All Outputs (115)

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.

Tailoring mathematical models to stem-cell derived cardiomyocyte lines can improve predictions of drug-induced changes to their electrophysiology (2017)
Journal Article
Lei, C.-L., 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., Wu, M., Wu, W. W., Colatsky, T., Strauss, D. G., & 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.-C. (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.

Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century (2016)
Journal Article
Hill, A. P., Perry, M. D., Abi-Gerges, N., Couderc, J.-P., Fermini, B., Hancox, J. C., …Vandenberg, J. I. (2016). Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century. Journal of Physiology, 594(23), 6893-6908. https://doi.org/10.1113/jp272015

Uncertainty and variability in computational and mathematical models of cardiac physiology: Uncertainty and variability in cardiac models (2016)
Journal Article
Mirams, G. R., Pathmanathan, P., Gray, R. A., Challenor, P., & Clayton, R. H. (2016). Uncertainty and variability in computational and mathematical models of cardiac physiology: Uncertainty and variability in cardiac models. Journal of Physiology, 594(23), 6833-6847. https://doi.org/10.1113/jp271671

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)
Presentation / Conference Contribution
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.

Recent developments in using mechanistic cardiac modelling for drug safety evaluation (2016)
Journal Article
Davies, M. R., Wang, K., Mirams, G. R., Caruso, A., Noble, D., Walz, A., …Polonchuk, L. (2016). Recent developments in using mechanistic cardiac modelling for drug safety evaluation. Drug Discovery Today, 21(6), 924-938. https://doi.org/10.1016/j.drudis.2016.02.003

The Cardiac Electrophysiology Web Lab (2016)
Journal Article

Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models? (2015)
Journal Article

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.