arXiv subjects

Radostin D. Simitev

Publications and source records attributed to Radostin D. Simitev.

At least 19 recordsLinked to original sources

arXiv2025

Dominant ionic currents in rabbit ventricular action potential dynamics

Mathematical models of cardiac cell electrical activity include numerous parameters, making calibration to experimental data and individual-specific modeling challenging. This study applies Sobol sensitivity analysis, a global variance-decomposition method, to identify the most influential parameters in the Shannon model of rabbit ventricular myocyte action potential (AP). The analysis highlights the background chloride current (IClb) as the dominant determinant of AP variability. Additionally, the inward rectifier potassium current (IK1), fast/slow delayed rectifier potassium currents (IKr, IKs), sodium-calcium exchanger current (INaCa), the slow component of the transient outward potassium current (Itos), and L-type calcium current (ICaL) significantly affect AP biomarkers, including duration, plateau potential, and resting potential. Exploiting these results, a hierarchical reduction of the model is performed and demonstrates that retaining only six key parameters can capture sufficiently well individual biomarkers, with a coefficient of determination exceeding 0.9 for selected cases. These findings improve the utility of the Shannon model for personalized simulations, aiding applications like digital twins and drug response predictions in biomedical research.

q-bio.OT↗

arXiv2025

A large population of cell-specific action potential models replicating fluorescence recordings of voltage in rabbit ventricular myocytes

Recent high-throughput experiments unveil substantial electrophysiological diversity among uncoupled healthy myocytes under identical conditions. To quantify inter-cell variability, the values of a subset of the parameters in a well-regarded mathematical model of the action potential of rabbit ventricular myocytes are estimated from fluorescence voltage measurements of a large number of cells. Statistical inference yields a population of nearly 1200 cell-specific model variants that, on a population-level replicate experimentally measured biomarker ranges and distributions, and in contrast to earlier studies, also match experimental biomarker values on a cell-by-cell basis. This model population may be regarded as a random sample from the phenotype of healthy rabbit ventricular myocytes. Uni-variate and bi-variate joint marginal distributions of the estimated parameters are presented, and the parameter dependencies of several commonly utilised electrophysiological biomarkers are revealed. Parameter values are weakly correlated, while summary metrics such as the action potential duration are not strongly dependent on any single electrophysiological characteristic of the myocyte. Our results demonstrate the feasibility of accurately and efficiently fitting entire action potential waveforms at scale. Keywords: cellular excitability, rabbit ventricular myocytes, fluorescence voltage measurements, action potential waveform, parameter estimation in differential equations, noisy time series

q-bio.QM↗

arXiv2023

Differential rotation in convecting spherical shells with non-uniform viscosity and entropy diffusivity

Contemporary three-dimensional physics-based simulations of the solar convection zone disagree with observations. They feature differential rotation substantially different from the true rotation inferred by solar helioseismology and exhibit a conveyor belt of convective "Busse" columns not found in observations. To help unravel this so-called "convection conundrum", we use a three-dimensional pseudospectral simulation code to investigate how radially non-uniform viscosity and entropy diffusivity affect differential rotation and convective flow patterns in density-stratified rotating spherical fluid shells. We find that radial non-uniformity in fluid properties enhances polar convection, which, in turn, induces non-negligible lateral entropy gradients that lead to large deviations from differential rotation geostrophy due to thermal wind balance. We report simulations wherein this mechanism maintains differential rotation patterns very similar to the true solar profile outside the tangent cylinder, although discrepancies remain at high latitudes. This is significant because differential rotation plays a key role in sustaining solar-like cyclic dipolar dynamos.

astro-ph.SR↗

arXiv2023

Phenomenological analysis of simple ion channel block in large populations of uncoupled cardiomyocytes

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and dAPD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or dAPD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data.

physics.med-ph↗

arXiv2022

A study of global magnetic helicity in self-consistent spherical dynamos

Magnetic helicity is a fundamental constraint in both ideal and resistive magnetohydrodynamics. Measurements of magnetic helicity density on the Sun and other stars are used to interpret the internal behaviour of the dynamo generating the global magnetic field. In this note, we study the behaviour of the global relative magnetic helicity in three self-consistent spherical dynamo solutions of increasing complexity. Magnetic helicity describes the global linkage of the poloidal and toroidal magnetic fields (weighted by magnetic flux), and our results indicate that there are preferred states of this linkage. This leads us to propose that global magnetic reversals are, perhaps, a means of preserving this linkage, since, when only one of the poloidal or toroidal fields reverses, the preferred state of linkage is lost. It is shown that magnetic helicity indicates the onset of reversals and that this signature may be observed at the outer surface.

astro-ph.SR↗

arXiv2022

Flute and kink instabilities in a dynamically twisted flux tube with anisotropic plasma viscosity

Magnetic flux tubes such as those in the solar corona are subject to a number of instabilities. Important among them is the kink instability which plays a central part in the nanoflare theory of coronal heating, and for this reason in numerical simulations it is usually induced by tightly-controlled perturbations and studied in isolation. In contrast, we find that when disturbances are introduced in our magnetohydrodynamic flux tube simulations by dynamic twisting of the flow at the boundaries fluting modes of instability are readily excited. We also find that the flute instability, which has been theorised but rarely observed in the coronal context, is strongly enhanced when plasma viscosity is assumed anisotropic. We proceed to investigate the co-existence and competition between flute and kink instabilities for a range of values of the resistivity and of the parameters of the anisotropic and isotropic models of viscosity. We conclude that while the flute instability cannot prevent the kink from ultimately dominating, it can significantly delay its development especially at strong viscous anisotropy induced by intense magnetic fields.

astro-ph.SR↗

arXiv2022

Estimation of Parameters for an Archetypal Model of Cardiomyocyte Membrane Potentials

Contemporary realistic mathematical models of single-cell cardiac electrical excitation are immensely detailed. Model complexity leads to parameter uncertainty, high computational cost and barriers to mechanistic understanding. There is a need for reduced models that are conceptually and mathematically simple but physiologically accurate. To this end, we consider an archetypal model of single-cell cardiac excitation that replicates the phase-space geometry of detailed cardiac models, but at the same time has a simple piecewise-linear form and a relatively low-dimensional configuration space. In order to make this archetypal model practically applicable, we develop and report a robust method for estimation of its parameter values from the morphology of single-stimulus action potentials derived from detailed ionic current models and from experimental myocyte measurements. The procedure is applied to five significant test cases and an excellent agreement with target biomarkers is achieved. Action potential duration restitution curves are also computed and compared to those of the target test models and data, demonstrating conservation of dynamical pacing behaviour by the fine-tuned archetypal model. An archetypal model that accurately reproduces a variety of wet-lab and synthetic electrophysiology data offers a number of specific advantages such as computational efficiency, as also demonstrated in the study. Open-source numerical code of the models and methods used is provided.

q-bio.TO↗

arXiv2021

On self and mutual winding helicity

The topological underpinning of magnetic fields connected to a planar boundary is naturally described by field line winding. This observation leads to the definition of winding helicity, which is closely related to the more commonly calculated relative helicity. Winding helicity, however, has several advantages, and we explore some of these in this work. In particular, we show, by splitting the domain into distinct subregions, that winding helicity can be decomposed naturally into "self" and "mutual" components and that these quantities can be calculated, in practice, for magnetic fields with complex geometries and topologies. Further, winding provides a unified topological description from which known expressions for self and mutual helicity can be readily derived and generalized. We illustrate the application of calculating self and mutual winding helicities in a simulation of an evolving magnetic field with non-trivial field line topology.

math-ph↗

arXiv2021

Modelling and simulation of electrical propagation in transmural slabs of scarred left ventricle tissue

We report three-dimensional and time-dependent numerical simulations of the propagation of electrical action potentials in a model of rabbit ventricular tissue. The simulations are performed using a finite-element method for the solution of the monodomain equations of cardiac electrical excitation. The parameters of a detailed ionic ventricular cell model are re-fitted to available experimental data and the model is then used for the description of the transmembrane current and calcium dynamics. A region with reduced conductivity is introduced to model a myocardial infarction scar. Electrical activation times and density maps of the transmembrane voltage are computed and compared with experimental measurements in rabbit preparations with myocardial infarction obtained by a panoramic optical mapping method.

q-bio.QM↗

arXiv2021

Addendum: Action potential propagation and block in a model of atrial tissue with myocyte-fibroblast coupling

The analytical theory of our earlier study (Mortensen et al. (2021), Mathematical Medicine and Biology, 38(1), pp. 106-131) is extended to address the outstanding cases of fibroblast barrier distribution and myocyte strait distribution. In particular, closed-form approximations to the resting membrane potential and to the critical parameter values for propagation are derived for these two non-uniform fibroblast distributions and are in good agreement with numerical estimates.

q-bio.TO↗

arXiv2020

Onset of inertial magnetoconvection in rotating fluid spheres

The onset of convection in the form of magneto-inertial waves in a rotating fluid sphere permeated by a constant axial electric current is studied through a perturbation analysis. Explicit expressions for the dependence of the Rayleigh number on the azimuthal wavenumber are derived in the limit of high thermal diffusivity. Results for the case of thermally infinitely conducting boundaries and for the case of nearly thermally insulating boundaries are obtained.

physics.flu-dyn↗

arXiv2020

Effects of shell thickness on cross-helicity generation in convection-driven spherical dynamos

The relative importance of the helicity and cross-helicity electromotive dynamo effects for self-sustained magnetic field generation by chaotic thermal convection in rotating spherical shells is investigated as a function of shell thickness. Two distinct branches of dynamo solutions are found to coexist in direct numerical simulations for shell aspect ratios between 0.25 and 0.6 - a mean-field dipolar regime and a fluctuating dipolar regime. The properties characterising the coexisting dynamo attractors are compared and contrasted, including differences in temporal behavior and spatial structures of both the magnetic field and rotating thermal convection. The helicity $α$-effect and the cross-helicity $γ$-effect are found to be comparable in intensity within the fluctuating dipolar dynamo regime, where their ratio does not vary significantly with the shell thickness. In contrast, within the mean-field dipolar dynamo regime the helicity $α$-effect dominates by approximately two orders of magnitude and becomes stronger with decreasing shell thickness.

physics.flu-dyn↗

arXiv2020

Action potential propagation and block in a model of atrial tissue with myocyte-fibroblast coupling

The electrical coupling between myocytes and fibroblasts and the spacial distribution of fibroblasts within myocardial tissues are significant factors in triggering and sustaining cardiac arrhythmias but their roles are poorly understood. This article describes both direct numerical simulations and an asymptotic theory of propagation and block of electrical excitation in a model of atrial tissue with myocyte-fibroblast coupling. In particular, three idealised fibroblast distributions are introduced: uniform distribution, fibroblast barrier and myocyte strait, all believed to be constituent blocks of realistic fibroblast distributions. Primary action potential biomarkers including conduction velocity, peak potential and triangulation index are estimated from direct simulations in all cases. Propagation block is found to occur at certain critical values of the parameters defining each idealised fibroblast distribution and these critical values are accurately determined. An asymptotic theory proposed earlier is extended and applied to the case of a uniform fibroblast distribution. Biomarker values are obtained from hybrid analytical-numerical solutions of coupled fast-time and slow-time periodic boundary value problems and compare well to direct numerical simulations. The boundary of absolute refractoriness is determined solely by the fast-time problem and is found to depend on the values of the myocyte potential and on the slow inactivation variable of the sodium current ahead of the propagating pulse. In turn, these quantities are estimated from the slow-time problem using a regular perturbation expansion to find the steady state of the coupled myocyte-fibroblast kinetics. The asymptotic theory gives a simple analytical expression that captures with remarkable accuracy the block of propagation in the presence of fibroblasts.

q-bio.TO↗

arXiv2020

Regimes of thermo-compositional convection and related dynamos in rotating spherical shells

Convection and magnetic field generation in the Earth and planetary interiors are driven by both thermal and compositional gradients. In this work numerical simulations of finite-amplitude double-diffusive convection and dynamo action in rapidly rotating spherical shells full of incompressible two-component electrically-conducting fluid are reported. Four distinct regimes of rotating double-diffusive convection identified in a recent linear analysis (Silva et al., 2019, Geophys. Astrophys. Fluid Dyn., doi:10.1080/03091929.2019.1640875) are found to persist significantly beyond the onset of instability while their regime transitions remain abrupt. In the semi-convecting and the fingering regimes characteristic flow velocities are small compared to those in the thermally- and compositionally-dominated overturning regimes, while zonal flows remain weak in all regimes apart from the thermally-dominated one. Compositionally-dominated overturning convection exhibits significantly narrower azimuthal structures compared to all other regimes while differential rotation becomes the dominant flow component in the thermally-dominated case as driving is increased. Dynamo action occurs in all regimes apart from the regime of fingering convection. While dynamos persist in the semi-convective regime they are very much impaired by small flow intensities and very weak differential rotation in this regime which makes poloidal to toroidal field conversion problematic. The dynamos in the thermally-dominated regime include oscillating dipolar, quadrupolar and multipolar cases similar to the ones known from earlier parameter studies. Dynamos in the compositionally-dominated regime exhibit subdued temporal variation and remain predominantly dipolar due to weak zonal flow in this regime. These results significantly enhance our understanding of the primary drivers of planetary core flows and magnetic fields.

physics.flu-dyn↗

arXiv2019

The onset of thermo-compositional convection in rotating spherical shells

Double-diffusive convection driven by both thermal and compositional buoyancy in a rotating spherical shell can exhibit a rather large number of behaviours often distinct from that of the single diffusive system. In order to understand how the differences in thermal and compositional molecular diffusivities determine the dynamics of thermo-compositional convection we investigate numerically the linear onset of convective instability in a double-diffusive setup. We construct an alternative equivalent formulation of the non-dimensional equations where the linearised double-diffusive problem is described by an effective Rayleigh number, $\text{Ra}$, measuring the amplitude of the combined buoyancy driving, and a second parameter, $α$, measuring the mixing of the thermal and compositional contributions. This formulation is useful in that it allows for the analysis of several limiting cases and reveals dynamical similarities in the parameters space which are not obvious otherwise. We analyse the structure of the critical curves in this $\text{Ra}-α$ space, explaining asymptotic behaviours in $α$, transitions between inertial and diffusive regimes, and transitions between large scale (fast drift) and small scale (slow drift) convection. We perform this analysis for a variety of diffusivities, rotation rates and shell aspect ratios showing where and when new modes of convection take place.

physics.flu-dyn↗

arXiv2018

Flows and dynamos in a model of stellar radiative zones

Stellar radiative zones are typically assumed to be motionless in standard models of stellar structure but there is sound theoretical and observational evidence that this cannot be the case. We investigate by direct numerical simulations a three-dimensional and time-dependent model of stellar radiation zones consisting of an electrically-conductive and stably-stratified anelastic fluid confined to a rotating spherical shell and driven by a baroclinic torque. As the baroclinic driving is gradually increased a sequence of transitions from an axisymmetric and equatorially-symmetric time-independent flow to flows with a strong poloidal component and lesser symmetry are found. It is shown that all flow regimes characterised with significant non-axisymmetric components are capable of generating self-sustained magnetic field. As the value of the Prandtl number is decreased and the value of the Ekman number is decreased flows become strongly time-dependent with progressively complex spatial structure and dynamos can be generated at lower values of the magnetic Prandtl number.

physics.flu-dyn↗

arXiv2017

Baroclinically-driven flows and dynamo action in rotating spherical fluid shells

The dynamics of stably stratified stellar radiative zones is of considerable interest due to the availability of increasingly detailed observations of Solar and stellar interiors. This article reports the first non-axisymmetric and time-dependent simulations of flows of anelastic fluids driven by baroclinic torques in stably stratified rotating spherical shells -- a system serving as an elemental model of a stellar radiative zone. With increasing baroclinicity a sequence of bifurcations from simpler to more complex flows is found in which some of the available symmetries of the problem are broken subsequently. The poloidal component of the flow grows relative to the dominant toroidal component with increasing baroclinicity. The possibility of magnetic field generation thus arises and this paper proceeds to provide some indications for self-sustained dynamo action in baroclinically-driven flows. We speculate that magnetic fields in stably stratified stellar interiors are thus not necessarily of fossil origin as it is often assumed.

physics.flu-dyn↗

arXiv2015

Modelling afferent nerve responses to bladder filling

A sensation of fullness in the bladder is a regular experience, yet the mechanisms that act to generate this sensation remain poorly understood. This is an important issue because of the clinical problems that can result when this system does not function properly. The aim of the study group activity was to develop mathematical models that describe the mechanics of bladder filling, and how stretch modulates the firing rate of afferent nerves. Several models were developed, which were qualitatively consistent with experimental data obtained from a mouse model.

q-bio.TO↗