Publications (17)80.52 Total impact
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Article: β-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets.
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ABSTRACT: Sympathetic stimulation regulates cardiac excitation-contraction coupling in hearts but can also trigger ventricular arrhythmic relationship between α and time IAS caused by early afterdepolarizations (EADs) in pathological conditions. Isoproterenol (ISO) stimulation can transiently cause EADs which could result from differential kinetics of L type calcium (Ca) current (ICaL) vs. delayed rectifier potassium current (IKs) effects, but multiple PKA targets complicate mechanistic analysis. Utilizing a biophysically detailed model integrating Ca and β-adrenergic signaling, we investigate how different phosphorylation kinetics and targets influence β-adrenergic-induced transient EADs. We found that: 1) The faster time course of ICaL vs. IKs increases recapitulated experimentally observed ISO-induced transient EADs (which are due to ICaL reactivation). These EADs disappear at steady state ISO and do not occur during more gradual ISO application. 2) This ICaL vs. IKs kinetic mismatch with ISO can also induce transient EADs due to spontaneous sarcoplasmic reticulum (SR) Ca release and Na/Ca exchange current. The increased ICaL, SR Ca uptake and action potential duration (APD) raise SR Ca to cause spontaneous SR Ca release, but eventual IKs activation and APD shortening abolish these EADs. 3) Phospholemman (PLM) phosphorylation decreases both types of EADs by increasing outward Na/K-ATPase current (INaK) for ICaL-mediated EADs, and reducing intracellular Na and Ca loading for SR Ca-release-mediated EADs. Slowing PLM phosphorylation kinetics abolishes this protective effect. 4) Blocking phospholamban (PLB) phosphorylation has little effect on ICaL-mediated transient EADs, but abolishes SR Ca-release-mediated transient EADs by limiting SR Ca loading. 5) RyR phosphorylation has little effect on either transient EAD type. Our study emphasizes the importance of understanding non-steady state kinetics of several systems in mediating β-adrenergic-induced EADs and arrhythmias. This article is part of a Special Issue entitled Calcium Signaling in Heart.Journal of Molecular and Cellular Cardiology 02/2013; · 5.17 Impact Factor -
Article: Bi-stable wave propagation and early afterdepolarization-mediated cardiac arrhythmias.
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ABSTRACT: In normal atrial and ventricular tissue, the electrical wavefronts are mediated by the fast sodium current (I(Na)), whereas in sinoatrial and atrioventricular nodal tissue, conduction is mediated by the slow L-type calcium current (I(Ca,L)). However, it has not been shown whether the same tissue can exhibit both the I(Na)-mediated and the I(Ca,L)-mediated conduction. This study sought to test the hypothesis that bi-stable cardiac wave conduction, mediated by I(Na) and I(Ca,L), respectively, can occur in the same tissue under conditions promoting early afterdepolarizations (EADs), and to study how this novel wave dynamics is related to the mechanisms of EAD-mediated arrhythmias. Computer models of two-dimensional (2D) tissue with a physiologically detailed action potential model were used to study the bi-stable wave dynamics. Theoretical predictions were tested experimentally by optical mapping in neonatal rat ventricular myocyte monolayers. In the same 2D homogeneous tissue, we could induce spiral waves that are mediated by either I(Na) or I(Ca,L) under conditions in which the action potential model exhibited EADs. This bi-stable wave propagation behavior was similar to bi-stability shown in many other nonlinear systems. Because the bi-stable states are also excitable, we call this novel behavior bi-excitability. In a 2D heterogeneous tissue, the I(Ca,L)-mediated spiral wave meanders, giving rise to a twisting electrocardiographic QRS axis, resembling torsades de pointes, whereas the coexistence and interplay between the I(Na)-mediated wavefronts and I(Ca,L)-mediated wavefronts give rise to polymorphic ventricular tachycardia. We also present experimental evidence for bi-excitability under EAD-promoting conditions in neonatal rat ventricular myocyte monolayers exposed to BayK8644 and isoproterenol. Under EAD-prone conditions, both I(Na)-mediated conduction and I(Ca,L)-mediated conduction can occur in the same tissue. These novel wave dynamics may be responsible for certain EAD-mediated arrhythmias, such as torsades de pointes and polymorphic ventricular tachycardia.Heart rhythm: the official journal of the Heart Rhythm Society 08/2011; 9(1):115-22. · 4.56 Impact Factor -
Article: So little source, so much sink: requirements for afterdepolarizations to propagate in tissue.
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ABSTRACT: How early (EADs) and delayed afterdepolarizations (DADs) overcome electrotonic source-sink mismatches in tissue to trigger premature ventricular complexes remains incompletely understood. To study this question, we used a rabbit ventricular action potential model to simulate tissues in which a central area of contiguous myocytes susceptible to EADs or DADs was surrounded by unsusceptible tissue. In 1D tissue with normal longitudinal conduction velocity (0.55 m/s), the numbers of contiguous susceptible myocytes required for an EAD and a barely suprathreshold DAD to trigger a propagating action potential were 70 and 80, respectively. In 2D tissue, these numbers increased to 6940 and 7854, and in 3D tissue to 696,910 and 817,280. These numbers were significantly decreased by reduced gap junction conductance, simulated fibrosis, reduced repolarization reserve and heart failure electrical remodeling. In conclusion, the source-sink mismatch in well-coupled cardiac tissue powerfully protects the heart from arrhythmias due to sporadic afterdepolarizations. Structural and electrophysiological remodeling decrease these numbers significantly but still require synchronization mechanisms for EADs and DADs to overcome the robust protective effects of source-sink mismatch.Biophysical Journal 09/2010; 99(5):1408-15. · 3.65 Impact Factor -
Article: Irregularly appearing early afterdepolarizations in cardiac myocytes: random fluctuations or dynamical chaos?
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ABSTRACT: Irregularly occurring early afterdepolarizations (EADs) in cardiac myocytes are traditionally hypothesized to be caused by random ion channel fluctuations. In this study, we combined 1), patch-clamp experiments in which action potentials were recorded at different pacing cycle lengths from isolated rabbit ventricular myocytes under several experimental conditions inducing EADs, including oxidative stress with hydrogen peroxide, calcium overload with BayK8644, and ionic stress with hypokalemia; 2), computer simulations using a physiologically detailed rabbit ventricular action potential model, in which repolarization reserve was reduced to generate EADs and random ion channel or path cycle length fluctuations were implemented; and 3), iterated maps with or without noise. By comparing experimental, modeling, and bifurcation analyses, we present evidence that noise-induced transitions between bistable states (i.e., between an action potential with and without an EAD) is not sufficient to account for the large variation in action potential duration fluctuations observed in experimental studies. We conclude that the irregular dynamics of EADs is intrinsically chaotic, with random fluctuations playing a nonessential, auxiliary role potentiating the complex dynamics.Biophysical Journal 08/2010; 99(3):765-73. · 3.65 Impact Factor -
Article: Acceleration of cardiac tissue simulation with graphic processing units.
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ABSTRACT: In this technical note we show the promise of using graphic processing units (GPUs) to accelerate simulations of electrical wave propagation in cardiac tissue, one of the more demanding computational problems in cardiology. We have found that the computational speed of two-dimensional (2D) tissue simulations with a single commercially available GPU is about 30 times faster than with a single 2.0 GHz Advanced Micro Devices (AMD) Opteron processor. We have also simulated wave conduction in the three-dimensional (3D) anatomic heart with GPUs where we found the computational speed with a single GPU is 1.6 times slower than with a 32-central processing unit (CPU) Opteron cluster. However, a cluster with two or four GPUs is faster than the CPU-based cluster. These results demonstrate that a commodity personal computer is able to perform a whole heart simulation of electrical wave conduction within times that enable the investigators to interact more easily with their simulations.Medical & Biological Engineering 09/2009; 47(9):1011-5. · 1.76 Impact Factor -
Article: Bifurcation and chaos in a model of cardiac early afterdepolarizations.
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ABSTRACT: Excitable cells can exhibit complex patterns of oscillations, such as spiking and bursting. In cardiac cells, pathological voltage oscillations, called early afterdepolarizations (EADs), have been widely observed under disease conditions, yet their dynamical mechanisms remain unknown. Here, we show that EADs are caused by Hopf and homoclinic bifurcations. During period pacing, chaos always occurs at the transition from no EAD to EADs as the stimulation frequency decreases, providing a distinct explanation for the irregular EAD behavior frequently observed in experiments.Physical Review Letters 07/2009; 102(25):258103. · 7.37 Impact Factor -
Article: Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias.
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ABSTRACT: The synchronization of coupled oscillators plays an important role in many biological systems, including the heart. In heart diseases, cardiac myocytes can exhibit abnormal electrical oscillations, such as early afterdepolarizations (EADs), which are associated with lethal arrhythmias. A key unanswered question is how cellular EADs partially synchronize in tissue, as is required for them to propagate. Here, we present evidence, from computational simulations and experiments in isolated myocytes, that irregular EAD behavior is dynamical chaos. We then show in electrically homogeneous tissue models that chaotic EADs synchronize globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electrotonic coupling can no longer globally synchronize EADs, resulting in regions of partial synchronization that shift in time and space. These regional partially synchronized EADs then form premature ventricular complexes that propagate into recovered tissue without EADs. This process creates multiple premature ventricular complexes that propagate as [corrected] "shifting" foci resembling polymorphic ventricular tachycardia. Shifting foci encountering shifting repolarization gradients can also develop localized wave breaks leading to reentry and fibrillation. As predicted by the theory, rabbit hearts exposed to oxidative stress (H(2)O(2)) exhibited multiple shifting foci causing polymorphic tachycardia and fibrillation. This mechanism explains how collective cellular behavior integrates at the tissue scale to generate lethal cardiac arrhythmias over a wide range of heart rates.Proceedings of the National Academy of Sciences 03/2009; 106(9):2983-8. · 9.68 Impact Factor -
Article: Intracellular Ca alternans: coordinated regulation by sarcoplasmic reticulum release, uptake, and leak.
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ABSTRACT: Beat-to-beat alternation in the cardiac intracellular Ca (Ca(i)) transient can drive action potential (AP) duration alternans, creating a highly arrhythmogenic substrate. Although a steep dependence of fractional sarcoplasmic reticulum (SR) Ca release on SR Ca load has been shown experimentally to promote Ca(i) alternans, theoretical studies predict that other factors are also important. Here we present an iterated map analysis of the coordinated effects of SR Ca release, uptake, and leak on the onset of Ca(i) alternans. Predictions were compared to numerical simulations using a physiologically realistic AP model as well as to AP clamp experiments in isolated patch-clamped rabbit ventricular myocytes exposed to 1), the Ca channel agonist BayK8644 (100 nM) to increase SR Ca load and release fraction, 2), overexpression of an adenoviral SERCA2a construct to increase SR Ca uptake, and 3), low-dose FK506 (20 microM) or ryanodine (1 microM) to increase SR Ca leak. Our findings show that SR Ca release, uptake, and leak all have independent direct effects that promote (release and leak) or suppress (uptake) Ca(i) alternans. However, since each factor affects the other by altering SR Ca load, the net balance of their direct and indirect effects determines whether they promote or suppress alternans. Thus, BayK8644 promotes, whereas Ad-SERCA2a overexpression, ryanodine, and FK506 suppress, Ca(i) alternans under AP clamp conditions.Biophysical Journal 07/2008; 95(6):3100-10. · 3.65 Impact Factor -
Article: A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates.
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ABSTRACT: Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Ca(i)) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (I(Ca,L)) and Ca(i) cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35-37 degrees C. Incorporating a minimal seven-state Markovian model of I(Ca,L) that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Ca(i) cycling model, the new model replicates experimentally observed action potential duration and Ca(i) transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing.Biophysical Journal 02/2008; 94(2):392-410. · 3.65 Impact Factor -
Article: Modifying L-type calcium current kinetics: consequences for cardiac excitation and arrhythmia dynamics.
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ABSTRACT: The L-type Ca current (I(Ca,L)), essential for normal cardiac function, also regulates dynamic action potential (AP) properties that promote ventricular fibrillation. Blocking I(Ca,L) can prevent ventricular fibrillation, but only at levels suppressing contractility. We speculated that, instead of blocking I(Ca,L), modifying its shape by altering kinetic features could produce equivalent anti-fibrillatory effects without depressing contractility. To test this concept experimentally, we overexpressed a mutant Ca-insensitive calmodulin (CaM(1234)) in rabbit ventricular myocytes to inhibit Ca-dependent I(Ca,L) inactivation, combined with the ATP-sensitive K current agonist pinacidil or I(Ca,L) blocker verapamil to maintain AP duration (APD) near control levels. Cell shortening was enhanced in pinacidil-treated myocytes, but depressed in verapamil-treated myocytes. Both combinations flattened APD restitution slope and prevented APD alternans, similar to I(Ca,L) blockade. To predict the arrhythmogenic consequences, we simulated the cellular effects using a new AP model, which reproduced flattening of APD restitution slope and prevention of APD/Ca(i) transient alternans but maintained a normal Ca(i) transient. In simulated two-dimensional cardiac tissue, these changes prevented the arrhythmogenic spatially discordant APD/Ca(i) transient alternans and spiral wave breakup. These findings provide a proof-of-concept test that I(Ca,L) can be targeted to increase dynamic wave stability without depressing contractility, which may have promise as an antifibrillatory strategy.Biophysical Journal 02/2008; 94(2):411-23. · 3.65 Impact Factor -
Article: MODIFYING L-TYPE CALCIUM CURRENT KINETICS: CONSEQUENCES FOR CARDIAC EXCITATION AND ARRHYTHMIA DYNAMICS.
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ABSTRACT: The L-type Ca current (ICa,L), essential for normal cardiac function, also regulates dynamic action potential (AP) properties that promote ventricular fibrillation (VF). Blocking ICa,L can prevent VF, but only at levels suppressing contractility. We speculated that, instead of blocking ICa,L, modifying its shape by altering kinetic features could produce equivalent anti-fibrillatory effects without depressing contractility. To test this concept experimentally, we over-expressed a mutant Ca-insensitive calmodulin (CaM1234) in rabbit ventricular myocytes to inhibit Ca-dependent ICa,L inactivation, combined with the ATP-sensitive K current agonist pinacidil or ICa,L blocker verapamil to maintain AP duration (APD) near control levels. Cell shortening was enhanced in pinacidil-treated myocytes, but depressed in verapamil-treated myocytes. Both combinations flattened APD restitution slope and prevented APD alternans, similar to ICa,L blockade. To predict the arrhythmogenic consequences, we simulated the cellular effects using a new AP model, which reproduced flattening of APD restitution slope and prevention of APD/Cai transient alternans but maintained a normal Cai transient. In simulated 2D cardiac tissue, these changes prevented the arrhythmogenic spatially discordant APD/Cai transient alternans and spiral wave break up. These findings provide a proof-of-concept test that ICa,L can be targeted to increase dynamic wave stability without depressing contractility, which may have promise as an anti-fibrillatory strategy.Biophysical Journal 11/2007; · 3.65 Impact Factor -
Article: Dispersion of refractoriness and induction of reentry due to chaos synchronization in a model of cardiac tissue.
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ABSTRACT: Ventricular fibrillation is a lethal condition caused by multiple chaotically wandering electrical wavelets in the heart, reentering their own and each other's territories. The development of effective therapies requires a detailed understanding of how these reentrant waves are initiated. In this Letter, we demonstrate a novel mechanism for inducing reentry, in which chaos synchronization causes large-scale heterogeneities of refractoriness transverse to the direction of propagation. These regions of increased refractoriness create localized conduction block, which induces spiral wave reentry.Physical Review Letters 10/2007; 99(11):118101. · 7.37 Impact Factor -
Article: A RABBIT VENTRICULAR ACTION POTENTIAL MODEL REPLICATING CARDIAC DYNAMICS AT RAPID HEART RATES.
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ABSTRACT: Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Cai) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using the rabbit ventricular action potential model by Shannon et al. (1), we modified the L-type calcium (Ca) current (ICa,L) and Cai cycling formulations based on new experimental patch clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35-37 degrees C. Incorporating a minimal seven-state Markov model of ICa,L that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Cai cycling model, the new model replicates experimentally-observed action potential duration (APD) and Cai transient alternans at rapid heart rates, and accurately reproduces experimental APD restitution curves obtained by either dynamic or S1S2 pacing.Biophysical Journal 06/2007; · 3.65 Impact Factor -
Article: Inferring the cellular origin of voltage and calcium alternans from the spatial scales of phase reversal during discordant alternans.
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ABSTRACT: Beat-to-beat alternation of the action potential duration (APD) in paced cardiac cells has been linked to the onset of lethal arrhythmias. Both experimental and theoretical studies have shown that alternans at the single cell level can be caused by unstable membrane voltage (V(m)) dynamics linked to steep APD-restitution, or unstable intracellular calcium (Ca) cycling linked to high sensitivity of Ca release from the sarcoplasmic reticulum on sarcoplasmic reticulum Ca load. Identifying which of these two mechanisms is the primary cause of cellular alternans, however, has remained difficult since Ca and V(m) are bidirectionally coupled. Here, we use numerical simulations of a physiologically detailed ionic model to show that the origin of alternans can be inferred by measuring the length scales over which APD and Ca(i) alternans reverse phase during spatially discordant alternans. The main conclusion is that these scales are comparable to a few millimeters and equal when alternans is driven by APD restitution, but differ markedly when alternans is driven predominantly by unstable Ca cycling. In the latter case, APD alternans still reverses phase on a millimeter tissue scale due to electrotonic coupling, while Ca alternans reverses phase on a submillimeter cellular scale. These results show that experimentally accessible measurements of Ca(i) and V(m) in cardiac tissue can be used to shed light on the cellular origin of alternans.Biophysical Journal 03/2007; 92(4):L33-5. · 3.65 Impact Factor -
Article: Dynamic origin of spatially discordant alternans in cardiac tissue.
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ABSTRACT: Alternans, a condition in which there is a beat-to-beat alternation in the electromechanical response of a periodically stimulated cardiac cell, has been linked to the genesis of life-threatening ventricular arrhythmias. Optical mapping of membrane voltage (V(m)) and intracellular calcium (Ca(i)) on the surface of animal hearts reveals complex spatial patterns of alternans. In particular, spatially discordant alternans has been observed in which regions with a large-small-large action potential duration (APD) alternate out-of-phase adjacent to regions of small-large-small APD. However, the underlying mechanisms that lead to the initiation of discordant alternans and govern its spatiotemporal properties are not well understood. Using mathematical modeling, we show that dynamic changes in the spatial distribution of discordant alternans can be used to pinpoint the underlying mechanisms. Optical mapping of V(m) and Ca(i) in paced rabbit hearts revealed that spatially discordant alternans induced by rapid pacing exhibits properties consistent with a purely dynamical mechanism as shown in theoretical studies. Our results support the viewpoint that spatially discordant alternans in the heart can be formed via a dynamical pattern formation process which does not require tissue heterogeneity.Biophysical Journal 02/2007; 92(2):448-60. · 3.65 Impact Factor -
Article: Spatially discordant alternans in cardiac tissue: role of calcium cycling.
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ABSTRACT: Spatially discordant alternans, where the action potential duration (APD) and intracellular calcium transient (Ca(i)) alternate with opposite phase in different regions of tissue, is known to promote wave break and reentry. However, this phenomenon is not completely understood. It is known that alternans at the cellular level can be caused by dynamical instabilities arising from either membrane voltage (V(m)) attributable to steep APD restitution or to calcium (Ca) cycling. Here, we used a mathematical model of intracellular Ca cycling, coupled with membrane ion currents, to investigate the dynamics of V(m) and Ca(i) transient alternans in an isolated cell, in two electrotonically coupled cells, and in 1D spatially homogeneous tissue. Our main finding is a novel instability mechanism in which the bidirectional coupling of V(m) and Ca(i) can drive the Ca(i) transient of two neighboring cells to be out of phase. This instability is manifested in cardiac tissue by the dynamical formation of spatially discordant alternans. In this case, Ca(i) transient alternans can reverse phase over a length scale of one cell, whereas APD alternans reverses phase over a much longer length scale set by the electrotonic coupling. We analyze this mechanism in detail and show that it is a robust consequence of experimentally established properties of the bidirectional coupling between Ca cycling and V(m) dynamics. Finally, we address the experimental relevance of these findings and suggest physiological conditions under which these patterns can be observed.Circulation Research 10/2006; 99(5):520-7. · 9.49 Impact Factor -
Article: Coupled dynamics of voltage and calcium in paced cardiac cells.
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ABSTRACT: We investigate numerically and analytically the coupled dynamics of transmembrane voltage and intracellular calcium cycling in paced cardiac cells using a detailed physiological model, and its reduction to a three-dimensional discrete map. The results provide a theoretical framework to interpret various experimentally observed modes of instability ranging from electromechanically concordant and discordant alternans to quasiperiodic oscillations of voltage and calcium.Physical Review E 03/2005; 71(2 Pt 1):021903. · 2.26 Impact Factor
Top co-authors
Top Journals
Institutions
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2007–2011
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University of California, Los Angeles
- Department of Integrative Biology and Physiology
Los Angeles, CA, USA -
Cedars-Sinai Medical Center
- Division of Cardiology
Los Angeles, CA, USA
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2008–2009
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UCLA Cardiovascular Research Laboratory
Los Angeles, CA, USA
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2005–2006
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Northeastern University
- Center for Interdisciplinary Research on Complex Systems (CIRCS)
Boston, MA, USA
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