@inbook {43294,
	title = {Impact of Pathological Vascular Remodelling on Right Ventricular Mechanics},
	booktitle = {Computational Physiology: Simula Summer School 2022- Student Reports},
	year = {2023},
	pages = {91{\textendash}109},
	publisher = {Springer},
	organization = {Springer},
	author = {Cui, Jiaxin and Mariluz Rojo {Domingo} and Konno, Ryan and Claudia A {Manetti} and Kagugube, George and Oscar O {Odeigah} and Sundnes, Joakim},
	editor = {Kimberly J {McCabe}}
}
@article {43400,
	title = {Multiscale computational modeling of the effects of 2{\textquoteright}-deoxy-ATP on cardiac muscle calcium handling},
	journal = {Journal of Applied Physics},
	volume = {134},
	year = {2023},
	month = {08/2023},
	publisher = {AIP Publishing},
	abstract = {2{\textquoteright}-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. Gaussian accelerated molecular dynamics simulations of human cardiac SERCA2A in the E1\&nbsp;apo, ATP-bound and dATP-bound states showed that dATP forms more stable contacts in the nucleotide binding pocket of SERCA and leads to increased closure of cytosolic domains. These structural changes ultimately lead to changes in calcium binding, which we assessed using Brownian dynamics simulations. We found that dATP increases calcium association rate constants to SERCA and that dATP binds to\&nbsp;apo\&nbsp;SERCA more rapidly than ATP. Using a compartmental ordinary differential equation model of human cardiomyocyte excitation-contraction coupling, we found that these increased association rate constants contributed to the accelerated rates of calcium transient decay observed experimentally. This study provides clear mechanistic evidence of enhancements in cardiac SERCA2A pump function due to interactions with dATP.},
	doi = {https://doi.org/10.1063/5.0157935},
	author = {Marcus T. {Hock} and Teitgen, Abigail and Kimberly J {McCabe} and Sophia P. {Hirakis} and Huber, Gary and Regnier, Michael and Rommie E. {Amaro} and Andrew J. {McCammon} and Andrew D. {McCulloch}}
}
@inbook {42469,
	title = {3D Simulations of Fetal and Maternal Ventricular Excitation for Investigating the Abdominal ECG},
	booktitle = {Computational Physiology - Simula Summer School 2021 - Student Reports},
	volume = {12},
	year = {2022},
	month = {05/2022},
	pages = {13 - 24},
	publisher = {Springer International Publishing},
	organization = {Springer International Publishing},
	address = {Cham},
	isbn = {978-3-031-05163-0},
	issn = {2512-1677},
	doi = {10.1007/978-3-031-05164-7_2},
	url = {https://doi.org/10.1007/978-3-031-05164-7_2},
	author = {Julie Johanne {Uv} and Myklebust, Lena and Hamid Khoshfekr {Rudsari} and Welle, Hannes and Arevalo, Hermenegild},
	editor = {Kimberly J {McCabe}}
}
@book {43127,
	title = {Computational Physiology: Simula Summer School 2021 - Student Reports},
	journal = {Simula SpringerBriefs on Computing},
	volume = {12},
	year = {2022},
	pages = {109},
	publisher = {Springer},
	address = {Cham},
	url = {https://doi.org/10.1007/978-3-031-05164-7},
	author = {Kimberly J {McCabe}}
}
@inbook {43019,
	title = {A Computational Study of Flow Instabilities in Aneurysms},
	booktitle = {Computational Physiology - Simula Summer School 2021 - Student Reports},
	volume = {12},
	year = {2022},
	pages = {63 - 75},
	publisher = {Springer International Publishing},
	organization = {Springer International Publishing},
	address = {Cham},
	isbn = {978-3-031-05163-0},
	issn = {2512-1677},
	doi = {10.1007/978-3-031-05164-710.1007/978-3-031-05164-7_6},
	url = {https://link.springer.com/chapter/10.1007/978-3-031-05164-7_6},
	author = {Berre, Nanna and Castro, Gabriela and Kjeldsberg, Henrik and Masri, Rami and Gjerde, Ingeborg},
	editor = {Kimberly J {McCabe}}
}
@inbook {42465,
	title = {Conduction Velocity in Cardiac Tissue as Function of Ion Channel Conductance and Distribution},
	booktitle = {Computational Physiology - Simula Summer School 2021 - Student Reports},
	volume = {12},
	year = {2022},
	month = {05/2022},
	pages = {41 - 50},
	publisher = {Springer International Publishing},
	organization = {Springer International Publishing},
	chapter = {4},
	address = {Cham},
	abstract = {Ion channels on the membrane of cardiomyocytes regulate the propagation of action potentials from cell to cell and hence are essential for the proper function of the heart. Through computer simulations with the classical monodomain model for cardiac tissue and the more recent extracellular-membrane-intracellular (EMI) model where individual cells are explicitly represented, we investigated how conduction velocity (CV) in cardiac tissue depends on the strength of various ion currents as well as on the spatial distribution of the ion channels. Our simulations show a sharp decrease in CV when reducing the strength of the sodium (Na+) currents, whereas independent reductions in the potassium (K1 and Kr) and L-type calcium currents have negligible effect on the CV. Furthermore, we find that an increase in number density of Na+ channels towards the cell ends increases the CV, whereas a higher number density of K1 channels slightly reduces the CV. These findings contribute to the understanding of ion channels (e.g. Na+ and K+ channels) in the propagation velocity of action potentials in the heart.},
	keywords = {conduction velocity, EMI model, ion channels},
	isbn = {978-3-031-05163-0},
	issn = {2512-1677},
	doi = {10.1007/978-3-031-05164-7_4},
	url = {https://link.springer.com/chapter/10.1007/978-3-031-05164-7_4},
	author = {Kristian Gregorius {Hustad} and Ivanovic, Ena and Adrian Llop {Recha} and Abinaya Abbi {Sakthivel}},
	editor = {Kimberly J {McCabe}}
}
@inbook {42517,
	title = {Identifying Ionic Channel Block in a Virtual Cardiomyocyte Population Using Machine Learning Classifiers},
	booktitle = {Computational Physiology - Simula Summer School 2021 - Student Reports},
	volume = {12},
	year = {2022},
	month = {05/2022},
	pages = {91 - 109},
	publisher = {Springer International Publishing},
	organization = {Springer International Publishing},
	address = {Cham},
	keywords = {action potential, AI, cardiomyocyte, classification},
	isbn = {978-3-031-05163-0},
	issn = {2512-1677},
	doi = {10.1007/978-3-031-05164-710.1007/978-3-031-05164-7_8},
	url = {https://link.springer.com/chapter/10.1007/978-3-031-05164-7_8},
	author = {Singstad, Bj{\o}rn-Jostein and Bendik Steinsv{\r a}g {Dalen} and Sihra, Sandhya and Forsch, Nickolas and Wall, Samuel},
	editor = {Kimberly J {McCabe}}
}
@article {42631,
	title = {Nanoscale organization of ryanodine receptor distribution and phosphorylation pattern determines the dynamics of calcium sparks},
	journal = {PLOS Computational Biology},
	volume = {18},
	year = {2022},
	month = {Jun-06-2022},
	pages = {e1010126},
	publisher = {PLOS},
	doi = {10.1371/journal.pcbi.1010126},
	url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203011/},
	author = {Mar{\'\i}a Hern{\'a}ndez {Mesa} and van den Brink, Jonas and William E. {Louch} and Kimberly J {McCabe} and Rangamani, Padmini},
	editor = {Jeffrey J. {Saucerman}}
}
@inbook {42524,
	title = {Ordinary Differential Equation-based Modeling of Cells in Human Cartilage},
	booktitle = {Computational Physiology - Simula Summer School 2021 - Student Reports},
	volume = {12},
	year = {2022},
	pages = {25 - 39},
	publisher = {Springer International Publishing},
	organization = {Springer International Publishing},
	address = {Cham},
	abstract = {Chondrocytes produce the extracellular cartilage matrix required for smooth joint mobility. As cartilage is not vascularised, and chondrocytes are not innervated by the nervous system, chondrocytes are therefore generally considered non-excitable. However, chondrocytes do express a range of ion channels, ion pumps, and receptors involved in cell homeostasis and cartilage maintenance. Dysfunction in these ion channels and pumps has been linked to degenerative disorders such as arthritis. Because the electrophysiological properties of chondrocytes are difficult to measure experimentally, mathematical modelling can instead be used to investigate the regulation of ionic currents. Such models can provide insight into the finely tuned parameters underlying fluctuations in membrane potential and cell behaviour in healthy and pathological conditions. Here, we introduce an open-source, intuitive, and extendable mathematical model of chondrocyte electrophysiology, implementing key proteins involved in regulating the membrane potential. Because of the inherent biological variability of cells and their physiological ranges of ionic concentrations, we describe a population of models that provides a robust computational representation of the biological data. This permits parameter variability in a manner mimicking biological variation, and we present a selection of parameter sets that suitably represent experimental data. Our mathematical model can be used to efficiently investigate the ionic currents underlying chondrocyte behaviour.},
	isbn = {978-3-031-05163-0},
	issn = {2512-1677},
	doi = {https://doi.org/10.1007/978-3-031-05164-7_3},
	url = {https://link.springer.com/chapter/10.1007/978-3-031-05164-7_3$\#$chapter-info},
	author = {Yamamoto, Kei and Fischer-Holzhausen, Sophie and Maria Perona {Fjelstad} and Maleckar, Molly},
	editor = {Kimberly J {McCabe}}
}
@article {27694,
	title = {Computational modeling approaches to cAMP/PKA signaling in cardiomyocytes},
	journal = {Journal of Molecular and Cellular Cardiology},
	volume = {154},
	year = {2021},
	pages = {32-40},
	publisher = {Elsevier},
	issn = {0022-2828},
	doi = {https://doi.org/10.1016/j.yjmcc.2021.01.008},
	author = {Kimberly J {McCabe} and Rangamani, Padmini}
}
@misc {27607,
	title = {Multiscale modelling determines mechanisms of action for 2{\textquoteright}-deoxy-ATP, a myosin activating therapeutic for heart failure},
	howpublished = {VPH 2020, Paris, France (Virtual)},
	year = {2020},
	publisher = {VPH 2020},
	author = {Kimberly J {McCabe} and Aboelkassem, Yasser and Teitgen, Abigail and Regnier, Michael and Andrew D. {McCulloch}}
}
@article {27460,
	title = {Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere},
	journal = {Archives of Biochemistry and Biophysics},
	volume = {695},
	year = {2020},
	month = {11/2020},
	pages = {108582},
	publisher = {Elsevier},
	abstract = {2{\textquoteright}-deoxy-ATP (dATP) is a naturally occurring small molecule that has shown promise as a therapeutic because it significantly increases cardiac myocyte force development even at low dATP/ATP ratios. To investigate mechanisms by which dATP alters myosin crossbridge dynamics, we used Brownian dynamics simulations to calculate association rates between actin and ADP- or dADP-bound myosin. These rates were then directly incorporated in a mechanistic Monte Carlo Markov Chain model of cooperative sarcomere contraction. A unique combination of increased powerstroke and detachment rates was required to match experimental steady-state and kinetic data for dATP force production in rat cardiac myocytes when the myosin attachment rate in the model was constrained by the results of a Brownian dynamics simulation. Nearest-neighbor cooperativity was seen to contribute to, but not fully explain, the steep relationship between dATP/ATP ratio and steady-state force-development observed at lower dATP concentrations. Dynamic twitch simulations performed using measured calcium transients as inputs showed that the effects of dATP on the crossbridge alone were not sufficient to explain experimentally observed enhancement of relaxation kinetics by dATP treatment. Hence, dATP may also affect calcium handling even at low concentrations. By enabling the effects of dATP on sarcomere mechanics to be predicted, this multi-scale modelling framework may elucidate the molecular mechanisms by which dATP can have therapeutic effects on cardiac contractile dysfunction.},
	doi = {10.1016/j.abb.2020.108582},
	author = {Kimberly J {McCabe} and Aboelkassem, Yasser and Teitgen, Abigail and Huber, Gary and Andrew J. {McCammon} and Regnier, Michael and Andrew D. {McCulloch}}
}
@article {26563,
	title = {Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin},
	journal = {Proceedings of the National Academy of Sciences},
	year = {2019},
	month = {05/2019},
	publisher = {PNAS},
	abstract = {The naturally occurring nucleotide 2-deoxy-adenosine 5'-triphosphate (dATP) can be used by cardiac muscle as an alternative energy substrate for myosin chemomechanical activity. We and others have previously shown that dATP increases contractile force in normal hearts and models of depressed systolic function, but the structural basis of these effects has remained unresolved. In this work, we combine multiple techniques to provide structural and functional information at the angstrom-nanometer and millisecond time scales, demonstrating the ability to make both structural measurements and quantitative kinetic estimates of weak actin{\textendash}myosin interactions that underpin sarcomere dynamics. Exploiting dATP as a molecular probe, we assess how small changes in myosin structure translate to electrostatic-based changes in sarcomere function to augment contractility in cardiac muscle. Through Brownian dynamics simulation and computational structural analysis, we found that deoxy-hydrolysis products [2-deoxy-adenosine 5'-diphosphate (dADP) and inorganic phosphate (Pi)] bound to prepowerstroke myosin induce an allosteric restructuring of the actin-binding surface on myosin to increase the rate of cross-bridge formation. We then show experimentally that this predicted effect translates into increased electrostatic interactions between actin and cardiac myosin in vitro. Finally, using small-angle X-ray diffraction analysis of sarcomere structure, we demonstrate that the proposed increased electrostatic affinity of myosin for actin causes a disruption of the resting conformation of myosin motors, resulting in their repositioning toward the thin filament before activation. The dATP-mediated structural alterations in myosin reported here may provide insight into an improved criterion for the design or selection of small molecules to be developed as therapeutic agents to treat systolic dysfunction.},
	issn = {0027-8424},
	doi = {10.1073/pnas.1905028116},
	url = {http://www.pnas.org/lookup/doi/10.1073/pnas.1905028116https://syndication.highwire.org/content/doi/10.1073/pnas.1905028116},
	author = {Joseph D {Powers} and Yuan, Chen-Ching and Kimberly J {McCabe} and Jason D {Murray} and Matthew Carter {Childers} and Galina V {Flint} and Moussavi-Harami, Farid and Mohran, Saffie and Castillo, Romi and Zuzek, Carla and Ma, Weikang and Daggett, Valerie and Andrew D. {McCulloch} and Thomas C {Irving} and Regnier, Michael}
}
@article {26787,
	title = {Multiscale Models of Cardiac Muscle Biophysics and Tissue Remodeling in Hypertrophic Cardiomyopathies},
	journal = {Current Opinion in Biomedical Engineering},
	volume = {11},
	year = {2019},
	pages = {35-44},
	publisher = {Elsevier},
	doi = {https://doi.org/10.1016/j.cobme.2019.09.005},
	author = {Aboelkassem, Yasser and Joseph D {Powers} and Kimberly J {McCabe} and Andrew D. {McCulloch}}
}
@article {26786,
	title = {A Stochastic Multiscale Model of Cardiac Thin Filament Activation Using Brownian-Langevin Dynamics},
	journal = {Biophysical Journal},
	volume = {117},
	year = {2019},
	pages = {2255-2272},
	publisher = {Cell Press},
	abstract = {We use Brownian-Langevin dynamics principles to derive a coarse-graining multiscale myofilament model that can describe the thin-filament activation process during contraction. The model links atomistic molecular simulations of protein-protein interactions in the thin-filament regulatory unit to sarcomere-level activation dynamics. We first calculate the molecular interaction energy between tropomyosin and actin surface using Brownian dynamics simulations. This energy profile is then generalized to account for the observed tropomyosin transitions between its regulatory stable states. The generalized energy landscape then served as a basis for developing a filament-scale model using Langevin dynamics. This integrated analysis, spanning molecular to thin-filament scales, is capable of tracking the events of the tropomyosin conformational changes as it moves over the actin surface. The tropomyosin coil with flexible overlap regions between adjacent tropomyosins is represented in the model as a system of coupled stochastic ordinary differential equations. The proposed multiscale approach provides a more detailed molecular connection between tropomyosin dynamics, the trompomyosin-actin interaction-energy landscape, and the generated force by the sarcomere.},
	doi = {10.1016/j.bpj.2019.08.003},
	author = {Aboelkassem, Yasser and Kimberly J {McCabe} and Huber, Gary and Regnier, Michael and Andrew J. {McCammon} and Andrew D. {McCulloch}}
}
@misc {26463,
	title = {A Markov State Model of the Sarcomere to Explain the  Effects of dATP on Cardiac Contraction},
	year = {2018},
	address = {Biophysical Society 62nd Annual Meeting, San Francisco CA},
	abstract = {2-deoxy-ATP is a naturally occurring homolog of ATP known to increase force production, enhance crossbridge cycling speed, and accelerate the removal of Ca2+ from the cytoplasm during cardiac muscle cell relaxation. At low ratios of dATP to ATP in cardiomyocytes, steady state force has been shown to increase nonlinearly at physiological [Ca2+]1. The purpose of this study is to discover specific mechanisms by which dATP alters myosin dynamics within the sarcomere using multiscale computational modeling. We have developed a comprehensive mechanistic Monte Carlo Markov State model of rat sarcomere contraction which includes cooperativity in both thin filament activation and crossbridge cycling through nearest-neighbor Tropomyosin (Tm) interactions as well as cross bridge attachment effect on neighboring myosin on the thick filament. This novel sarcomere model was used to test the effects of dATP on contractility within the sarcomere.\&nbsp; We combined experimental data on the subcellular, cellular, and organ level as well as Molecular Dynamics (MD) data to parameterize and validate the model. We tested combinations of 4 possible kinetic transitions in which dATP is hypothesized to affect crossbridge cycling and tested various degrees of cooperativity in the system to find a likely combination of mechanisms by which dATP affects contraction.},
	author = {Kimberly J {McCabe} and Aboelkassem, Yasser and Dewan, Sukriti and Regnier, Michael and Andrew D. {McCulloch}}
}
@misc {aboelkassem2018turning,
	title = {Turning the Azimuthal Motions of Adjacent Tropomyosins into a Coupled N-body Problem in a Brownian Model of Cardiac Thin Filament Activation},
	howpublished = {Biophysical Journal},
	year = {2018},
	publisher = {Elsevier},
	address = {San Francisco, California/U.S.A.},
	author = {Aboelkassem, Yasser and Kimberly J {McCabe} and Huber, Gary and Sundnes, Joakim and Andrew D. {McCulloch}}
}
@article {26458,
	title = {Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants{\textemdash}Genotype to Cellular Phenotype},
	journal = {Frontiers in Physiology},
	volume = {14},
	number = {151},
	year = {2017},
	month = {03/2017},
	publisher = {Frontiers in Physiology},
	doi = {10.3389/fphys.2017.00151},
	url = {http://journal.frontiersin.org/article/10.3389/fphys.2017.00151/fullhttp://journal.frontiersin.org/article/10.3389/fphys.2017.00151/full},
	author = {Dewan, Sukriti and Kimberly J {McCabe} and Regnier, Michael and Andrew D. {McCulloch}}
}
@article {26459,
	title = {Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation{\textemdash}An Integrated Multiscale Modeling Study},
	journal = {The Journal of Physical Chemistry B},
	volume = {120},
	year = {2016},
	month = {08/2016},
	pages = {8264 - 8275},
	publisher = {The Journal of Physical Chemistry B},
	issn = {1520-6106},
	doi = {10.1021/acs.jpcb.6b01950},
	url = {http://pubs.acs.org/doi/10.1021/acs.jpcb.6b01950http://pubs.acs.org/doi/pdf/10.1021/acs.jpcb.6b01950},
	author = {Dewan, Sukriti and Kimberly J {McCabe} and Regnier, Michael and Andrew D. {McCulloch} and Lindert, Steffen}
}
@article {26460,
	title = {Contributions of Ca 2+ -Independent Thin Filament Activation to Cardiac Muscle Function},
	journal = {Biophysical Journal},
	volume = {109},
	year = {2015},
	month = {Jan-11-2015},
	pages = {2101 - 2112},
	publisher = {Biophysical Journal},
	issn = {00063495},
	doi = {10.1016/j.bpj.2015.09.028},
	url = {https://linkinghub.elsevier.com/retrieve/pii/S0006349515009996https://api.elsevier.com/content/article/PII:S0006349515009996?httpAccept=text/xmlhttps://api.elsevier.com/content/article/PII:S0006349515009996?httpAccept=text/plain},
	author = {Aboelkassem, Yasser and Jordan A. {Bonilla} and Kimberly J {McCabe} and Stuart G. {Campbell}}
}
