JP2004129626A - Modeling apparatus for biological cell intracellular reaction and method and program therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a modeling apparatus for intracellular reaction in biological cells that can assist the time and space simulation of the change in biological cells. <P>SOLUTION: The complicated shapes of the whole part or a part of biological cells are divided into compartments with a reduced number of parameters to form a model. Then, the whole work for allocating biochemical reactions, diffusion and membrane potential equations to individual compartments are carried out through GUI (graphical user interface), in addition, to generate the simulation program and display the results graphically. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an apparatus for modeling a reaction in a biological cell, which supports simulation of changes in the biological cell, a method thereof, and a program thereof.
[0002]
[Prior art]
With the prospect of the human genome project and the genetic analysis of many organisms progressing greatly, as the next target, we will clarify the interaction of proteins in biological cells, elucidate the complex signal processing that organisms are doing, Research for drug discovery, disease diagnosis, and the technicalization of biological information processing is being conducted. In order to conduct such research and development, we model the morphology of biological cells with complex shapes, especially neurons, and use the spatiotemporal dynamics of protein-protein interactions in more than 20,000 biological cells. Need to be simulated. Many systems for modeling biochemical reactions, performing numerical calculations, and displaying the results have been developed so far. For example, A-Ce11 (Patent Document 1 and Non-Patent Document 1), GEPASI (Non-Patent Document 2), SCAMP (Non-Patent Document 3), E-Ce11 (Non-Patent Document 4) and the like are known. In these systems, it is possible to model and simulate a membrane potential described by a biochemical reaction or the Hodgkin-Huxley equation. However, they could not model the complex neuronal morphology and treated the whole cell as a homogeneous point model. Therefore, it has not been possible to simulate the effects of changes in biochemical substances and membrane potential locally occurring in cells on signal processing and cell physiology of nerve cells.
On the other hand, Genesis (Non-patent document 5) and NEURON (Non-patent document 6) model the morphology of neurons and can handle changes in membrane potential described by the biochemical reaction and the Hodgkin-Hux1ey equation. I have to. However, even if only a simple form can be modeled, or a complicated form can be modeled, the form description is performed using a character-based script. For example, FIG. 20 shows a part of a script of a form description in NEURON. In such a description method, since it is a description in a character string, the entire image of the form cannot be grasped, the description is troublesome, and there are many errors, and it is impossible to freely change the form and construct a model. there were.
It is important for biological cells such as nerve cells to have generally complex morphology and locally change, in order to express the functions of the biological cells. Therefore, a tool for freely modeling the morphology of a living cell, dividing the morphology into many compartments, and easily simulating local changes progressing in each compartment in a short time was required.
[0003]
[Patent Document 1] Japanese Patent Application No. 2000-185394
[Non-Patent Document 1] K. Ichikawa, "A-Ce11: graphical user interface for the construction of biochemical 1 reaction mode 1s", Bioinformatics Vol 1.17 (2001), pp. 1-35. 483-484.
[Non-Patent Document 2] Mendes, P (1993) "Biochemistry by numbers: simulation of biochemical paths with Gepathi 3" Trends Biochem. Sci. , 22, pp. 361-363.
[Non-Patent Document 3] Sauro, H .; M. (1993) "SCAMIP: a genera1 purose simulator and metabolic control analysis system" Comp. Applic. Biosci. , 9, pp. 441-450.
[Non-Patent Document 4] Tomita, M .; , Hashimoto, K .; , Takahashi, K .; Shimizu, T .; S. , Matsuzaki, Y .; Miyoshi, F .; , Saito, K .; , Tanida, S .; Yugi, K .; Venter, J. et al. C. , And Hutchison III, C.I. A. (1999) "E-Ce11: software environment for whole-cell simulation", Bioinfo. , 15, pp. 72-84.
[Non-Patent Document 5] Wi1son, M .; A. Bhalla, U.S.A. S. Uhley, J .; D. , And Bower, J .; M. (1989) "GENESIS: A system for simulating neural networks. In" Advances in Neural Information Processing Systems. D. Tourtzky, editor. See Morgan Kaufmann, San Mateo, CA. Pp. 485-492
[Non-Patent Document 6] Hines, M .; (1993) "NEURON-a program for simulation of neural equations", Neural Systems: Analysis and Modeling, Ed. F. Eeckman, Kluer Academic Pub. Pp. 127-136
[Problems to be solved by the invention]
The present invention has been made in view of the above-described circumstances, and generates a morphological model in which a complex morphology of an entire biological cell or a part thereof is generated with a small number of parameters and divided into compartments, and a biochemical reaction and diffusion are performed in each compartment. The whole work of allocating the membrane potential equation, etc. is performed by GUI (Graphical User Interface), and based on the generated morphological model, the biochemical reaction, diffusion, and membrane potential equation allocated to each compartment, etc. It provides an integrated environment for automatically generating simulation programs and graphically displaying the results.
[0004]
[Means for Solving the Problems]
[Data structuring device]
In order to achieve the above object, an apparatus for modeling a reaction in a biological cell according to the present invention comprises: a form generating means for generating a form of a biological cell; and a form for graphically displaying the form of the biological cell generated by the form generating means. A display unit; and an allocating unit that allocates a physical or chemical change model to at least a part of the morphology of the biological cell generated by the morphological generation unit.
[0005]
Preferably, the morphological generating means has a dividing means for dividing the form of the biological cell into compartments, and the morphological display means displays the form of the biological cell in a state where the morphological display is divided by the dividing means. .
[0006]
Preferably, the allocating means allocates the change model for each compartment divided by the dividing means.
[0007]
Preferably, the morphology display means three-dimensionally displays the morphology of the biological cell.
[0008]
Preferably, the allocating unit receives a specifying operation of specifying one or more compartments from among the compartments displayed three-dimensionally by the morphological display unit, and allocates the change model to the specified compartment.
[0009]
Preferably, a spatio-temporal simulation of a biological substance is performed based on the form of the biological cell generated by the form generating means and the change model assigned to the form of the biological cell by the assigning means. There is further provided a program generation means for generating a numerical calculation program.
[0010]
Preferably, the apparatus further comprises a result display unit for graphically displaying an execution result of the numerical calculation program generated by the program generation unit.
[0011]
Preferably, the form generation means has at least one basic form as a template, and the form display means displays at least one of the basic forms.
[0012]
Preferably, the morphology generating means generates a morphology of the nerve cell in response to the input of the parameter, and the morphology display means displays the morphology of the nerve cell generated by the morphology generation means.
[0013]
Preferably, the morphological generation means generates at least a part of the morphology of the biological cell, and the morphology display means displays at least a part of the morphology of the biological cell generated by the morphological generation means.
[0014]
Preferably, the apparatus further includes attribute setting means for setting at least a part of the compartment divided by the dividing means to a film attribute or a solution attribute.
[0015]
Preferably, the allocating means receives a specification operation for specifying a plurality of compartments at a specific position, and allocates the change model to the compartment at the specified specific position.
[0016]
Preferably, the morphology display means displays a cross section of the morphology of the biological cell, and the allocating means receives a designation operation of designating one or more compartments from compartments in the displayed cross section, and designates the designated section. Assign the change model to a compartment.
[0017]
Preferably, there is further provided a canceling means for canceling the assigned change model with respect to at least a part of the form of the biological cell to which the change model is assigned by the assigning means.
[0018]
Preferably, the apparatus further includes a confirmation display unit that accepts a designation operation for designating at least a part of the form of the biological cell displayed by the form display unit and confirms a change model assigned to the designated part.
[0019]
Preferably, a variable input means for accepting a variable relating to a substance contained in the compartment in association with a film attribute or a solution attribute, and the program generating means converts one variable of the film attribute and the solution attribute to the other variable Then, the numerical calculation program is generated.
[0020]
Preferably, the apparatus further includes variable input means for receiving, for each substance contained in the compartment, a diffusion constant in each of the compartment having a membrane attribute and the compartment having a solution attribute.
[0021]
Preferably, the allocating means allocates at least one selected from a biochemical reaction model, an electric equivalent circuit model, and a diffusion model as the change model.
[0022]
Preferably, the morphology of the biological cell generated by the morphological generation means, and the biochemical reaction model, the electrical equivalent circuit model, and the diffusion model allocated to the morphology of the biological cell by the allocating means And a program generation means for generating a numerical calculation program for performing a spatiotemporal simulation of a biological substance based on the above.
[0023]
Preferably, based on the form of the biological cell generated by the form generating means and the electrical equivalent circuit allocated to the form of the biological cell by the allocating means, the potential propagation in the biological cell And a program generation means for generating a numerical calculation program for performing the simulation.
[0024]
Preferably, the program generation means includes a membrane potential based on a biochemical change in a biological cell based on a relationship among a biochemical reaction parameter having a solution attribute, a biochemical reaction parameter having a membrane attribute, and a parameter of an electrical equivalent circuit. Generate a numerical calculation program that simulates the change of
[0025]
Preferably, based on the execution result of the numerical calculation program generated by the program generating means, the spatiotemporal change of the biological substance and the local potential in the biological cell represents the biological substance and the local potential at two or more time points. The image processing apparatus further includes a result display unit for displaying the image using the image.
[0026]
Preferably, the result display means displays a spatiotemporal change of a biological substance and a local potential in a cross section of the biological cell.
[0027]
Preferably, there is further provided a graph display means for receiving a designation operation for designating a part of the biological cell and graphically displaying a change over time of a biological substance and a local potential with respect to the designated part based on the numerical calculation program.
[0028]
Further, the method for modeling a reaction in a biological cell according to the present invention generates a form of a biological cell, graphically displays the form of the generated biological cell, and at least a part of the form of the generated biological cell, Assign a physical or chemical change model.
[0029]
Also, the program according to the present invention, in a biological intracellular reaction modeling device including a computer, a step of generating a form of a biological cell, a step of graphically displaying the generated form of the biological cell, Allocating a physical or chemical change model to at least a part of the morphology of the biological cell.
[0030]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, embodiments of the present invention will be described with reference to the drawings.
FIG. 1 is a diagram illustrating a hardware configuration of a biological intracellular reaction modeling device 2 according to the present invention. As shown in FIG. 1, a biological intracellular reaction modeling device 2 includes a monitor 22 such as an LCD display or a CRT display, an input device 24 such as a keyboard and a pointing device, a processing device 26 including a CPU 262 and a memory 264, and the like. It comprises a recording device 28 such as an HDD / CD device and a communication device 29.
[0031]
FIG. 2 is a diagram exemplifying a configuration of a reaction modeling program 5 that is executed by the biological cell reaction modeling device 2 and realizes the biological cell reaction modeling method according to the present invention. As shown in FIG. 2, the reaction modeling program 5 includes a template display unit 502, a form editor unit 504, a form generation unit 510, a form display unit 520, an attribute setting unit 522, an allocation unit 530, a variable input unit 540, and a program generation unit. A unit 542, a program execution unit 544, a result display unit 546, and a model input / output unit 550.
Further, the form generation unit 510 includes a division unit 512, and the allocation unit 530 includes a change model display unit 532, a confirmation display unit 534, and a cancellation unit 536. The model input / output unit 550 includes an encryption unit 552, a decryption unit 554, and a change history management unit 556.
The reaction modeling program 5 is supplied to the control device 26 via the recording medium 280, for example, and is loaded into the memory 264 and executed.
[0032]
The template display unit 502 has a basic form of a morphological model corresponding to a part of a biological cell or the entire three-dimensional shape of a biological cell as a template in advance, and displays these templates on the monitor 22. When detecting the selection of a template via the input device 24, the template display unit 502 notifies the selected template to the form generation unit 510.
The template of the template display unit 502 may be edited by the form editor 504. The form editor 504 may deform a prepared template or construct a form model from the beginning according to the operation of the operator. For example, when an operator constructs a morphological model of a neuron, an algorithm for automatically generating the morphology of dendrites (for example, Tamori, Y., Phys. Rev. E, Vol. 48 (1993), pp. 3124) (See −3129) to generate a morphological model composed of complicated dendrites by specifying a small number of parameters.
[0033]
The division unit 512 determines the division position of the template according to the number of divisions input by the operator. The form generation unit 510 generates a form model obtained by dividing the form of the template notified from the template display unit 502 at the division position determined by the division unit 512, and outputs the generated form model to the form display unit 520. Each component of the morphological model divided by the dividing unit 512 is called a compartment.
The form display unit 520 displays the form model input from the form generation unit 510 on the monitor 22. In addition, the form display unit 520 performs rotation, enlargement, reduction, cross-sectional display, and the like of the form model according to the operation of the operator.
[0034]
The attribute setting unit 522 sets each compartment to a membrane attribute or a solution attribute according to an operation by the operator. Here, the membrane attribute means having the property of a biological membrane of a biological cell, and a variable or the like is set in the compartment set as the membrane attribute so as to indicate the property as a biological membrane. The solution attribute means having the property of a soluble substance in a biological cell, and a variable or the like is set in the compartment set in the solution attribute so as to indicate, for example, the property as a cytoplasm.
[0035]
The allocating unit 530 allocates a change model to a compartment according to an operation of the operator. First, the change model display unit 532 generates and displays a differential equation of a biochemical reaction model and a membrane potential model by a method disclosed in, for example, JP-A-2002-007380. The allocating unit 530 allocates the generated differential equation to each compartment according to an operation of the operator. When the operator checks the assigned change model, the confirmation display unit 534 displays information indicating the assigned change model in accordance with the operation of the operator. When the operator cancels the assigned change model, the canceling unit 536 cancels the assigned change model according to the operation of the operator. Here, the change model is a model indicating a chemical and physical change occurring in a biological cell, and includes an external stimulus model, a biochemical reaction model, an electrical equivalent circuit model, and the like.
[0036]
The variable input unit 540 receives, from the operator via the input device 24, variables indicating the amount of substance (concentration, etc.) and the diffusion constant contained in each compartment in association with the film attribute or the solution attribute, and the program generation unit. 542.
[0037]
The program generation unit 542 is based on the morphological model input from the morphological display unit 520, the attribute input from the attribute setting unit 522, the change model input from the allocation unit 530, and the variable input from the variable input unit 540. Thus, a program for simulating a biochemical reaction and potential propagation occurring in a biological cell is generated and output to the program execution unit 544. For example, the program generation unit 542 constructs a spatio-temporal model that reflects the influence of diffusion occurring in the morphological model on the change model (biochemical reaction model, electrical equivalent circuit, etc.) assigned to each compartment, Converts spatio-temporal dynamics into a simulation program that performs numerical integration.
In addition, the program generation unit 542 outputs a model constructed based on the morphological model and the change model to the model input / output unit 550.
[0038]
When receiving an initial value such as a substance amount from the operator, the program execution unit 544 executes the program input from the program generation unit 542, performs a numerical simulation, and outputs a simulation result to the result display unit 546. . As described above, since the initial conditions are generated independently as a separate file from the program generated by the program generation unit 542, simulations under various initial conditions can be performed without recompiling the program.
The result display unit 546 causes the monitor 22 to display the simulation result input from the program execution unit 544 in a display method according to the operator's request.
[0039]
The model input / output unit 550 inputs / outputs a model file (hereinafter, a model file) obtained by integrating the morphological model and the change model to / from an external terminal via the recording device 28 or the communication device 29. The encryption unit 552 encrypts a model file to be output to the outside. Further, the decryption unit 554 decrypts the model file input from the outside and outputs it to the program generation unit 542. The change history management unit 556 encrypts the edit history such as the name of the editor who constructed or changed the model file, its affiliation, and the date and time of the edit, and attaches the encrypted edit history to the model file.
[0040]
[Display screen]
Next, a display screen for inputting a variable or the like and displaying a result will be described.
FIG. 3 is a diagram exemplifying a template of a morphological model displayed on the monitor 22 by the template display unit 502.
As shown in FIG. 3, the template display unit 502 displays a main window 700 and child windows such as a template window 710. The main window 700 and the child windows can be operated independently to change the display position and the display area.
The main window 700 displays a toolbar 702 and a main display area 730.
A toolbar 702 is a clickable area for receiving file operations, printing, display changes, and the like. For example, the toolbars 702a, 702b, 702c, 702d, 702e, and 702f respectively display a morphological model template, assign a change model, display a symbol list (such as a substance name), generate a simulation program, and input an initial value. An operation for instructing display of a screen is received.
The main display area 730 displays a morphological model, a simulation result, and the like.
The template window 710 displays a template 712 of the morphological model. The templates 712a, 712b, 712c, 712d, 712e, and 712f are morphological models corresponding to a part or whole shape of a biological cell, and are models having shapes of a rectangular parallelepiped, a cylinder, a sphere, a cone, a spine, and a neuron, respectively. is there.
[0041]
FIG. 4 is a diagram illustrating a template edited by the form editor 504.
As shown in FIG. 4, when the desired morphological model is not included in the template, the morphological editor 504 can generate the desired morphological model by receiving a small number of parameters from the operator. This figure shows an example in which the morphological editor 504 has generated a morphological model of a neuron.
[0042]
FIG. 5 is a diagram illustrating a division variable input window 720 displayed on the monitor 22 by the division unit 512.
As shown in FIG. 5, the division unit 512 displays a division variable input window 720 for receiving the number of divisions and the size of the morphological model as a child window. The division variable input window 720 displays, for each part constituting the morphological model, a size input area 722 for receiving the size of this part and a division number input area 724 for receiving the number of divisions for dividing this part. The size input area 722 and the division number input area 724 are provided, for example, for each part of the morphological model divided based on the size and shape. In the case of this example, a size input area 722a and a division number input area 724a are provided in the spherical part of the spine, and a size input area 722b and a division number in the rotationally symmetric axis direction are provided in the cylindrical part connected to the spherical part. An input area 724b, a size input area 722d and a division number input area 724d are provided in the diameter direction of the cylinder, respectively.
Further, the split variable input window 720 displays an attribute input area 728 in each part of the morphological model. The attribute input area 728 receives an operation for setting a film attribute or a solution attribute for each part of the morphological model.
[0043]
FIG. 6 is a diagram exemplifying a morphological model displayed on the monitor 22 by the morphological display unit 520.
As shown in FIG. 6, form display section 520 displays compartment designation area 734, variable display area 736 and form model display area 738 in main display area 730. The compartment designation area 734 accepts an operation for setting a compartment designation method. For example, the compartment designation area 734a allows designation of one compartment by a click operation of the operator.
The compartment designation areas 734b, 734c, 734d, and 734e allow designation of a plurality of compartments at a specific position. For example, the compartment designation area 734b allows a batch designation of compartments located on the surface of the morphological model by a click operation of the operator, and the compartment designation area 734c allows batch designation of all compartments located on the surface. In addition, the compartment designation area 734d enables collective designation of all compartments included in the morphological model, and the compartment designation area 734e allows collective designation of all compartments located inside the morphological model.
The variable display area 736 displays the file name of the form model, the number of compartments included in the form model, and the size of the compartment in order from the top.
The form model display area 738 displays the form model in a state divided into compartments. The morphological model display area 738 can change the size of the morphological model or rotate the morphological model according to an operation on the toolbar 702.
[0044]
FIGS. 7A and 7B are diagrams exemplifying a screen in which the allocating unit 530 receives a change model allocating operation.
When the operator specifies a predetermined compartment in the morphological model displayed by morphological display section 520, allocating section 530 changes the display of the specified compartment and allocates menu 739 as shown in FIG. Is displayed. The allocation menu 739 includes a change model allocation (Embed Reaction), a display for confirming the allocated change model (View Embedded Reaction), a symbol list (Symbol List), a symbol status (Symbol Status), and a temporary deletion of a compartment ( Invisible) and release of the compartment temporary deletion state (Visible) are displayed as a menu, and any of these is received.
Also, as shown in FIG. 7B, when the operator displays a cross section of the morphological model on the morphological display unit 520 and specifies a compartment in the displayed cross section, the allocation unit 530 allocates the cross section to the compartment. Accept the operation.
[0045]
FIG. 8 is a diagram illustrating a change model display window 740 displayed on the monitor 22 by the change model display unit 532.
As shown in FIG. 8, the change model display window 740 displays an external stimulus model area 742, a biochemical reaction model area 744, and a differential equation area 746. The external stimulus model area 742 receives an external stimulus model. The biochemical reaction model area 744 receives a biochemical reaction model in the form of a chemical reaction expression. The differential equation area 740 receives a model of a chemical reaction, a physical phenomenon, or the like in a differential equation display format.
[0046]
FIG. 9 is a diagram illustrating a symbol list display window 750 displayed on the monitor 22 by the variable input unit 540.
As shown in FIG. 9, the symbol list display window 750 includes a variable display 752 for displaying variables set for the substances included in the compartment, and an attribute input area 754 for receiving an input of an attribute (membrane attribute or solution attribute) for each variable. , A diffusion constant input area 756 for receiving an input of a diffusion constant, and a global symbol setting area 758 for receiving a setting of a global symbol.
The variable input unit 540 generates a differential equation for calculating the flow of the substance between the compartments based on the input diffusion constant, and is combined with the differential equation of the biochemical reaction generated by the allocation unit 530. Thus, the reaction modeling program 5 automatically generates a reaction diffusion equation.
The variable display 752 displays the set substance amount and the like in association with the attribute. In this example, "M" shown at the left end indicates that the attribute is set to the film attribute.
The attribute input area 754 receives an operation for setting a film attribute or a solution attribute. The diffusion constant input area 756 receives the input of the diffusion constant of each substance. The global symbol setting area 758 receives global symbol settings. The global symbol is a flag set for a variable that shows uniform behavior in the morphological model. Since the variable in which the global symbol is set shows a uniform behavior throughout the morphological model, it is set so as to directly refer to the value calculated in one place. That is, the calculation amount can be reduced by setting the global symbol.
As described above, when the substances of the change model are classified into an insoluble substance (that is, a membrane attribute) and a soluble substance (that is, a solution attribute), the variable input unit 540 displays the biochemistry between the membrane attribute substance and the solution attribute substance. Perform the transformation in the reaction. This conversion is necessary because the method of expressing the concentration is different between a substance with a film attribute and a substance with a solution attribute. When converting a substance “M” with a film attribute to a substance “S” with a solution attribute, Calculated as "S" = Aa * "M". Here, Aa = 1 / (NA * v), NA is Avogadro's number, and v is the compartment volume.
By performing the conversion in this manner, the reaction between the film attribute substance and the solution substance can be handled in a unified manner.
[0047]
FIG. 10 is a diagram exemplifying a program window 760 displaying the program generated by the program generation unit 542.
As shown in FIG. 10, the program window 760 displays a program generation button 762, a program write button 764, and a program display area 766. When the program generation button 762 is clicked or the like, the program generation unit 542 generates a program for performing a numerical simulation in a predetermined program language (C language in this example) based on the morphological model and the change model. When the program write button 764 is clicked or the like, the model input / output unit 550 writes the generated program to the hard disk. The program display area 766 displays the generated program.
[0048]
FIG. 11 is a diagram exemplifying an initial value window 770 for receiving an initial value of a program generated by the program generating unit 542.
As shown in FIG. 11, the initial value window 770 displays a calculation parameter area 772, a symbol parameter area 776, and a substance amount parameter area 778. The calculation parameter area 772 displays the initial value file name, the file name of the simulation result, the total time for performing the simulation, the unit time of the operation in the numerical simulation, and the time interval for outputting the result of the numerical simulation. Accept. The symbol parameter area 776 displays a list of symbols processed in the simulation and a list of symbols to be output. The substance amount parameter area 778 displays the initial value of each symbol and accepts these inputs.
[0049]
FIG. 12 is a diagram illustrating a result display window 780 in which the result display unit 546 displays the simulation results in a time series.
As shown in FIG. 12, the result display window 780 displays a parameter display area 782, a display control area 784, and a result display area 786. The parameter display area 782 displays calculation time parameters of the numerical simulation. For example, the parameter display area 782a displays the entire time interval of the numerical simulation, and the parameter display area 782b displays the time interval for outputting the result of the numerical simulation and the calculation time interval in the numerical simulation. The display control area 784 displays the type of output parameter to be output, the page to be output, the display time interval of the slide show, and the like, and accepts an operation for changing them. The result display area 786 displays the morphological model at each time point in 3D graphic display, and displays output parameters (such as the amount of substance) at that time point in graphic form (color display according to numerical values). In this example, a to d in the figure indicate that the substance concentration is larger in order. Each of the regions a to d is displayed so as to be distinguishable by color or pattern. The output parameters are graphically displayed at an arbitrary number of gradations according to a combination of color and density.
[0050]
FIG. 13 is a diagram illustrating a result display window 780 in which the result display unit 546 displays a simulation result in a cross section of the morphological model.
As shown in FIG. 13, the result display area 786 of this example displays a section 786a of the morphological model, and graphically displays output parameters on the section 786a. The position of the cross section 786a in the morphological model can be moved by a toolbar (a button on which an arrow is displayed) provided above the result display window 780.
[0051]
FIG. 14 is a diagram illustrating a graph display window 790 in which the result display unit 546 displays the simulation result in a graph.
As shown in FIG. 14, the graph display window 790 displays an output parameter selection area 792, a graph display area 794, and a numerical value display area 796. The output parameter selection area 792 displays the type of output parameter displayed in a graph, and accepts the selection of the type of output parameter. The graph display area 794 displays a graph in which the selected output parameter is plotted with respect to time. The numerical value display area 796 defines the size of the vertical axis of the graph displayed in the graph display area 794 by the numerical values in the “min” column and the “max” column. Further, the graph display area 794 displays a numerical value (concentration of a substance, etc.) of the simulation result in a “value” column according to the position of the cursor 794a displayed in the graph display area 794.
[0052]
[motion]
Next, an operation of constructing a model of a biological cell using the biological intracellular reaction modeling device 2 and performing spatiotemporal simulation will be described.
FIG. 15 is a flowchart of the spatiotemporal simulation process (S10) using the biological intracellular reaction modeling device 2.
As shown in FIG. 15, in step 100 (S100), when the operator clicks on toolbar 702a of main window 700, template display unit 502 displays a template of the morphological model in template window 710. The operator selects a morphological model similar to the morphology of the biological cell from the displayed templates and deforms the morphological model as necessary.
[0053]
In step 120 (S120), the biological cell is composed of a cytoplasm filled with a water-soluble substance and a cell membrane surrounding the cytoplasm. In order to simulate a biochemical reaction and a membrane potential, the cell must be distinguished from the cell membrane. Therefore, the operator sets a membrane attribute or a solution attribute for each compartment of the morphological model in the attribute input area 728 of the split variable input window 720. The attribute setting unit 522 sets a film attribute or a solution attribute to each part of the morphological model according to an instruction in the attribute input area 728.
[0054]
In step 130 (S130), when accepting the designation of a compartment in form model display area 738 of main window 700, allocating section 530 displays layout menu 739 in form model display area 730. When the operator clicks “Embed Reaction” from the allocation menu 739, the allocation unit 530 displays a change model display window 740, and displays an external stimulus model, a biochemical reaction model, and a membrane potential model (electrically equivalent circuit). ) Input is accepted.
[0055]
In step 150 (S150), when the toolbar 702d of the main window 700 is clicked, the program generation unit 542 displays the program window 760 and accepts a spatio-temporal simulation program generation instruction. When the program generation button 762 is clicked, the program generation unit 542 generates a spatio-temporal simulation program and displays it in the program display area 766.
[0056]
In step 160 (S160), after compiling the generated spatiotemporal program, the program execution unit 544 displays the initial value window 770 to perform the simulation, the time interval of the numerical operation, and the material at the start of the simulation. Accepts input of initial parameters such as concentration.
[0057]
In step 170 (S170), when the start of the simulation is instructed, the program execution unit 544 executes the compiled spatiotemporal program to perform a numerical operation on the change in the biological cell based on the input initial parameters. And a spatio-temporal simulation.
[0058]
In step 180 (S180), the result display unit 546 outputs the result of the spatiotemporal simulation.
[0059]
FIG. 16 is a flowchart illustrating the form model setting process (S100) shown in FIG. 15 in more detail.
As shown in FIG. 16, in step 102 (S102), when the operator clicks on toolbar 702a of main window 700, template display unit 502 displays a template of the morphological model in template window 710. The operator selects a morphological model similar to the morphology of the biological cell from the displayed templates.
In step 104 (S104), when deforming the selected template, the operator inputs morphological parameters. The reaction modeling program 5 proceeds to the process of S106 when the morphological parameter is input, and proceeds to the process of S110 otherwise.
In step 106 (S106), the form editor 504 receives a form parameter for deforming the form of the form model. In step 108 (S108), the form editor 504 deforms the form of the form model according to the received form parameter.
In step 110 (S110), the division unit 512 displays the division variable input window 720 and accepts the input of the size and the number of divisions of each part of the morphological model.
In step 112 (S112), the form generation unit 510 generates form model data of the size and the number of divisions of the template input in the division variable input window 720. In step 114 (S114), form display unit 520 displays the generated form model data on main window 710.
[0060]
FIG. 17 is a flowchart illustrating the change model setting process (S130) illustrated in FIG. 15 in more detail.
As shown in FIG. 17, in step 132 (S132), form display unit 520 displays a form model in form model display area 738 of main window 700.
In step 134 (S134), the change modeling program 5 proceeds to the process of S136 when rotating the morphological model, proceeds to S138 when displaying the cross section of the morphological model, and proceeds to S140 otherwise.
In step 136 (S136), the form display unit 520 displays the rotated form model in the form model display area 738. In step 138 (S138), the form display unit 520 displays a cross section of the form model in the form model display area 738.
In step 140 (S140), when the operator clicks a compartment in morphological model display area 738, allocating section 530 specifies the compartment displayed at the clicked position, and morphological display section 520 specifies the compartment of the specified compartment. The display color is changed, and an allocation menu 739 is displayed.
In step 141 (S141), the operator clicks one of the displayed allocation menus 739. The reaction modeling program 5 proceeds to the process of S142 when “Embedded Reaction” is clicked, proceeds to the process of S144 when “View Embedded Reaction” is clicked, and executes the process when “Symbol List” is clicked. The process proceeds to S146.
In step 142 (S142), the model display unit 532 displays a change model display window 740 to input a change model such as an external stimulus model, a biochemical reaction model, and a membrane potential model (electrically equivalent circuit). Accept. The allocating unit 530 allocates the input change model to the specified compartment.
In step 144 (S144), the confirmation display unit 532 displays the change model assigned to the designated compartment. The operator can check the displayed change model and cancel the change model as necessary.
In step 146 (S146), the variable input unit 540 displays the symbol list display window 750, and receives the input of the concentration, the attribute, and the diffusion constant of the substance in the biological cell, and the designation of the global symbol.
In step 148 (S148), when the operator inputs that the change model setting process is to be ended, the reaction modeling program 5 ends the process of S130, and otherwise moves to the process of S134.
[0061]
FIG. 18 is a flowchart illustrating the result display process (S180) illustrated in FIG. 15 in more detail.
As shown in FIG. 18, in step 182 (S182), the operator selects a display method of the simulation result. The reaction modeling program 5 proceeds to S184 when the 3D display is selected, proceeds to S186 when the graph display is selected, and proceeds to S188 when the cross-sectional display is selected.
In step 184 (S184), the result display unit 546 displays a 3D image showing the morphological model and the concentration of the specific substance at each time in the result display area 786 of the result display window 780. When the operator supports the slide show by inputting the display time interval of the slide show in the display control area 784, the result display unit 546 displays the 3D image at each point in time in the input display time interval.
In step 186 (S186), when the operator clicks a desired compartment in the result display area of the result display window 780, the result display unit 546 displays a simulation result of the clicked compartment in the graph display window 790. . When the operator drags the cursor 794a to change the position on the horizontal axis (time axis), the result display unit 546 displays the substance concentration and the like at the time when the position of the cursor 794a corresponds to the “value” column.
In step 188 (S188), the result display unit 546 displays the section 786a of the morphological model in the result display area 786 of the result display window 780, and graphically displays the substance concentration and the like at each time point on the section 786a.
In step 190 (S190), the reaction modeling program 5 ends the process of S180 when the end of the result display is input, and moves to the process of S182 otherwise.
In this way, the result display window 780 can grasp the whole image, but cannot know the concentration of the substance at a specific time in a specific compartment. Thus, the graph display window 790 graphically displays the time change of the substance in the selected specific compartment, and Displays the value at the cursor time. The result display unit 546 displays the inside by cutting at an arbitrary cross section in addition to these display methods.
[0062]
As described above, the biological intracellular reaction modeling apparatus 2 of the present invention can easily model a complex form of a biological cell, particularly a nerve cell by designating a small number of parameters, and can proceed with a variety of proteins progressing there. By graphically constructing a model for biochemical reaction diffusion and generation / propagation of membrane potential, the problem of character-based script expression, which was a It enables the realization of an environment. The present invention has not provided a great utility when the actual biological cells are handled in an extremely simplified manner as in the conventional models. However, in the case of constructing a model of all proteins in a cell on a computer in consideration of cell morphology, which is a major goal of life science in the future, it is complicated without the graphical integrated environment enabled by the present invention. It is difficult to construct uncertain biological cell models and realize bioinformatics.
[0063]
[Modification]
In addition, there are many types of substances (particularly proteins) in living cells, and it is difficult to construct a model including all the change models. Therefore, it is realistic that a plurality of operators respectively build models, and integrate files of the built models to build a model in a biological cell.
Therefore, the biological cell reaction modeling device 2 can read and use a model file from the outside.
[0064]
FIG. 19 is a flowchart in the case where the biological intracellular reaction modeling device 2 reads a model file from the outside and performs a simulation. 19, those substantially the same as those in FIG. 15 are denoted by the same reference numerals.
As shown in FIG. 19, in step 200 (S200), the model input / output unit 550 reads a model file from the recording device 28 or the communication device 29.
In step 205 (S205), the decoding unit 554 decodes the read model file and outputs it to the program generation unit 542.
In step 210 (S210), the program generation unit 542 changes the model file input from the decoding unit 554 according to the input by the operator.
The reaction modeling program 5 proceeds to the processing of S215 when the model file has been changed, and otherwise proceeds to the processing of S150.
In step 215 (S215), the change history management unit 556 adds the name of the person who changed the model file, the affiliation, and the date and time of the change to the edit history list.
In step 220 (S220), when the operator instructs to output the model file, the encryption unit 552 encrypts the model file, and the model input / output unit 550 stores the encrypted model file in the recording device 28 or Output to the outside via the communication device 29.
[0065]
In this way, by encrypting the model file, it is possible to prevent tampering of the model. Further, by managing the editing history, it is possible to ensure the honor of the model builder and to inform the editing process and the like.
[0066]
Further, the reaction modeling apparatus 2 for living cells may be connected to a workstation (not shown), and the processing performed by the program execution unit 544 may be executed on the workstation. In this case, the biological intracellular reaction modeling device 2 transmits the program generated by the program generating unit 542 and the initial value input by the operator to the workstation via the communication device 29, and Receive the results of the spatial simulation.
At this time, it is preferable that the biological intracellular reaction modeling device 2 be converted into a program language executable on a workstation (for example, a program language such as C language, Visual Basic, Fortran, etc.) and transmitted.
[0067]
【The invention's effect】
【The invention's effect】
As described above, the biological intracellular reaction modeling device according to the present invention can support spatiotemporal simulation of changes in biological cells.
[Brief description of the drawings]
FIG. 1 is a diagram illustrating a hardware configuration of a biological intracellular reaction modeling device 2 according to the present invention.
FIG. 2 is a diagram exemplifying a configuration of a reaction modeling program 5 that is executed by the biological intracellular reaction modeling device 2 and realizes the biological intracellular reaction modeling method according to the present invention.
FIG. 3 is a diagram exemplifying a template of a morphological model displayed on a monitor 22 by a template display unit 502;
FIG. 4 is a diagram exemplifying a template edited by a form editor 504;
FIG. 5 is a diagram illustrating a division variable input window 720 displayed on a monitor 22 by a division unit 512.
FIG. 6 is a diagram illustrating an example of a form model displayed on a monitor 22 by a form display unit 520.
FIGS. 7A and 7B are diagrams exemplifying screens in which an allocating unit 530 receives a change model allocating operation;
FIG. 8 is a view exemplifying a change model display window 740 displayed on a monitor 22 by a change model display unit 532.
FIG. 9 is a diagram illustrating a symbol list display window 750 displayed on the monitor 22 by the variable input unit 540.
FIG. 10 is a diagram exemplifying a program window 760 displaying a program generated by a program generation unit 542.
FIG. 11 is a diagram illustrating an example of an initial value window 770 for receiving an initial value of a program generated by the program generating unit 542.
FIG. 12 is a diagram illustrating a result display window 780 in which a result display unit 546 arranges and displays simulation results in a time series.
FIG. 13 is a diagram illustrating a result display window 780 in which a result display unit 546 displays a simulation result in a cross section of a morphological model.
FIG. 14 is a diagram illustrating a graph display window 790 in which a result display unit 546 displays a simulation result in a graph.
FIG. 15 is a flowchart of a spatiotemporal simulation process (S10) using the intracellular reaction modeling apparatus 2;
FIG. 16 is a flowchart illustrating the form model setting process (S100) shown in FIG. 15 in more detail;
FIG. 17 is a flowchart illustrating the change model setting process (S130) illustrated in FIG. 15 in more detail.
18 is a flowchart illustrating the result display process (S180) illustrated in FIG. 15 in more detail.
FIG. 19 is a flowchart in the case where the biological intracellular reaction modeling device 2 reads a model file from the outside and performs a simulation.
FIG. 20 is a diagram illustrating an example of a morphological description script for modeling the morphology of a cell.
[Explanation of symbols]
2 ... Data structuring device
22 Monitor
24 ・ ・ ・ Input device
26 Processing unit
262 ... CPU
264 ... memory
28 ・ ・ ・ Recording device
280: Recording medium
29 ・ ・ ・ Communication device
5 ... Reaction modeling program
502: template display unit
504: Form editor section
510 ... form generation unit
512: division unit
520... Form display unit
522... Attribute setting unit
530 ··· Assignment section
532... Change model display section
534: Confirmation display section
536 ・ ・ ・ Cancellation unit
540... Variable input section
542: Program generation unit
544... Program execution unit
546: Result display section
550 ・ ・ ・ Model input / output unit
552: encryption unit
554... Decoding part
556: Change history management unit

Claims (26)

A morphological generating means for generating a morphology of a biological cell,
Form display means for graphically displaying the form of the biological cell generated by the form generation means,
An intracellular reaction modeling apparatus, comprising: an assignment unit that assigns a physical or chemical change model to at least a part of the form of the biological cell generated by the form generation unit. The morphological generating means has a dividing means for dividing the form of the biological cell into compartments,
The biological intracellular reaction modeling device according to claim 1, wherein the morphological display means displays the morphology of the biological cell in a state where the biological cell is divided by the dividing means. The biological intracellular reaction modeling device according to claim 2, wherein the allocating unit allocates the change model for each compartment divided by the dividing unit. The biological cell intracellular reaction modeling apparatus according to claim 3, wherein the morphological display means displays the morphology of the biological cell three-dimensionally. 5. The allocating unit according to claim 4, wherein the allocating unit receives a specification operation for specifying one or more compartments from the compartments displayed three-dimensionally by the morphological display unit, and allocates the change model to the specified compartment. 6. Biological cell modeling system. A numerical calculation program for performing a spatiotemporal simulation of a biological substance based on the form of the biological cell generated by the form generating means and the change model assigned to the form of the biological cell by the assigning means. The biological intracellular reaction modeling device according to any one of claims 1 to 5, further comprising a program generating means for generating the program. The biological intracellular reaction modeling apparatus according to claim 6, further comprising a result display unit that graphically displays an execution result of the numerical calculation program generated by the program generation unit. The form generating means has at least one basic form as a template,
The biological intracellular reaction modeling device according to any one of claims 1 to 7, wherein the morphological display means displays at least one of the basic morphologies. The morphology generating means generates a morphology of a nerve cell according to the input of the parameter,
The biological intracellular reaction modeling device according to any one of claims 1 to 7, wherein the morphological display means displays a morphology of the nerve cell generated by the morphological generation means. The morphological generation means generates at least a part of the morphology of the biological cell,
The biological intracellular reaction modeling device according to any one of claims 1 to 7, wherein the morphological display means displays at least a part of the morphology of the biological cell generated by the morphological generation means. The biological intracellular reaction modeling apparatus according to any one of claims 2 to 10, further comprising an attribute setting unit configured to set at least a part of the compartment divided by the dividing unit to a membrane attribute or a solution attribute. The biological intracellular reaction modeling apparatus according to claim 1, wherein the allocating unit receives a specification operation for specifying a plurality of compartments at a specific position and allocates the change model to the specified compartment at the specific position. The form display means displays a cross section of the form of the biological cell,
The biological intracellular reaction modeling apparatus according to claim 4, wherein the allocating means receives a specification operation of specifying one or more compartments from the compartments in the displayed cross section, and allocates the change model to the specified compartment. The biological intracellular reaction modeling apparatus according to claim 1, further comprising a canceling unit for canceling the assigned change model with respect to at least a part of the form of the biological cell to which the change model is assigned by the assigning unit. 2. The confirmation display unit according to claim 1, further comprising a confirmation display unit that receives a designation operation for designating at least a part of the form of the biological cell displayed by the form display unit and confirms a change model assigned to the designated part. Biological cell modeling system. Variable input means for accepting variables related to the substance contained in the compartment in association with a membrane attribute or a solution attribute,
7. The biological intracellular reaction modeling device according to claim 6, wherein the program generation means converts one of the membrane attribute and the solution attribute into the other variable to generate the numerical calculation program. 3. The biological intracellular reaction modeling apparatus according to claim 2, further comprising a variable input unit that receives, for each substance included in the compartment, a diffusion constant in each of the membrane attribute compartment and the solution attribute compartment. The biological intracellular reaction modeling device according to claim 1, wherein the allocating means allocates at least one selected from a biochemical reaction model, an electrical equivalent circuit model, and a diffusion model as the change model. Based on the form of the biological cell generated by the form generating means and the biochemical reaction model, the electrical equivalent circuit model, and the diffusion model assigned to the form of the biological cell by the assigning means. 19. The biological intracellular reaction modeling apparatus according to claim 18, further comprising a program generating means for generating a numerical calculation program for performing a spatiotemporal simulation of a biological substance. Simulation of potential propagation in the biological cell is performed based on the form of the biological cell generated by the form generating means and the electrical equivalent circuit allocated to the form of the biological cell by the allocating means. 19. The biological intracellular reaction modeling device according to claim 18, further comprising a program generating means for generating a numerical calculation program. The program generating means simulates a change in membrane potential based on a biochemical change in a biological cell based on a relationship among a biochemical reaction parameter of a solution attribute, a biochemical reaction parameter of a membrane attribute, and a parameter of an electrical equivalent circuit. The biological intracellular reaction modeling device according to claim 16, which generates a numerical calculation program to be executed. Based on the execution result of the numerical calculation program generated by the program generating means, the spatio-temporal change of the biological substance and the local potential in the biological cell is calculated using images representing the biological substance and the local potential at two or more time points. 20. The biological intracellular reaction modeling device according to claim 19, further comprising a result display means for displaying. The biological intracellular reaction modeling device according to claim 22, wherein the result display means displays a spatiotemporal change of a biological substance and a local potential in a cross section of the biological cell. 20. The apparatus according to claim 19, further comprising: a graph display unit that receives a designation operation of designating a part of the biological cell, and graphically displays a temporal change of a biological substance and a local potential with respect to the designated part based on the numerical calculation program. Biological reaction modeling equipment. Produce the morphology of biological cells,
Graphically display the generated form of the biological cell,
A method for modeling a reaction in a biological cell, in which a physical or chemical change model is assigned to at least a part of the generated form of the biological cell in response to an instruction from an operator. In a biological reaction modeling device including a computer,
Generating a morphology of a biological cell;
Graphically displaying the generated morphology of the biological cell;
Assigning a physical or chemical change model to at least a part of the form of the biological cell thus generated, by a computer of the biological intracellular reaction modeling device.

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