependence.