Details of a Researcher - FUNAHASHI Akira

Papers - FUNAHASHI Akira

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Novère Nicolas Le, Hucka Michael, Mi Huaiyu, Moodie Stuart, Schreiber Falk, Sorokin Anatoly, Demir Emek, Wegner Katja, Aladjem Mirit I, Wimalaratne Sarala M, Bergman Frank T, Gauges Ralph, Ghazal Peter, Kawaji Hideya, Li Lu, Matsuoka Yukiko, Villéger Alice, Boyd Sarah E, Calzone Laurence, Courtot Melanie, Dogrusoz Ugur, Freeman Tom C, FUNAHASHI AKIRA, Ghosh Samik, Jouraku Akiya, Kim Sohyoung, Kolpakov Fedor, Luna Augustin, Sahle Sven, Schmidt Esther, Watterson Steven, Wu Guanming, Goryanin Igor, Kell Douglas B, Sander Chris, Sauro Herbert, Snoep Jacky, L Kohn Kurt, Kitano Hiroaki

Nature Biotechnology 27 ( 8 ) 735-741 - 741 2009.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1087-0156

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Using process diagrams for the graphical representation of biological networks

Kitano Hiroaki, Funahashi Akira, Matsuoka Yukiko, Oda Kanae

Nature Biotechnology 23 ( 8 ) 961 - 966 2005.08

ISSN 1087-0156

With the increased interest in understanding biological networks, such as protein-protein interaction networks and gene regulatory networks, methods for representing and communicating such networks in both human- and machine-readable form have become increasingly important. Although there has been significant progress in machine-readable representation of networks, as exemplified by the Systems Biology Mark-up Language (SBML) (http://www.sbml.org) issues in human-readable representation have been largely ignored. This article discusses human-readable diagrammatic representations and proposes a set of notations that enhances the formality and richness of the information represented. The process diagram is a fully state transition-based diagram that can be translated into machine-readable forms such as SBML in a straightforward way. It is supported by CellDesigner, a diagrammatic network editing software (http://www.celldesigner. org/), and has been used to represent a variety of networks of various sizes (from only a few components to several hundred components).

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A comprehensive pathway map of epidermal growth factor receptor signaling.

Oda, K., Matsuoka, Y., Funahashi, A., and Kitano, H.

Nature Molecular Systems Biology 1 ( 1 ) 1-17 2005.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1744-4292

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3D convolutional neural networks-based segmentation to acquire quantitative criteria of the nucleus during mouse embryogenesis

Tokuoka Y, Yamada T.G, Mashiko D, Ikeda Z, Hiroi N.F, Kobayashi T.J, Yamagata K, Funahashi A

npj Systems Biology and Applications (npj Systems Biology and Applications) 6 ( 1 ) 32 2020.12

Research paper (scientific journal), Joint Work, Accepted

© 2020, The Author(s). During embryogenesis, cells repeatedly divide and dynamically change their positions in three-dimensional (3D) space. A robust and accurate algorithm to acquire the 3D positions of the cells would help to reveal the mechanisms of embryogenesis. To acquire quantitative criteria of embryogenesis from time-series 3D microscopic images, image processing algorithms such as segmentation have been applied. Because the cells in embryos are considerably crowded, an algorithm to segment individual cells in detail and accurately is needed. To quantify the nuclear region of every cell from a time-series 3D fluorescence microscopic image of living cells, we developed QCANet, a convolutional neural network-based segmentation algorithm for 3D fluorescence bioimages. We demonstrated that QCANet outperformed 3D Mask R-CNN, which is currently considered as the best algorithm of instance segmentation. We showed that QCANet can be applied not only to developing mouse embryos but also to developing embryos of two other model species. Using QCANet, we were able to extract several quantitative criteria of embryogenesis from 11 early mouse embryos. We showed that the extracted criteria could be used to evaluate the differences between individual embryos. This study contributes to the development of fundamental approaches for assessing embryogenesis on the basis of extracted quantitative criteria.

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BioSimulators: a central registry of simulation engines and services for recommending specific tools

B Shaikh, LP Smith, D Vasilescu, G Marupilla, M Wilson, E Agmon, ...

Nucleic acids research 50 (W1), W108-W114 (Nucleic Acids Research) 50 ( W1 ) W108 - W114 2022.07

Joint Work, Accepted, ISSN 03051048

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.

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COVID19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

M Ostaszewski, A Niarakis, A Mazein, I Kuperstein, R Phair, ...

Molecular systems biology 17 (10), e10387 (Molecular Systems Biology) 17 ( 10 ) e10387 2021.10

Joint Work, Accepted, ISSN 1744-4292

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

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The principles of whole-cell modeling

Karr Jonathan R., Takahashi Koichi, Funahashi Akira

Current Opinion in Microbiology (Elsevier {BV}) 27 18 - 24 2015.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1369-5274

Whole-cell models which comprehensively predict how phenotypes emerge from genotype promise to enable rational bioengineering and precision medicine. Here, we outline the key principles of whole-cell modeling which have emerged from our work developing bacterial whole-cell models: single-cellularity; functional, genetic, molecular, and temporal completeness; biophysical realism including temporal dynamics and stochastic variation; species-specificity; and model integration and reproducibility. We also outline the whole-cell model construction process, highlighting existing resources. Numerous challenges remain to achieving fully complete models including developing new experimental tools to more completely characterize cells and developing a strong theoretical understanding of hybrid mathematics. Solving these challenges requires collaboration among computational and experimental biologists, biophysicists, biochemists, applied mathematicians, computer scientists, and software engineers.

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Acceleration of discrete stochastic biochemical simulation using GPGPU

Sumiyoshi, Kei, Hirata, Kazuki, Hiroi, Noriko, Funahashi, Akira

FRONTIERS IN PHYSIOLOGY 6 155 - 169 2015.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1664-042X

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SBML Level 3: an extensible format for the exchange and reuse of biological models

SM Keating, D Waltemath, M König, F Zhang, A Dräger, C Chaouiya, ...

Molecular systems biology 16 (8), e9110 16 ( 8 ) e9110 2020.08

Joint Work, Accepted, ISSN 1744-4292

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High-speed microscopy with an electrically tunable lens to image the dynamics of in vivo molecular complexes

Yuichiro Nakai; Mitsunori Ozeki; Takumi Hiraiwa; Ryuichi Tanimoto; Akira Funahashi; Noriko Hiroi; Atsushi Taniguchi; Shigenori Nonaka; Viviane Boilot; Roshan Shrestha; Joanna Clark; Naoka Tamura; Viji M. Draviam; Hiromasa Oku

Review of Scientific Instruments 86 ( 1 ) 013707 2015.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0034-6748

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Symbolic integration by integrating learning models with different strengths and weaknesses

H Kubota, Y Tokuoka, TG Yamada, A Funahashi

IEEE Access 10, 47000-47010 (IEEE Access) 10 47000 - 47010 2022

Joint Work, Accepted, ISSN 2169-3536

Integration is indispensable, not only in mathematics, but also in a wide range of other fields. A deep learning method has recently been developed and shown to be capable of integrating mathematical functions that could not previously be integrated on a computer. However, that method treats integration as equivalent to natural language translation and does not reflect mathematical information. In this study, we adjusted the learning model to take mathematical information into account and developed a wide range of learning models that learn the order of numerical operations more robustly. In this way, we achieved a 98.80% correct answer rate with symbolic integration, a higher rate than that of any existing method. We judged the correctness of the integration based on whether the derivative of the primitive function was consistent with the integrand. By building an integrated model based on this strategy, we achieved a 99.79% rate of correct answers with symbolic integration. In summary, we have developed a more accurate method of selecting the correct model than the existing method by judging the result of symbolic integration based on whether the output of the model equals the input formula when the output is differentiated.

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Identification of a master transcription factor and a regulatory mechanism for desiccation tolerance in the anhydrobiotic cell line Pv11

TG Yamada, Y Hiki, NF Hiroi, E Shagimardanova, O Gusev, R Cornette, ...

PLoS One 15 (3), e0230218 (PLoS ONE) 15 ( 3 ) e0230218 2020.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1932-6203

Copyright: © 2020 Yamada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Water is essential for living organisms. Terrestrial organisms are incessantly exposed to the stress of losing water, desiccation stress. Avoiding the mortality caused by desiccation stress, many organisms acquired molecular mechanisms to tolerate desiccation. Larvae of the African midge, Polypedilum vanderplanki, and its embryonic cell line Pv11 tolerate desiccation stress by entering an ametabolic state, anhydrobiosis, and return to active life after rehydration. The genes related to desiccation tolerance have been comprehensively analyzed, but transcriptional regulatory mechanisms to induce these genes after desiccation or rehydration remain unclear. Here, we comprehensively analyzed the gene regulatory network in Pv11 cells and compared it with that of Drosophila melanogaster, a desiccation sensitive species. We demonstrated that nuclear transcription factor Y subunit gamma-like, which is important for drought stress tolerance in plants, and its transcriptional regulation of downstream positive feedback loops have a pivotal role in regulating various anhydrobiosis-related genes. This study provides an initial insight into the systemic mechanism of desiccation tolerance.

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Predicting the future direction of cell movement with convolutional neural networks

S Nishimoto, Y Tokuoka, TG Yamada, NF Hiroi, A Funahashi

PloS one 14 (9), e0221245 (PLoS ONE) 14 ( 9 ) e0221245 2019.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1932-6203

© 2019 Nishimoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Image-based deep learning systems, such as convolutional neural networks (CNNs), have recently been applied to cell classification, producing impressive results; however, application of CNNs has been confined to classification of the current cell state from the image. Here, we focused on cell movement where current and/or past cell shape can influence the future cell movement. We demonstrate that CNNs prospectively predicted the future direction of cell movement with high accuracy from a single image patch of a cell at a certain time. Furthermore, by visualizing the image features that were learned by the CNNs, we could identify morphological features, e.g., the protrusions and trailing edge that have been experimentally reported to determine the direction of cell movement. Our results indicate that CNNs have the potential to predict the future direction of cell movement from current cell shape, and can be used to automatically identify those morphological features that influence future cell movement.

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Detection of Temperature Difference in Neuronal Cells

Tanimoto, Ryuichi, Hiraiwa, Takumi, Nakai, Yuichiro, Shindo, Yutaka, Oka, Kotaro, Hiroi, Noriko, Funahashi, Akira

SCIENTIFIC REPORTS 6 22071 2016.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 2045-2322

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Metabolic Tug-of-War between Glycolysis and Translation Revealed by Biochemical Reconstitution

G Sato, S Kinoshita, TG Yamada, S Arai, T Kitaguchi, A Funahashi, N Doi, ...

ACS Synthetic Biology (ACS Synthetic Biology) 13 ( 5 ) 1572 - 1581 2024.05

Joint Work, Accepted, ISSN 2161-5063

Inside cells, various biological systems work cooperatively for homeostasis and self-replication. These systems do not work independently as they compete for shared elements like ATP and NADH. However, it has been believed that such competition is not a problem in codependent biological systems such as the energy-supplying glycolysis and the energy-consuming translation system. In this study, we biochemically reconstituted the coupling system of glycolysis and translation using purified elements and found that the competition for ATP between glycolysis and protein synthesis interferes with their coupling. Both experiments and simulations revealed that this interference is derived from a metabolic tug-of-war between glycolysis and translation based on their reaction rates, which changes the threshold of the initial substrate concentration for the success coupling. By the metabolic tug-of-war, translation energized by strong glycolysis is facilitated by an exogenous ATPase, which normally inhibits translation. These findings provide chemical insights into the mechanism of competition among biological systems in living cells and provide a framework for the construction of synthetic metabolism in vitro.

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Switching from weak to strong cortical attachment of microtubules accounts for the transition from nuclear centration to spindle elongation in metazoans

S Tada, Y Yamazaki, K Yamamoto, K Fujii, TG Yamada, NF Hiroi, ...

Heliyon (Heliyon) 10 ( 3 ) e25494 2024.02

Joint Work, Accepted, ISSN 24058440

The centrosome is a major microtubule organizing center in animal cells. The position of the centrosomes inside the cell is important for cell functions such as cell cycle, and thus should be tightly regulated. Theoretical models based on the forces generated along the microtubules have been proposed to account for the dynamic movements of the centrosomes during the cell cycle. These models, however, often adopted inconsistent assumptions to explain distinct but successive movements, thus preventing a unified model for centrosome positioning. For the centration of the centrosomes, weak attachment of the astral microtubules to the cell cortex was assumed. In contrast, for the separation of the centrosomes during spindle elongation, strong attachment was assumed. Here, we mathematically analyzed these processes at steady state and found that the different assumptions are proper for each process. We experimentally validated our conclusion using nematode and sea urchin embryos by manipulating their shapes. Our results suggest the existence of a molecular mechanism that converts the cortical attachment from weak to strong during the transition from centrosome centration to spindle elongation.

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SBML level 3 package: spatial processes, version 1, release 1

JC Schaff, A Lakshminarayana, RF Murphy, FT Bergmann, A Funahashi, ...

Journal of Integrative Bioinformatics 20 (1), 20220054 20 ( 1 ) 2023.03

Joint Work, Accepted

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Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

A Niarakis, M Ostaszewski, A Mazein, I Kuperstein, M Kutmon, ...

Frontiers in Immunology 14, 1282859 (Frontiers in Immunology) 14 1282859 2023

Joint Work, Accepted, ISSN 1664-3224

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors. Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

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Titanium Culture Vessel Presenting Temperature Gradation for the Thermotolerance Estimation of Cells

C Imashiro, Y Jin, M Hayama, TG Yamada, A Funahashi, K Sakaguchi, ...

Cyborg and Bionic Systems 4, 0049 (Cyborg and Bionic Systems) 4 0049 2023

Joint Work, Accepted, ISSN 20971087

Hyperthermia can be induced to exploit the thermal intolerance of cancer cells, which is worse than that of normal cells, as a potential noninvasive cancer treatment. To develop an effective hyperthermia treatment, thermal cytotoxicity of cells should be comprehensively investigated. However, to conduct such investigations, the culture temperature must be accurately regulated. We previously reported a culture system in which the culture temperature could be accurately regulated by employing metallic culture vessels. However, appropriate temperature conditions for hyperthermia depend on the cell species. Consequently, several experiments need to be conducted, which is a bottleneck of inducing hyperthermia. Hence, we developed a cell culture system with temperature gradation on a metallic culture surface. Michigan Cancer Foundation-7 cells and normal human dermal fibroblasts were used as cancer and normal cell models, respectively. Normal cells showed stronger thermal tolerance; this was because the novel system immediately exhibited a temperature gradation. Thus, the developed culture system can be used to investigate the optimum thermal conditions for effective hyperthermia treatment. Furthermore, as the reactions of cultured cells can be effectively assessed with the present results, further research involving the thermal stimulation of cells is possible.

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Development of non-bias phenotypic drug screening for cardiomyocyte hypertrophy by image segmentation using deep learning

J Komuro, Y Tokuoka, T Seki, D Kusumoto, H Hashimoto, T Katsuki, ...

Biochemical and Biophysical Research Communications 632, 181-188 (Biochemical and Biophysical Research Communications) 632 181 - 188 2022.12

Joint Work, Accepted, ISSN 0006291X

The number of patients with heart failure and related deaths is rapidly increasing worldwide, making it a major problem. Cardiac hypertrophy is a crucial preliminary step in heart failure, but its treatment has not yet been fully successful. In this study, we established a system to evaluate cardiomyocyte hypertrophy using a deep learning-based high-throughput screening system and identified drugs that inhibit it. First, primary cultured cardiomyocytes from neonatal rats were stimulated by both angiotensin II and endothelin-1, and cellular images were captured using a phase-contrast microscope. Subsequently, we used a deep learning model for instance segmentation and established a system to automatically and unbiasedly evaluate the cardiomyocyte size and perimeter. Using this system, we screened 100 FDA-approved drugs library and identified 12 drugs that inhibited cardiomyocyte hypertrophy. We focused on ezetimibe, a cholesterol absorption inhibitor, that inhibited cardiomyocyte hypertrophy in a dose-dependent manner in vitro. Additionally, ezetimibe improved the cardiac dysfunction induced by pressure overload in mice. These results suggest that the deep learning-based system is useful for the evaluation of cardiomyocyte hypertrophy and drug screening, leading to the development of new treatments for heart failure.

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人工知能および高速レーザー照射システムの統合による高品質ヒト心筋細胞の作製と臨床応用

遠山周吾, 舟橋啓

福田記念医療技術振興財団情報 ((公財)福田記念医療技術振興財団) ( 35 ) 181 - 186 2022.12

Joint Work, Accepted

自動高速レーザー照射システムにより目的外細胞を除去し、ロット差の極めて少ない心筋細胞を作製するための前段階として、AIによる機械学習を用いて目的細胞と目的外細胞を識別する手法を開発することを目的とした。自動化心筋細胞拍動評価システムを用いて培養皿上で拍動する心筋細胞の動画を効率よく撮影し、拍動方向のベクトル解析により心筋領域を同定することで非心筋細胞との領域の判別が可能となった。セグメンテーション精度と心筋領域の割合の関係を定性的に確認すると、心筋領域の割合が高い画像のセグメンテーション精度は約80%に達したが、心筋領域の割合が低い画像のセグメンテーションは約1%と非常に低いことが確認された。

Intercellular interaction mechanisms promote diversity in intracellular ATP concentration in Escherichia coli populations

RJ Nakatani, M Itabashi, TG Yamada, NF Hiroi, A Funahashi

Scientific reports 12 (1), 17946 (Scientific Reports) 12 ( 1 ) 17946 2022.12

Joint Work, Accepted

In fluctuating environments, many microorganisms acquire phenotypic heterogeneity as a survival tactic to increase the likelihood of survival of the overall population. One example of this interindividual heterogeneity is the diversity of ATP concentration among members of Escherichia coli populations under glucose deprivation. Despite the importance of such environmentally driven phenotypic heterogeneity, how the differences in intracellular ATP concentration emerge among individual E. coli organisms is unknown. In this study, we focused on the mechanism through which individual E. coli achieve high intracellular ATP concentrations. First, we measured the ATP retained by E. coli over time when cultured at low (0.1 mM) and control (22.2 mM) concentrations of glucose and obtained the chronological change in ATP concentrations. Then, by comparing these chronological change of ATP concentrations and analyzing whether stochastic state transitions, periodic oscillations, cellular age, and intercellular communication—which have been reported as molecular biological mechanisms for generating interindividual heterogeneity—are involved, we showed that the appearance of high ATP-holding individuals observed among E. coli can be explained only by intercellular transmission. By performing metabolomic analysis of post-culture medium, we revealed a significant increase in the ATP, especially at low glucose, and that the number of E. coli that retain significantly higher ATP can be controlled by adding large amounts of ATP to the medium, even in populations cultured under control glucose concentrations. These results reveal for the first time that ATP-mediated intercellular transmission enables some individuals in E. coli populations grown at low glucose to retain large amounts of ATP.

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An explainable deep learning-based algorithm with an attention mechanism for predicting the live birth potential of mouse embryos

Y Tokuoka, TG Yamada, D Mashiko, Z Ikeda, TJ Kobayashi, K Yamagata, ...

Artificial Intelligence in Medicine 134, 102432 (Artificial Intelligence in Medicine) 134 102432 2022.12

Joint Work, Accepted, ISSN 09333657

In assisted reproductive technology (ART), embryos produced by in vitro fertilization (IVF) are graded according to their live birth potential, and high-grade embryos are preferentially transplanted. However, rates of live birth following clinical ART remain low worldwide. Grading is based on the embryo shape at a limited number of stages and does not consider the shape of embryos and intracellular structures, e.g., nuclei, at various stages important for normal embryogenesis. Here, we developed a Normalized Multi-View Attention Network (NVAN) that directly predicts live birth potential from the nuclear structure in live-cell fluorescence images of mouse embryos from zygote to across a wide range of stages. The input is morphological features of cell nuclei, which were extracted as multivariate time-series data by using the segmentation algorithm for mouse embryos. The classification accuracy of our method (83.87%) greatly exceeded that of existing machine-learning methods and that of visual inspection by embryo culture specialists. Our method also has a new attention mechanism that allows us to determine which values of multivariate time-series data, used to describe nuclear morphology, were the basis for the prediction. By visualizing the features that contributed most to the prediction of live birth potential, we found that the size and shape of the nucleus at the morula stage and at the time of cell division were important for live birth prediction. We anticipate that our method will help ART and developmental engineering as a new basic technology for IVF embryo selection.

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High quality genome assembly of the anhydrobiotic midge provides insights on a single chromosome-based emergence of extreme desiccation tolerance

Y Yoshida, N Shaikhutdinov, O Kozlova, M Itoh, M Tagami, M Murata, ...

NAR Genomics and Bioinformatics 4 (2), lqac029 (NAR Genomics and Bioinformatics) 4 ( 2 ) lqac029 2022.06

Joint Work, Accepted

Non-biting midges (Chironomidae) are known to inhabit a wide range of environments, and certain species can tolerate extreme conditions, where the rest of insects cannot survive. In particular, the sleeping chironomid Polypedilum vanderplanki is known for the remarkable ability of its larvae to withstand almost complete desiccation by entering a state called anhydrobiosis. Chromosome numbers in chironomids are higher than in other dipterans and this extra genomic resource might facilitate rapid adaptation to novel environments. We used improved sequencing strategies to assemble a chromosome-level genome sequence for P. vanderplanki for deep comparative analysis of genomic location of genes associated with desiccation tolerance. Using whole genome-based cross-species and intra-species analysis, we provide evidence for the unique functional specialization of Chromosome 4 through extensive acquisition of novel genes. In contrast to other insect genomes, in the sleeping chironomid a uniquely high degree of subfunctionalization in paralogous anhydrobiosis genes occurs in this chromosome, as well as pseudogenization in a highly duplicated gene family. Our findings suggest that the Chromosome 4 in Polypedilum is a site of high genetic turnover, allowing it to act as a 'sandbox' for evolutionary experiments, thus facilitating the rapid adaptation of midges to harsh environments.

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Temperature elevation detection in migrating cells

T Nakamura, J Sakamoto, K Okabe, A Taniguchi, TG Yamada, S Nonaka, ...

Optics Continuum 1 (5), 1085-1097 (OSA Continuum) 1 ( 5 ) 1085 - 1097 2022.05

Joint Work, Accepted

Active and dynamic migration and deformation of cells are universal research targets in cell biology. The leader cells that develop at the wound edge are required to actively reorganize their structure for migration and deformation. Such active reorganization of cellular morphology possibly affects the temperature inside the cells via biochemical reactions. On the other hand, it is also possible that changes of intracellular temperature may first trigger and induce active migration and cellular deformation. Recent development of temperature sensors for cells enables the display of temperature difference between two adjacent cell populations such as the leader and follower cells around a wound. We used two different temperature measurement methods to check the temperature of leader and follower cells in a wound healing assay system and found that leader cells were 10° ∼ 101°C warmer than follower cells. We also confirmed that, when the cells were artificially warmed with an infrared laser, they started moving, and when the laser was stopped, the cells also stopped moving. These results suggest that the warmth of the leader cells is not simply a result of their active movement, but also can play the role of a trigger for cell migration and deformation. Our results shed light on the possibility that various observed cases of intracellular temperature increase may trigger associated biological phenomena.

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Analyzing the submodule structure in deep learning models to reduce the search space of Neural Architecture Search

TOMIYAMA Mamoru, HIKI Yusuke, SHIBUYA Yusuke, TOKUOKA Yuta, YAMADA Takahiro G., FUNAHASHI Akira

Proceedings of the Annual Conference of JSAI (The Japanese Society for Artificial Intelligence) JSAI2022 ( 0 ) 3Yin204 - 3Yin204 2022

Joint Work, Accepted

Neural Architecture Search (NAS) is a method to automatically design architectures of deep learning. In NAS, the optimal architecture is determined from search space, which is a set of architecture substructures. However, the search space of the existing NAS is limited due to the huge amount of computation, so there is a possibility of missing high-performance architectures. Therefore, we hypothesized architectures with task-specific substructures are high-performance, and proposed a method to identify task-specific substructures that contribute to design efficient search space in NAS. We developed a method based on Graph Convolutional Network outputs task specificity for each substructure. We confirmed the correlation between task specificity and task accuracy for each substructure, so our method can identify task-specific substructures that contribute to accuracy. Our method is expected to contribute to NAS development that determines high-performance architectures with reduced computational complexity.

Cas9-mediated genome editing reveals a significant contribution of calcium signaling pathways to anhydrobiosis in Pv11 cells

Yugo Miyata, Hiroto Fuse, Shoko Tokumoto, Yusuke Hiki, Ruslan Deviatiiarov, Yuki Yoshida, Takahiro G. Yamada, Richard Cornette, Oleg Gusev, Elena Shagimardanova, Akira Funahashi, Takahiro Kikawada

Scientific Reports (Springer Science and Business Media LLC) 11 ( 1 ) 19698 2021.12

Joint Work, Accepted, ISSN 2045-2322

<title>Abstract</title>Pv11 is an insect cell line established from the midge <italic>Polypedilum vanderplanki</italic>, whose larval form exhibits an extreme desiccation tolerance known as anhydrobiosis. Pv11 itself is also capable of anhydrobiosis, which is induced by trehalose treatment. Here we report the successful construction of a genome editing system for Pv11 cells and its application to the identification of signaling pathways involved in anhydrobiosis. Using the Cas9-mediated gene knock-in system, we established Pv11 cells that stably expressed GCaMP3 to monitor intracellular Ca2+ mobilization. Intriguingly, trehalose treatment evoked a transient increase in cytosolic Ca2+ concentration, and further experiments revealed that the calmodulin–calcineurin–NFAT pathway contributes to tolerance of trehalose treatment as well as desiccation tolerance, while the calmodulin–calmodulin kinase–CREB pathway conferred only desiccation tolerance on Pv11 cells. Thus, our results show a critical contribution of the trehalose-induced Ca2+ surge to anhydrobiosis and demonstrate temporally different roles for each signaling pathway.

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Sbmlwebapp: Web-based simulation, steady-state analysis, and parameter estimation of systems biology models

Yamada T.G., Ii K., König M., Feierabend M., Dräger A., Funahashi A.

Processes (Processes) 9 ( 10 ) 2021.10

Joint Work, Accepted

In systems biology, biological phenomena are often modeled by Ordinary Differential Equations (ODEs) and distributed in the de facto standard file format SBML. The primary analyses performed with such models are dynamic simulation, steady-state analysis, and parameter estimation. These methodologies are mathematically formalized, and libraries for such analyses have been published. Several tools exist to create, simulate, or visualize models encoded in SBML. However, setting up and establishing analysis environments is a crucial hurdle for non-modelers. Therefore, easy access to perform fundamental analyses of ODE models is a significant challenge. We developed SBMLWebApp, a web-based service to execute SBML-based simulation, steady-state analysis, and parameter estimation directly in the browser without the need for any setup or prior knowledge to address this issue. SBMLWebApp visualizes the result and numerical table of each analysis and provides a download of the results. SBMLWebApp allows users to select and analyze SBML models directly from the BioModels Database. Taken together, SBMLWebApp provides barrier-free access to an SBML analysis environment for simulation, steady-state analysis, and parameter estimation for SBML models. SBMLWebApp is implemented in Java™ based on an Apache Tomcat® web server using COPASI, the Systems Biology Simulation Core Library (SBSCL), and LibSBMLSim as simulation engines. SBMLWebApp is licensed under MIT with source code freely available. At the end of this article, the Data Availability Statement gives the internet links to the two websites to find the source code and run the program online.

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Genome-Wide Role of HSF1 in Transcriptional Regulation of Desiccation Tolerance in the Anhydrobiotic Cell Line, Pv11.

Shoko Tokumoto, Yugo Miyata, Ruslan Deviatiiarov, Takahiro G Yamada, Yusuke Hiki, Olga Kozlova, Yuki Yoshida, Richard Cornette, Akira Funahashi, Elena Shagimardanova, Oleg Gusev, Takahiro Kikawada

International journal of molecular sciences (International Journal of Molecular Sciences) 22 ( 11 ) 2021.06

Joint Work, Accepted, ISSN 16616596

The Pv11, an insect cell line established from the midge Polypedilum vanderplanki, is capable of extreme hypometabolic desiccation tolerance, so-called anhydrobiosis. We previously discovered that heat shock factor 1 (HSF1) contributes to the acquisition of desiccation tolerance by Pv11 cells, but the mechanistic details have yet to be elucidated. Here, by analyzing the gene expression profiles of newly established HSF1-knockout and -rescue cell lines, we show that HSF1 has a genome-wide effect on gene regulation in Pv11. The HSF1-knockout cells exhibit a reduced desiccation survival rate, but this is completely restored in HSF1-rescue cells. By comparing mRNA profiles of the two cell lines, we reveal that HSF1 induces anhydrobiosis-related genes, especially genes encoding late embryogenesis abundant proteins and thioredoxins, but represses a group of genes involved in basal cellular processes, thus promoting an extreme hypometabolism state in the cell. In addition, HSF1 binding motifs are enriched in the promoters of anhydrobiosis-related genes and we demonstrate binding of HSF1 to these promoters by ChIP-qPCR. Thus, HSF1 directly regulates the transcription of anhydrobiosis-related genes and consequently plays a pivotal role in the induction of anhydrobiotic ability in Pv11 cells.

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Electrical Field Chamber with Dinamically Adaptable Stimuli for Myocyte Orientation During Cultivation

SRM Ramirez, T Yamada, A Funahashi, H Onoe

2021 IEEE 34th International Conference on Micro Electro Mechanical Systems … (Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS)) 2021-January 498 - 501 2021.01

Joint Work, Accepted, ISSN 10846999

Tissue engineering is a promising technology for both its possible applications in the fields of regenerative medicine and medical research. One of its challenges is to create an environment which allows the cell cultures to develop correctly. This environment is far from static and normally is modified by the cells themselves. To this end, adaptable systems have to be developed to ensure a successful development of the in-vitro tissue. This research focuses on a system which is able to modify an external electrical stimulus on a culture chamber, during its cultivation. This system, through a variation of the stimulus direction, successfully improved the orientation of the developing myocytes.

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Control and measurement of nano/micro-space temperature that changes cellular behavior

T Nakamura, T Saito, R Tanimoto, T Yamada, A Funahashi, A Taniguchi, ...

JSAP-OSA Joint Symposia, 10p_N404_14 (Optics InfoBase Conference Papers) 2021

Joint Work, Accepted

COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms

M Ostaszewski, A Mazein, ME Gillespie, I Kuperstein, A Niarakis, ...

Scientific data 7 (1), 136 7 ( 1 ) 136 2020.05

Joint Work, Accepted, ISSN 2052-4463

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Neural differentiation dynamics controlled by multiple feedback loops in a comprehensive molecular interaction network

T Iwasaki, R Takiguchi, T Hiraiwa, TG Yamada, K Yamazaki, NF Hiroi, ...

Processes 8 (2), 166 (Processes) 8 ( 2 ) 2020.02

Research paper (scientific journal), Joint Work, Accepted

© 2020 by the authors. Mathematical model simulation is a useful method for understanding the complex behavior of a living system. The construction of mathematical models using comprehensive information is one of the techniques of model construction. Such a comprehensive knowledge-based network tends to become a large-scale network. As a result, the variation of analyses is limited to a particular kind of analysis because of the size and complexity of the model. To analyze a large-scale regulatory network of neural differentiation, we propose a contractive method that preserves the dynamic behavior of a large network. The method consists of the following two steps: comprehensive network building and network reduction. The reduction phase can extract network loop structures from a large-scale regulatory network, and the subnetworks were combined to preserve the dynamics of the original large-scale network. We confirmed that the extracted loop combination reproduced the known dynamics of HES1 and ASCL1 before and after differentiation, including oscillation and equilibrium of their concentrations. The model also reproduced the effects of the overexpression and knockdown of the Id2 gene. Our model suggests that the characteristic change in HES1 and ASCL1 expression in the large-scale regulatory network is controlled by a combination of four feedback loops, including a large loop, which has not been focused on. The model extracted by our method has the potential to reveal the critical mechanisms of neural differentiation. The method is applicable to other biological events.

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Direct cell counting using macro-scale smartphone images of cell aggregates

C Imashiro, Y Tokuoka, K Kikuhara, TG Yamada, K Takemura, ...

IEEE Access 8, 170033-170043 (Institute of Electrical and Electronics Engineers ({IEEE})) 8 170033 - 170043 2020

Joint Work, Accepted, ISSN 2169-3536

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Deep Learning for Non-Invasive Determination of the Differentiation Status of Human Neuronal Cells by Using Phase-Contrast Photomicrographs

M Ooka, Y Tokuoka, S Nishimoto, NF Hiroi, TG Yamada, A Funahashi

Applied Sciences 9 (24), 5503 (Applied Sciences (Switzerland)) 9 ( 24 ) 2019.12

Research paper (scientific journal), Joint Work, Accepted

© 2019 by the authors. Regenerative medicine using neural stem cells (NSCs), which self-renew and have pluripotency, has recently attracted a lot of interest. Much research has focused on the transplantation of differentiated NSCs to damaged tissues for the treatment of various neurodegenerative diseases and spinal cord injuries. However, current approaches for distinguishing differentiated from non-differentiated NSCs at the single-cell level have low reproducibility or are invasive to the cells. Here, we developed a fully automated, non-invasive convolutional neural network-based model to determine the differentiation status of human NSCs at the single-cell level from phase-contrast photomicrographs; after training, our model showed an accuracy of identification greater than 94%. To understand how our model distinguished between differentiated and non-differentiated NSCs, we evaluated the informative features it learned for the two cell types and found that it had learned several biologically relevant features related to NSC shape during differentiation. We also used our model to examine the differentiation of NSCs over time; the findings confirmed our model's ability to distinguish between non-differentiated and differentiated NSCs. Thus, our model was able to non-invasively and quantitatively identify differentiated NSCs with high accuracy and reproducibility, and, therefore, could be an ideal means of identifying differentiated NSCs in the clinic.

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Xitosbml: A modeling tool for creating spatial systems biology markup language models from microscopic images

K Ii, K Mashimo, M Ozeki, TG Yamada, N Hiroi, A Funahashi

Frontiers in genetics 10, 1027 (Frontiers in Genetics) 10 1027 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1664-8021

© Copyright © 2019 Ii, Mashimo, Ozeki, Yamada, Hiroi and Funahashi. XitoSBML is a software tool designed to create an SBML (Systems Biology Markup Language) Level 3 Version 1 document from microscopic cellular images. It is implemented as an ImageJ plug-in and is designed to create spatial models that reflect the three-dimensional cellular geometry. With XitoSBML, users can perform spatial model simulations based on realistic cellular geometry by using SBML-supported software tools, including simulators such as Virtual Cell and Spatial Simulator. XitoSBML is open-source and is available at https://github.com/spatialsimulator/XitoSBML/. XitoSBML is confirmed to run on most 32/64-bit operating systems: Windows, MacOS, and Linux.

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Activation of cell migration via morphological changes in focal adhesions depends on shear stress in MYCN-amplified neuroblastoma cells

Hiraiwa T., Yamada T., Miki N., Funahashi A., Hiroi N.

Journal of the Royal Society, Interface (Journal of the Royal Society, Interface) 16 ( 152 ) 20180934 2019.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 17425689

Neuroblastoma is the most common solid tumour of childhood, and it metastasizes to distant organs. However, the mechanism of metastasis, which generally depends on the cell motility of the neuroblastoma, remains unclear. In many solid tumours, it has been reported that shear stress promotes metastasis. Here, we investigated the relationship between shear stress and cell motility in the MYCN-amplified human neuroblastoma cell line IMR32, using a microfluidic device. We confirmed that most of the cells migrated downstream, and cell motility increased dramatically when the cells were exposed to a shear stress of 0.4 Pa, equivalent to that expected in vivo. We observed that the morphological features of focal adhesion were changed under a shear stress of 0.4 Pa. We also investigated the relationship between malignancy and the motility of IMR32 cells under shear stress. Decreasing the expression of MYCN in IMR32 cells via siRNA transfection inhibited cell motility by a shear stress of 0.4 Pa. These results suggest that MYCN-amplified neuroblastoma cells under high shear stress migrate to distant organs due to high cell motility, allowing cell migration to lymphatic vessels and venules.

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ネムリユスリカの培養細胞の乾燥耐性に迫る

Kikawada Takahiro

バイオサイエンスとインダストリー(B&I) ((一般財団法人)バイオインダストリー協会(JBA)) 77 ( 4 ) 310 - 311 2019

Joint Work

画像解析と深層学習を用いた診断の基礎

舟橋啓

病理と臨床 37 631 - 635 2019

Joint Work, Accepted

Quantitative analysis of sensitivity to a Wnt3a gradient in determination of the pole-to-pole axis of mitotic cells by using a microfluidic device

Hiraiwa T., Nakai Y., Yamada T., Tanimoto R., Kimura H., Matsumoto Y., Miki N., Hiroi N., Funahashi A.

FEBS Open Bio (FEBS Open Bio) 8 ( 12 ) 1920 - 1935 2018.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 22115463

© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. Proper determination of the cell division axis is essential during development. Wnt3a is a known regulator of the cell division axis; however, the sensitivity of cells to Wnt3a signalling and its role in determining the cell division axis have not been measured to date. To address this gap, we took advantage of the asymmetric distribution of outer dense fibre 2 (ODF2/cenexin) proteins on centrosomes in dividing cells. To precisely quantify the sensitivity of cells to Wnt3a signalling, we developed a microfluidic cell culture device, which can produce a quantitative gradient of signalling molecules. We confirmed that mitotic SH-SY5Y neuroblastoma cells could detect a 2.5 ~ 5 × 10−3 nm·μm−1 Wnt3a concentration gradient and demonstrated that this gradient is sufficient to affect the determination of the pole-to-pole axis of cell division during the later stages of mitosis.

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Transcriptome analysis of the anhydrobiotic cell line Pv11 infers the mechanism of desiccation tolerance and recovery

Yamada T., Suetsugu Y., Deviatiiarov R., Gusev O., Cornette R., Nesmelov A., Hiroi N., Kikawada T., Funahashi A.

Scientific Reports (Scientific Reports) 8 ( 1 ) 17941 2018.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2045-2322

© 2018, The Author(s). The larvae of the African midge, Polypedilum vanderplanki, can enter an ametabolic state called anhydrobiosis to overcome fatal desiccation stress. The Pv11 cell line, derived from P. vanderplanki embryo, shows desiccation tolerance when treated with trehalose before desiccation and resumes proliferation after rehydration. However, the molecular mechanisms of this desiccation tolerance remain unknown. Here, we performed high-throughput CAGE-seq of mRNA and a differentially expressed gene analysis in trehalose-treated, desiccated, and rehydrated Pv11 cells, followed by gene ontology analysis of the identified differentially expressed genes. We detected differentially expressed genes after trehalose treatment involved in various stress responses, detoxification of harmful chemicals, and regulation of oxidoreduction that were upregulated. In the desiccation phase, L-isoaspartyl methyltransferase and heat shock proteins were upregulated and ribosomal proteins were downregulated. Analysis of differentially expressed genes during rehydration supported the notion that homologous recombination, nucleotide excision repair, and non-homologous recombination were involv

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Convolutional neural network-based instance segmentation algorithm to acquire quantitative criteria of early mouse development

Y Tokuoka, TG Yamada, N Hiroi, TJ Kobayashi, K Yamagata, ...

BioRxiv, 324186 2018.06

Research paper (scientific journal), Joint Work, Accepted

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Quantitative analysis of sensitivity to a Wnt3a gradient in determination of the pole‐to‐pole axis of mitotic cells by using a microfluidic device

T Hiraiwa, Y Nakai, TG Yamada, R Tanimoto, H Kimura, Y Matsumoto, ...

FEBS open bio 8 (12), 1920-1935 2018

Research paper (scientific journal), Joint Work, Accepted

Requirement of spatiotemporal resolution for imaging intracellular temperature distribution

N Hiroi, R Tanimoto, K Ii, M Ozeki, K Mashimo, A Funahashi

Biomedical Imaging and Sensing Conference 10251, 102510Q 10251 2017.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 978-1-5106-1004-0

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Editorial: Quantitative Biology: Dynamics of Living Systems

Hiroi, Noriko, Draviam, Viji M., Funahashi, Akira

FRONTIERS IN PHYSIOLOGY 7 196 2016.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1664-042X

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Simulation technology and its application in Systems Biology.

FUNAHASHI Akira, HIROI Noriko

Folia pharmacologica Japonica (The Japanese Pharmacological Society) 147 ( 2 ) 101 - 106 2016.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 0015-5691

生命現象の理解には個別のコンポーネントについての理解に加え，それらの統合されたふるまいを知る必要がある．このような様々な分子のダイナミクスの背景にあるメカニズムを理解する上で強力なツールとなるのが数理モデルである．システムバイオロジーでは，数理モデルを用いて生命現象を司るメカニズムを理解する手法を頻用する．歴史的には解析的に解くことが可能なモデルが用いられたが，コンピュータの発達により，常微分方程式モデル，偏微分方程式モデル，確率モデル，これらのハイブリッドモデルなど多岐に渡る形式で記述されたモデルを数値計算によって解くようになった．こうした背景から，作成したモデルの正しい挙動を数値的に得るための，正確な数値計算技術が不可欠の要素となっている．本稿では，各モデル化手法の特徴を概説した後，システムバイオロジー研究において広く利用されている代表的なアプリケーション（シミュレータ）について，ソフトウェアの全体像から実装されているアルゴリズムまで，原典を挙げて解説する．数値計算手法の実装内容を正確に知ることは，ユーザにとってはモデルが備えるべき内容を理解し，結果を正しく解釈するために有用となる．また開発者にとっては，不必要な重複を避け，新しいブレークスルーを実現するための技術が何であるか，自らの創造性の発端を得るためにより重要な知識となるだろう．

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Reconstitution of Developmental Dynamics of Mammalian Embryogenesis from 3D Confocal Microscope Images

KOBAYASHI Tetsuya, OZEKI Mitsunori, YAMAGATA Kazuo, Funahashi Akira

IEICE technical report. (The Institute of Electronics, Information and Communication Engineers) 114 ( 482 ) 1 - 6 2015.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0913-5685

Reconstruction of developmental dynamics of mammalian preimplantation embryos from bioimaging data by using image analysis is now becoming an important challenge in the fields of basic science and assisted reproductive technology. In this work, we firstly review the recent progress on the image analysis techniques to reconstruct cell lineage from bioimaging data, and then introduce our recent result on the tracking of developmental dynamics of mammalian embryo by using integer programing.

A proteomic study of mitotic phase-specific interactors of EB1 reveals a role for SXIP-mediated protein interactions in anaphase onset

Tamura, Naoka, Simon, Judith E., Nayak, Arnab, Shenoy, Rajesh, Hiroi, Noriko, Boilot, Viviane, Funahashi, Akira, Draviam, Viji M.

BIOLOGY OPEN 4 ( 2 ) 155 - 169 2015.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 2046-6390

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Bioimage Analysis for Quantitative Biology and Its Application to Mammalian Embryogenesis

KOBAYASHI Tetsuya J., BASHAR Md. Khayrul, FUNAHASHI Akira, FUJIMORI Toshihiko, YAMAGATA Kazuo

Medical Imaging Technology (The Japanese Society of Medical Imaging Technology) 33 ( 3 ) 84 - 89 2015

Joint Work, Accepted, ISSN 0288450X

増大特集生命動態システム科学 Ⅰ.定量生物学 1.分子・細胞の計測 1)基本技術 (2)生命現象のシステムレベルでの理解に向けた基盤技術開発

舟橋啓

生体の科学 (株式会社医学書院) 65 ( 5 ) 388 - 389 2014.10

Joint Work, Accepted, ISSN 03709531

Fabrication method to a high resolution control in the space of cell culturing environment with microfluidic system

Takumi Hiraiwa, Tadamasa Kimura, Yuma Takenaka, Ryo Tanamoto, Hiroki Ota, Hiroshi Kimura, Yoshihiro Taguchi, Norihisa Miki, Yoshinori Matsumoto, Kotaro Oka, Akira Funahashi, Noriko Hiroi

IEEE 27th International Conference on Micro Electro Mechanical Systems (MEMS) 264 - 267 2014.01

Research paper (international conference proceedings), Joint Work, Accepted

Assessing uncertainty in model parameters based on sparse and noisy experimental data

Noriko Hiroi, Maciej Swat, Akira Funahashi

Frontiers in physiology (Frontiers Media SA) 5 128 2014

Research paper (scientific journal), Joint Work, Accepted, ISSN 1664-042X

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Modeling and simulation using CellDesigner

Matsuoka Yukiko, Funahashi Akira, Ghosh Samik, Kitano Hiroaki

Methods in molecular biology (Clifton, N.J.) 1164 121 - 145 2014

Research paper (scientific journal), Joint Work, Accepted, ISSN 1064-3745

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Automated tracking of mitotic spindle pole positions shows that LGN is required for spindle rotation but not orientation maintenance

Corrigan, Adam M., Shrestha, Roshan L., Zulkipli, Ihsan, Hiroi, Noriko, Liu, Yingjun, Tamura, Naoka, Yang, Bing, Patel, Jessica, Funahashi, Akira, Donald, Athene, Draviam, Viji M.

CELL CYCLE 12 ( 16 ) 2643 - 2655 2013.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1538-4101

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in vivo oriented modeling with consideration of intracellular crowding

N Hiroi, K Iba, A Tabira, T Okuhara, T Kubojima, T Hiraiwa, T J Kobayashi, K Oka, A Funahashi

35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) 2013 2716 - 2719 2013.07

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 1557-170X

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The systems biology simulation core algorithm

Keller, Roland, Doerr, Alexander, Tabira, Akito, Funahashi, Akira, Ziller, Michael J., Adams, Richard, Rodriguez, Nicolas, Le Novere, Nicolas, Hiroi, Noriko, Planatscher, Hannes, Zell, Andreas, Draeger, Andreas

BMC SYSTEMS BIOLOGY 7 2643 - 2655 2013.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1752-0509

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LibSBMLSim: a reference implementation of fully functional SBML simulator

TAKIZAWA Hiromu, NAKAMURA Kazushige, TABIRA Akito, CHIKAHARA Yoichi, MATSUI Tatsuhiro, HIROI Noriko, FUNAHASHI Akira

BIOINFORMATICS 29 ( 11 ) 1474 - 1476 2013.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1367-4803

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Meeting report of the International Workshop on Quantitative Biology 2012: mesoscopic and microscopic worlds meet

Viji M Draviam, Akira Funahashi, Noriko Hiroi, Akatsuki Kimura, Tetsuya J Kobayashi

Frontiers in physiology (Frontiers Media SA) 3 479 2013.01

Research paper (scientific journal), Joint Work, Accepted

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Mathematical Modeling of Sustainable Synaptogenesis by Repetitive Stimuli Suggests Signaling Mechanisms In Vivo

TAKIZAWA Hiromu, HIROI Noriko, FUNAHASHI Akira

PLOS ONE 7 ( 12 ) e51000 2012.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1932-6203

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Software support for SBGN maps: SBGN-ML and LibSBGN

van Iersel, Martijn P., Villeger, Alice C., Czauderna, Tobias, Boyd, Sarah E., Bergmann, Frank T., Luna, Augustin, Demir, Emek, Sorokin, Anatoly, Dogrusoz, Ugur, Matsuoka, Yukiko, Funahashi, Akira, Aladjem, Mirit I., Mi, Huaiyu, Moodie, Stuart L., Kitano, Hiroaki, Le Novere, Nicolas, Schreiber, Falk

BIOINFORMATICS 28 ( 15 ) 2016 - 2021 2012.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1367-4803

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Physiological intracellular crowdedness is defined by the perimeter-to-area ratio of sub-cellular compartments

Noriko Hiroi, Takahiro Okuhara, Takeshi Kubojima, Keisuke Iba, Akito Tabira, Shuji Yamashita, Yasunori Okada, Tetsuya J Kobayashi, Akira Funahashi

Frontiers in physiology (Frontiers Media SA) 3 293 2012.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1664-042X

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From microscopy data to in silico environments for in vivo-oriented simulations

Noriko Hiroi, Michael Klann, Keisuke Iba, Pablo de Heras Ciechomski, Shuji Yamashita, Akito Tabira, Takahiro Okuhara, Takeshi Kubojima, Yasunori Okada, Kotaro Oka, Robin Mange, Michael Unger, Akira Funahashi, Heinz Koeppl

EURASIP Journal on Bioinformatics and Systems Biology (Springer International Publishing AG) 2012 ( 1 ) 7 2012

Research paper (scientific journal), Joint Work, Accepted, ISSN 1687-4145

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BioPAX support in CellDesigner

Mi, Huaiyu, Muruganujan, Anushya, Demir, Emek, Matsuoka, Yukiko, Funahashi, Akira, Kitano, Hiroaki, Thomas, Paul D.

BIOINFORMATICS 27 ( 24 ) 3437 - 3438 2011.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1367-4803

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Physiological environment induces quick response–slow exhaustion reactions

Noriko Hiroi, James Lu, Keisuke Iba, Akito Tabira, Shuji Yamashita, Yasunori Okada, Christoph Flamm, Kotaro Oka, Gottfried Köhler, Akira Funahashi

Frontiers in physiology (Frontiers Media SA) 2 50 2011.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1664-042X

In vivo environments are highly crowded and inhomogeneous, which may affect reaction processes in cells. In this study we examined the effects of intracellular crowding and an inhomogeneity on the behavior of in vivo reactions by calculating the spectral dimension (d(s)), which can be translated into the reaction rate function. We compared estimates of anomaly parameters obtained from fluorescence correlation spectroscopy (FCS) data with fractal dimensions derived from transmission electron microscopy (TEM) image analysis. FCS analysis indicated that the anomalous property was linked to physiological structure. Subsequent TEM analysis provided an in vivo illustration; soluble molecules likely percolate between intracellular clusters, which are constructed in a self-organizing manner. We estimated a cytoplasmic spectral dimension d(s) to be 1.39 +/- 0.084. This result suggests that in vivo reactions initially run faster than the same reactions in a homogeneous space; this conclusion is consistent with the anomalous character indicated by FCS analysis. We further showed that these results were compatible with our Monte-Carlo simulation in which the anomalous behavior of mobile molecules correlates with the intracellular environment, leading to description as a percolation cluster, as demonstrated using TEM analysis. We confirmed by the simulation that the above-mentioned in vivo like properties are different from those of homogeneously concentrated environments. Additionally, simulation results indicated that crowding level of an environment might affect diffusion rate of reactant. Such knowledge of the spatial information enables us to construct realistic models for in vivo diffusion and reaction systems.

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The DBCLS BioHackathon: standardization and interoperability for bioinformatics web services and workflows.

Toshiaki Katayama, Kazuharu Arakawa, Mitsuteru Nakao, Keiichiro Ono, Kiyoko F Aoki-Kinoshita, Yasunori Yamamoto, Atsuko Yamaguchi, Shuichi Kawashima, Hong-Woo Chun, Jan Aerts, Bruno Aranda, Lord Hendrix Barboza, Raoul JP Bonnal, Richard Bruskiewich, Jan C Bryne, José M Fernández, Akira Funahashi, Paul MK Gordon, Naohisa Goto, Andreas Groscurth, Alex Gutteridge, Richard Holland, Yoshinobu Kano, Edward A Kawas, Arnaud Kerhornou, Eri Kibukawa, Akira R Kinjo, Michael Kuhn, Hilmar Lapp, Heikki Lehvaslaiho, Hiroyuki Nakamura, Yasukazu Nakamura, Tatsuya Nishizawa, Chikashi Nobata, Tamotsu Noguchi, Thomas M Oinn, Shinobu Okamoto, Stuart Owen, Evangelos Pafilis, Matthew Pocock, Pjotr Prins, René Ranzinger, Florian Reisinger, Lukasz Salwinski, Mark Schreiber, Martin Senger, Yasumasa Shigemoto, Daron M Standley, Hideaki Sugawara, Toshiyuki Tashiro, Oswaldo Trelles, Rutger A Vos, Mark D Wilkinson, William York, Christian M Zmasek, Kiyoshi Asai, Toshihisa Takagi

Journal of biomedical semantics (BioMed Central) 1 ( 1 ) 1 - 19 2010.12

Research paper (scientific journal), Joint Work, Accepted

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A datapath classification method for FPGA-based scientific application accelerator systems

Yui Ogawa, Tomonori Ooya, Yasunori Osana, Masato Yoshimi, Yuri Nishikawa, Akira Funahashi, Noriko Hiroi, Hideharu Amano, Yuichiro Shibata, Kiyoshi Oguri

International Conference on Field-Programmable Technology (FPT) (IEEE) 441 - 444 2010.12

Research paper (international conference proceedings), Joint Work, Accepted

Resource reduction design techniques play an important role to implement large-scale FPGA-based accelerator systems in floating point applications since available resources on FPGAs are limited. This paper proposes a dataflow graph classification method which makes groups of graphs based on their similarity in order to bring out efficient graph combining. Aiming at finding effective parameters for the k-means algorithm, various parameter combinations are evaluated and compared in terms of resource reduction effects and performance. The experimental results using an FPGA-based biochemical simulator reveal that the graph clustering that uses information on the maximum common subgraphs achieve 73.3% of resource reduction rate while alleviating the performance degradation. © 2010 IEEE.

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Design and Implementation of CellDesigner

FUNAHASHI Akira, MATSUOKA Yukiko, JOURAKU Akiya, TAKIZAWA Hiromu, HIROI Noriko, GHOSH Samik, KIKUCHI Norihiro, KITANO Hiroaki

Journal of The Society of Instrument and Control Engineers (The Society of Instrument and Control Engineers) 49 ( 8 ) 531 - 536 2010.08

Joint Work, Accepted, ISSN 04534662

Automatic Pipeline Construction Focused on Similarity of Rate Law Functions for an FPGA-based Biochemical Simulator

Hideki Yamada, Yui Ogawa, Tomonori Ooya, Tomoya Ishimori, Yasunori Osana, Masato Yoshimi, Yuri Nishikawa,Akira Funahashi, Noriko Hiroi, Hideharu Amano, Yuichiro Shibata, Kiyoshi Oguri

IPSJ Transactions on System LSI Design Methodology (一般社団法人情報処理学会) 3 ( 3 ) 244 - 256 2010.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1882-6687

For FPGA-based scientific simulation systems, hardware design technique that can reduce required amount of hardware resources is a key issue, since the size of simulation target is often limited by the size of the FPGA. Focusing on FPGA-based biochemical simulation, this paper proposes hardware design methodology which finds and combines common datapath for similar rate law functions appeared in simulation target models, so as to generate area-effective pipelined hardware modules. In addition, similarity-based clustering techniques of rate law functions are also presented in order to alleviate negative effects on performance for combined pipelines. Empirical evaluation with a practical biochemical model reveals that our method enables the simulation with 66% of the original hardware resources at a reasonable cost of 20% performance overhead.

A Modular Approach to Heterogeneous Biochemical Model Simulation on an FPGA

Hideki Yamada, Yasunori Osana, Tomoya Ishimori, Tomonori Ooya, Masato Yoshimi, Yuri Nishikawa, Akira Funahashi, Noriko Hiroi, Hideharu Amano, Yuichiro Shibata, Kiyoshi Oguri

International Conference on Reconfigurable Computing and FPGAs, 2009. ReConFig'09. (IEEE) 125 - 130 2009.12

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-1-4244-5293-4

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Configuring area and performance: Empirical evaluation on an FPGA-based biochemical simulator

Tomonori Ooya, Hideki Yamada, Tomoya Ishimori, Yuichiro Shibata, Yasunori Osana, Kiyoshi Oguri, Masato Yoshimi, Yuri Nishikawa, Akira Funahashi, Noriko Hiroi, Hideharu Amano

International Conference on Field Programmable Logic and Applications, 2009. FPL 2009 (IEEE) 679 - 682 2009.08

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 1946-1488

One of the obvious advantages of FPGA-based reconfigurable computing is customizability of a tradeoff point between performance and hardware costs. However, this tradeoff has rarely been discussed in a whole application level, which is the most important view for application users. This paper presents empirical evaluation of a hardware module sharing technique which can shift a tradeoff point of area and performance on an FPGA-based biochemical simulator. The biochemical simulation results are discussed in terms of hardware costs, simulation throughput, parallelism extracted in simulation hardware, and data transfer overheads.

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Pipeline Scheduling with Input Port Constraints for an FPGA-Based Biochemical Simulator

Tomoya Ishimori, Hideki Yamada, Yuichiro Shibata, Yasunori Osana, Masato Yoshimi, Yuri Nishikawa, Hideharu Amano, Akira Funahashi, Noriko Hiroi, Kiyoshi Oguri

5th International Workshop, ARC 2009, Proceedings (Springer) 5453 ( 2009 ) 368 - 373 2009.03

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-3-642-00640-1

High-throughput circuit design under device resource constraints is important for FPGA-based biochemical simulators. In this papers, we propose novel arithmetic pipeline scheduling techniques which effectively reduce hardware costs under given input bandwidth constraints. By assigning data-input timing based on an appropriate priority, arithmetic scheduling process is hardly affected by input bandwidth constraints. Evaluation results revealed that our method reduces hardware costs by 7.6% on average compared to the conventional ALAP scheduling.

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3P-239 Effect of molecular crowding on in vivo macromolecular reactions(Mathematical biology,The 47th Annual Meeting of the Biophysical Society of Japan)

Yashima Kenta, Hiroi Noriko, Funahashi Akira, Oka Kotaro

Seibutsu Butsuri (The Biophysical Society of Japan General Incorporated Association) 49 ( supplement ) S191 2009

Joint Work, Accepted, ISSN 05824052

Design and Evaluation of an FPGA-based Stochastic Biochemical Simulator for High-throughput Execution

YOSHIMI Masato, NISHIKAWA Yuri, OSANA Yasunori, FUNAHASHI Akira, HIROI Noriko, SHIBATA Yuuichirou, YAMADA Hideki, KITANO Hiroaki, AMANO Hideharu

IPSJ Transactions on Advanced Computing System (情報処理学会) 1 ( 3 ) 120-135 - 135 2008.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1882-7829

Stochastic biochemical simulation algorithms (SSAs) are generally known as exact methods to trace stochastic behaviors of target biochemical models. Due to vast amount of computation attributed to the nature of Monte Carlo Method, which SSAs are originated from, there is a strong urge for high-throughput execution environment. This paper proposes an FPGA implementation of a stochastic simulation system based on a computationally-efficient SSA called the Next Reaction Method, and studies the evaluation results of area and throughput in detail. The system conducts high-throughput multi-thread execution, using multiple thread modules accessing shared arithmetic and data modules. The network between modules are configurable, and supports flexible network structure according to target FPGAs. In order to evaluate the proposed design, the stochastic simulation system, which is capable of running 16 threads in parallel, was implemented on a middle-range FPGA. As the result of comparing the throughput in RTL simulation with software simulation run on Core 2 Quad Q6600, the system marked 4.2 times higher throughput using a real biochemical model called HSR. When several versions of virtually largescale models were tested on the same simulation environment, maximum of 5.4 times higher throughput was confirmed.

Practical implementation of a network-based stochastic biochemical simulation system on an FPGA

Masato Yoshimi, Yuri Nishikawa, Yasunori Osana, Akira Funahashi, Yuichiro Shibata, Hideki Yamada, Noriko Hiroi, Hiroaki Kitano, Hideharu Amano

International Conference on Field Programmable Logic and Applications, 2008. FPL 2008 (IEEE) 663 - 666 2008.09

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-1-4244-1960-9

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FPGA上でのシミュレーションに向けた生化学コンパイラの実装

IWAOKA Yo, OSANA Yasunori, YOSHIMI Masato, NISHIKAWA Yuri, KOJIMA Toshinori, FUNAHASHI Akira, HIROI Noriko, SHIBATA Yuuichirou, IWANAGA Naoki, KITANO Hiroaki, AMANO Hideharu

電子情報通信学会論文誌 D J91-D ( 9 ) 2205-2216 2008.09

Research paper (scientific journal), Single Work, Accepted

CellDesigner 3.5: A Versatile Modeling Tool for Biochemical Networks

FUNAHASHI Akira, MATSUOKA Yukiko, JOURAKU Akiya, MOROHASHI Mineo, KIKUCHI Norihiro, KITANO Hiroaki

IEEE Special Issue: Computational Systems Biology 96 ( 8 ) 1254-1265 - 1265 2008.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0018-9219

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A framework for implementing a network-based stochastic biochemical simulator on an fpga

Masato Yoshimi, Yuri Nishikawa, Toshinori Kojima, Yasunori Osana, Akira Funahashi, Noriko Hiroi, Yuichiro Shibata, Hideki Yamada, Hiroaki Kitano, Hideharu Amano

International Conference on Field-Programmable Technology, 2007. ICFPT 2007. (IEEE) 193 - 200 2007.12

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-1-4244-1471-0

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Deduction of intracellular sub-systems from a topological description of the network.

NORDLING Torbjorn, HIROI, Noriko, FUNAHASHI Akira and KITANO Hiroaki

Molecular Biosystems 3 ( 8 ) 523-529 2007.08

Research paper (scientific journal), Joint Work, Accepted

A Combining Technique of Rate Law Functions for a Cost-Effective Reconfigurable Biological Simulator

Hideki Yamada, Naoki Iwanaga, Yuichiro Shibata, Yasunori Osana, Masato Yoshimi, Yow Iwaoka, Yuri Nishikawa, Toshinori Kojima, Hideharu Amano, Akira Funahashi, Noriko Hiroi, Hiroaki Kitano, Kiyoshi Oguri

International Conference on Field Programmable Logic and Applications, 2007. FPL 2007 (IEEE) 808 - 811 2007.08

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 1946-1488

In order to simulate large scale biological models with a reconfigurable FPGA-based biochemical simulator system, reduction of required resources are essential. This paper proposes a method which combines common terms in rate law functions appeared in biochemical models and generates a shared hardware module used for numerical integration. In this approach, two functions are combined in a tree structure level, followed by pipeline scheduling and arithmetic module binding. The evaluation result reveals that this approach reduces hardware resources by 31.4 % on average at the cost of 14.4 % throughput degradation.

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FPGA implementation of a data-driven stochastic biochemical simulator with the next reaction method

Masato Yoshimi, Yow Iwaoka, Yuri Nishikawa, Toshinori Kojima, Yasunori Osana, Akira Funahashi, Noriko Hiroi, Yuichiro Shibata, Naoki Iwanaga, Hideki Yamada, Hiroaki Kitano, Hideharu Amano

International Conference on Field Programmable Logic and Applications, 2007. FPL 2007 (IEEE) 254 - 259 2007.08

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-1-4244-1059-0

ReCSiP: An FPGA-Based Biochemical Simulator

Osana, Y., Yoshimi, M., Iwaoka, Y., Kojima, T., Nishikawa, Y., Funahashi, A., Hiroi, N., Shibata, Y., Iwanaga, N., Kitano, H., and Amano, H

Electronics and Communications in Japan (Part II: Electronics) 90 ( 7 ) 1-10 2007.07

Research paper (scientific journal), Joint Work, Accepted

An integration of CellDesigner and SABIO-RK

FUNAHASHI Akira, JOURAKU Akiya, MATSUOKA Yukiko, KITANO Hiroaki

In Silico Biology 7 ( 2 ) S81-S90. 2007.03

Research paper (scientific journal), Joint Work, Accepted

FPGA-Based Stochastic Biochemical Simulator

Yoshimi, M., Osana, Y., Iwaoka, Y., Nishikawa, Y., Kojima, T., Shibata, Y., Iwanaga, N., Funahashi, A., Hiroi, N., Kitano, H., and Amano, H.

IPSJ Transactions on Advanced Computing System (Information Processing Society of Japan (IPSJ)) 48 ( SIG 3 (ACS 17) ) 45-58 - 58 2007.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1882-7829

This paper discusses an FPGA implementation and evaluation of a Stochastic Simulation Algorithm (SSA) called the First Reaction Method. SSAs are widely known as rigorous methods for simulating the stochastic behaviors of various biochemical systems, but also as CPU-hogging applications due to vast repetition of the algorithm. This work accelerates the execution by achieving high throughput with concurrent simulations of highly utilized pipelined arithmetic units. For upgrading practical utility, the design stores intermediate data in a BlockRAM so that reconfiguration is unnecessary for different target biochemical systems. Benchmark results on an FPGA (Xilinx XC2VP70-5) have shown that the circuit provides throughput of approximately 83 times and 95 times compared to software execution on Xeon 2.80GHz when it was evaluated with biochemical models called TIS and D4S, respectively.

Integration of cell designer and SABIO-RK

Funahashi Akira, Jouraku Akiya, Matsuoka Yukiko, Kitano Hiroaki

In Silico Biology 7 ( SUPPL. 2 ) 81 - 90 2007

Research paper (scientific journal), Joint Work, Accepted, ISSN 1386-6338

Understanding the logic and dynamics of gene-regulatory and biochemical networks is a major challenge for systems biology. To facilitate this research topic, we have developed CellDesigner to visualize, model and simulate biochemical networks. CellDesigner allows the users to easily create networks using solidly defined and comprehensive graphical notation. CellDesigner utilizes SBML to described models and can simulate models using an integrated SBML ODE Solver or third party simulation engine; thus enabling users to simulate through a sophisticated graphical user interface. Although CellDesigner can integrate with existing databases (KEGG, PubMed, BioModels, etc.), by calling a web browser, or connecting to its web page through HTTP, integration with SABIO-RK has the potential to expand connectivity and semi-automate visualization and model building. SABIO-RK contains information about biochemical reactions, related kinetic equations and parameters. Also information about the experimental conditions under which these parameters were measured is stored. By using the Web service API provided by the SABIO-RK team, we have succeeded to directly connect to the database, send search queries by ID or name of its component, and then import the query results into CellDesigner. © 2007 IOS Press. All rights reserved.

SBML models and MathSBML

Shapiro Bruce E., Finney Andrew, Hucka Michael, Bornstein Benjamin, Funahashi Akira, Jouraku Akiya, Keating Sarah M., Le Novère Nicolas, Matthews Joanne, Schilstra Maria J.

395 - 421 2007

MathSBML is an open-source, freely downloadable Mathematica package that facilitates working with Systems Biology Markup Language (SBML) models. SBML is a tool-neutral, computer-readable format for representing models of biochemical reaction networks, and it is applicable to metabolic networks, cell signaling pathways, genomic regulatory networks, and other modeling problems in systems biology that is widely supported by the systems biology community. SBML is based on XML, which is a standard medium for representing and transporting data that is widely supported on the Internet, as well as in computational biology and bioinformatics. Because SBML is tool-independent, it enables model transportability, reuse, publication, and survival. In addition to Math- SBML, a number of other tools that support SBML model examination and manipulation are provided on the http://sbml.org Web site, including libSBML, which is a C/C++ library for reading SBML models; an SBML Toolbox for MATLAB; file conversion programs; an SBML model validator and visualizer; and SBML specifications and schemas. MathSBML enables SBML file import to and export from Mathematica, as well as providing an API for model manipulation and simulation. © 2007 Humana Press Inc.

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Kinetics of dimension-restricted conditions

Hiroi Noriko, Funahashi Akira

Introduction to Systems Biology, 261-281 261 - 281 2007

Research paper (scientific journal), Joint Work, Accepted

The intracellular environment is crowded with skeletal proteins, organelle membranes, ribosomes, and so on. When molecular movement is restricted by such environments, some biochemical reaction processes cannot be represented by classical models, which assume that reactions occur in simple Newtonian fluids. Dimension-restricted reaction kinetics (DRRK) modeling is a method that can represent dimension-restricted reactions. We introduce the methods of DRRK in each case of reaction type. DRRK has another advantage in that it can be quantitatively evaluated by biochemical experiments. We also introduce the procedure of applying it for experimental results. This modeling method may provide the basis for in vivo-oriented modeling. © 2007 Humana Press Inc.

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Deduction of intracellular sub-systems from a topological description of the network

Nordling Torbjörn E M, Hiroi Noriko, Funahashi Akira, Kitano Hiroaki

Molecular BioSystems 3 ( 8 ) 523 - 529 2007

ISSN 1742-206X

Non-linear behaviour of biochemical networks, such as intracellular gene, protein or metabolic networks, is commonly represented using graphs of the underlying topology. Nodes represent abundance of molecules and edges interactions between pairs of molecules. These graphs are linear and thus based on an implicit linearization of the kinetic reactions in one or several dynamic modes of the total system. It is common to use data from different sources - experiments conducted under different conditions or even on different species - meaning that the graph will be a superposition of linearizations made in many different modes. The mixing of different modes makes it hard to identify functional modules, that is sub-systems that carry out a specific biological function, since the graph will contain many interactions that do not naturally occur at the same time. The ability to establish a boundary between the sub-system and its environment is critical in the definition of a module, contrary to a motif in which only internal interactions count. Identification of functional modules should therefore be done on graphs depicting the mode in which their function is carried out, i.e. graphs that only contain edges representing interactions active in the specific mode. In general, when an interaction between two molecules is established, one should always state the mode of the system in which it is active. This journal is © The Royal Society of Chemistry.

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CellDesigner

Funahashi Akira, Morohashi Mineo, Matsuoka Yukiko, Jouraku Akiya, Kitano Hiroaki

422 - 434 2007

Understanding the logic and dynamics of gene-regulatory and biochemical networks is a major challenge of systems biology. To facilitate this research topic, we have developed CellDesigner, a modeling tool of gene-regulatory and biochemical networks. CellDesigner supports users to easily create such networks, using solidly defined and comprehensive graphical representation (SBGN, systems biology graphical notation). CellDesigner is systems biology markup language (SBML) compliant, and has Systems Biology Workbench(SBW)-enabled software so that it can import/export SBML-described documents and integrate with other SBW-enabled simulation/analysis software packages. CellDesigner also supports simulation and parameter search, which is supported by integration with SBML ordinary differential equation (ODE) Solver, enabling us to simulate through our sophisticated graphical user interface. We can also browse and modify existing SBML models with references to existing databases. CellDesigner is implemented in Java; thus, it runs on various platforms such as Windows, Linux, and MacOS X. CellDesigner is freely available from our Web site at http://celldesigner.org/. © 2007 Humana Press Inc.

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Introduction to systems biology

S Choi

Humana press 2007

Research paper (scientific journal), Joint Work, Accepted

CellDesigner: a modeling tool for biochemical networks

Akira Funahashi, Yukiko Matsuoka, Akiya Jouraku, Hiroaki Kitano, Norihiro Kikuchi

Proceedings of the 38th conference on Winter simulation conference (WSC'06) (Winter Simulation Conference) 1707 - 1712 2006.12

Research paper (international conference proceedings), Joint Work, Accepted

Performance Evaluation of an Fpga-Based Biochemical Simulator ReCSip

Yasunori Osana, Masato Yoshimi, Yow Iwaoka, Toshinori Kojima, Yuri Nishikawa, Akira Funahashi, Noriko Hiroi, Yuichiro Shibata, Naoki Iwanaga, N Kitano, Hideharu Amano

International Conference on Field Programmable Logic and Applications, 2006. FPL'06. (IEEE) 1 - 6 2006.08

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-1-4244-0312-7

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An FPGA implementation of high throughput stochastic simulator for large-scale biochemical systems

Masato Yoshimi, Yasunori Osana, Yow Iwaoka, Yuri Nishikawa, Toshinori Kojima, Akira Funahashi, Noriko Hiroi, Yuichiro Shibata, Naoki Iwanaga, Hiroaki Kitano, Hideharu Amano

International Conference on Field Programmable Logic and Applications, 2006. FPL'06. (IEEE) 1 - 6 2006.08

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 978-1-4244-0312-7

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ReCSiP : An FPGA-Based General Purpose Biochemical Simulator

OSANA Yasunori, YOSHIMI Masato, IWAOKA Yow, KOJIMA Toshinori, NISHIKAWA Yuri, FUNAHASHI Akira, HIROI Noriko, SHIBATA Yuichiro, IWANAGA Naoki, KITANO Hiroaki, AMANO Hideharu

The IEICE transactions on information and systems (The Institute of Electronics, Information and Communication Engineers) 89 ( 6 ) 1163 - 1172 2006.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 18804535

細胞内部の生化学反応を数理モデルとして記述し,シミュレーションを行うことで生命現象をシステムとして理解しようとする試みが盛んになっている.しかしながら,汎用のマイクロプロセッサで得られる処理能力は決して十分とはいえず,シミュレーションを高速に実行できる計算基盤が求められている.本論文では,FPGAを用いて常微分方程式を用いた生化学モデルのシミュレーションを高速に実行するシステムであるReCSiPの構成とハードウェアの実装について述べる.評価の結果,最大スループットはXilinx社のFPGAであるXC2VP70-5を用いて,Intel Pentium4 3.2GHzの50〜80倍のスループットを達成することができた.

ReCSiP: an FPGA-Based General Purpose Biochemical Simulator

Osana, Y., Yoshimi, M., Iwaoka, Y., Kojima, T., Nishikawa, Y., Funahashi, A., Hiroi, N., Shibata, Y., Iwanaga, N., Kitano, H., and Amano, H.

IEICE Transactions on Information and Systems J89-D ( 6 ) 1163-1172 - 10 2006.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 8756-663X

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Comparative studies of suppression of malignant cancer cell phenotype by antisense oligo DNA and small interfering RNA.

Hiroi, N., Funahashi, A., and Kitano, H.

Cancer Gene Therapy (Nature Publishing Group) 13 ( 1 ) 7-12 - 12 2006.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0929-1903

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Analysis for Dimension-Restricted Kinetics with Bacterial Endonuclease Movement.

Hiroi, N., Funahashi, A., and Kitano, H.

WSEAS Transactions on Biology and Biomedicine 3 ( 1 ) 1-6 2006.01

Research paper (scientific journal), Joint Work, Accepted

The design of scalable stochastic biochemical simulator on FPGA

Masato Yoshimi, Yasunori Osana, Yow Iwaoka, Akira Funahashi, Noriko Hiroi, Yuichiro Shibata, Naoki Iwanaga, Hiroaki Kitano, Hideharu Amano

IEEE International Conference on Field-Programmable Technology, 2005. (IEEE) 339 - 340 2005.12

Research paper (international conference proceedings), Joint Work, Accepted, ISSN 0-7803-9407-0

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Efficient scheduling of rate law functions for ODE-based multimodel biochemical simulation on an FPGA

Naoki Iwanaga, Yuichiro Shibata, Masato Yoshimi, Yasunori Osana, Yow Iwaoka, Tomonori Fukushima, Hideharu Amano, Akira Funahashi, Noriko Hiroi, Hiroaki Kitano, Kiyoshi Oguri

International Conference on Field Programmable Logic and Applications, 2005. (IEEE) 2005 666 - 669 2005.08

Research paper (international conference proceedings), Joint Work, Accepted

A reconfigurable biochemical simulator by solving ordinary differential equations has received attention as a personal high speed environment for biochemical researchers. For efficient use of the reconfigurable hardware, static scheduling of high-throughput arithmetic pipeline structures is essential. This paper shows and compares some scheduling alternatives, and analyzes the tradeoffs between performance and hardware amount. Through the evaluation, it is shown that the sharing first scheduling reduces the hardware cost by 33.8% in average, with the up to 11.5% throughput degradation. Effects of sharing of rate law functions are also analyzed. © 2005 IEEE.

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A framework for ODE-based multimodel biochemical simulations on an FPGAs

Yasunori Osana, T Fukushima, M Yoshimi, Y Iwaoka, H Amano, A Funahashi, N Hiroi, H Kitano, Y Shibata, N Iwanaga

International Conference on Field Programmable Logic and Applications, 2005 (IEEE) 2005 574 - 577 2005.08

Research paper (international conference proceedings), Joint Work, Accepted

Today, mathematical modeling and simulation of biochemical pathways take a major role in biological researches. However, modern microprocessors cannot provide enough throughput to explore the large parameter space of target pathways. To address this problem, ReCSiP (a ReConfigurable Cell Simulation Platform), an FPGA-based biochemical simulator is proposed. It's an ODE-based simulator, which solves the rate-law functions. The framework proposed in this paper, enables to simulate pathways consisting many different types of chemical reactions by connecting the rate-law modules (solvers) on an FPGA. It provides the solver-to-solver communication mechanism on an FPGA and automatic configuration software to generate the circuit. © 2005 IEEE.

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An FPGA-based, multi-model simulation method for biochemical systems

Yasunori Osana, Tomonori Fukushima, Masato Yoshimi, Yow Iwaoka, A Funahashi, N Hiroi, Y Shibata, H Kitano, Hideharu Amano

Proceedings. 19th IEEE International Parallel and Distributed Processing Symposium, 2005. (IEEE) 2005 4 2005.04

Research paper (international conference proceedings), Joint Work, Accepted

Modeling and simulation of a cellular system on computers are now becoming an essential process in biological researches. However, modern PCs can't provide enough performance to simulate large-scale biochemical networks. ReCSiP is the alternative FPGA-based solution for biochemical simulations. In this paper, the novel method of biochemical simulation with multiple reaction models on an FPGA is proposed. The method generates optimal circuit and its optimal schedule for each simulation models written in SBML, the standard markup language in systems biology. ReCSiP has a Xilinx's XC2VP70 and achieved over 20-fold speedup compared to Intel's PentiumIII 1.13GHz.

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An I/O mechanism on a dynamically reconfigurable processor-which should be moved: data or configuration?

H Amano, S Abe, K Deguchi, Y Hasegawa

International Conference on Field Programmable Logic and Applications, 2005 … 2005 347 - 352 2005

Research paper (scientific journal), Joint Work, Accepted

In some applications on Dynamically Reconfigurable Processor (DRP), the input/output of data stream occupies about 20% of total execution time. In order to hide the overhead of input/output, the separation of the I/O context and double-buffering mechanism are proposed. Using the mechanism, I/O overhead of six streaming processing programs can be completely hidden. Based on the analysis of I/O performance, two alternatives for executing parallel processing with multiple DRP Cores are compared and discussed. © 2005 IEEE.

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Evolving a lingua franca and associated software infrastructure for computational systems biology: the Systems Biology Markup Language (SBML) project.

Hucka, M., Finney, A., Bornstein, B. J., Keating, S. M., Shapiro, B. E., Matthews, J., Kovitz, B. L., Schilstra, M. J., Funahashi, A., Doyle J. C., and Kitano, H.

IEE Systems Biology 1 ( 1 ) 41-53 - 53 2004.09

Research paper (scientific journal), Joint Work, Accepted

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Molecular Interaction Map of Macrophage.

Oda, K., Kimura, T, Matsuoka, Y., Funahashi, A., Muramatsu, M., and Kitano, H.

AfCS Report 2 ( 14 ) 1-12 2004.08

Research paper (scientific journal), Joint Work

Molecular interaction map of a macrophage

K Oda, T Kimura, Y Matsuoka, A Funahashi, M Muramatsu, H Kitano

AfCS Research Reports 2 (14), 1-12 2004

Research paper (scientific journal), Joint Work, Accepted

CellDesigner: a process diagram editor for gene-regulatory and biochemical networks.

Funahashi, A., Tanimura, N., Morohashi, M., and Kitano, H.

BioSilico 1 ( 5 ) 159-162 2003.11

Research paper (scientific journal), Joint Work

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[The ERATO Systems Biology Workbench and Systems Biology Markup Language: an integrated environment and standardization for systems biology].

Funahashi A

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 48 ( 7 ) 810 - 6 2003.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0039-9450

The ERATO Systems Biology Workbench and Systems Biology Markup Language

Funahashi Akira

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 48 ( 7 ) 810 - 816 2003

ISSN 0039-9450

Z-routing: Adaptive routing on irregular networks

Igawa, Y. and Funahashi, A.

IPSJ Journal 43 ( 3 ) 754-763 2002.03

Research paper (scientific journal), Joint Work, Accepted

An Output Selection Function based on the characteristic of virtual channel

Sugiyama, S. and Funahashi, A.

IPSJ Journal 43 ( 3 ) 764-775 2002.03

Research paper (scientific journal), Joint Work, Accepted

Routing algorithms based on 2D turn model for irregular networks

Jouraku, A; Koibuchi, M; Amano, H; Funahashi, A

I-SPAN'02: INTERNATIONAL SYMPOSIUM ON PARALLEL ARCHITECTURES, ALGORITHMS AND NETWORKS, PROCEEDINGS 289 - 294 2002

Joint Work, Accepted

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The Impact of Output Selection Function on Adaptive Routing.

Funahashi, A., Koibuchi, M., Jouraku, A., and Amano, H.

ISCA Information: An International Journal 4 ( 4 ) 541-550 2001.11

Research paper (scientific journal), Joint Work, Accepted

L-turn routing: An Adaptive Routing in Irregular Networks

Koibuchi, M., Funahashi, A., Jouraku, A., and Amano, H.

IPSJ Journal of High Performance Computing System (Information Processing Society of Japan (IPSJ)) 42 ( SIG9 ) 119-134 - 134 2001.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0-7695-1257-7

Network-based parallel processing using commodity personal computers has been widely developed. Since such systems require high degree of flexibility and scalability of wiring, a high-speed network with an irregular topology is often needed. In traditional routing algorithms for irregular networks, available paths are considerably restricted in order to avoid deadlocks. In this paper, we propose a novel routing algorithm called Left-up-first turn routing(L-turn routing), which makes a better traffic balancing in irregular networks by building a specific directed-graph. Result of simulations shows that L-turn routing achieves better performance than traditional ones with each topology.

Recursive Diagonal Torus: an interconnection network for massively parallel computers.

Yang, Y., Funahashi, A., Jouraku, A., Nishi, H., Amano, H., and Sueyoshi, T.

IEEE Trans. on Parallel and Distributed Systems 12 ( 7 ) 701-715 - 715 2001.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1045-9219

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The Impact of Output Selection Function on Adaptive Routing.

Koibuchi, M., Funahashi, A., Jouraku, A., and Amano, H.

IPSJ Journal 42 ( 4 ) 704-713 2001.04

Research paper (scientific journal), Joint Work, Accepted

Adaptive routing for Recursive Diagonal Torus.

Funahashi, A., Jouraku, A., and Amano, H.

IEICE Transactions on Information and Systems (The Institute of Electronics, Information and Communication Engineers) J89-D-I ( 11 ) 1143-1153 - 1153 2000.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 09151915

相互結合網RDTは再帰構造をもつTorusの重なりから構成されており, 超並列計算機のプロセッサ間接続を行うために優れた性質を多くもっている.超並列計算機に用いられる相互結合網において, 混雑若しくは故障したノードを回避できるルーチングアルゴリズムは必要不可欠である.既存のベクトルルーチングはシンプルではあるが, 固定ルーチング(deterministic routing)であるためこのようなノードを迂回することはできない.本研究では, Duatoによる必要十分条件を用いることによりRDT(2, 4, 1)/α上でデッドロックフリーなadaptive routing algorithim D-RDTとFD-RDTを提案し, デッドロックフリーであることを証明し, 評価を行った.D-RDTは各ランク内のトーラスではfully adaptive routingを行うが, e-cube routingをベースにしているため使用するランク順が固定される.FD-RDTは自由にランクを使用することが可能なバーチャルチャネルを付加したことにより, D-RDTに比べルーチングの自由度は高い.シミュレーションによる評価の結果, 両アリゴリズムとも既存のdeterministic routingに比べ通過率, レイテンシともに性能向上が見られ, 特にFD-RDTを用いたルーチングでは顕著であった.

Torus assignment for an interconnection network recursive diagonal torus

Fan Qin, Yang Yulu, Funahashi Akira, Amano Hideharu

Proceedings of the International Symposium on Parallel Architectures, Algorithms and Networks, I-SPAN 74 - 79 1999

Joint Work, Accepted, ISSN 1087-4089

Recursive Diagonal Torus (RDT) is a class of interconnection network consisting of recursively overlaid two-dimensional square diagonal tori for massively parallel computers with up to 2¹⁶ nodes. Connection structures of the RDT vary according to the assignment of upper rank diagonal tori into a node. Although traditional simple assignment called RDT(2, 4, 1)/α shows enough performance under the uniform traffic, the congestion of low rank tori degrades the performance when local communication is dominant. In this paper, RDT(2, 4, 1)/β torus assignment is proposed, focusing on improving the performance for local communication. With a simplified simulation algorithm, results shows that RDT(2, 4, 1)/β improves the average distance compared with RDT(2, 4, 1)/α assignment when considering local area.

A torus assignment for an interconnection network recursive diagonal torus

Q Fan, Y Yang, A Funahashi, H Amano

Proceedings Fourth International Symposium on Parallel Architectures … (IEEE COMPUTER SOC) 74 - 79 1999

Research paper (scientific journal), Joint Work, Accepted

Recursive Diagonal Torus (RDT) is a class of interconnection network consisting of recursively overlaid two-dimensional square diagonal tori for massively parallel computers with up to 2(16) nodes. Connection structures of the RDT vary according to the assignment of tipper rank diagonal tori into a node: Although traditional simple assignment called RDT(2,4,1)/alpha shows enough performance under the uniform traffic, the congestion of low rank tori degrades the performance when local communication is dominant.
In this paper RDT(2,4,1)/beta torus assignment is proposed, focusing an improving the performance for local communication. With a simplified simulation algorithm, result shows that RDT(2,4,1)/beta improves the average distance compared with RDT(2,4,1)/alpha assignment when considering local area.

Adaptive routing on the recursive Diagonal torus

A Funahashi, T Hanawa, T Kudoh, H Amano

International Symposium on High Performance Computing, 171-182 1997

Research paper (scientific journal), Joint Work, Accepted

Fault tolerance of the TBSF (Tandem Banyan Switching Fabrics) and PBSF (Piled Banyan Switching Fabrics).

Funahashi, A., Hanawa, T., and Amano, H.

IEICE Transactions on Information and Systems (IEICE-INST ELECTRONICS INFORMATION COMMUNICATIONS ENG) E79-D ( 8 ) 1180-1189 - 1189 1996.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 09168532

Multistage Interconnection Networks (MIN) with multiple outlets are networks which can support higher bandwidth than those of nonblocking networks by passing multiple packets to the same destination. Fault recovery mechanisms are proposed for two of such networks (TBSF/PBSF) with the best use of their inherent Fault tolerant capability. With these mechanisms, on-the-try fault recovery is possible for multiple faults on switching elements. For the link fault, the networks are reconfigured after fault diagnosis, and the network is available with some performance degradation. The bandwidth degradation under multiple faults on link/element is analyzed with both theoretical models and simulation. Through the analysis, F-PBSF shows high fault tolerance under high traffic load and low reliability by using 3 or more banyan networks.

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