Details of a Researcher - FUNAHASHI Akira

Reviews, Commentaries, etc. - FUNAHASHI Akira

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がん医療におけるAI-ここまで進んだ臨床応用-　乳がんの形態学的特徴を規定する分子メカニズム解明のための新たな医学研究手法の開発

黒住献, 片山彩香, 渡辺由佳子, 本田周子, 関根速子, 横堀武彦, 潮見隆之, 舟橋啓, 調憲, Ball Graham, Rakha Emad, 浅尾高行, 小山徹也, 藤井孝明, 堀口淳

日本癌治療学会学術集会抄録集 ((一社)日本癌治療学会) 60回 SSY2 - 6 2022.10

Joint Work

生物学者が機械学習を導入するための基礎知識

舟橋啓

日本獣医学会学術集会講演要旨集 ((公社)日本獣医学会) 165回 [K3A - S 2022.09

Joint Work, ISSN 1347-8621

クローズアップ実験法(series334)　遠心が1回で済む!スマートフォンによる細胞計数

舟橋啓, 徳岡雄大, 今城哉裕

実験医学 ((株)羊土社) 39 ( 8 ) 1283 - 1290 2021.05

Joint Work, ISSN 0288-5514

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

Marek Ostaszewski, Alexander Mazein, Marc E. Gillespie, Inna Kuperstein, Anna Niarakis, Henning Hermjakob, Alexander R. Pico, Egon L. Willighagen, Chris T. Evelo, Jan Hasenauer, Falk Schreiber, Andreas Dräger, Emek Demir, Olaf Wolkenhauer, Laura I. Furlong, Emmanuel Barillot, Joaquin Dopazo, Aurelio Orta-Resendiz, Francesco Messina, Alfonso Valencia, Akira Funahashi, Hiroaki Kitano, Charles Auffray, Rudi Balling, Reinhard Schneider

Scientific Data (Springer Science and Business Media LLC) 7 ( 1 ) 2020.12

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 2052-4463

Access to Document (DOI)

機械学習によるバイオイメージセグメンテーション

徳岡雄大, 山田貴大, 舟橋啓

機械学習を生命科学に使う! シークエンスや画像データをどう解析し、新たな生物学的発見につなげるか? 38 134 - 141 2020.12

Joint Work, Last author, Corresponding author

Google Colaboratory入門―機械学習を体験しよう

舟橋啓, 徳岡雄大, 山田貴大

機械学習を生命科学に使う! シークエンスや画像データをどう解析し、新たな生物学的発見につなげるか? 38 16 - 35 2020.12

Joint Work, Lead author, Corresponding author

クラシフィケーションの原理と生物・医療への応用

山田貴大, 徳岡雄大, 尾関光徳, 井伊海人, 広井賀子, 舟橋啓

機械学習を生命科学に使う! シークエンスや画像データをどう解析し、新たな生物学的発見につなげるか? 38 109 - 117 2020.12

Joint Work, Last author, Corresponding author

【機械学習を生命科学に使う!シークエンスや画像データをどう解析し、新たな生物学的発見につなげるか?】(第1章)機械学習入門　Google Colaboratory入門　機械学習を体験しよう

舟橋啓, 徳岡雄大, 山田貴大

実験医学 ((株)羊土社) 38 ( 20 ) 3322 - 3341 2020.12

Joint Work, ISSN 0288-5514

本稿はGoogle Colaboratoryを使用して機械学習を体験していただくことを目的としている。題材は位相差顕微鏡で撮像されたHeLa細胞の生死分類である。できるだけ機械学習の前提知識のない読者でもとりあえず機械学習のプログラムを実行し、精度評価までたどり着けるような構成にしたつもりである。プログラムはgithubにアップロードされているものを実行してもらう形式にしているため、インターネットに接続されているPC、Macや、iPad、iPhone等のタブレット、スマートフォンさえあれば誰でも試せる構成になっている。本稿を契機に機械学習を利用した生命科学研究が増えることを期待している。(著者抄録)

【機械学習を生命科学に使う!シークエンスや画像データをどう解析し、新たな生物学的発見につなげるか?】(第3章)画像解析　画像の分類・特徴化　クラシフィケーションの原理と生物・医療への応用

山田貴大, 徳岡雄大, 尾関光徳, 井伊海人, 広井賀子, 舟橋啓

実験医学 ((株)羊土社) 38 ( 20 ) 3415 - 3423 2020.12

Joint Work, ISSN 0288-5514

"分類"を意味するクラシフィケーションの応用事例は幅広く、迷惑メールフィルタのような一般生活に根ざしたものから、近年では病理診断や再生医療などの医療分野への適用事例が報告されはじめている。本稿では、クラシフィケーションの数理的な原理を概説したうえで、近年発展の著しい深層学習に基づくクラシフィケーションについて解説する。最後にクラシフィケーションを生命現象の解明や医療応用へ向けた研究事例としてわれわれが取り組んでいる課題について紹介する。(著者抄録)

【機械学習を生命科学に使う!シークエンスや画像データをどう解析し、新たな生物学的発見につなげるか?】(第3章)画像解析　画像からの細胞・運動情報抽出　機械学習によるバイオイメージセグメンテーション

徳岡雄大, 山田貴大, 舟橋啓

実験医学 ((株)羊土社) 38 ( 20 ) 3440 - 3447 2020.12

Joint Work, ISSN 0288-5514

近年、機械学習を用いたセグメンテーション技術は目まぐるしい進歩を遂げており、バイオイメージへの応用も多数報告されている。本稿では、そのような機械学習によるバイオイメージセグメンテーションの技術的基礎と背景を中心に概説する。また、近年の研究動向や技術的課題などについても包括的に触れ、最後にわれわれが取り組んでいる課題についても紹介したい。(著者抄録)

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

Sarah M Keating, Dagmar Waltemath, Matthias König, Fengkai Zhang, Andreas Dräger, Claudine Chaouiya, Frank T Bergmann, Andrew Finney, Colin S Gillespie, Tomáš Helikar, Stefan Hoops, Rahuman S Malik‐Sheriff, Stuart L Moodie, Ion I Moraru, Chris J Myers, Aurélien Naldi, Brett G Olivier, Sven Sahle, James C Schaff, Lucian P Smith, Maciej J Swat, Denis Thieffry, Leandro Watanabe, Darren J Wilkinson, Michael L Blinov, Kimberly Begley, James R Faeder, Harold F Gómez, Thomas M Hamm, Yuichiro Inagaki, Wolfram Liebermeister, Allyson L Lister, Daniel Lucio, Eric Mjolsness, Carole J Proctor, Karthik Raman, Nicolas Rodriguez, Clifford A Shaffer, Bruce E Shapiro, Joerg Stelling, Neil Swainston, Naoki Tanimura, John Wagner, Martin Meier‐Schellersheim, Herbert M Sauro, Bernhard Palsson, Hamid Bolouri, Hiroaki Kitano, Akira Funahashi, Henning Hermjakob, John C Doyle, Michael Hucka, Richard R Adams, Nicholas A Allen, Bastian R Angermann, Marco Antoniotti, Gary D Bader, Jan Červený, Mélanie Courtot, Chris D Cox, Piero Dalle Pezze, Emek Demir, William S Denney, Harish Dharuri, Julien Dorier, Dirk Drasdo, Ali Ebrahim, Johannes Eichner, Johan Elf, Lukas Endler, Chris T Evelo, Christoph Flamm, Ronan MT Fleming, Martina Fröhlich, Mihai Glont, Emanuel Gonçalves, Martin Golebiewski, Hovakim Grabski, Alex Gutteridge, Damon Hachmeister, Leonard A Harris, Benjamin D Heavner, Ron Henkel, William S Hlavacek, Bin Hu, Daniel R Hyduke, Hidde Jong, Nick Juty, Peter D Karp, Jonathan R Karr, Douglas B Kell, Roland Keller, Ilya Kiselev, Steffen Klamt, Edda Klipp, Christian Knüpfer, Fedor Kolpakov, Falko Krause, Martina Kutmon, Camille Laibe, Conor Lawless, Lu Li, Leslie M Loew, Rainer Machne, Yukiko Matsuoka, Pedro Mendes, Huaiyu Mi, Florian Mittag, Pedro T Monteiro, Kedar Nath Natarajan, Poul MF Nielsen, Tramy Nguyen, Alida Palmisano, Jean‐Baptiste Pettit, Thomas Pfau, Robert D Phair, Tomas Radivoyevitch, Johann M Rohwer, Oliver A Ruebenacker, Julio Saez‐Rodriguez, Martin Scharm, Henning Schmidt, Falk Schreiber, Michael Schubert, Roman Schulte, Stuart C Sealfon, Kieran Smallbone, Sylvain Soliman, Melanie I Stefan, Devin P Sullivan, Koichi Takahashi, Bas Teusink, David Tolnay, Ibrahim Vazirabad, Axel Kamp, Ulrike Wittig, Clemens Wrzodek, Finja Wrzodek, Ioannis Xenarios, Anna Zhukova, Jeremy Zucker

Molecular Systems Biology (EMBO) 16 ( 8 ) 2020.08

Joint Work, ISSN 1744-4292

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

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

Takahiro G. Yamada, Axel Imhof, Yusuke Hiki, Noriko F. Hiroi, Elena Shagimardanova, Oleg Gusev, Richard Cornette, Takahiro Kikawada, Akira Funahashi

PLOS ONE (PLoS ONE) 15 ( 3 ) e0230218 2020.03

Joint Work, Last author, Corresponding author

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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Neural Differentiation Dynamics Controlled by Multiple Feedback Loops in a Comprehensive Molecular Interaction Network

Tsuyoshi Iwasaki, Ryo Takiguchi, Takumi Hiraiwa, Takahiro G. Yamada, Kazuto Yamazaki, Noriko F. Hiroi, Akira Funahashi

Processes (Processes) 8 ( 2 ) 2020.02

Joint Work, Last author

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

Chikahiro Imashiro, Yuta Tokuoka, Kaito Kikuhara, Takahiro G. Yamada, Kenjiro Takemura, Akira Funahashi

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

Joint Work, Last author, Corresponding author

The field of bioengineering depends on technologies for stable cell culture. Conventionally, every process involved in cell culture has been performed manually, so the culture efficiency and stability can vary between trials or depending on the technician. Among these processes, cell counting is particularly important because cell density affects cell function. Conventional cell counting techniques for cell number estimation are inefficient and unstable because they involve the manual work of collecting a sample of the cell suspension. Thus, a cell counting method that is not susceptible to human error is needed. In this study, we present a novel cell counting method based on smartphone imaging and convolutional neural network-based image processing. Cells are aggregated by centrifuging in a tube and then imaged using a smartphone. The image is transferred to a server, and the cell number is predicted using convolutional neural networks on the server. All processes are performed by a custom-developed smartphone-compatible web app. Compared with the conventional method using a hemocytometer, our method yields more stable cell counting. Furthermore, the time and labor required for cell counting are significantly reduced. Our new method could potentially replace conventional cell counting techniques and thus enhance the stability and efficiency of bioengineering studies that require cell culture.

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

Maya Ooka, Yuta Tokuoka, Shori Nishimoto, Noriko Hiroi, Takahiro G Yamada, Akira Funahashi

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

Joint Work, Last author, Corresponding author

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

Kaito Ii, Kota Mashimo, Mitsunori Ozeki, Takahiro G. Yamada, Noriko Hiroi, Akira Funahashi

Frontiers in Genetics (Frontiers Media SA) 10 1027 2019.10

Joint Work, Last author, Corresponding author

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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電気式焦点可変レンズによる三次元計測システムの構築

舟橋啓, 仲井祐一郎, 広井賀子

実験医学 ((株)羊土社) 37 ( 18 ) 3116 - 3120 2019.10

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 0288-5514

Predicting the future direction of cell movement with convolutional neural networks

Shori Nishimoto, Kaiming Li, Yuta Tokuoka, Takahiro G. Yamada, Noriko F. Hiroi, Akira Funahashi

PLOS ONE (PLoS ONE) 14 ( 9 ) e0221245 2019.09

Joint Work, Last author, Corresponding author, 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 automatical

【病理形態学の新技術】画像解析と深層学習を用いた診断の基礎

舟橋啓, 徳岡雄大, 大岡麻耶, 西本勝利, 山田貴大, 広井賀子

病理と臨床 ((株)文光堂) 37 ( 7 ) 631 - 635 2019.07

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 0287-3745

ネムリユスリカの培養細胞の乾燥耐性に迫る

山田貴大, 舟橋啓, 黄川田隆洋

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 ) 2019.07

Article, review, commentary, editorial, etc. (scientific journal)

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

Takumi Hiraiwa, Takahiro G. Yamada, Norihisa Miki, Akira Funahashi, Noriko Hiroi

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

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

Takumi Hiraiwa, Yuichiro Nakai, Takahiro G. Yamada, Ryuichi Tanimoto, Hiroshi Kimura, Yoshinori Matsumoto, Norihisa Miki, Noriko Hiroi, Akira Funahashi

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

Joint Work, Last author, ISSN 2211-5463

© 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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Detection of Temperature Difference in Neuronal Cells

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

Scientific Reports (Springer Science and Business Media LLC) 6 ( 1 ) 22071 2016.03

Joint Work, Last author, ISSN 2045-2322

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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

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, 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。(著者抄録)

Editorial: Quantitative Biology: Dynamics of Living Systems

Noriko Hiroi, Viji M. Draviam, Akira Funahashi

Frontiers in Physiology (Frontiers Media SA) 7 196 2016

Joint Work, Last author, ISSN 1664-042X

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【バイオイメージング】定量的生命科学のためのバイオ画像解析とその哺乳類発生動態への応用

小林徹也, バシャール・カイルル , 舟橋啓, 藤森俊彦, 山縣一夫

MEDICAL IMAGING TECHNOLOGY (日本医用画像工学会) 33 ( 3 ) 84 - 89 2015.05

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 0288-450X

バイオイメージング技術の発展と普及とともに、顕微鏡イメージから生命システムの動態に関する情報を定量的に取得する方法としてバイオ画像解析技術は大きく注目されている。本稿では、イメージングデータへの画像解析の応用事例について概説するとともに、哺乳類着床前胚の発生動態と細胞系譜の再構成を目的とするわれわれの研究の進展について紹介する。(著者抄録)

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

Nakai, Y., Ozeki, M., Hiraiwa, T., Tanimoto, R., Funahashi, A., Hiroi, N., Taniguchi, A., Nonaka, S., Boilot, V., Shrestha, R., Clark, J., Tamura, N., Draviam, V. M., Oku, H.

Review of Scientific Instruments 86 ( 1 ) 013707 2015

Joint Work, ISSN 0034-6748

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

Tamura, N., Simon, J. E., Nayak, A., Shenoy, R., Hiroi, N., Boilot, V., Funahashi, A., Draviam, V. M.

Biology Open 4 ( 2 ) 155 - 169 2015

Joint Work, ISSN 2046-6390

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Acceleration of discrete stochastic biochemical simulation using GPGPU

Sumiyoshi, K., Hirata, K., Hiroi, N., Funahashi, A.

Frontiers in Physiology 6 ( FEB ) 42 - 169 2015

Joint Work, ISSN 1664-042X

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【生命動態システム科学】定量生物学　分子・細胞の計測　基本技術　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 ((公財)金原一郎記念医学医療振興財団) 65 ( 5 ) 388 - 389 2014.10

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 0370-9531

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

Hiroi, N., Swat, M., Funahashi, A.

Frontiers in Physiology (FRONTIERS RESEARCH FOUNDATION) 5 128 2014

Joint Work, ISSN 1664-042X

To perform parametric identification of mathematical models of biological events, experimental data are rare to be sufficient to estimate target behaviors produced by complex non-linear systems. We performed parameter fitting to a cell cycle model with experimental data as an in silico experiment. We calibrated model parameters with the generalized least squares method with randomized initial values and checked local and global sensitivity of the model. Sensitivity analyses showed that parameter optimization induced less sensitivity except for those related to the metabolism of the transcription factors c-Myc and E2F, which are required to overcome a restriction point (R-point). We performed bifurcation analyses with the optimized parameters and found the bimodality was lost. This result suggests that accumulation of c-Myc and E2F induced dysfunction of R-point. We performed a second parameter optimization based on the results of sensitivity analyses and incorporating additional derived from recent in vivo data. This optimization returned the bimodal characteristics of the model with a narrower range of hysteresis than the original. This result suggests that the optimized model can more easily go through R-point and come back to the gap phase after once having overcome it. Two parameter space analyses showed metabolism of c-Myc is transformed as it can allow cell bimodal behavior with weak stimuli of growth factors. This result is compatible with the character of the cell line used in our experiments. At the same time, Rb, an inhibitor of E2F, can allow cell bimodal behavior with only a limited range of stimuli when it is activated, but with a wider range of stimuli when it is inactive. These results provide two insights; biologically, the two transcription factors play an essential role in malignant cells to overcome R-point with weaker growth factor stimuli, and theoretically, sparse time-course data can be used to change a model to a biologically expected state.

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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

Joint Work, ISSN 1538-4101

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

Hiroi, N., Okuhara, T., Kubojima, T., Iba, K., Tabira, A., Yamashita, S., Okada, Y., Kobayashi, T. J., Funahashi, A.

Frontiers in Physiology (FRONTIERS RESEARCH FOUNDATION) 3 293 2012

Joint Work, ISSN 1664-042X

The intracellular environment is known to be a crowded and inhomogeneous space. Such an in vivo environment differs from a well-diluted, homogeneous environment for biochemical reactions. However, the effects of both crowdedness and the inhomogeneity of environment on the behavior of a mobile particle have not yet been investigated sufficiently. As described in this paper, we constructed artificial reaction spaces with fractal models, which are assumed to be non-reactive solid obstacles in a reaction space with crevices that function as operating ranges for mobile particles threading the space. Because of the homogeneity of the structures of artificial reaction spaces, the models succeeded in reproducing the physiological fractal dimension of solid structures with a smaller number of non-reactive obstacles than in the physiological condition. This incomplete compatibility was mitigated when we chose a suitable condition of a perimeter-to-area ratio of the operating range to our model. Our results also show that a simulation space is partitioned into convenient reaction compartments as an in vivo environment with the exact amount of solid structures estimated from TEM images. The characteristics of these compartments engender larger mean square displacement of a mobile particle than that of particles in smaller compartments. Subsequently, the particles start to show confined particle-like behavior. These results are compatible with our previously presented results, which predicted that a physiological environment would produce quick response and slow exhaustion reactions.

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

Hiroi, N., Klann, M., Iba, K., Heras Ciechomski, P.D., Yamashita, S., Tabira, A., Okuhara, T., Kubojima, T., Okada, Y., Oka, K., Mange, R., Unger, M., Funahashi, A., Koeppl, H.

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

Joint Work, 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 (OXFORD UNIV PRESS) 27 ( 24 ) 3437 - 3438 2011

Joint Work, ISSN 1367-4803

Motivation: BioPAX is a standard language for representing and exchanging models of biological processes at the molecular and cellular levels. It is widely used by different pathway databases and genomics data analysis software. Currently, the primary source of BioPAX data is direct exports from the curated pathway databases. It is still uncommon for wet-lab biologists to share and exchange pathway knowledge using BioPAX. Instead, pathways are usually represented as informal diagrams in the literature. In order to encourage formal representation of pathways, we describe a software package that allows users to create pathway diagrams using CellDesigner, a user-friendly graphical pathway-editing tool and save the pathway data in BioPAX Level 3 format.

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MULTI-GPUsによる高速配列解析環境の構築(Design and Implementation of high-performance sequence analysis environment using MULTI-GPUs)

平田一樹, 太田信行, 上樂明也, 広井賀子, 舟橋啓, 末次克行

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 ((公社)日本生化学会) 83回・33回 4P - 1224 2010.12

Joint Work

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

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

IPSJ Transactions on System LSI Design Methodology (Information Processing Society of Japan) 3 244 - 256 2010

Joint Work, ISSN 18826687

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.

CellDesigner 3.5: A versatile modeling tool for biochemical networks

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

Proceedings of the Ieee 96 ( 8 ) 1254 - 1265 2008.08

Joint Work, ISSN 0018-9219

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

ISHIMORI Tomoya, YAMADA Hideki, SHIBATA Yuichiro, OSANA Yasunori, YOSHIMI Masato, NISHIKAWA Yuri, KOJIMA Toshinori, AMANO Hideharu, FUNAHASHI Akira, HIROI Noriko, OGURI Kiyoshi

IEICE technical report (The Institute of Electronics, Information and Communication Engineers) 108 ( 48 ) 113 - 118 2008.05

Joint Work, ISSN 0913-5685

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.

FPGAを用いた汎用生化学シミュレータReCSiP

長名保範, 吉見真聡, 岩岡洋, 小嶋利紀, 西川由理, 舟橋啓, 広井賀子, 柴田裕一郎, 岩永直樹, 北野宏明, 天野英晴

電子情報通信学会論文誌D: 情報・システム ((一社)電子情報通信学会) 89 ( 6 ) 1163 - 1172 2006.06

Joint Work, ISSN 1880-4535

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(著者抄録)

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

Hiroi, N, Funahashi, A, Kitano, H

Cancer Gene Therapy (Nature Publishing Group) 13 ( 1 ) 7 - 12 2006

Joint Work, ISSN 0929-1903

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システムバイオロジー研究のためのソフトウェア標準化

舟橋啓

バイオテクノロジージャーナル (羊土社) 5 ( 1 ) 39 - 46 2005.01

Article, review, commentary, editorial, etc. (scientific journal), Single Work, ISSN 1349-7448

A comprehensive pathway map of epidermal growth factor receptor signaling.

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

Molecular systems biology [electronic resource]. 1 ( 1 ) 2005.0010 2005

Joint Work, ISSN 1744-4292

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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., Kitano, H.

Systems biology 1 ( 1 ) 41 - 53 2004

Joint Work