35 research outputs found
CardiacModelling/model-reduction-manifold-boundaries: Published version
No full textScripts and data for ion channel model reduction using the manifold boundary approximation method (MBAM) and parameter inference using Myokit and PINTS modules in Python. This code is associated with the paper:
"Ion channel model reduction using manifold boundaries". Royal Society Interface. Whittaker, D.G., Wang, J., Shuttleworth, J.G., Venkateshappa, R., Kemp, J.M., Claydon, T.W., Mirams, G.R. (2022
Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment
No full textAs 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 able to integrate drugs effect on ionic currents and generate the resulting AP. However, a mathematical description of drug effects is required, which could be inaccurate. Dynamic Clamp has been proposed for drug cardiac safety assessment. In the dynamic action potential clamp (dAPC) configuration it creates an hybrid model connecting a real cell with a computer simulation. This way, drugs could be administrated directly to real cells, and effects on currents can be taken into account when generating the AP. Here we design and simulate a parallel multichannel dAPC system. The system includes the real cells overexpressing the currents of interest, the voltage clamp acquisition system, and the AP in silico model
mRNA expression levels in failing human hearts predict cellular electrophysiological remodelling: A population−based simulation study
No full textDifferences 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 human heart failure and atrial fibrillation, such as action potential (AP) prolongation, increased AP triangulation, decreased intracellular calcium transient (CaT) magnitude and decreased CaT triangulation. Our goal is to investigate whether the information contained in mRNA measurements can be used to predict cardiac electrophysiological remodeling in heart failure using computational modeling. Using mRNA data recently obtained from failing and non-failing human hearts, we construct failing and non-failing cell populations incorporating natural variability and up/down regulation of channel conductivities. Six biomarkers are calculated for each cell in each population, at cycle lengths between 1500 ms and 300 ms. Regression analysis is performed to determine which ion channels drive biomarker variability in failing versus non-failing cardiomyocytes. Our models suggest that reported mRNA expression changes are consistent with AP prolongation, increased AP triangulation, increased CaT duration, decreased CaT triangulation and amplitude, and increased delay between AP and CaT upstrokes in the failing population. Regression analysis reveals that changes in AP biomarkers are driven primarily by reduction in I, and changes in CaT biomarkers are driven predominantly by reduction in I and SERCA. In particular, the role of I is pacing rate dependent. Additionally, alternans developed at fast pacing rates for both failing and non-failing cardiomyocytes, but the underlying mechanisms are different in control and heart failure
Is it time for in silico simulation of drug cardiac side effects?
No full textCardiac simulation is used to integrate information on drug action to predict side effects on the whole heart. Could simulation begin to replace animal models
Stochasticity in Action Potential duration Enhances Dispersion of Repolarisation at Fast Pacing Rates
No full textPatch clamp recordings of isolated ventricular myocytes frequently display a temporal variability in the action potential duration. Intercellular coupling through gap junctions has been shown to reduce such variability which may return as coupling is reduced. A phenomenological model capable of accurately capturing action potential morphology and variability observed in experimental data has been developed with tunable restitution properties. The phenomenological formulation also allows fast simulation compared with biophysically detailed models. This model is now used to investigate the effects of action potential variability over prolonged periods. A two dimensional tissue slab is simulated using a monodomain model and the simulation software Chaste. Simulations are performed with and without variability in the action potential model. Different coupling strengths are used with a physiological conductivity corresponding to a conduction velocity of 71cm/s. Simulations are performed at full conductivity, and with the conductivity scaled by factors of 0.5, 0.1 and 0.05. At a pacing cycle length of 1000ms with physiological coupling and differences in action potential duration with and without variability are negligible. Under reduced coupling, the difference increases to a maximum of 2ms. No correlation is observed between beats. At a cycle length of 230ms, temporal variability drives the cell model to alternans. This effect is reduced in tissue at all conductivities. Tissue was paced for 40 beats at a cycle length of 230ms before a cycle length reduction of 4ms. The process was repeated until propagation failed. At a cycle length of 222ms a spatially discordant alternans of magnitude 2ms was observed. In conclusion, stochastic effects are masked at physiological conductivity values and effects do not accumulate over time. At significantly reduced conductivity heterogeneities in repolarisation can be induced
Mallacoota Inlet National Park : the forgotten park
No full textThis thesis was scanned from the print manuscript for digital preservation and is copyright the author.
Researchers can access this thesis by asking their local university, institution or public library to
make a request on their behalf. Monash staff and postgraduate students can use the link in the References field
A multiple timescale analysis of a mathematical model of the Wnt/beta-catenin signalling pathway.
No full textThe Wnt signalling pathway is involved in stem cell maintenance, differentiation and tissue development. Its disregulation has also been implicated in many cancers. Beta-catenin is a protein that regulates both transcription of many genes and cell-cell adhesion; in response to an external Wnt stimulus the intracellular levels of beta-catenin are controlled by the proteins which make up the Wnt/beta-catenin signalling pathway. In this paper we present a systematic asymptotic analysis of an existing model of the Wnt signalling pathway due to Lee et al. (PLoS Biol 1:116-132, 2003), highlighting the operation of different pathway components over different timescales. Guided by this analysis we derive a simplified model which is shown to retain the essential behaviour of the full Wnt pathway, recreating the accumulation and degradation of beta-catenin in response to a Wnt stimulus
Dreams and realities: E.J. Brady and Mallacoota
No full textEdwin James Brady (1869-1952) is best known as a minor figure from the political and literary world of the 1890s and the author of Australia Unlimited, a book and a phrase that has come to represent the development ethos that characterised Australia in the inter-war years. Brady has been described as a writer who celebrated nature, but also encouraged the unsustainable exploitation of Australia’s natural resources. This biographical study, informed by environmental history, attempts to ‘flesh out’ the man behind ‘Australia Unlimited’ by exploring the relationship he had with the place he came to regard as his own domain, the small coastal settlement of Mallacoota, in far East Gippsland. This study traces Brady’s journey to Mallacoota, explores what expectations he had of this place and whether they were realised. I consider how the physical environment of Mallacoota and far East Gippsland helped shape the human experience of Brady and the local community, and how humans shaped and changed this environment over time. Brady came to see in Mallacoota’s wild beauty a place of poetic inspiration and solitude and also a source of natural wealth that should be closely populated and developed for the good of the nation. His dream was to create, in far East Gippsland, a model for a democratic and prosperous Australia. Brady was inspired by the social idealism of the 1890s, the progressive agenda of post Federation Australia, his commitment to socialism, as well as individual needs and desires. His visions for Mallacoota were formed and shaped by national and international events such as war, depression and technological change. In Mallacoota Brady wrote, farmed, ran a tourist business, helped establish a utopian socialist settlement and acted as an advocate for the region. This became his home for forty years and as such this study also considers his personal domestic life, and relationships between people living in this small remote community. This study, through the central figures of Mallacoota and Brady, therefore draws together national, local and domestic themes. Ultimately Brady failed to transform Mallacoota into a closely populated, economically diverse rural region through immigration and the exploitation of its natural resources. His principal legacy was rather to help shape the idea of Mallacoota as a tourist retreat for visitors, who wanted to experience the solitude and natural beauty that originally drew him there
Selective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters
No full text© 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 discrete loci where peripheral endoplasmic reticulum juxtaposes the plasma membrane. Stimulation evokes numerous STIM1-Orai1 clusters but whether distinct signal transduction pathways require different cluster numbers is unknown. Here, we show that two Ca2+-dependent transcription factors, NFAT1 and c-fos, have different requirements for the number of STIM1-Orai1 clusters and on the Ca2+ flux through them. NFAT activation requires fewer clusters and is more robustly activated than c-fos by low concentrations of agonist. For similar cluster numbers, transcription factor recruitment occurs sequentially, arising from intrinsic differences in Ca2+ sensitivities. Variations in the number of STIM1-Orai1 clusters and Ca2+ flux through them regulate the robustness of signalling to the nucleus whilst imparting a mechanism for selective recruitment of different Ca2+-dependent transcription factors
