Reviews, Commentaries, etc. - FUNAHASHI Akira

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

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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

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© 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

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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)

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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

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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

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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

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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

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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

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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.

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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

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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

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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)