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Human-based modelling and simulations are becoming ubiquitous in biomedical science due to their ability to augment experimental and clinical investigations. Cardiac electrophysiology is one of the most advanced areas, with cardiac modelling and simulation being considered for virtual testing of pharmacological therapies and medical devices. Current models present inconsistencies with experimental data, which limit further progress. In this study, we present the design, development, calibration and independent validation of a human-based ventricular model (ToR-ORd) for simulations of electrophysiology and excitation-contraction coupling, from ionic to whole-organ dynamics, including the electrocardiogram. Validation based on substantial multiscale simulations supports the credibility of the ToR-ORd model under healthy and key disease conditions, as well as drug blockade. In addition, the process uncovers new theoretical insights into the biophysical properties of the L-type calcium current, which are critical for sodium and calcium dynamics.

These insights enable the reformulation of L-type calcium current, as well as replacement of the hERG current model. ELife digest. Decades of intensive experimental and clinical research have revealed much about how the human heart works. Though incomplete, this knowledge has been used to construct computer models that represent the activity of this organ as a whole, and of its individual chambers (the atria and ventricles), tissues and cells. Such models have been used to better understand life-threatening irregular heartbeats; they are also beginning to be used to guide decisions about the treatment of patients and the development of new drugs by the pharmaceutical industry.Yet existing computer models of the electrical activity of the human heart are sometimes inconsistent with experimental data.

This problem led Tomek et al. To try to create a new model that was consistent with established biophysical knowledge and experimental data for a wide range of conditions including disease and drug action.Tomek et al. Designed a strategy that explicitly separated the construction and validation of a model that could recreate the electrical activity of the ventricles in a human heart. This model was able to integrate and explain a wide range of properties of both healthy and diseased hearts, including their response to different drugs. The development of the model also uncovered and resolved theoretical inconsistencies that have been present in almost all models of the heart from the last 25 years.

Hope that their new human heart model will enable more basic, translational and clinical research into a range of heart diseases and accelerate the development of new therapies. Human-based computer modelling and simulation are a fundamental asset of biomedical research. They augment experimental and clinical research through enabling detailed mechanistic and systematic investigations.

Owing to a large body of research across biomedicine, their credibility has expanded beyond academia, with vigorous activity also in regulatory and industrial settings. Thus, human in silico clinical trials are now becoming a central paradigm, for example, in the development of medical therapies. They exploit mature human-based modelling and simulation technology to perform virtual testing of pharmacological therapies or devices.Human cardiac electrophysiology is one of the most advanced areas in physiological modelling and simulation. Current human models of cardiac electrophysiology include detailed information on the ionic processes underlying the action potential such as the sodium, potassium and calcium ionic currents, exchangers such as the Na/Ca exchanger and pumps such as the Na/K pump.

They also include representation of the excitation-contraction coupling system in the sarcoplasmic reticulum, an important modulator of the calcium transient, through the calcium-induced calcium-release mechanisms and the SERCA pump. Several human models have been proposed for ventricular electrophysiology, and amongst them the ORd model. Its key strengths are the representation of CaMKII signalling, capability to manifest arrhythmia precursors such as alternans and early afterdepolarisation, and good response to simulated drug block and disease remodelling (;;; ).

Consequently, ORd was selected by a panel of experts as the model best suited for regulatory purposes.Most of the ORd model development has focused on repolarisation properties such as its response to drug block, repolarisation abnormalities and its rate dependence. However, a more holistic comparison of ORd-based simulations with human ventricular experimental data reveals important inconsistencies. Firstly, the plateau of the action potential (AP) is significantly higher in the ORd model than in experimental data used for ORd model construction (; ) and in data from additional studies using human cardiomyocytes (; ).

Secondly, the dynamics of accommodation of the AP duration (APD) to heart rate acceleration, which are known to be modulated by sodium dynamics, show only limited agreement with a comparable experimental dataset (; ). Thirdly, we identify that simulations of the sodium current block has an inotropic effect in the ORd model, increasing the amplitude of the calcium transient, in disagreement with its established negatively inotropic effect in experimental/clinical data (encainide, flecainide, and TTX) (;;; ).

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All those properties, namely AP plateau potential, APD adaptation and response to sodium current block, have strong dependencies on sodium and calcium dynamics. We therefore hypothesise that ionic balances during repolarisation require further research. We specifically focus on an in-depth re-evaluation of the L-type calcium current (I CaL) formulation, given its fundamental role in determining the AP, the calcium transient and sodium homeostasis through the Na/Ca exchanger. The second main focus is the re-assessment of the rapid delayed rectifier current (I Kr), the dominant repolarisation current in human ventricle, under conditions that reflect experimental data-driven plateau potentials.Using a development strategy based on strictly separated model calibration and validation, we sought to design, develop, calibrate and validate a novel model of human ventricular electrophysiology and excitation contraction coupling, the ToR-ORd model (for Tomek, Rodriguez – following ORd).

Our aim for simulations using the ToR-ORd model is to be able to reproduce all key depolarisation, repolarisation and calcium dynamics properties in healthy ventricular cardiomyocytes, under drug block, and in key diseased conditions such as hyperkalemia (central to acute myocardial ischemia), and hypertrophic cardiomyopathy. Materials and methods. Lists the properties (left column) and key references (right column) of experimental and clinical datasets considered for the calibration (top) and independent validation (bottom) of the ToR-ORd model. This represents a comprehensive list of properties, known to characterize human ventricular electrophysiology under multiple stimulation rates, and also drug action and disease. The recordings in were obtained in human ventricular preparations primarily using measurements with microelectrode recordings, unipolar electrograms, and monophasic APs, therefore avoiding photon scattering effects or potential dye artefacts present in optical mapping experiments. In addition, the ToR-ORd model was calibrated to manifest depolarisation of resting membrane potential in response to an I K1 block, based on evidence in a range of studies summarised in. The calibration criteria are chosen to be fundamental properties of ionic currents, action potential and single-cell pro-arrhythmic phenomena (described in more detail in Appendix 1-1).

The validation criteria include response to rate changes, drug action and disease, to explore the predictive power of the model under clinically-relevant conditions. CalibrationAction potential morphology(;; )Calcium transient time to peak, duration, and amplitudeI-V relationship and steady-state inactivation of L-type calcium currentSodium blockade is negatively inotropic(;;; ).L-type calcium current blockade shortens the action potentialEarly depolarisation formation under hERG blockAlternans formation at rapid pacingConduction velocity of ca.

65 m/sValidationAction potential accommodationS1-S2 restitutionDrug blocks and action potential duration(; )Hyperkalemia promotes postrepolarisation refractorinessHypertrophic cardiomyopathy phenotypeDrug safety prediction using populations of modelsPhysiological QRS and QT intervals in ECG(;;; )We initially performed the evaluation of the ORd model by conducting simulations for each of the calibration criteria in. Further details are described throughout the Materials and methods section and Appendix 1-15.1. Simulations with the existing versions of the ORd model failed to fulfil key criteria such as AP morphology, calcium transient duration, several properties of the L-type calcium current, negative inotropic effect of sodium blockers, or the depolarising effect of I K1 block. The results are later demonstrated in Figures 2 and 3, and Methods: Calibration of I K1 block and resting membrane potential. Secondly, we attempted parameter optimisation using a multiobjective genetic algorithm. However, simulations with the ORd-based models were unable to fulfil key criteria such as AP and Ca morphology, and the effect of sodium and calcium block on calcium transient amplitude and APD, respectively.We then proceeded to reevaluate the ionic current formulations based on experimental data and biophysical knowledge.

Key currents included I CaL and specifically its driving force and activation, as well as the I Na, I Kr, I K1 and chloride currents. The multiobjective genetic algorithm optimisation was repeated several times, throughout the introduction of structural changes to the model.

. 2.6k DownloadsPart of thebook series (MIMB, volume 1484) AbstractIntrinsically disordered proteins and regions (IDPs and IDRs) are involved in a wide range of cellular functions and they often facilitate interactions with RNAs, DNAs, and proteins. Although many computational methods can predict IDPs and IDRs in protein sequences, only a few methods predict their functions and these functions primarily concern protein binding. We describe how to use the first computational method DisoRDPbind for high-throughput prediction of multiple functions of disordered regions. Our method predicts the RNA-, DNA-, and protein-binding residues located in IDRs in the input protein sequences.

DisoRDPbind provides accurate predictions and is sufficiently fast to make predictions for full genomes. Our method is implemented as a user-friendly webserver that is freely available at. We overview our predictor, discuss how to run the webserver, and show how to interpret the corresponding results. We also demonstrate the utility of our method based on two case studies, human BRCA1 protein that binds various proteins and DNA, and yeast 60S ribosomal protein L4 that interacts with proteins and RNA.