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All Outputs (117)

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 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.

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.

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), Article 2516. 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., de Boer, T. P., & 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.