Skip to main content

Research Repository

Advanced Search

Outputs (99)

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.

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.

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.

Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current (2022)
Conference Proceeding
Agrawal, A., Clerx, M., Wang, K., Polonchuk, L., Gavaghan, D. J., & Mirams, G. R. (2022). Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current. In 2022 Computing in Cardiology (CinC). https://doi.org/10.22489/CinC.2022.051

The L-type calcium current (ICaL) is a key current of the heart playing an important role in the contraction of the cardiomyocyte. Patch-clamp recordings of ionic currents can be associated with a reduction of the current magnitude with time (termed... Read More about Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current.

Uncertainty and error in SARS-CoV-2 epidemiological parameters inferred from population-level epidemic models (2022)
Journal Article
Whittaker, D. G., Herrera-Reyes, A. D., Hendrix, M., Owen, M. R., Band, L. R., Mirams, G. R., …Preston, S. P. (2023). Uncertainty and error in SARS-CoV-2 epidemiological parameters inferred from population-level epidemic models. Journal of Theoretical Biology, 558, Article 111337. https://doi.org/10.1016/j.jtbi.2022.111337

During the SARS-CoV2 pandemic, epidemic models have been central to policy-making. Public health responses have been shaped by model-based projections and inferences, especially related to the impact of various non-pharmaceutical interventions. Accom... Read More about Uncertainty and error in SARS-CoV-2 epidemiological parameters inferred from population-level epidemic models.

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., 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.

Models of the cardiac L-type calcium current: A quantitative review (2022)
Journal Article
Agrawal, A., Wang, K., Polonchuk, L., Cooper, J., Hendrix, M., Gavaghan, D. J., …Clerx, M. (2022). Models of the cardiac L-type calcium current: A quantitative review. Wiley Interdisciplinary Reviews: Mechanisms of Disease, 15(1), Article e1581. https://doi.org/10.1002/wsbm.1581

The L-type calcium current ((Formula presented.)) plays a critical role in cardiac electrophysiology, and models of (Formula presented.) are vital tools to predict arrhythmogenicity of drugs and mutations. Five decades of measuring and modeling (Form... Read More about Models of the cardiac L-type calcium current: A quantitative review.

Ion channel model reduction using manifold boundaries (2022)
Journal Article
Whittaker, D. G., Wang, J., Shuttleworth, J., Venkateshappa, R., Kemp, J. M., Claydon, T. W., & Mirams, G. R. (2022). Ion channel model reduction using manifold boundaries. Journal of the Royal Society, Interface, 19(193), Article 20220193. https://doi.org/10.1098/rsif.2022.0193

Mathematical models of voltage-gated ion channels are used in basic research, industrial and clinical settings. These models range in complexity, but typically contain numerous variables representing the proportion of channels in a given state, and p... Read More about Ion channel model reduction using manifold boundaries.

cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians (2022)
Journal Article
Hendrix, M., Clerx, M., Tamuri, A. U., Keating, S. M., Johnstone, R. H., Cooper, J., & Mirams, G. R. (2022). cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians. Wellcome Open Research, 6, Article 261. https://doi.org/10.12688/wellcomeopenres.17206.2

Hundreds of different mathematical models have been proposed for describing electrophysiology of various cell types. These models are quite complex (nonlinear systems of typically tens of ODEs and sometimes hundreds of parameters) and software packag... Read More about cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians.

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.

chaste codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians (2022)
Journal Article
Hendrix, M., Clerx, M., Tamuri, A. U., Keating, S. M., Johnstone, R. H., Cooper, J., & Mirams, G. R. (2022). chaste codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians. Wellcome Open Research, 6, Article 261. https://doi.org/10.12688/wellcomeopenres.17206.1

Hundreds of different mathematical models have been proposed for describing electrophysiology of various cell types. These models are quite complex (nonlinear systems of typically tens of ODEs and sometimes hundreds of parameters) and software packag... Read More about chaste codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians.

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., …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.

Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243 (2021)
Journal Article
Kemp, J. M., Whittaker, D. G., Venkateshappa, R., Pang, Z. K., Johal, R., Sergeev, V., …Claydon, T. W. (2021). Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243. Journal of General Physiology, 153(10), Article e202112923. https://doi.org/10.1085/jgp.202112923

Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) and arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity f... Read More about Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243.

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.

Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine (2021)
Journal Article
Whittaker, D. G., Capel, R. A., Hendrix, M., Chan, X. H. S., Herring, N., White, N. J., …Burton, R. A. B. (2021). Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine. Royal Society Open Science, 8(4), https://doi.org/10.1098/rsos.210235

Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-1... Read More about Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine.

Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment (2020)
Conference Proceeding
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.

Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments (2020)
Journal Article
Clerx, M., Lei, C. L., Whittaker, D. G., Gavaghan, D. J., de Boer, T. P., & Mirams, G. R. (2020). Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments. Philosophical Transactions A: Mathematical, Physical and Engineering Sciences, 378(2173), Article 20190348. https://doi.org/10.1098/rsta.2019.0348

Mathematical models of ion channels, which constitute indispensable components of action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study, we fitted cell-specific models to hERG1a (Kv11.1) reco... Read More about Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments.

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.

Calibration of ionic and cellular cardiac electrophysiology models (2020)
Journal Article
Whittaker, D. G., Clerx, M., Lei, C. L., Christini, D. J., & Mirams, G. R. (2020). Calibration of ionic and cellular cardiac electrophysiology models. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 12(4), https://doi.org/10.1002/wsbm.1482

© 2020 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. Cardiac electrophysiology models are among the most mature and well-studied mathematical models of biological systems. This maturity is bringing new challenge... Read More about Calibration of ionic and cellular cardiac electrophysiology models.

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.

Rapid Characterization of hERG Channel Kinetics I: Using an Automated High-Throughput System (2019)
Journal Article
Lei, C. L., Clerx, M., Gavaghan, D. J., Polonchuk, L., Mirams, G. R., & Wang, K. (2019). Rapid Characterization of hERG Channel Kinetics I: Using an Automated High-Throughput System. Biophysical Journal, 117(12), 2438-2454. https://doi.org/10.1016/j.bpj.2019.07.029

Predicting how pharmaceuticals may affect heart rhythm is a crucial step in drug-development, and requires a deep understanding of a compound’s action on ion channels. In vitro hERG-channel current recordings are an important step in evaluating the p... Read More about Rapid Characterization of hERG Channel Kinetics I: Using an Automated High-Throughput System.

Probabilistic Inference on Noisy Time Series (PINTS) (2019)
Journal Article
Clerx, M., Robinson, M., Lambert, B., Lei, C. L., Ghosh, S., Mirams, G. R., & Gavaghan, D. J. (2019). Probabilistic Inference on Noisy Time Series (PINTS). Journal of Open Research Software, 7(1), 23. https://doi.org/10.5334/jors.252

Time series models are ubiquitous in science, arising in any situation where researchers seek to understand how a system’s behaviour changes over time. A key problem in time series modelling is inference; determining properties of the underlying syst... Read More about Probabilistic Inference on Noisy Time Series (PINTS).

Selective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters (2019)
Journal Article
Lin, Y., Bakowski, D., Mirams, G. R., & Parekh, A. B. (2019). Selective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters. Nature Communications, 10(1), https://doi.org/10.1038/s41467-019-10329-3

© 2019, The Author(s). Store-operated Ca2+ entry, involving endoplasmic reticulum Ca2+ sensing STIM proteins and plasma membrane Orai1 channels, is a widespread and evolutionary conserved Ca2+ influx pathway. This form of Ca2+ influx occurs at discre... Read More about Selective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters.

Defining vitamin D status using multi-metabolite mathematical modelling: a pregnancy perspective (2019)
Journal Article
Beentjes, C., Taylor-King, J., Bayani, A., Davis, C., Dunster, J., Jabbari, S., …Tamblyn, J. (2019). Defining vitamin D status using multi-metabolite mathematical modelling: a pregnancy perspective. Journal of Steroid Biochemistry and Molecular Biology, 190, 152-160. https://doi.org/10.1016/j.jsbmb.2019.03.024

Vitamin D deficiency is linked to adverse pregnancy outcomes such as pre-eclampsia (PET) but remains defined by serum measurement of 25-hydroxyvitamin D3 (25(OH)D3) alone. To identify broader changes in vitamin D metabolism during normal and PET preg... Read More about Defining vitamin D status using multi-metabolite mathematical modelling: a pregnancy perspective.

Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology (2018)
Journal Article
Bowler, L. A., Gavaghan, D. J., Mirams, G. R., & Whiteley, J. P. (2019). Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology. Bulletin of Mathematical Biology, 81(1), 7–38. https://doi.org/10.1007/s11538-018-0516-1

Distinct electrophysiological phenotypes are exhibited 1 by biological cells that have differentiated into particular cell types. The usual approach when simulating the cardiac electrophysiology of tissue that includes different cell types is to mode... Read More about Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology.

Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative (2018)
Journal Article
Li, Z., Wu, W. W., Sheng, J., Tran, P. N., Wu, M., Ranolph, A., …Strauss, D. G. (2019). Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative. Clinical Pharmacology and Therapeutics, 105(2), 466-475. https://doi.org/10.1002/cpt.1184

International Council on Harmonization S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are proarrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates mult... Read More about Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative.

Reproducible model development in the Cardiac Electrophysiology Web Lab (2018)
Journal Article
Daly, A. C., Clerx, M., Beattie, K. A., Cooper, J., Gavaghan, D. J., & Mirams, G. R. (2018). Reproducible model development in the Cardiac Electrophysiology Web Lab. Progress in Biophysics and Molecular Biology, 139, 3-14. https://doi.org/10.1016/j.pbiomolbio.2018.05.011

The modelling of the electrophysiology of cardiac cells is one of the most mature areas of systems biology. This extended concentration of research effort brings with it new challenges, foremost among which is that of choosing which of these models i... Read More about Reproducible model development in the Cardiac Electrophysiology Web Lab.

Gaussian process emulation for discontinuous response surfaces with applications for cardiac electrophysiology models (2018)
Other
Ghosh, S., J. Gavaghan, D., & R. Mirams, G. Gaussian process emulation for discontinuous response surfaces with applications for cardiac electrophysiology models

Mathematical models of biological systems are beginning to be used for safety-critical applications, where large numbers of repeated model evaluations are required to perform uncertainty quantification and sensitivity analysis. Most of these models a... Read More about Gaussian process emulation for discontinuous response surfaces with applications for cardiac electrophysiology models.

Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics (2018)
Journal Article
Beattie, K., Hill, A. P., Bardenet, R., Cui, Y., Vandenberg, J. I., Gavaghan, D. J., …Mirams, G. R. (2018). Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics. Journal of Physiology, 596(10), 1813-1828. https://doi.org/10.1113/JP275733

Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to p... Read More about Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics.

Sequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria (2018)
Journal Article
Samanta, K., Mirams, G. R., & Parekh, A. B. (in press). Sequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria. Nature Communications, 9, Article 156. https://doi.org/10.1038/s41467-017-02638-2

Mitochondrial Ca2+ homoeostasis regulates aerobic metabolism and cell survival. Ca2+ flux into mitochondria is mediated by the mitochondrial calcium uniporter (MCU) channel whereas Ca2+ export is often through an electrogenic Na+–Ca2+ exchanger. Here... Read More about Sequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria.

Tailoring mathematical models to stem-cell derived cardiomyocyte lines can improve predictions of drug-induced changes to their electrophysiology (2017)
Journal Article
Lei, C., Wang, K., Clerx, M., Johnstone, R. H., Hortigon-Vinagre, M. P., Zamora, V., …Polonchuk, L. (2017). Tailoring mathematical models to stem-cell derived cardiomyocyte lines can improve predictions of drug-induced changes to their electrophysiology. Frontiers in Physiology, 8, Article 986. https://doi.org/10.3389/fphys.2017.00986

Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in disease modeling, cell therapy, drug screening and personalized medicine. Computational models can be used to interpret experimental findings in iPSC-CMs, prov... Read More about Tailoring mathematical models to stem-cell derived cardiomyocyte lines can improve predictions of drug-induced changes to their electrophysiology.

Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment (2017)
Journal Article
Chang, K., Dutta, S., Mirams, G. R., Beattie, K., Sheng, J., Tran, P. N., …Li, Z. (2017). Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment. Frontiers in Physiology, 8, Article 917. https://doi.org/10.3389/fphys.2017.00917

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Poin... Read More about Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment.

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies (2017)
Journal Article
Ligneau, X., Shah, R. R., Berrebi-Bertrand, I., Mirams, G. R., Robert, P., Landais, L., …Schwartz, J. (2017). Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies. British Journal of Pharmacology, 174, https://doi.org/10.1111/bph.14047

Background and purpose: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. Experimental approach: Nonclinical studies envisaged both in the ICH S7B guideline and Comprehensive in vitro P... Read More about Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies.

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator (2017)
Journal Article
McMillan, B., Gavaghan, D. J., & Mirams, G. R. (2017). Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator. Toxicology Research, 6, 912-921. https://doi.org/10.1039/C7TX00141J

Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the m... Read More about Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator.

Systems Toxicology: Real World Applications and Opportunities (2017)
Journal Article
Hartung, T., FitzGerald, R. E., Jennings, P., Mirams, G. R., Peitsch, M. C., Rostami-Hodjegan, A., …Sturla, S. J. (2017). Systems Toxicology: Real World Applications and Opportunities. Chemical Research in Toxicology, 30(4), 870-882. https://doi.org/10.1021/acs.chemrestox.7b00003

Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxico... Read More about Systems Toxicology: Real World Applications and Opportunities.

Hierarchical Bayesian inference for ion channel screening dose-response data [version 2; peer review: 2 approved] (2017)
Journal Article
Johnstone, R. H., Gavaghan, D. J., Johnstone, R. H., Bardenet, R., Gavaghan, D. J., & Mirams, G. R. (2017). Hierarchical Bayesian inference for ion channel screening dose-response data [version 2; peer review: 2 approved]. Wellcome Open Research, 1, 1-23. https://doi.org/10.12688/wellcomeopenres.9945.2

Dose-response (or 'concentration-effect') relationships commonly occur in biological and pharmacological systems and are well characterised by Hill curves. These curves are described by an equation with two parameters: the inhibitory concentration 50... Read More about Hierarchical Bayesian inference for ion channel screening dose-response data [version 2; peer review: 2 approved].

High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart (2017)
Journal Article
Aston, D., Capel, R. A., Ford, K. L., Christian, H. C., Mirams, G. R., Rog-Zielinska, E. A., …Terrar, D. A. (2017). High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart. Scientific Reports, 7, Article 40620. https://doi.org/10.1038/srep40620

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under b... Read More about High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart.

Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca 2+ Signals (2016)
Journal Article
Kar, P., Mirams, G. R., Christian, H. C., & Parekh, A. B. (2016). Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca 2+ Signals. Molecular Cell, 64(4), 746-759. https://doi.org/10.1016/j.molcel.2016.11.011

© 2016 The Author(s) Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activa... Read More about Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca 2+ Signals.

Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart (2016)
Journal Article
Mahoney, V., Mezzano, V., Mirams, G., Maass, K., Li, Z., Cerrone, M., …Morley, G. (2016). Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart. Scientific Reports, 6(1), Article 26744. https://doi.org/10.1038/srep26744

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electro... Read More about Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart.

Hierarchical Bayesian modelling of variability and uncertainty in synthetic action potential traces (2016)
Journal Article
Johnstone, R. H., Bardenet, R., Gavaghan, D. J., Polonchuk, L., Davies, M. R., & Mirams, G. R. (2016). Hierarchical Bayesian modelling of variability and uncertainty in synthetic action potential traces. Computing in cardiology, 43, 1089-1092

© 2016 CCAL. There are many sources of uncertainty in the recording and modelling of membrane action potentials (APs) from cardiomyocytes. For example, there are measurement, parameter, and model uncertainties. There is also extrinsic variability bet... Read More about Hierarchical Bayesian modelling of variability and uncertainty in synthetic action potential traces.

Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models? (2015)
Journal Article
Johnstone, R. H., Chang, E. T., Bardenet, R., de Boer, T. P., Gavaghan, D. J., Pathmanathan, P., …Mirams, G. R. (2016). Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models?. Journal of Molecular and Cellular Cardiology, 96, 49-62. https://doi.org/10.1016/j.yjmcc.2015.11.018

Cardiac electrophysiology models have been developed for over 50 years, and now include detailed descriptions of individual ion currents and sub-cellular calcium handling. It is commonly accepted that there are many uncertainties in these systems, wi... Read More about Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models?.

Mathematical Modelling of Heart Rate Changes in the Mouse (2015)
Report
Christie, M., Nandi, M., Borg, Y., Carapella, V., Mirams, G., Aston, P., …Chakrabarti, B. Mathematical Modelling of Heart Rate Changes in the Mouse. NC3Rs

The CVS is composed of numerous interacting and dynamically regulated physiological subsystems which each generate measurable periodic components such that the CVS can itself be presented as a system of weakly coupled oscillators. The interactions be... Read More about Mathematical Modelling of Heart Rate Changes in the Mouse.

Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential (2015)
Journal Article
Capel, R. A., Herring, N., Kalla, M., Yavari, A., Mirams, G. R., Douglas, G., …Burton, R. A. B. (2015). Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential. Heart Rhythm, 12(10), 2186-2194. https://doi.org/10.1016/j.hrthm.2015.05.027

© 2015 Heart Rhythm Society. Background Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption. Objectives The purpose of this study... Read More about Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential.

Ca2+ Channel Re-localization to Plasma-Membrane Microdomains Strengthens Activation of Ca2+-Dependent Nuclear Gene Expression (2015)
Journal Article
Samanta, K., Kar, P., Mirams, G. R., & Parekh, A. B. (2015). Ca2+ Channel Re-localization to Plasma-Membrane Microdomains Strengthens Activation of Ca2+-Dependent Nuclear Gene Expression. Cell Reports, 12(2), 203-216. https://doi.org/10.1016/j.celrep.2015.06.018

© 2015 The Authors. In polarized cells or cells with complex geometry, clustering of plasma-membrane (PM) ion channels is an effective mechanism for eliciting spatially restricted signals. However, channel clustering is also seen in cells with relati... Read More about Ca2+ Channel Re-localization to Plasma-Membrane Microdomains Strengthens Activation of Ca2+-Dependent Nuclear Gene Expression.

A web portal for in-silico action potential predictions (2015)
Journal Article
Williams, G., & Mirams, G. R. (2015). A web portal for in-silico action potential predictions. Journal of Pharmacological and Toxicological Methods, 75, 10-16. https://doi.org/10.1016/j.vascn.2015.05.002

© 2015 . Introduction: Multiple cardiac ion channels are prone to block by pharmaceutical compounds, and this can have large implications for cardiac safety. The effect of a compound on individual ion currents can now be measured in automated patch c... Read More about A web portal for in-silico action potential predictions.

Cardiac tissue slices: Preparation, handling, and successful optical mapping (2015)
Journal Article
Wang, K., Lee, P., Mirams, G. R., Sarathchandra, P., Borg, T. K., Gavaghan, D. J., …Bollensdorff, C. (2015). Cardiac tissue slices: Preparation, handling, and successful optical mapping. AJP - Heart and Circulatory Physiology, 308(9), H1112-H1125. https://doi.org/10.1152/ajpheart.00556.2014

© 2015 the American Physiological Society. Cardiac tissue slices are becoming increasingly popular as a model system for cardiac electrophysiology and pharmacology research and development. Here, we describe in detail the preparation, handling, and o... Read More about Cardiac tissue slices: Preparation, handling, and successful optical mapping.

Cellular cardiac electrophysiology modeling with Chaste and CellML (2015)
Journal Article
Cooper, J., Spiteri, R. J., & Mirams, G. R. (2015). Cellular cardiac electrophysiology modeling with Chaste and CellML. Frontiers in Physiology, 5, https://doi.org/10.3389/fphys.2014.00511

© 2015 Cooper, Spiteri and Mirams. Chaste is an open-source C++ library for computational biology that has well-developed cardiac electrophysiology tissue simulation support. In this paper, we introduce the features available for performing cardiac e... Read More about Cellular cardiac electrophysiology modeling with Chaste and CellML.

Estimation of Conductivity Tensors from Human Ventricular Optical Mapping Recordings (2013)
Book Chapter
Walmsley, J., Mirams, G. R., Efimov, I. R., Burrage, K., & Rodriguez, B. (2013). Estimation of Conductivity Tensors from Human Ventricular Optical Mapping Recordings. In S. Ourselin, D. Rueckert, & N. Smith (Eds.), Functional Imaging and Modeling of the Heart: 7th International Conference, FIMH 2013, London, UK, June 20-22, 2013. Proceedings (224-231). Springer Verlag. https://doi.org/10.1007/978-3-642-38899-6_27

Experimental recordings of transmural activation in the human left ventricle show variability in recorded activation times. In this paper we demonstrate a framework for fitting the conductivity tensor of a monodomain model to reproduce activation tim... Read More about Estimation of Conductivity Tensors from Human Ventricular Optical Mapping Recordings.

Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment (2013)
Journal Article
Elkins, R. C., Davies, M. R., Brough, S. J., Gavaghan, D. J., Cui, Y., Abi-Gerges, N., & Mirams, G. R. (2013). Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment. Journal of Pharmacological and Toxicological Methods, 68(1), 112-122. https://doi.org/10.1016/j.vascn.2013.04.007

Introduction: Unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for safety pharmacology teams to detect block of cardiac ion channels, and ne... Read More about Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment.

Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge (2013)
Journal Article
Beattie, K. A., Luscombe, C., Williams, G., Munoz-Muriedas, J., Gavaghan, D. J., Cui, Y., & Mirams, G. R. (2013). Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge. Journal of Pharmacological and Toxicological Methods, 68(1), 88-96. https://doi.org/10.1016/j.vascn.2013.04.004

Introduction Drugs that prolong the QT interval on the electrocardiogram present a major safety concern for pharmaceutical companies and regulatory agencies. Despite a range of assays performed to assess compound effects on the QT interval, QT prolo... Read More about Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge.

Chaste: An Open Source C++ Library for Computational Physiology and Biology (2013)
Journal Article
Mirams, G. R., Arthurs, C. J., Bernabeu, M. O., Bordas, R., Cooper, J., Corrias, A., …Gavaghan, D. J. (2013). Chaste: An Open Source C++ Library for Computational Physiology and Biology. PLoS Computational Biology, 9(3), e1002970. https://doi.org/10.1371/journal.pcbi.1002970

Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac ele... Read More about Chaste: An Open Source C++ Library for Computational Physiology and Biology.

mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study (2013)
Journal Article
Walmsley, J., Rodriguez, J. F., Mirams, G. R., Burrage, K., Efimov, I. R., & Rodriguez, B. (2013). mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study. PLoS ONE, 8(2), https://doi.org/10.1371/journal.pone.0056359

Differences in mRNA expression levels have been observed in failing versus non-failing human hearts for several membrane channel proteins and accessory subunits. These differences may play a causal role in electrophysiological changes observed in hum... Read More about mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study.

Computational assessment of drug-induced effects on the electrocardiogram: From ion channel to body surface potentials (2013)
Journal Article
Zemzemi, N., Bernabeu, M. O., Saiz, J., Cooper, J., Pathmanathan, P., Mirams, G. R., …Rodriguez, B. (2013). Computational assessment of drug-induced effects on the electrocardiogram: From ion channel to body surface potentials. British Journal of Pharmacology, 168(3), 718-733. https://doi.org/10.1111/j.1476-5381.2012.02200.x

Background and Purpose: Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug actio... Read More about Computational assessment of drug-induced effects on the electrocardiogram: From ion channel to body surface potentials.

Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing (2012)
Journal Article
Mirams, G. R., Davies, M. R., Cui, Y., Kohl, P., & Noble, D. (2012). Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing. British Journal of Pharmacology, 167(5), 932-945. https://doi.org/10.1111/j.1476-5381.2012.02020.x

Concerns over cardiac side effects are the largest single cause of compound attrition during pharmaceutical drug development. For a number of years, biophysically detailed mathematical models of cardiac electrical activity have been used to explore h... Read More about Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing.

A theoretical investigation of the effect of proliferation and adhesion on monoclonal conversion in the colonic crypt (2012)
Journal Article
Mirams, G. R., Fletcher, A. G., Maini, P. K., & Byrne, H. M. (2012). A theoretical investigation of the effect of proliferation and adhesion on monoclonal conversion in the colonic crypt. Journal of Theoretical Biology, 312, 143-156. https://doi.org/10.1016/j.jtbi.2012.08.002

The surface epithelium lining the intestinal tract renews itself rapidly by a coordinated programme of cell proliferation, migration and differentiation events that is initiated in the crypts of Lieberkühn. It is generally believed that colorectal ca... Read More about A theoretical investigation of the effect of proliferation and adhesion on monoclonal conversion in the colonic crypt.

Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG (2012)
Journal Article
Jonsson, M. K., Vos, M. A., Mirams, G. R., Duker, G., Sartipy, P., De Boer, T. P., & Van Veen, T. A. (2012). Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. Journal of Molecular and Cellular Cardiology, 52(5), 998-1008. https://doi.org/10.1016/j.yjmcc.2012.02.002

Human embryonic stem cell-derived cardiomyocytes (hESC-CM) have been proposed as a new model for safety pharmacology. So far, a thorough description of their basic electrophysiology and extensive testing, and mechanistic explanations, of their overal... Read More about Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG.

Distinguishing possible mechanisms for auxin-mediated developmental control in Arabidopsis: Models with two Aux/IAA and ARF proteins, and two target gene-sets (2011)
Journal Article
Bridge, L. J., Mirams, G. R., Kieffer, M. L., King, J. R., & Kepinski, S. (2012). Distinguishing possible mechanisms for auxin-mediated developmental control in Arabidopsis: Models with two Aux/IAA and ARF proteins, and two target gene-sets. Mathematical Biosciences, 235(1), 32-44. https://doi.org/10.1016/j.mbs.2011.10.005

New models of gene transcriptional responses to auxin signalling in Arabidopsis are presented. This work extends a previous model of auxin signalling to include networks of gene-sets which may control developmental responses along auxin gradients. Ke... Read More about Distinguishing possible mechanisms for auxin-mediated developmental control in Arabidopsis: Models with two Aux/IAA and ARF proteins, and two target gene-sets.

A local sensitivity analysis method for developing biological models with identifiable parameters: Application to cardiac ionic channel modelling (2011)
Journal Article
Sher, A. A., Wang, K., Wathen, A., Maybank, P. J., Mirams, G. R., Abramson, D., …Gavaghan, D. J. (2013). A local sensitivity analysis method for developing biological models with identifiable parameters: Application to cardiac ionic channel modelling. Future Generation Computer Systems, 29(2), 591-598. https://doi.org/10.1016/j.future.2011.09.006

Computational cardiac models provide important insights into the underlying mechanisms of heart function. Parameter estimation in these models is an ongoing challenge with many existing models being overparameterised. Sensitivity analysis presents a... Read More about A local sensitivity analysis method for developing biological models with identifiable parameters: Application to cardiac ionic channel modelling.

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing (2011)
Journal Article
Quinn, T. A., Granite, S., Allessie, M. A., Antzelevitch, C., Bollensdorff, C., Bub, G., …Kohl, P. (2011). Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing. Progress in Biophysics and Molecular Biology, 107(1), 4-10. https://doi.org/10.1016/j.pbiomolbio.2011.07.001

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information... Read More about Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing.

High-throughput functional curation of cellular electrophysiology models (2011)
Journal Article
Cooper, J., Mirams, G. R., & Niederer, S. A. (2011). High-throughput functional curation of cellular electrophysiology models. Progress in Biophysics and Molecular Biology, 107(1), 11-20. https://doi.org/10.1016/j.pbiomolbio.2011.06.003

Effective reuse of a quantitative mathematical model requires not just access to curated versions of the model equations, but also an understanding of the functional capabilities of the model, and the advisable scope of its application. To enable thi... Read More about High-throughput functional curation of cellular electrophysiology models.

Novel approaches to assessing cardiac safety - Proceedings of a workshop: Regulators, industry and academia discuss the future of in silico cardiac modelling to predict the proarrhythmic safety of drugs (2011)
Journal Article
Fletcher, K., Shah, R. R., Thomas, A., Tobin, F., Rodriguez, B., Mirams, G. R., …Noble, D. (2011). Novel approaches to assessing cardiac safety - Proceedings of a workshop: Regulators, industry and academia discuss the future of in silico cardiac modelling to predict the proarrhythmic safety of drugs. Drug Safety, 34(5), 439-443. https://doi.org/10.2165/11591950-000000000-00000

The significant effect of the choice of ionic current integration method in cardiac electro-physiological simulations (2011)
Journal Article
Pathmanathan, P., Mirams, G. R., Southern, J., & Whiteley, J. P. (2011). The significant effect of the choice of ionic current integration method in cardiac electro-physiological simulations. International Journal for Numerical Methods in Biomedical Engineering, 27(11), 1751-1770. https://doi.org/10.1002/cnm.1438

Finite element (FE) cardiac electro-physiology solvers commonly have ionic current determined at mesh nodes but required element interiors. We consider two interpolation approaches: (i) ionic current interpolation (ICI), where nodal ionic currents ar... Read More about The significant effect of the choice of ionic current integration method in cardiac electro-physiological simulations.

Simulation of multiple ion channel block provides improved prediction of compounds’ clinical torsadogenic risk (2011)
Journal Article
Mirams, G. R., Cui, Y., Sher, A., Fink, M., Cooper, J., Heath, B. M., …Noble, D. (2011). Simulation of multiple ion channel block provides improved prediction of compounds’ clinical torsadogenic risk. Cardiovascular Research, 91(1), 53-61. https://doi.org/10.1093/cvr/cvr044

© 2011 The Author. Aims The level of inhibition of the human Ether - go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the... Read More about Simulation of multiple ion channel block provides improved prediction of compounds’ clinical torsadogenic risk.

A hybrid approach to multi-scale modelling of cancer (2010)
Journal Article
Osborne, J. M., Walter, A., Kershaw, S. K., Mirams, G. R., Fletcher, A. G., Pathmanathan, P., …Byrne, H. M. (2010). A hybrid approach to multi-scale modelling of cancer. Philosophical Transactions A: Mathematical, Physical and Engineering Sciences, 368(1930), 5013-5028. https://doi.org/10.1098/rsta.2010.0173

In this paper, we review multi-scale models of solid tumour growth and discuss a middleout framework that tracks individual cells. By focusing on the cellular dynamics of a healthy colorectal crypt and its invasion by mutant, cancerous cells, we comp... Read More about A hybrid approach to multi-scale modelling of cancer.

Phenomenological modeling of cell-to-cell and beat-to-beat variability in isolated guinea pig ventricular myocytes (2010)
Conference Proceeding
Walmsley, J., Mirams, G., Bahoshy, M., Bollensdorff, C., Rodriguez, B., & Burrage, K. (2010). Phenomenological modeling of cell-to-cell and beat-to-beat variability in isolated guinea pig ventricular myocytes. In 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology, (1457-1460). https://doi.org/10.1109/IEMBS.2010.5626858

Experimental action potential (AP) recordings in isolated ventricular myoctes display significant temporal beatto- beat variability in morphology and duration. Furthermore, significant cell-to-cell differences in AP also exist even for isolated cells... Read More about Phenomenological modeling of cell-to-cell and beat-to-beat variability in isolated guinea pig ventricular myocytes.

Modelling spatially regulated ?-catenin dynamics and invasion in intestinal crypts (2010)
Journal Article
Murray, P. J., Kang, J. W., Mirams, G. R., Shin, S. Y., Byrne, H. M., Maini, P. K., & Cho, K. H. (2010). Modelling spatially regulated ?-catenin dynamics and invasion in intestinal crypts. Biophysical Journal, 99(3), 716-725. https://doi.org/10.1016/j.bpj.2010.05.016

Experimental data (e.g., genetic lineage and cell population studies) on intestinal crypts reveal that regulatory features of crypt behavior, such as control via morphogen gradients, are remarkably well conserved among numerous organisms (e.g., from... Read More about Modelling spatially regulated ?-catenin dynamics and invasion in intestinal crypts.

Multiscale modeling of colonic crypts and early colorectal cancer (2010)
Book Chapter
Fletcher, A. G., Mirams, G. R., Murray, P. J., Walter, A., Kang, J. W., Cho, K. H., …Byrne, H. M. (2010). Multiscale modeling of colonic crypts and early colorectal cancer. In T. S. Deisboeck, & G. Stamatakos (Eds.), Multiscale Cancer Modeling (111-131). CRC Press. https://doi.org/10.1201/b10407

© 2011 by Taylor & Francis Group, LLC. Colorectal cancer accounts for 13% of all cancers in the United Kingdom, with around 35,300 new diagnoses and 16,000 deaths occurring each year (http://info.cancerresearchuk.org). Colorectal cancer is predomin... Read More about Multiscale modeling of colonic crypts and early colorectal cancer.

An integrative computational model for intestinal tissue renewal (2009)
Journal Article
Van Leeuwen, I. M., Mirams, G. R., Walter, A., Fletcher, A., Murray, P., Osborne, J., …Byrne, H. M. (2009). An integrative computational model for intestinal tissue renewal. Cell Proliferation, 42(5), 617-636. https://doi.org/10.1111/j.1365-2184.2009.00627.x

Objectives: The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoreti... Read More about An integrative computational model for intestinal tissue renewal.

Chaste: A test-driven approach to software development for biological modelling (2009)
Journal Article
Pitt-Francis, J., Pathmanathan, P., Bernabeu, M. O., Bordas, R., Cooper, J., Fletcher, A. G., …Gavaghan, D. J. (2009). Chaste: A test-driven approach to software development for biological modelling. Computer Physics Communications, 180(12), 2452-2471. https://doi.org/10.1016/j.cpc.2009.07.019

Chaste ('Cancer, heart and soft-tissue environment') is a software library and a set of test suites for computational simulations in the domain of biology. Current functionality has arisen from modelling in the fields of cancer, cardiac physiology an... Read More about Chaste: A test-driven approach to software development for biological modelling.

A multiple timescale analysis of a mathematical model of the Wnt/?-catenin signalling pathway (2009)
Journal Article
Mirams, G. R., Byrne, H. M., & King, J. R. (2010). A multiple timescale analysis of a mathematical model of the Wnt/?-catenin signalling pathway. Journal of Mathematical Biology, 60(1), 131-160. https://doi.org/10.1007/s00285-009-0262-y

The Wnt signalling pathway is involved in stem cell maintenance, differentiation and tissue development. Its disregulation has also been implicated in many cancers. β-catenin is a protein that regulates both transcription of many genes and cell-cell... Read More about A multiple timescale analysis of a mathematical model of the Wnt/?-catenin signalling pathway.

A computational study of discrete mechanical tissue models (2009)
Journal Article
Pathmanathan, P., Cooper, J., Fletcher, A., Mirams, G., Murray, P., Osborne, J., …Chapman, S. J. (2009). A computational study of discrete mechanical tissue models. Physical Biology, 6(3), Article 036001. https://doi.org/10.1088/1478-3975/6/3/036001

A computational study of discrete 'cell-centre' approaches to modelling the evolution of a collection of cells is undertaken. The study focuses on the mechanical aspects of the tissue, in order to separate the passive mechanical response of the model... Read More about A computational study of discrete mechanical tissue models.