A5036632412- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Mormonism, Religion, and History
- American Constitutional Law and Politics
- Terrorism, Counterterrorism, and Political Violence
- Global Peace and Security Dynamics
- Neuroscience and Neural Engineering
- Receptor Mechanisms and Signaling
- ECG Monitoring and Analysis
- American History and Culture
- Religious Studies and Spiritual Practices
- Cardiovascular Function and Risk Factors
- Cardiac pacing and defibrillation studies
- Race, History, and American Society
- Academic Freedom and Politics
- Youth Development and Social Support
- Probabilistic and Robust Engineering Design
- Archaeology and Natural History
- Teacher Education and Leadership Studies
- Animal testing and alternatives
- Agricultural risk and resilience
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- Education Systems and Policy
- Musicology and Musical Analysis
- Influenza Virus Research Studies
University of Nottingham
2019-2024
Age UK
2023
University of Manchester
2015-2023
University of Leeds
2018-2020
Astronomy and Space
2016
Brigham Young University
1982-2015
University of Oxford
2015
Teesside University
2004-2013
Hinchingbrooke Hospital
2010
University of British Columbia
1985
Mathematical models of ion channels, which constitute indispensable components action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study, we fitted cell-specific hERG1a (Kv11.1) recordings simultaneously measured using an automated high-throughput system, and studied cell-cell variability inspecting the resulting model parameters. However, origin observed was not identified. Here, study source constructing that describes just current...
This study compares highly committed members of the Free Speech Movement at Berkeley with student population large on three sociopsychological foci: general biographical data, religious orientation, and rigidity-flexibility. Questionnaires were administered to 172 FSM selected by chance from ten twelve hundred who entered "sat-in" Administration Building University California December 2, 1964. A comparative sample 146 respondents, randomly directory, was obtained mail. Results indicated that...
Abstract When using mathematical models to make quantitative predictions for clinical or industrial use, it is important that come with a reliable estimate of their accuracy (uncertainty quantification). Because complex biological systems are always large simplifications, model discrepancy arises—models fail perfectly recapitulate the true data generating process. This presents particular challenge making accurate predictions, and especially accurately quantifying uncertainty in these...
Simultaneous block of both atrial-specific ultra-rapid delayed rectifier potassium (K+) current (IKur) and the Na+ (INa) has been hypothesised to be anti-atrial fibrillation (AF), without inducing ventricular side effects. However, advantage simultaneously blocking these two channels in AF remains documented. IKur blockers such as acacetin AVE0118, partially inhibit other K+ currents atria. Whether this multi-K+-block produces greater anti-AF effects compared with selective IKur-block not...
Uncertainty quantification (UQ) is a vital step in using mathematical models and simulations to take decisions. The field of cardiac simulation has begun explore adopt UQ methods characterise uncertainty model inputs how that propagates through outputs or predictions. In this perspective piece we draw attention an important under-addressed source our predictions -- the structure equations themselves. difference between imperfect reality termed discrepancy, are often uncertain as size...
Voltage-clamp waveforms are imposed in the patch-clamp electrophysiology technique to provoke ion currents, particular waveform that is used known as "voltage-clamp protocol". Designing protocols probe and quantify how gating for a channel occurs has typically been done manually results suite of long protocols. It desirable gain same, or even more, information shorter time, also automate process designing these In this paper we introduce new optimal experimental design objective...
Objectives: In silico clinical trials are a well-accepted model-informed drug development (MIDD) tool to understand, optimize and predict the effect of drugs across diverse populations [1,2]. Generation selection virtual patients for simulating in remains an open area research not least due challenges selecting that representative underlying physiological characteristics individual subjects enrolled into [3]. While can be obtained by sampling sets parameters from calibrated non-linear mixed...
The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment Na+ & K+ channel blocking Class 1a anti-arrhythmic agents has demonstrated some efficacy. This study used computational modelling gain mechanistic insights into actions of two such drugs, disopyramide quinidine, setting SQT1. O'Hara-Rudy...
Drug-induced reduction of the rapid delayed rectifier potassium current carried by human Ether-à-go-go-Related Gene (hERG) channel is associated with increased risk arrhythmias. Recent updates to drug safety regulatory guidelines attempt capture each drug's hERG binding mechanism combining in vitro assays silico simulations. In this study, we investigate impact on proarrhythmic predictions due uncertainty and physiological model.
Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated mechanistic link between SQT3 and arrhythmogenesis, potential ion channel targets for treatment SQT3. A contemporary model action (AP) was modified to recapitulate functional changes IK1 due heterozygous homozygous forms D172N E299V mutations....
Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, IKs. However, mechanism(s) underlying increased atrial arrhythmogenesis impaired cardiac pacemaking activity arising from IKs remain unclear. Possible pharmacological interventions AF SQT2 condition also to be elucidated. Using...
Short QT syndrome (SQTS) is a rare condition characterized by abnormally 'short' intervals on the ECG and increased susceptibility to cardiac arrhythmias sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with SQT2-related V307L KCNQ1 'gain-of-function' mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) mutant IKs kinetics was incorporated into of...
Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity for targeted treatment of LQTS. However, limiting concern is over-activation resurgent current during the action potential abbreviated repolarization. Activators that slow deactivation gating (type I), such as RPR260243, may enhance repolarizing...
Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in treatment rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and being studied for prevention COVID-19. Here, we investigate through mathematical modelling safety profile HCQ, CQ other QT-prolonging anti-infective agents to determine their risk categories Torsade de Pointes (TdP) arrhythmia. We performed with uncertainty quantification using a classifier based on qNet torsade...
We provide details of a series short voltage-clamp protocols designed for gathering large amount information on hERG (K v 11.1) ion channel gating. The have limited number steps and consist only ramps, making them easy to implement any patch clamp setup, including automated platforms. primary objective is assist with parameterisation, selection refinement mathematical models detail manual model-driven designs, together an explanation their rationale design criteria. Although the are intended...