Authors: Masanori Nakamura, Shigeo Wada, Takahito Miki, Yasuhiro Shimada, Yuji Suda, Gen Tamura

Remarkable advances in computed tomography (CT) technology geared our research toward investigating the integrative function of the lung and the development of a database of the airway tree that incorporates anatomic and functional data with computational models. As part of this project, we are developing the algorithm to construct an anatomically realistic geometric model of airways from CT images. The basic concept of the algorithm is to segment as many airway trees as possible from CT images and later correct quantified parameters based on CT values. CT images are acquired with a 64-channel multidetector CT, and the airway is then extracted from them by the region-growing method while maintaining connectivity. Using this method, we extracted 428 airways up to the 14th branching generation. Although the airway diameters up to the 4th generation showed good agreement with those reported in an autopsy study, those in later generations were all greater than the reported values because of the limited resolution of the CT images. We corrected the errors in diameters by assessing the relationship between the diameter and median value of Hounsfield unit (HU) intensity of each airway; consequently, the diameters up to generation 8 agreed well with the reported values. Based on these results, we conclude that the use of HU-based correction algorithm combined with rough segmentation can be another way to improve data accuracy in the morphometric analysis of airways from CTs.

Authors: Atsushi Inanobe, Narutoshi Kamiya, Shingo Murakami, Yoshifumi Fukunishi, Haruki Nakamura, Yoshihisa Kurachi

A variety of compounds with different chemical properties directly interact with the cardiac repolarizing K⁺ channel encoded by the human ether-a-go-go-related gene (hERG). This causes acquired forms of QT prolongation, which can result in lethal cardiac arrhythmias including torsades de pointes one of the most serious adverse effects of various therapeutic agents. Prediction of this phenomenon will improve the safety of pharmacological therapy and also facilitate the process of drug development. Here we propose a strategy for the development of an in silico system to predict the potency of chemical compounds to block hERG. The system consists of two sequential processes. The first process is a ligand-based prediction to estimate half-maximal concentrations for the block of compounds inhibiting hERG current using the relationship between chemical features and activities of compounds. The second process is a protein-based prediction that comprises homology modeling of hERG, docking simulation of chemical-channel interaction, analysis of the shape of the channel pore cavity, and Brownian dynamics simulation to estimate hERG currents in the presence and absence of chemical blockers. Since each process is a combination of various calculations, the criterion for assessment at each calculation and the strategy to integrate these steps are significant for the construction of the system to predict a chemical's block of hERG current and also to predict the risk of inducing cardiac arrhythmias from the chemical information. The principles and criteria of elemental computations along this strategy are described.

Authors: Yoshiyuki Asai, Yasuyuki Suzuki, Yoshiyuki Kido, Hideki Oka, Eric Heien, Masao Nakanishi, Takahito Urai, Kenichi Hagihara, Yoshihisa Kurachi, Taishin Nomura

An extensible markup language format, insilicoML (ISML), version 0.1, describing multilevel biophysical models has been developed and is available in the public domain. ISML is fully compatible with CellML 1.0, a model description standard developed by the IUPS Physiome Project, for enhancing knowledge integration and model sharing. This article illustrates the new specifications of ISML 1.0 that largely extend the capability of ISML 0.1. ISML 1.0 can describe various types of mathematical models, including ordinary/partial differential/difference equations representing the dynamics of physiological functions and the geometry of living organisms underlying the functions. ISML 1.0 describes a model using a set of functional elements (modules), each of which can specify mathematical expressions of the module functions. Structural and logical relationships between any two modules are specified by edges, which allow modular, hierarchical, and/or network representations of the model. The role of edgerelationships is enriched by key words in order for use in constructing a physiological ontology. The ontology is further improved by the traceability of history of the model's development and by linking between different ISML models stored in the model's database using meta-information. ISML 1.0 is designed to operate with a model database and integrated environments for model development and simulations for knowledge integration and discovery.

Authors: Eun Bo Shim, Siwoo Lee, Jong Yeol Kim, Yung E Earm

Sasang Constitutional Medicine (SCM) is a traditional Korean form of medicine widely used in the clinical diagnosis and treatment of disease. This paper reviews the main aspects of SCM and “physiome” with emphasis on integrative and holistic characteristics. Methodological and physiological aspects of SCM are summarized with reference to existing studies. The main characteristics of SCM, such as the four physical constitutions and diagnostic methods, are introduced. Moreover, physiome and systems medicine are introduced as plausible candidates for integrative medicine and are compared to reductionism-based molecular biology. We also discuss the conceptual similarity of SCM with predictive, preventive, personalized, and participatory (P4) medicine. It is emphasized that the integrative and creative combination of SCM and physiome will unlock a new era of holistic medicine.

Authors: Marco Viceconti, Gordon Clapworthy, Serge Van Sint Jan

The Virtual Physiological Human (VPH) is an initiative, strongly supported by the European Commission (EC), that seeks to develop an integrated model of human physiology at multiple scales from the whole body through the organ, tissue, cell and molecular levels to the genomic level. VPH had its beginnings in 2005 with informal discussions amongst like-minded scientists, which led to the STEP project, a Coordination Action funded by the EC that began in early 2006. The STEP project greatly accelerated the progress of the VPH and proved to be a catalyst for wide-ranging discussions within Europe and for outreach activities designed to develop a broad international approach to the huge scientific and technological challenges involved in this area. This paper provides an overview of the VPH and the developments it has engendered in the rapidly expanding worldwide activities associated with the physiome. It then uses one particular project, the Living Human Project, to illustrate the type of advances that are taking place to further the aims of the VPH and similar initiatives worldwide.

Authors: Yoshihiro Ujihara, Hiroshi Miyazaki, Shigeo Wada

The role of actin filaments and microtubules in 3D cell morphology was investigated using confocal laser scanning microscopy and image analysis based on a region-growing method. Fibroblasts were treated with cytochalasin D or colchicine to disrupt the actin filaments or microtubules, respectively, and the structure and distribution of these cytoskeletal filaments were observed using a confocal laser scanning microscope. From the 3D reconstructed fluorescence images of the cytoskeleton, morphological parameters such as volume, adhesion area, height, and volume ratio of individual cells were determined. The volume ratio was defined as the ratio of the partial volume for every 10% of the height to the total cell volume. The cell volume decreased slightly after the disruption of actin filaments and microtubules, but the change was not significant. The cell adhesion area was significantly decreased after the disruption of actin filaments and microtubules, and was significantly smaller in actin filament-disrupted cells than in microtubule-disrupted cells. Cell height increased significantly after actin filament disruption, whereas it remained almost unchanged after microtubule disruption. Analysis of the volume ratio revealed that the cell shape changed from a cone to a hemisphere after disruption of actin filaments and slightly shifted toward a hemisphere-like shape after microtubule disruption. These results suggest that actin filaments are the major component responsible for the maintenance of global cell shape and that the contribution of microtubules to global cell morphology is much less than that of actin filaments.

Authors: Toshihiro Kawazu, Shingo Murakami, Satomi Adachi-Akahane, Ian Findlay, Rachid Ait-Haddou, Yoshihisa Kurachi, Taishin Nomura

Ca²⁺ dynamics underlying cardiac excitation-contraction coupling are essential for heart functions. In this study, we constructed microstructure-based models of Ca²⁺ dynamics to simulate Ca²⁺ influx through individual L-type Calcium channels (LCCs), an effective Ca²⁺ diffusion within the cytoplasmic space and in the dyadic space, and the experimentally observed calcium-dependent inactivation (CDI) of the LCCs induced by local and global Ca²⁺ sensing. The models consisted of LCCs with distal and proximal Ca²⁺ (Calmodulin-Ca²⁺ complex) binding sites. In one model, the intracellular space was organelle-free cytoplasmic space, and the other was with a dyadic space including sarcoplasmic reticulum membrane. The Ca²⁺ dynamics and CDI of the LCCs in the model with and without the dyadic space were then simulated using the Monte Carlo method. We first showed that an appropriate set of parameter values of the models with effectively extra-slow Ca²⁺ diffusion enabled the models to reproduce major features of the CDI process induced by the local and global sensing of Ca²⁺ near LCCs as measured with single and two spatially separated LCCs by Imredy and Yue (Neuron. 1992;9:197-207). The effective slow Ca²⁺ diffusion might be due to association and dissociation of Ca²⁺ and Calmodulin (CaM). We then examined how the local and global CDIs were affected by the presence of the dyadic space. The results suggested that in microstructure modeling of Ca²⁺ dynamics in cardiac myocytes, the effective Ca²⁺ diffusion under CaM-Ca²⁺ interaction, the nanodomain structure of LCCs for detailed CDI, and the geometry of subcellular space for modeling dyadic space should be considered.

Authors: Jun Hasegawa, Tetsuya Yagi

We describe a novel real-time system that emulates the architecture and functionality of the vertebrate retina. This system reconstructs the neural images formed by the retinal neurons in real time by using a combination of analog and digital systems consisting of a neuromorphic silicon retina chip, a field-programmable gate array, and a digital computer. While the silicon retina carries out the spatial filtering of input images instantaneously, using the embedded resistive networks that emulate the receptive field structure of the outer retinal neurons, the digital computer carries out the temporal filtering of the spatially filtered images to emulate the dynamic properties of the outer retinal circuits. The emulations of the neural image, including 128 × 128 bipolar cells, are carried out at a frame rate of 62.5 Hz. The emulation of the response to the Hermann grid and a spot of light and an annulus of light has demonstrated that the system responds as expected by previous physiological and psychophysical observations. Furthermore, the emulated dynamics of neural images in response to natural scenes revealed the complex nature of retinal neuron activity. We have concluded that the system reflects the spatiotemporal responses of bipolar cells in the vertebrate retina. The proposed emulation system is expected to aid in understanding the visual computation in the retina and the brain.

Authors: Peter Hunter, Yoshihisa Kurachi, Denis Noble, Marco Viceconti

Authors: Takashi Ijiri, Takashi Ashihara, Takeshi Yamaguchi, Kenshi Takayama, Takeo Igarashi, Tatsuo Shimada, Tsunetoyo Namba, Ryo Haraguchi, Kazuo Nakazawa

The Purkinje fibers are located in the ventricular walls of the heart, just beneath the endocardium and conduct excitation from the right and left bundle branches to the ventricular myocardium. Recently, anatomists succeeded in photographing the Purkinje fibers of a sheep, which clearly showed the mesh structure of the Purkinje fibers. In this study, we present a technique for modeling the mesh structure of Purkinje fibers semiautomatically using an extended L-system. The L-system is a formal grammar that defines the growth of a fractal structure by generating rules (or rewriting rules) and an initial structure. It was originally formulated to describe the growth of plant cells, and has subsequently been applied for various purposes in computer graphics such as modeling plants, buildings, streets, and ornaments. For our purpose, we extended the growth process of the L-system as follows: 1) each growing branch keeps away from existing branches as much as possible to create a uniform distribution, and 2) when branches collide, we connect the colliding branches to construct a closed mesh structure. We designed a generating rule based on observations of the photograph of Purkinje fibers and manually specified three terminal positions on a three-dimensional (3D) heart model: those of the right bundle branch, the anterior fascicle, and the left posterior fascicle of the left branch. Then, we grew fibers starting from each of the three positions based on the specified generating rule. We achieved to generate 3D models of Purkinje fibers of which physical appearances closely resembled the real photograph. The generation takes a few seconds. Variations of the Purkinje fibers could be constructed easily by modifying the generating rules and parameters.

Authors: Kenshi Takayama, Takashi Ashihara, Takashi Ijiri, Takeo Igarashi, Ryo Haraguchi, Kazuo Nakazawa

We propose a sketch-based interface for modeling the myocardial fiber orientation required in the electrophysiological simulation of the heart, especially the ventricles. The user can create a volumetric vector field that represents the myocardial fiber orientation in two steps. First, a depth field over the three-dimensional (3D) ventricular model is defined to create layers of myocardium. The user can then peel these layers and draw strokes on them to specify the myocardial fiber orientation in each layer. We represent the 3D ventricular model as a tetrahedral mesh and perform Laplacian smoothing over the mesh vertices to interpolate the vector field defined by the user-drawn strokes. Our method also allows the user to perform deformations on volumetric models of myocardial fiber orientation, which is very important for studying heart disease associated with morphological abnormalities. We created several examples of myocardial fiber orientation and applied them to a simplified simulator to demonstrate the effectiveness of our method.