Takashi Naka | Kyushu Sangyo University (original) (raw)

Papers by Takashi Naka

Introduction A computer simulation of mathematical models on cellular biochemical networks has be... more Introduction A computer simulation of mathematical models on cellular biochemical networks has been recognized as a useful tool for biological researchers to understand the dynamics and regulation mechanism of biochemical behavior and to set up subsequent working hypotheses for their future experiments. Until now, several programs such as Gepasi [5], E-Cell [7], Virtual Cell [4] and GENESIS [6] have been available for such purposes. Mathematical modeling requires a set of parameters (kinetic constants and physiological concentration of the cellular components), however, there are no experimental methods to measure all of such parameters with accuracy. Therefore, estimation of biological parameters based on any observable wet-lab data is essential for construction of the model. And, this estimation process often requires huge computer resources which one organization cannot a#ord. 2 Method We developed OBIYagns (Yet Another Gene Network Simulator) with parameter estimators distribute

PLOS ONE, 2022

The signal transduction system, which is known as a regulatory mechanism for biochemical reaction... more The signal transduction system, which is known as a regulatory mechanism for biochemical reaction systems in the cell, has been the subject of intensive research in recent years, and its design methods have become necessary from the viewpoint of synthetic biology. We proposed the partition representation of enzymatic reaction networks consisting of post-translational modification reactions such as phosphorylation, which is an important basic component of signal transduction systems, and attempted to find enzymatic reaction networks with bistability to demonstrate the effectiveness of the proposed representation method. The partition modifiers can be naturally introduced into the partition representation of enzymatic reaction networks when applied to search. By randomly applying the partition modifiers as appropriate, we searched for bistable and resettable enzymatic reaction networks consisting of four post-translational modification reactions. The proposed search algorithm worked w...

Cellular signaling systems regulate biochemical reactions operating in cells for various function... more Cellular signaling systems regulate biochemical reactions operating in cells for various functions. The regulatory mechanisms have been recently studied intensively since the malfunction of the regulation is thought to be one of the substantial causes of cancer formation. However, it is rather difficult to develop the theoretical framework for investigation of the regulatory mechanisms due to their complexity and nonlinearity. In this study, more general approach is proposed for elucidation of emergence of the bi-stability in cellular signaling systems by construction of mathematical models for a class of cellular signaling systems and the exhaustive simulation analysis over the variation of network architectures and the values of parameters. The model system is formulated as regulatory network in which every node represents an activation-inactivation cyclic reaction for respective constituent enzyme of the network and the regulatory interactions between the reactions are depicted b...

Genome Informatics, 2002

For the study of the dynamics of signal transduction pathways, the computer simulation is one of ... more For the study of the dynamics of signal transduction pathways, the computer simulation is one of the most effective methods. However, a computer simulation often requires several kinetic parameters which are unmesurable by the existing experimental techniques. Therefore, it is important that unknown parameters can be estimated from experimentally mesurable data. Considering this point, we developed a simulator for biochemical systems, YAGNS (Yet Another Gene Network Simulator), which has a function to estimate unknown kinetic parameters. In this poster, we describe the system configuration of YAGNS.

Thesis (Ph. D. in Engineering)--University of Tsukuba, (B), no. 1408, 1998.3.23 A Compartment mod... more Thesis (Ph. D. in Engineering)--University of Tsukuba, (B), no. 1408, 1998.3.23 A Compartment model representing the chemical transmission process of acetylcholine (Ach) at the neuromuscular junction for generation of the miniature endplate current (MEPC) is constructed as a reaction-diffusion system (RD system) in a two-dimensional space of axissymetrical disc of the synaptic cleft. The model is defined as the standard to have the critical radius of 500nm and the respective compartment numbers of 3 and 10 on the transverse and radial coordinates. Besides the transverse and radial diffusion processes, the model can include the release mechanism of Ach as the release rate and the release area of Ach, and the junctional fold as a concentric cylinder attached to the disc at the postsynaptic membrane. The model might be regarded as the two-dimensional extension of the similar models proposed previously, which essentially behave as one-dimensional compartment models because the diffusion...

MAPK signaling cascade initiated by the activation of EGF receptor (EGFR) has been experimentally... more MAPK signaling cascade initiated by the activation of EGF receptor (EGFR) has been experimentally well studied and analyzed by mathematical modeling extensively [1, 3, 5]. Recently, several studies showed that some of growth hormone-stimulated membrane tyrosine kinase receptors interact with Shc adaptor protein and phosphatidylinositol 3'-kinase (PI3K), and consequently PI3K-activated Akt inhibits Raf-1 and the following ERK activity which locates at the downstream of Shc signaling [2, 4]. This inhibition of Raf-1 activity by Akt is called Raf-Akt cross-talk. Since these two Shc-Raf and PI3K-Akt pathways exert opposite e ects on cell proliferation and di erentiation, a regulation balance of these two pathways is critical to de ne the cell fate. Based on the experimental proof reported to date, we developed a computational simulation model for a signal transduction cascade possessing Raf-Akt cross-talk to understand the regulation mechanism by analyzing the dynamics of kinase act...

2010 International Conference on Computational Science and Its Applications, 2010

ABSTRACT Simplified kinase cascade pathways in cellular signaling are analyzed from the viewpoint... more ABSTRACT Simplified kinase cascade pathways in cellular signaling are analyzed from the viewpoint of the stochastic fluctuations of each activated constituent kinases. The analytical representations of the kinetics of the kinases are obtained by approximation for the two extreme cases of far-from-saturation with the substrate and of the saturation in enzymes. These stochastic models predict the attenuations of the stochastic fluctuations along downward in the cascade tiers for the case of far-from-saturation and the accumulations of the fluctuations for the case of the saturation. These predictions are further confirmed by the Gillespie simulations. Hence, kinase cascade pathways could work as both of the stochastic fluctuation attenuator and the accumulator, depending on the kinase saturation levels with the substrates.

2009 International Conference on Computational Science and Its Applications, 2009

ABSTRACT Newly developed microscopic technology has recently made it possible to directly visuali... more ABSTRACT Newly developed microscopic technology has recently made it possible to directly visualize lateral signaling events in a single cell in which the local stimulation of EGFR with EGF yields global phosphorylation of EGFR on the whole cell membrane. The putative feedback mechanism of receptor phosphorylation by ligand-free phosphorylated receptors has been proposed to explain the events. A computational model of the reaction-diffusion system (RD model) on the cell surface is constructed in order to examine the feasibility of this putative feedback mechanism. The simulation analysis reveals that the feedback mechanism in the RD model reproduces the observed lateral signal propagation for the parameter values within the physiologically available range.

PLoS ONE, 2008

Ligand-induced homo-and hetero-dimer formation of ErbB receptors results in different biological ... more Ligand-induced homo-and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins. Earlier experimental research indicated that cells expressing both EGFR (epidermal growth factor receptor) and the ErbB4 receptor (E1/4 cells) induced E1/4 cell-specific B-Raf activation and higher extracellular signal-regulated kinase (ERK) activation, followed by cellular transformation, than cells solely expressing EGFR (E1 cells) in Chinese hamster ovary (CHO) cells. Since our experimental data revealed the presence of positive feedback by ERK on upstream pathways, it was estimated that the cross-talk/feedback pathway structure of the Raf-MEK-ERK cascade might affect ERK activation dynamics in our cell system. To uncover the regulatory mechanism concerning the ERK dynamics, we used topological models and performed parameter estimation for all candidate structures that possessed ERKmediated positive feedback regulation of Raf. The structure that reliably reproduced a series of experimental data regarding signal amplitude and duration of the signaling molecules was selected as a solution. We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1. Steady-state analysis of the estimated structure indicated that the amplitude of Ras activity might critically affect ERK activity through ERK-B-Raf positive feedback coordination with sustained B-Raf activation in E1/4 cells. However, Rap1 that positively regulates B-Raf activity might be less effective concerning ERK and B-Raf activity. Furthermore, we investigated how such Ras activity in E1/4 cells can be regulated by EGFR/ErbB4 heterodimer-mediated signaling. From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high. Such characteristics of the signaling cause the preferential binding of the Grb2-SOS complex to heterodimer-mediated signaling molecules.

Mathematics and Computers in Simulation, 2002

ABSTRACT Arrival of an action potential to a nerve terminal at the neuromuscular junction induces... more ABSTRACT Arrival of an action potential to a nerve terminal at the neuromuscular junction induces the release of a few hundred quanta of acetylcholine (ACh) into the synaptic cleft, resulting in depolarization of the muscle cell which is observed as the endplate current (EPC). The release of each quantum of ACh invokes the miniature endplate current (MEPC), so that an EPC could be generated by summation of the MEPCs both in time during evolution of the EPC and in space for a certain area of the post-synaptic membrane. In this study, a mathematical model for EPC generation is developed as a reaction–diffusion system (RD system) which represents the dynamic behavior of ACh in the chemical transmission process with the simultaneous quantum release of ACh. The RD system for ACh is mathematically expressed by a two-dimensional diffusion equation with nonlinear reaction terms due to the rate processes for acetylcholinesterase (AChE) and ACh receptor (AChR). Numerical solution of the governing equation with the method of lines and the Gear method yields temporal changes in relative concentrations of the open channel form of AChR which is assumed to be equivalent to the EPC. Analysis of the behavior of the RD system with respect to the various distances between the release sites of ACh on the pre-synaptic membrane demonstrates that the amplitude of EPC is quite sensitive to the distances around 0.5μm, but independent of the values of the diffusion coefficient of ACh in the synaptic cleft.

BMC Systems Biology, 2011

Background: Epidermal growth factor receptor (EGFR) signaling plays an important role in the regu... more Background: Epidermal growth factor receptor (EGFR) signaling plays an important role in the regulation of cell proliferation, survival, metastasis, and invasion in various tumors. Earlier studies showed that the EGFR is frequently overexpressed in non-small-cell lung cancer (NSCLC) and EGFR mutations at specific amino acid residues in the kinase domain induce altered responsiveness to gefitinib, a small molecule EGFR tyrosine kinase inhibitor. However, the mechanism underlying the drug response modulated by EGFR mutation is still largely unknown. To elucidate drug response in EGFR signal transduction pathway in which complex dynamics of multiple molecules involved, a systematic approach is necessary. In this paper, we performed experimental and computational analyses to clarify the underlying mechanism of EGFR signaling and cell-specific gefitinib responsiveness in three H1299-derived NSCLC cell lines; H1299 wild type (H1299WT), H1299 with an overexpressed wild type EGFR (H1299EGFR-WT), and H1299 with an overexpressed mutant EGFR L858R (H1299L858R; gefitinib sensitive mutant). Results: We predicted and experimentally verified that Mig6, which is a known negative regulator of EGFR and specifically expressed in H1299L858R cells, synergized with gefitinib to suppress cellular growth. Computational analyses indicated that this inhibitory effect is amplified at the phosphorylation/dephosphorylation steps of MEK and ERK. Conclusions: Thus, we showed that L858R receptor mutation in combination with expression of its negative regulator, Mig6, alters signaling outcomes and results in variable drug sensitivity.

Biosystems, 1999

The process of neurotransmitter release at the neuromuscular junction needs to be represented app... more The process of neurotransmitter release at the neuromuscular junction needs to be represented appropriately in modeling of the synaptic chemical transmission as a reaction-diffusion system. The release mechanisms of the expanding pore and the acceleration are analyzed by the computer simulation with respect to the effects of the characteristic parameters in the mechanisms on spontaneous generation of the miniature endplate current (MEPC), leading to the following evaluation. In the expanding pore mechanism the expanding rate of the pore more than 10 nm ms −1 and the diffusion coefficient of acetylcholine in the synaptic cleft (D c) of about 1.0×10 − 6 cm 2 s − 1 yield the maximum amplitude, the rise time and the decay time constant of the MEPC in agreement with the empirical data. In the active release mechanism the 10-fold acceleration of the natural diffusion and a similar value of D c are required to suit for the empirical MEPC.

Biosystems, 1997

A minimal compartment model of the reaction-diffusion system (RD system) of a neurotransmitter in... more A minimal compartment model of the reaction-diffusion system (RD system) of a neurotransmitter in a two-dimensional space of axis-symmetrical disc is proposed to represent the chemical transmission process of a quantum of acetylcholine (ACh) in the synaptic cleft at the neuromuscular junction. The behavior of the RD system for ACh is expressed by a two-dimensional diffusion equation with nonlinear reaction terms due to the rate processes for ACh receptor and acetylcholinesterase. The simulation analysis of the RD system reveals that the radial diffusion process of ACh has more distinctive effects on spontaneous generation of the miniature endplate current (MEPC) than the transverse process. The anisotropic diffusion is effective in the RD system since the diffusion coefficient of ACh in the radial direction is evaluated to be about 1.0 ×10 − 6 cm 2 sec − 1 for appropriate characterization of the MEPC, on which the diffusion coefficient in the transverse direction larger than 2.0 ×10 − 6 cm 2 sec − 1 has virtually no effects. The compartment model is thus appropriately constructed to comprise three elements on the transverse coordinate and ten elements on the radial coordinate in the disc with 500 nm of radius and 50 nm of height.

Biosystems, 1986

A transfer-function representation of reaction velocity is devised to describe analytically and a... more A transfer-function representation of reaction velocity is devised to describe analytically and approximately an input-output response of allosteric enzyme around a steady state. The transfer function is derived on assuming an exponential change in reaction velocity for the indicial response to substrate influx rate. The validity of the representation with variation in the kinetic parameters and flow rates is examined for the response of Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) dimeric models by comparing with the exact response obtained from the computer simulation, that is, by numerical integration of the rate equation. The representation has a wider valid region with a decrease in influx rate than with an increase. For the KNF model the representation is valid for negative cooperativity, but invalid for positive cooperativity. For the MWC model the validity decreases with stronger cooperativity. With the transfer functions valid for the Michaelis-Menten and allosteric reactions, we may derive the transfer-function representation for many metabolic pathways.

Biosystems, 1999

A two-dimensional compartment model devised for the appropriate representation of the transient p... more A two-dimensional compartment model devised for the appropriate representation of the transient process of the spontaneous generation of miniature endplate current (MEPC) at the neuromuscular junction is applied for clarifying the biochemical significance of the quantal release mechanism of acetylcholine (ACh), a typical neurotransmitter, in the synaptic chemical transmission process. The simulation analysis with the model demonstrates that the localization of the ACh release due to the fusion of a synaptic vesicle with the presynaptic membrane has significant effects on the amplitude of MEPC and that the stronger effects are caused with the smaller diffusion coefficients of ACh in the cleft. The sharpest and highest response of MEPC is achieved when the release area is about 4 times to the natural release through the narrow pore. On the other hand, the actual localization corresponding to the natural release of ACh makes the amplitude of MEPC higher by a factor about 2.5 compared with that in the most extended release of ACh examined, implying that the natural release mechanism works as an amplifier of the MEPC with the fixed amount of ACh available.

Bioinformatics, 2004

OBIYagns (yet another gene network simulator) is a biochemical system simulator that comprises a ... more OBIYagns (yet another gene network simulator) is a biochemical system simulator that comprises a multipleuser Web-based graphical interface, an ordinary differential equation solver and a parameter estimators distributed over an open bioinformatics grid (OBIGrid). This grid-based biochemical simulation system can achieve high performance and provide a secure simulation environment for estimating kinetic parameters in an acceptable time period. OBIYagns can be applied to larger system biology-oriented simulation projects.

Introduction A computer simulation of mathematical models on cellular biochemical networks has be... more Introduction A computer simulation of mathematical models on cellular biochemical networks has been recognized as a useful tool for biological researchers to understand the dynamics and regulation mechanism of biochemical behavior and to set up subsequent working hypotheses for their future experiments. Until now, several programs such as Gepasi [5], E-Cell [7], Virtual Cell [4] and GENESIS [6] have been available for such purposes. Mathematical modeling requires a set of parameters (kinetic constants and physiological concentration of the cellular components), however, there are no experimental methods to measure all of such parameters with accuracy. Therefore, estimation of biological parameters based on any observable wet-lab data is essential for construction of the model. And, this estimation process often requires huge computer resources which one organization cannot a#ord. 2 Method We developed OBIYagns (Yet Another Gene Network Simulator) with parameter estimators distribute

PLOS ONE, 2022

The signal transduction system, which is known as a regulatory mechanism for biochemical reaction... more The signal transduction system, which is known as a regulatory mechanism for biochemical reaction systems in the cell, has been the subject of intensive research in recent years, and its design methods have become necessary from the viewpoint of synthetic biology. We proposed the partition representation of enzymatic reaction networks consisting of post-translational modification reactions such as phosphorylation, which is an important basic component of signal transduction systems, and attempted to find enzymatic reaction networks with bistability to demonstrate the effectiveness of the proposed representation method. The partition modifiers can be naturally introduced into the partition representation of enzymatic reaction networks when applied to search. By randomly applying the partition modifiers as appropriate, we searched for bistable and resettable enzymatic reaction networks consisting of four post-translational modification reactions. The proposed search algorithm worked w...

Cellular signaling systems regulate biochemical reactions operating in cells for various function... more Cellular signaling systems regulate biochemical reactions operating in cells for various functions. The regulatory mechanisms have been recently studied intensively since the malfunction of the regulation is thought to be one of the substantial causes of cancer formation. However, it is rather difficult to develop the theoretical framework for investigation of the regulatory mechanisms due to their complexity and nonlinearity. In this study, more general approach is proposed for elucidation of emergence of the bi-stability in cellular signaling systems by construction of mathematical models for a class of cellular signaling systems and the exhaustive simulation analysis over the variation of network architectures and the values of parameters. The model system is formulated as regulatory network in which every node represents an activation-inactivation cyclic reaction for respective constituent enzyme of the network and the regulatory interactions between the reactions are depicted b...

Genome Informatics, 2002

For the study of the dynamics of signal transduction pathways, the computer simulation is one of ... more For the study of the dynamics of signal transduction pathways, the computer simulation is one of the most effective methods. However, a computer simulation often requires several kinetic parameters which are unmesurable by the existing experimental techniques. Therefore, it is important that unknown parameters can be estimated from experimentally mesurable data. Considering this point, we developed a simulator for biochemical systems, YAGNS (Yet Another Gene Network Simulator), which has a function to estimate unknown kinetic parameters. In this poster, we describe the system configuration of YAGNS.

Thesis (Ph. D. in Engineering)--University of Tsukuba, (B), no. 1408, 1998.3.23 A Compartment mod... more Thesis (Ph. D. in Engineering)--University of Tsukuba, (B), no. 1408, 1998.3.23 A Compartment model representing the chemical transmission process of acetylcholine (Ach) at the neuromuscular junction for generation of the miniature endplate current (MEPC) is constructed as a reaction-diffusion system (RD system) in a two-dimensional space of axissymetrical disc of the synaptic cleft. The model is defined as the standard to have the critical radius of 500nm and the respective compartment numbers of 3 and 10 on the transverse and radial coordinates. Besides the transverse and radial diffusion processes, the model can include the release mechanism of Ach as the release rate and the release area of Ach, and the junctional fold as a concentric cylinder attached to the disc at the postsynaptic membrane. The model might be regarded as the two-dimensional extension of the similar models proposed previously, which essentially behave as one-dimensional compartment models because the diffusion...

MAPK signaling cascade initiated by the activation of EGF receptor (EGFR) has been experimentally... more MAPK signaling cascade initiated by the activation of EGF receptor (EGFR) has been experimentally well studied and analyzed by mathematical modeling extensively [1, 3, 5]. Recently, several studies showed that some of growth hormone-stimulated membrane tyrosine kinase receptors interact with Shc adaptor protein and phosphatidylinositol 3'-kinase (PI3K), and consequently PI3K-activated Akt inhibits Raf-1 and the following ERK activity which locates at the downstream of Shc signaling [2, 4]. This inhibition of Raf-1 activity by Akt is called Raf-Akt cross-talk. Since these two Shc-Raf and PI3K-Akt pathways exert opposite e ects on cell proliferation and di erentiation, a regulation balance of these two pathways is critical to de ne the cell fate. Based on the experimental proof reported to date, we developed a computational simulation model for a signal transduction cascade possessing Raf-Akt cross-talk to understand the regulation mechanism by analyzing the dynamics of kinase act...

2010 International Conference on Computational Science and Its Applications, 2010

ABSTRACT Simplified kinase cascade pathways in cellular signaling are analyzed from the viewpoint... more ABSTRACT Simplified kinase cascade pathways in cellular signaling are analyzed from the viewpoint of the stochastic fluctuations of each activated constituent kinases. The analytical representations of the kinetics of the kinases are obtained by approximation for the two extreme cases of far-from-saturation with the substrate and of the saturation in enzymes. These stochastic models predict the attenuations of the stochastic fluctuations along downward in the cascade tiers for the case of far-from-saturation and the accumulations of the fluctuations for the case of the saturation. These predictions are further confirmed by the Gillespie simulations. Hence, kinase cascade pathways could work as both of the stochastic fluctuation attenuator and the accumulator, depending on the kinase saturation levels with the substrates.

2009 International Conference on Computational Science and Its Applications, 2009

ABSTRACT Newly developed microscopic technology has recently made it possible to directly visuali... more ABSTRACT Newly developed microscopic technology has recently made it possible to directly visualize lateral signaling events in a single cell in which the local stimulation of EGFR with EGF yields global phosphorylation of EGFR on the whole cell membrane. The putative feedback mechanism of receptor phosphorylation by ligand-free phosphorylated receptors has been proposed to explain the events. A computational model of the reaction-diffusion system (RD model) on the cell surface is constructed in order to examine the feasibility of this putative feedback mechanism. The simulation analysis reveals that the feedback mechanism in the RD model reproduces the observed lateral signal propagation for the parameter values within the physiologically available range.

PLoS ONE, 2008

Ligand-induced homo-and hetero-dimer formation of ErbB receptors results in different biological ... more Ligand-induced homo-and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins. Earlier experimental research indicated that cells expressing both EGFR (epidermal growth factor receptor) and the ErbB4 receptor (E1/4 cells) induced E1/4 cell-specific B-Raf activation and higher extracellular signal-regulated kinase (ERK) activation, followed by cellular transformation, than cells solely expressing EGFR (E1 cells) in Chinese hamster ovary (CHO) cells. Since our experimental data revealed the presence of positive feedback by ERK on upstream pathways, it was estimated that the cross-talk/feedback pathway structure of the Raf-MEK-ERK cascade might affect ERK activation dynamics in our cell system. To uncover the regulatory mechanism concerning the ERK dynamics, we used topological models and performed parameter estimation for all candidate structures that possessed ERKmediated positive feedback regulation of Raf. The structure that reliably reproduced a series of experimental data regarding signal amplitude and duration of the signaling molecules was selected as a solution. We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1. Steady-state analysis of the estimated structure indicated that the amplitude of Ras activity might critically affect ERK activity through ERK-B-Raf positive feedback coordination with sustained B-Raf activation in E1/4 cells. However, Rap1 that positively regulates B-Raf activity might be less effective concerning ERK and B-Raf activity. Furthermore, we investigated how such Ras activity in E1/4 cells can be regulated by EGFR/ErbB4 heterodimer-mediated signaling. From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high. Such characteristics of the signaling cause the preferential binding of the Grb2-SOS complex to heterodimer-mediated signaling molecules.

Mathematics and Computers in Simulation, 2002

ABSTRACT Arrival of an action potential to a nerve terminal at the neuromuscular junction induces... more ABSTRACT Arrival of an action potential to a nerve terminal at the neuromuscular junction induces the release of a few hundred quanta of acetylcholine (ACh) into the synaptic cleft, resulting in depolarization of the muscle cell which is observed as the endplate current (EPC). The release of each quantum of ACh invokes the miniature endplate current (MEPC), so that an EPC could be generated by summation of the MEPCs both in time during evolution of the EPC and in space for a certain area of the post-synaptic membrane. In this study, a mathematical model for EPC generation is developed as a reaction–diffusion system (RD system) which represents the dynamic behavior of ACh in the chemical transmission process with the simultaneous quantum release of ACh. The RD system for ACh is mathematically expressed by a two-dimensional diffusion equation with nonlinear reaction terms due to the rate processes for acetylcholinesterase (AChE) and ACh receptor (AChR). Numerical solution of the governing equation with the method of lines and the Gear method yields temporal changes in relative concentrations of the open channel form of AChR which is assumed to be equivalent to the EPC. Analysis of the behavior of the RD system with respect to the various distances between the release sites of ACh on the pre-synaptic membrane demonstrates that the amplitude of EPC is quite sensitive to the distances around 0.5μm, but independent of the values of the diffusion coefficient of ACh in the synaptic cleft.

BMC Systems Biology, 2011

Background: Epidermal growth factor receptor (EGFR) signaling plays an important role in the regu... more Background: Epidermal growth factor receptor (EGFR) signaling plays an important role in the regulation of cell proliferation, survival, metastasis, and invasion in various tumors. Earlier studies showed that the EGFR is frequently overexpressed in non-small-cell lung cancer (NSCLC) and EGFR mutations at specific amino acid residues in the kinase domain induce altered responsiveness to gefitinib, a small molecule EGFR tyrosine kinase inhibitor. However, the mechanism underlying the drug response modulated by EGFR mutation is still largely unknown. To elucidate drug response in EGFR signal transduction pathway in which complex dynamics of multiple molecules involved, a systematic approach is necessary. In this paper, we performed experimental and computational analyses to clarify the underlying mechanism of EGFR signaling and cell-specific gefitinib responsiveness in three H1299-derived NSCLC cell lines; H1299 wild type (H1299WT), H1299 with an overexpressed wild type EGFR (H1299EGFR-WT), and H1299 with an overexpressed mutant EGFR L858R (H1299L858R; gefitinib sensitive mutant). Results: We predicted and experimentally verified that Mig6, which is a known negative regulator of EGFR and specifically expressed in H1299L858R cells, synergized with gefitinib to suppress cellular growth. Computational analyses indicated that this inhibitory effect is amplified at the phosphorylation/dephosphorylation steps of MEK and ERK. Conclusions: Thus, we showed that L858R receptor mutation in combination with expression of its negative regulator, Mig6, alters signaling outcomes and results in variable drug sensitivity.

Biosystems, 1999

The process of neurotransmitter release at the neuromuscular junction needs to be represented app... more The process of neurotransmitter release at the neuromuscular junction needs to be represented appropriately in modeling of the synaptic chemical transmission as a reaction-diffusion system. The release mechanisms of the expanding pore and the acceleration are analyzed by the computer simulation with respect to the effects of the characteristic parameters in the mechanisms on spontaneous generation of the miniature endplate current (MEPC), leading to the following evaluation. In the expanding pore mechanism the expanding rate of the pore more than 10 nm ms −1 and the diffusion coefficient of acetylcholine in the synaptic cleft (D c) of about 1.0×10 − 6 cm 2 s − 1 yield the maximum amplitude, the rise time and the decay time constant of the MEPC in agreement with the empirical data. In the active release mechanism the 10-fold acceleration of the natural diffusion and a similar value of D c are required to suit for the empirical MEPC.

Biosystems, 1997

A minimal compartment model of the reaction-diffusion system (RD system) of a neurotransmitter in... more A minimal compartment model of the reaction-diffusion system (RD system) of a neurotransmitter in a two-dimensional space of axis-symmetrical disc is proposed to represent the chemical transmission process of a quantum of acetylcholine (ACh) in the synaptic cleft at the neuromuscular junction. The behavior of the RD system for ACh is expressed by a two-dimensional diffusion equation with nonlinear reaction terms due to the rate processes for ACh receptor and acetylcholinesterase. The simulation analysis of the RD system reveals that the radial diffusion process of ACh has more distinctive effects on spontaneous generation of the miniature endplate current (MEPC) than the transverse process. The anisotropic diffusion is effective in the RD system since the diffusion coefficient of ACh in the radial direction is evaluated to be about 1.0 ×10 − 6 cm 2 sec − 1 for appropriate characterization of the MEPC, on which the diffusion coefficient in the transverse direction larger than 2.0 ×10 − 6 cm 2 sec − 1 has virtually no effects. The compartment model is thus appropriately constructed to comprise three elements on the transverse coordinate and ten elements on the radial coordinate in the disc with 500 nm of radius and 50 nm of height.

Biosystems, 1986

A transfer-function representation of reaction velocity is devised to describe analytically and a... more A transfer-function representation of reaction velocity is devised to describe analytically and approximately an input-output response of allosteric enzyme around a steady state. The transfer function is derived on assuming an exponential change in reaction velocity for the indicial response to substrate influx rate. The validity of the representation with variation in the kinetic parameters and flow rates is examined for the response of Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) dimeric models by comparing with the exact response obtained from the computer simulation, that is, by numerical integration of the rate equation. The representation has a wider valid region with a decrease in influx rate than with an increase. For the KNF model the representation is valid for negative cooperativity, but invalid for positive cooperativity. For the MWC model the validity decreases with stronger cooperativity. With the transfer functions valid for the Michaelis-Menten and allosteric reactions, we may derive the transfer-function representation for many metabolic pathways.

Biosystems, 1999

A two-dimensional compartment model devised for the appropriate representation of the transient p... more A two-dimensional compartment model devised for the appropriate representation of the transient process of the spontaneous generation of miniature endplate current (MEPC) at the neuromuscular junction is applied for clarifying the biochemical significance of the quantal release mechanism of acetylcholine (ACh), a typical neurotransmitter, in the synaptic chemical transmission process. The simulation analysis with the model demonstrates that the localization of the ACh release due to the fusion of a synaptic vesicle with the presynaptic membrane has significant effects on the amplitude of MEPC and that the stronger effects are caused with the smaller diffusion coefficients of ACh in the cleft. The sharpest and highest response of MEPC is achieved when the release area is about 4 times to the natural release through the narrow pore. On the other hand, the actual localization corresponding to the natural release of ACh makes the amplitude of MEPC higher by a factor about 2.5 compared with that in the most extended release of ACh examined, implying that the natural release mechanism works as an amplifier of the MEPC with the fixed amount of ACh available.

Bioinformatics, 2004

OBIYagns (yet another gene network simulator) is a biochemical system simulator that comprises a ... more OBIYagns (yet another gene network simulator) is a biochemical system simulator that comprises a multipleuser Web-based graphical interface, an ordinary differential equation solver and a parameter estimators distributed over an open bioinformatics grid (OBIGrid). This grid-based biochemical simulation system can achieve high performance and provide a secure simulation environment for estimating kinetic parameters in an acceptable time period. OBIYagns can be applied to larger system biology-oriented simulation projects.