Publications
346 results found
Iribe G, Ward CW, Camelliti P, et al., 2009, Axial Stretch of Rat Single Ventricular Cardiomyocytes Causes an Acute and Transient Increase in Ca(2+) Spark Rate, Vol: 104, Pages: 787-U141, ISSN: 0009-7330
We investigate acute effects of axial stretch, applied by carbon fibers (CFs), on diastolic Ca(2+) spark rate in rat isolated cardiomyocytes. CFs were attached either to both cell ends (to maximize the stretched region), or to the center and one end of the cell (to compare responses in stretched and nonstretched half-cells). Sarcomere length was increased by 8.01 +/- 0.94% in the stretched cell fraction, and time series of XY confocal images were recorded to monitor diastolic Ca(2+) spark frequency and dynamics. Whole-cell stretch causes an acute increase of Ca(2+) spark rate (to 130.7 +/- 6.4%) within 5 seconds, followed by a return to near background levels (to 104.4 +/- 5.1%) within 1 minute of sustained distension. Spark rate increased only in the stretched cell region, without significant differences in spark amplitude, time to peak, and decay time constants of sparks in stretched and nonstretched areas. Block of stretch-activated ion channels (2 mu mol/L GsMTx-4), perfusion with Na(+)/Ca(2+)-free solution, and block of nitric oxide synthesis (1 mmol/L L-NAME) all had no effect on the stretch-induced acute increase in Ca(2+) spark rate. Conversely, interference with cytoskeletal integrity (2 hours of 10 mu mol/L colchicine) abolished the response. Subsequent electron microscopic tomography confirmed the close approximation of microtubules with the T-tubular-sarcoplasmic reticulum complex (to within approximate to 10(-8)m). In conclusion, axial stretch of rat cardiomyocytes acutely and transiently increases sarcoplasmic reticulum Ca(2+) spark rate via a mechanism that is independent of sarcolemmal stretch-activated ion channels, nitric oxide synthesis, or availability of extracellular calcium but that requires cytoskeletal integrity. The potential of microtubule-mediated modulation of ryanodine receptor function warrants further investigation. (Circ Res. 2009; 104: 787-795.)
Xie YF, Garfinkel A, Camelliti P, et al., 2009, Effects of fibroblast-myocyte coupling on cardiac conduction and vulnerability to reentry: A computational study, Vol: 6, Pages: 1641-1649, ISSN: 1547-5271
BACKGROUND Recent experimental studies have documented that functional gap junctions form between fibroblasts and myocytes, raising the possibility that fibroblasts play roles in cardiac electrophysiology that extend beyond acting as passive electrical insulators. OBJECTIVE The purpose of this study was to use computational models to investigate how fibroblasts may affect cardiac conduction and vulnerability to reentry under different fibroblast-myocyte coupling conditions and tissue structures. METHODS Computational models of two-dimensional tissue with fibroblast-myocyte coupling were developed and numerically simulated. Myocytes were modeled by the phase I of the Luo-Rudy model, and fibroblasts were modeled by a passive model. RESULTS Besides slowing conduction by cardiomyocyte decoupling and electrotonic loading, fibroblast coupling to myocytes elevates myocyte resting membrane potential, causing conduction velocity to first increase and then decrease as fibroblast content increases, until conduction failure occurs. Fibroblast-myocyte coupling can also enhance conduction by connecting uncoupled myocytes. These competing effects of fibroblasts on conduction give rise to different conduction patterns under different fibroblast-myocyte coupling conditions and tissue structures. Elevation of myocyte resting potential due to fibroblast-myocyte coupling slows sodium channel recovery, which extends postrepolarization refractoriness. Owing to this prolongation of the myocyte refractory period, reentry was more readily induced by a premature stimulation in heterogeneous tissue models when fibroblasts were electrotonically coupled to myocytes compared with uncoupled fibroblasts acting as pure passive electrical insulators. CONCLUSIONS Fibroblasts affect cardiac conduction by acting as obstacles or. by creating electrotonic loading and elevating myocyte resting potential. Functional fibroblast-myocyte coupling prolongs the myocyte refractory period, which may facilitate in
Jeremy Rice J, Kohl P, 2008, Mechanoelectrical interactions and their role in electrical function of the heart, Electrical Diseases of the Heart: Genetics, Mechanisms, Treatment, Prevention, Pages: 145-160, ISBN: 9781846288531
The heart is an electrically controlled and chemically powered mechanical pump. There are complex interactions between cardiac electrophysiology, metabolism, and mechanics, with a multitude of interdigitating regulatory loops. This chapter will focus on the cross-talk between electrical and mechanical activity of the heart, and in particular its relevance for heart rhythm. © 2008 Springer-Verlag London Limited.
Kohl P, Coveney P, Clapworthy G, et al., 2008, The virtual physiological human. Editorial., Philos Trans A Math Phys Eng Sci, Vol: 366, Pages: 3223-3224, ISSN: 1364-503X
Kohl P, Noble D, 2008, Life and mechanosensitivity, Progress in Biophysics & Molecular Biology, Vol: 97, Pages: 159-162, ISSN: 0079-6107
Plotkowiak M, Rodriguez B, Plank G, et al., 2008, High performance computer simulations of cardiac electrical function based on high resolution MRI datasets, Computational Science - Iccs 2008, Pt 1, Editors: Bubak, VanAlbada, Dongarra, Sloot, Pages: 571-580, ISBN: 978-3-540-69383-3
In this paper, we present a set of applications that allow performance of electrophysiological simulations on individualized models generated using high-resolution MRI data of rabbit hearts. For this purpose, we propose a pipeline consisting of: extraction of significant structures from the images, generation of meshes, and application of an electrophysiological solver. In order to make it as useful as possible, we impose several requirements on the development of the pipeline. It has to be fast, aiming towards real time in the future. As much as possible, it must use non-commercial, freely available software (mostly open source). In order to verify the methodology, a set of high resolution MRI images of a rabbit heart is investigated and tested; results are presented in this work.
Camelliti P, Bub G, Stuckey DJ, et al., 2008, Two Photon Microscopy Measurements Of Sub-epicardial Sarcomere Length In Perfused Rat Hearts, Circulation, Pages: S543-S543, ISSN: 0009-7322
Kohl P, Coveney P, Clapworthy G, et al., 2008, Untitled, Vol: 366, Pages: 3223-3224, ISSN: 1364-503X
Clapworthy G, Viceconti M, Coveney PV, et al., 2008, The virtual physiological human: building a framework for computational biomedicine, Philos Transact A Math Phys Eng Sci, Vol: 366, Pages: 2975-2978, ISSN: 1364-503X
Fenner JW, Brook B, Clapworthy G, et al., 2008, The EuroPhysiome, STEP and a roadmap for the virtual physiological human, Philos Transact A Math Phys Eng Sci, Vol: 366, Pages: 2979-2999, ISSN: 1364-503X
Biomedical science and its allied disciplines are entering a new era in which computational methods and technologies are poised to play a prevalent role in supporting collaborative investigation of the human body. Within Europe, this has its focus in the virtual physiological human (VPH), which is an evolving entity that has emerged from the EuroPhysiome initiative and the strategy for the EuroPhysiome (STEP) consortium. The VPH is intended to be a solution to common infrastructure needs for physiome projects across the globe, providing a unifying architecture that facilitates integration and prediction, ultimately creating a framework capable of describing Homo sapiens in silico. The routine reliance of the biomedical industry, biomedical research and clinical practice on information technology (IT) highlights the importance of a tailor-made and robust IT infrastructure, but numerous challenges need to be addressed if the VPH is to become a mature technological reality. Appropriate investment will reap considerable rewards, since it is anticipated that the VPH will influence all sectors of society, with implications predominantly for improved healthcare, improved competitiveness in industry and greater understanding of (patho) physiological processes. This paper considers issues pertinent to the development of the VPH, highlighted by the work of the STEP consortium.
Iribe G, Kohl P, 2008, Axial stretch enhances sarcoplasmic reticulum Ca2+ leak and cellular Ca2+ reuptake in guinea pig ventricular myocytes: Experiments and models, Circulation Research, Vol: 97, Pages: 298-311, ISSN: 0079-6107
Cardiac cellular calcium (Ca2+) handling is the well-investigated mediator of excitation-contraction coupling, the process that translates cardiac electrical activation into mechanical events. The reverse-effects of mechanical stimulation on cardiomyocyte Ca2+ handling-are much less well understood, in particular during the inter-beat period, called 'diastole'. We have investigated the effects of diastolic length changes, applied axially using a pair of carbon fibres attached to opposite ends of Guinea pig isolated ventricular myocytes, on the availability of Ca2+ in the main cellular stores (the sarcoplasmic reticulum; SR), by studying the rest-decay of SR Ca2+ content [Ca2+](SR), and the reloading of the SR after prior depletion of Ca2+ from the cell. Cells were loaded with Fura-2 AM (an indicator of the cytosolic 'free' Ca2+ concentration, [Ca2+](i)), and preconditioned by field-stimulation (2Hz) at 37 degrees C, while [Ca2+](i) transients and sarcomere length (SL) were recorded simultaneously. After reaching a steady state in the behaviour of observed parameters, stimulation was interrupted for between 5 and 60 s, while cells were either held at resting length, or stretched (controlled to cause a 10% increase in SL, to aid inter-individual comparison). Thereafter, each cell was returned to its original resting length, followed by swift administration of 10mM of caffeine (in Na+/Ca2+ -free solution), which causes the release of Ca2+ from the SR (caffeine), but largely prevents extrusion of Ca2+ from the cytosol to the cell exterior (Na+/Ca2+-free solution). By comparing the [Ca2+](i) in cells exposed/not exposed to diastolic stretch of different duration, we assessed the rest-decay dynamics of [Ca2+](SR). To assess SR reloading after initial Ca2+ depletion, the same stretch protocol was implemented after prior emptying of the cell by application of 10 mM of caffeine in normal Tyrode solution (which causes Ca2+ to be released from the SR and extruded from the cell
Ho MY, Fajardo G, Bollensdorff C, et al., 2008, The Apelin-APJ Pathway Is an Endogenous Regulator of Cardiac Function, Circulation Research, Pages: E52-E52, ISSN: 0009-7330
Pellis T, Link M, Antzelevitch C, et al., 2007, Rare syndromes, commotio cordis, sudden death in athletes, Cardiac Arrest: The Science and Practice of Resuscitation Medicine, Pages: 1148-1198, ISBN: 9780521847001
Introduction: Athletes deliberately expose themselves to extreme environments (such as high altitude mountaineering and deep-sea diving) and physical challenges (from weight lifting to marathon running), which may give rise to the manifestation of rare cardiac conditions, or cause sudden death (SD). Indeed, the renowned Athenian long distance runner Pheidippides suffered SD in 490 BC after running from the battlefield of Marathon to Athens to announce the great victory of the Greeks over the invaders. An analysis of the very dissimilar physical and environmental conditions to which athletes are exposed, and related health risks, is beyond the scope of this chapter and will not be conducted. Instead, we will focus on SD from cardiac causes. Incidence: Sudden cardiac death: It is commonly understood, and substantiated by clinical evidence, that regular moderate physical exercise has beneficial cardiovascular effects. Several prospective epidemiological studies consistently associate exercise with a reduced risk of coronary artery disease (CAD) and sudden cardiac death (SCD). The incidence of SCD in adolescents and young adults (here defined as the age group >35 years) is about 1 in 100 000 per year; this is 100 times less than in the older population (1 in 1000 per year; Fig. 65.1). Predominant causes of SCD in athletes change with age. In those over 35 years of age, the most common etiology is atherosclerotic CAD, often severe and diffuse, even in individuals without known risk factors or symptoms. In contrast, in younger athletes, a variety of cardiac diseases, largely congenital and often rare, account for the majority of SCD.
Wagner G, Bub G, Kohl P, et al., 2007, Electrocardiography and imaging, Vol: 40, Pages: S66-S70, ISSN: 0022-0736
Kohl P, Camelliti P, 2007, Cardiac myocyte-nonmyocyte electrotonic coupling: Implications for ventricular arrhythmogenesis, Vol: 4, Pages: 233-235, ISSN: 1547-5271
Iribe G, Helmes M, Kohl P, 2007, Modeling study of load-(in)dependency in single myocardial cell mechanics, Pages: 476A-476A, ISSN: 0006-3495
Clapworthy GJ, Kohl P, Gregerson H, et al., 2007, Digital human modelling: A global vision and a European perspective, Digital Human Modeling, Editors: Duffy, Pages: 549-558, ISBN: 978-3-540-73318-8
The Physiome is an unibrella term that refers to human modelling with mathematics and computational methods, accommodating cross-disciplinary science (chemistry, biology, physics) and a breadth of dimensional and temporal scale (sub-cellular to organs, sub-microsecond to tens-of-years). The Virtual Physiological Human is a European initiative that is intended to provide a unifying architecture for the integration and cooperation of multi-scale physiome models, thereby creating a predictive platform for the description of human beings in silico. Unlike the Genorne, the challenge of the Physiome may be almost unbounded, as the desire for increased detail imposes a continuing pressure for ever-finer data granularity, and the necessary Information Technology (IT) infrastructure spawns innovations that Surpass conventional solutions. It is foreseen that maturing physiome activities will increasingly influence medicine, biomedical research and commercial developments, and the central role of IT highlights the need for a specific and robust IT infrastructure. The European Commission has experience of supporting challenging technical endeavours through its Framework Programmes of research, and in the forthcoming 7th Framework Programme, it will invite researchers from within and outside Europe to unite in seeking solutions to key issues of the Physiome. The Virtual Physiological Human (VPH) investment programme will establish the necessary infrastructure and address the grand technical challenges identified by experts. This paper examines the background to the stategy and the ways in which the programme's structure has been determined.
Goodyer CE, Grau V, Mansoori T, et al., 2007, 3D visualization of cardiac anatomical MRI data with para-cellular resolution, 2007 Annual International Conference of the Ieee Engineering in Medicine and Biology Society, Vols 1-16, Pages: 147-151, ISBN: 978-1-4244-0787-3
Advances in research and clinical techniques are providing increasing quantities of data at improved spatio-temporal resolution. It is therefore imperative to develop matching approaches for efficient analysis and intuitive presentation of this data. Using the example of advanced magnetic resonance imaging, this article will illustrate the challenges involved in computational reconstruction and interactive visualization of the three-dimensional cardiac anatomy, based on magnetic resonance imaging data with para-cellular resolution.
Iribe G, Helmes M, Kohl P, 2007, Force-length relations in isolated intact cardiomyocytes subjected to dynamic changes in mechanical load, Vol: 292, Pages: H1487-H1497, ISSN: 0363-6135
We developed a dynamic force- length ( FL) control system for single intact cardiomyocytes that uses a pair of compliant, computer- controlled, and piezo translator ( PZT)- positioned carbon fibers ( CF). CF are attached to opposite cell ends to afford dynamic and bidirectional control of the cell's mechanical environment. PZT and CF tip positions, as well as sarcomere length ( SL), are simultaneously monitored in real time, and passive/ active forces are calculated from CF bending. Cell force and length were dynamically adjusted by corresponding changes in PZT position, to achieve isometric, isotonic, or work- loop style contractions. Functionality of the technique was assessed by studying FL behavior of guinea pig intact cardiomyocytes. End- diastolic and end- systolic FL relations, obtained with varying preload and/ or afterloads, were near linear, independent of the mode of contraction, and overlapping for the range of end- diastolic SLs tested ( 1.85 - 2.05 mu m). Instantaneous elastance curves, obtained from FL relation curves, showed an afterload- dependent decrease in time to peak elastance and slowed relaxation with both increased preload and afterload. The ability of the present system to independently and dynamically control preload, afterload, and transition between end- diastolic and endsystolic FL coordinates provides a valuable extension to the range of tools available for the study of single cardiomyocyte mechanics, to foster its interrelation with whole heart pathophysiology.
Mansoori T, Plank G, Burton R, et al., 2007, An iterative method for registration of high-resolution cardiac histoanatomical and MRI images, 2007 4th Ieee International Symposium on Biomedical Imaging : Macro to Nano, Vols 1-3, Pages: 572-575, ISBN: 978-1-4244-0671-5
Cardiac computational models of electrical conduction, mechanical activation, hemodynamics and metabolism require detailed information about the structural arrangement of functionally heterogeneous cardiac cell types. However, current state-of-the-art models lack anatomically accurate cell type localization, which limits their utility. Histological sections combine unique resolution with discrimination of tissues and anatomical structures, but they suffer from alignment and deformation problems. On the other hand, MRI datasets preserve the correct geometry, but provide less micro structural detail. This paper presents a method for aligning MM and histological datasets to obtain a highly detailed, geometrically correct anatomical description of the heart. An iterative process is used to correct the various 2D and 3D, rigid and non-rigid transforms, introduced in the histology preparation and acquisition. Validation is performed by calculating distances between anatomical landmarks in both datasets, and by quantifying tissue overlap. Results illustrate the suitability of the proposed algorithm to produce detailed, accurate cardiac models.
Swietach P, Camelliti P, Kohl P, et al., 2007, Generating local acid-loads in multicellular strands of cultured neonatal myocytes using flash-photolysis, Biophysical Journal, Pages: 254A-254A, ISSN: 0006-3495
Kohl P, Richard S, 2006, From funny current to current physiome, Vol: 90, Pages: 1-4, ISSN: 0079-6107
Li WH, Kohl P, Trayanova N, 2006, Myocardial ischemia lowers precordial thump efficacy: An inquiry into mechanisms using three-dimensional simulations, Vol: 3, Pages: 179-186, ISSN: 1547-5271
BACKGROUND Precordial thump is the first International Liaison Committee on Resuscitation-prescribed procedure for advanced life support in witnessed cardiac arrest. Success rates vary and, according to clinical evidence, are significantly reduced under ischemic conditions. OBJECTIVES The purpose of this study was to elucidate the mechanisms involved in termination of ventricular tachycardia (VT) by precordial thump and its decreased rate of success in ischemia using a three-dimensional realistic model of electrical behavior in the rabbit ventricles. METHODS The electrophysiologic effect of precordial thump was represented by recruitment of mechanosensitive channels in the regions affected by precordial thump. In normoxia, precordial thump opened cation nonselective stretch-activated channels (SAC-NS, reversal potential -20 mV). In ischemia, precordial thump was assumed to additionally activate ATP-sensitive K+ (K-ATP) channels (reversal potential -95 mV). Ten randomly selected cases of VT were used, and for each case the effect of precordial thump on VT was examined for normoxia and under ischemic conditions of varying severity. RESULTS Precordial thump was found to have a 60% success rate in normoxia and 30% in ischemia. Results demonstrate that precordial thump-induced SAC-NS opening in normoxia reduced heterogeneity in transmembrane potential by partially repolarizing excited tissue and depolarizing resting myocardium, potentially causing foci of excitation that eradicate the excitable gap, thus facilitating VT termination. Decreased precordial thump efficacy in ischemia was caused by recruitment of K-ATP, which diminished the depolarizing effect of SAC-NS on resting tissue and caused pronounced action potential shortening, thus facilitating establishment of reentry. CONCLUSION This study provides mechanistic insight into precordial thump mechanisms and its reduced clinical utility in patients with myocardial ischemia.
Moskvin AS, Philiplev MP, Solovyova OE, et al., 2006, Electron-conformational model of ryanodine receptor lattice dynamics, Vol: 90, Pages: 88-103, ISSN: 0079-6107
We propose a simple, physically reasonable electron-conformational model for the ryanodine receptor (RyR) and, on that basis, present a theory to describe RyR lattice responses to L-type channel triggering as an induced non-equilibrium phase transition. Each RyR is modelled with a single open and a single closed (electronic) state only, described utilizing a s = 1/2 pseudospin approach. In addition to the fast electronic degree of freedom, the RyR channel is characterized by a slow classical conformational coordinate, Q, which specifies the RyR channel calcium conductance and provides a multimodal continuum of possible RyR states. The cooperativity in the RyR lattice is assumed to be determined by inter-channel conformational coupling. Given a threshold sarcoplasmic reticulum (SR) calcium load, the RyR lattice fires due to a nucleation process with a step-by-step domino-like opening of a fraction of lattice channels, providing for a sufficient release to generate calcium sparks. The optimal mode of RyR lattice functioning during calcium-induced calcium release implies a fractional release with a robust termination due to a decrease in SR calcium load, accompanied by a respective change in effective conformational strain of the lattice. SR calcium overload is shown to result in excitation of RyR lattice auto-oscillations with spontaneous RyR channel opening and closure. (c) 2005 Elsevier Ltd. All rights reserved.
Solovyova O, Katsnelson LB, Konovalov P, et al., 2006, Activation sequence as a key factor in spatio-temporal optimization of myocardial function, Vol: 364, Pages: 1367-1383, ISSN: 1364-503X
Using one-dimensional models of myocardial tissue, implemented as chains of virtual ventricular muscle segments that are kinematically connected in series, we studied the role of the excitation sequence in spatio-temporal organization of cardiac function. Each model element was represented by a well-verified mathematical model of cardiac electromechanical activity. We found that homogeneous chains, consisting of identical elements, respond to non-simultaneous stimulation by generation of complex spatio-temporal heterogeneities in element deformation. These are accompanied by the establishment of marked gradients in local electro-mechanical properties of the elements (heterogeneity in action potential duration, Ca2+ transient characteristics and sarcoplasmic reticulum Ca2+ loading). In heterogeneous chains, composed of elements simulating fast and slow contracting cardiomyocytes from different transmural layers, we found that only activation sequences where stimulation of the slower elements preceded that of faster ones gave rise to optimization of the system's electro-mechanical function. which was confirmed experimentally. Based on the results obtained, we hypothesize that the sequence of activation of cardiomyocytes in different ventricular layers is one of the key factors of spatio-temporal organization of myocardium. Moreover, activation sequence and regional differences in intrinsic electro-mechanical properties of cardiac muscle must be matched in order to optimize myocardial function.
Kohl P, Camelliti P, Burton FL, et al., 2006, Fibroblast-myocyte interrelation in the mammalian heart: Experiments and models, Faseb Journal, Pages: A847-A847, ISSN: 0892-6638
Camelliti P, Gallagher JO, Kohl P, et al., 2006, Micropatterned cell cultures on elastic membranes as an in vitro model of myocardium, Vol: 1, Pages: 1379-1391, ISSN: 1754-2189
We describe here a new in vitro protocol for structuring cardiac cell cultures to mimic important aspects of the in vivo ventricular myocardial phenotype by controlling the location and mechanical environment of cultured cells. Microlithography is used to engineer microstructured silicon metal wafers. Those are used to fabricate either microgrooved silicone membranes or silicone molds for microfluidic application of extracellular matrix proteins onto elastic membranes (involving flow control at micrometer resolution). The physically or microfluidically structured membranes serve as a cell culture growth substrate that supports cell alignment and allows the application of stretch. The latter is achieved with a stretching device that can deliver isotropic or anisotropic stretch. Neonatal ventricular cardiomyocytes, grown on these micropatterned membranes, develop an in vivo-like morphology with regular sarcomeric patterns. The entire process from fabrication of the micropatterned silicon metal wafers to casting of silicone molds, microfluidic patterning and cell isolation and seeding takes approximately 7 days.
Kohl P, Garny A, Maini PK, et al., 2006, Biomathematical modelling II - Preface, Vol: 364, Pages: 1331-1331, ISSN: 1364-503X
Kohl P, Bollensdorff C, Garny A, 2006, Effects of mechanosensitive ion channels on ventricular electrophysiology: experimental and theoretical models, Vol: 91, Pages: 307-321, ISSN: 0958-0670
The heart is an electrically driven mechanical pump, somewhat like an electric motor. Interestingly, like an electric motor in 'dynamo mode', the heart can also convert mechanical stimuli into electrical signals. This feedback from cardiac mechanics to electrical activity involves mechanosensitive ion channels, whose properties and pathophysiological relevance are reviewed in the context of experimental and theoretical modelling of ventricular beat-by-beat electromechanical function.
Burton RAB, Plank G, Schneider JE, et al., 2006, Three-dimensional models of individual cardiac histoanatomy: Tools and challenges, Interactive and Integrative Cardiology, Editors: Sideman, Beyar, Landesberg, Pages: 301-319, ISBN: 978-1-57331-651-4
There is a need for, and utility in, the acquisition of data sets of cardiac histoanatomy, with the vision of reconstructing individual hearts on the basis of noninvasive imaging, such as MRI, enriched by reference to detailed atlases of serial histology obtained from representative samples. These data sets would be useful not only as a repository of knowledge regarding the specifics of cardiac histoanatomy, but could form the basis for generation of individualized high-resolution cardiac structure-function models. The current article presents a step in this general direction: it illustrates how whole-heart noninvasive imaging can be combined with whole-heart histology in an approach to achieve automated construction of histoanatomically detailed models of cardiac 3D structure and function at hitherto unprecedented resolution and accuracy (based on 26.4 x 26.4 x 24.4 mu m MRI voxel size, and enriched by histological detail). It provides an overview of the tools used in this quest and outlines challenges posed by the approach in the light of applications that may benefit from the availability of such data and tools.
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