Researcher Database

Shinji Nakaoka
Faculty of Advanced Life Science Advanced Transdisciplinary Science Tissue Organization Science
Associate Professor

Researcher Profile and Settings


  • Faculty of Advanced Life Science Advanced Transdisciplinary Science Tissue Organization Science

Job Title

  • Associate Professor


  • Ph.D. of Science(Shizuoka University)


Research funding number

  • 30512040

J-Global ID

Research Interests

  • mathematical biology   systems biology   bioinformatics   immune system   dynamical systems   

Research Areas

  • Informatics / Biological, health, and medical informatics
  • Informatics / Computational science
  • Natural sciences / Applied mathematics and statistics
  • Natural sciences / Basic mathematics

Academic & Professional Experience

  • 2016 - 2018 科学技術振興機構 さきがけ 専任研究員
  • 2018 北海道大学大学院 先端生命科学研究院 特任講師
  • 2016 - 2016 The University of Tokyo Institute of Industrial Science
  • 2014 - 2016 東京大学大学院 医学系研究科 助教
  • 2013 - 2014 理化学研究所 統合生命医科学研究センター 上級研究員
  • 2011 - 2013 理化学研究所 免疫アレルギー科学総合研究センター 上級研究員
  • 2013 RIKEN
  • 2011 - 2011 科学技術振興機構 FIRST 合原複雑数理モデルプロジェクト 研究員
  • 2008 - 2011 日本学術振興会 特別研究員 PD
  • 2007 - 2008 科学技術振興機構 ERATO 合原複雑数理モデルプロジェクト 研究員


  • 2004 - 2007  Shizuoka University  Graduate School of Science and Engineering
  • 2002 - 2004  Osaka Prefecture University  Graduate School of Engineering
  • 1998 - 2002  Osaka Prefecture University  School of Engineering  Department of Mathematical Sciences
  • 1995 - 1998  大阪府立三国丘高校

Research Activities

Published Papers

  • Tatsuya Kurusu, Kwang Su Kim, Yoshiki Koizumi, Shinji Nakaoka, Keisuke Ejima, Naoko Misawa, Yoshio Koyanagi, Kei Sato, Shingo Iwami
    Journal of Theoretical Biology 498 110295 - 110295 0022-5193 2020/08 [Refereed][Not invited]
  • Shoya Iwanami, Kosaku Kitagawa, Hirofumi Ohashi, Yusuke Asai, Kaho Shionoya, Wakana Saso, Kazane Nishioka, Hisashi Inaba, Shinji Nakaoka, Takaji Wakita, Odo Diekmann, Shingo Iwami, Koichi Watashi
    PLOS Biology 18 (7) e3000562 - e3000562 2020/07/30 [Refereed][Not invited]
  • Hirofumi Aso, Shumpei Nagaoka, Eiryo Kawakami, Jumpei Ito, Saiful Islam, Benjy Jek Yang Tan, Shinji Nakaoka, Koichi Ashizaki, Katsuyuki Shiroguchi, Yutaka Suzuki, Yorifumi Satou, Yoshio Koyanagi, Kei Sato
    Cell reports 32 (2) 107887 - 107887 2020/07/14 [Refereed][Not invited]
    For eradication of HIV-1 infection, it is important to elucidate the detailed features and heterogeneity of HIV-1-infected cells in vivo. To reveal multiple characteristics of HIV-1-producing cells in vivo, we use a hematopoietic-stem-cell-transplanted humanized mouse model infected with GFP-encoding replication-competent HIV-1. We perform multiomics experiments using recently developed technology to identify the features of HIV-1-infected cells. Genome-wide HIV-1 integration-site analysis reveals that productive HIV-1 infection tends to occur in cells with viral integration into transcriptionally active genomic regions. Bulk transcriptome analysis reveals that a high level of viral mRNA is transcribed in HIV-1-infected cells. Moreover, single-cell transcriptome analysis shows the heterogeneity of HIV-1-infected cells, including CXCL13high cells and a subpopulation with low expression of interferon-stimulated genes, which can contribute to efficient viral spread in vivo. Our findings describe multiple characteristics of HIV-1-producing cells in vivo, which could provide clues for the development of an HIV-1 cure.
  • Akane Hara, Shoya Iwanami, Yusuke Ito, Tomoyuki Miura, Shinji Nakaoka, Shingo Iwami
    Journal of theoretical biology 479 29 - 36 2019/10/21 [Refereed][Not invited]
    Since chimeric simian and human immunodeficiency viruses (SHIVs) used here, that is, SHIV-#64 and -KS661 utilize both CCR5 and CXCR4 chemokine receptors, they have broad target cell properties. A highly pathogenic SHIV strain, SHIV-KS661, causes an infection that systemically depletes the CD4+ T cells of Rhesus macaques, while a less pathogenic strain, SHIV-#64, does not cause severe symptoms in the macaques. In our previous studies, we established in vitro quantification system for virus infection dynamics, and concluded that SHIV-KS661 effectively produces infectious virions compared with SHIV-#64 in the HSC-F cell culture. However, in vivo dynamics of SHIV infection have not been well understood. To quantify SHIV-#64 and -KS661 infection dynamics in Rhesus macaques, we developed a novel approach and analyzed total CD4+ T cells and viral load in peripheral blood, and reproduced the expected dynamics for the uninfected and infected CD4+ T cells in silico. Using our previous cell culture experimental datasets, we revealed that an infection rate constant is different between SHIV-#64 and -KS661, but the viral production rate and the death rate are similar for the both strains. Thus, here, we assumed these relations in our in vivo data and carried out the data fitting. We performed Bayesian estimation for the whole dataset using MCMC sampling, and simultaneously fitted our novel model to total CD4+ T cells and viral load of SHIV-#64 and -KS661 infection. Our analyses explained that the Malthusian parameter (i.e., fitness of virus infection) and the basic reproduction number (i.e., potential of virus infection) for SHIV-KS661 are significantly higher than those of SHIV-#64. In addition, we demonstrated that the number of uninfected CD4+ T cells in SHIV-KS661 infected Rhesus macaques decreases to the significantly lower value than that before the inoculation several days earlier compared with SHIV-#64 infection. Taken together, the differences between SHIV-#64 and -KS661 infection before the peak viral load might determine the subsequent destiny, that is, whether the systemic CD4+ T cell depletion occurs or the host immune response develop.
  • Kosaku Kitagawa, Toshikazu Kuniya, Shinji Nakaoka, Yusuke Asai, Koichi Watashi, Shingo Iwami
    Bulletin of Mathematical Biology 81 (5) 1427 - 1441 0092-8240 2019/05 [Refereed][Not invited]
  • Yueping Dong, Yasuhiro Takeuchi, Shinji Nakaoka
    Nonlinear Analysis: Real World Applications 43 1 - 17 1468-1218 2018/10/01 [Refereed][Not invited]
    Recent biological studies on the gut microbiota have revealed associations between imbalance of microbial community composition and diverse types of disease development. Composition change or reduced diversity of the gut microbiota has been identified by metagenomic samples of the gut microbiota from patients of chronic inflammatory diseases. Not only artificial but also natural antibiotics potentially regulate abnormal microbial species composition. In this paper, we propose a novel mathematical model for a feedback control system of the gut microbiota: a moderate amount of antibiotics injection as negative feedback regulator to abundances of microbial populations measured via metagenomic data with time delay. A class of autonomous N-species Lotka–Volterra type competitive system with discrete delays, representing population dynamics of the gut microbiota with delayed negative feedback via antibiotics injection, is considered to quantitatively characterize effect of multiple delayed feedback regulations on the microbial populations. Explicit formula for the corresponding characteristic equation evaluated at the positive equilibrium of the main model is successfully derived. Analytic results as well as numerical simulations are given for the two species case to quantitatively evaluate allowable ranges of time delay for avoiding population oscillations.
  • Toju H, Peay KG, Yamamichi M, Narisawa K, Hiruma K, Naito K, Fukuda S, Ushio M, Nakaoka S, Onoda Y, Yoshida K, Schlaeppi K, Bai Y, Sugiura R, Ichihashi Y, Minamisawa K, Kiers ET
    Nature plants 4 (9) 733  2018/09 [Refereed][Not invited]
  • Kosaku Kitagawa, Shinji Nakaoka, Yusuke Asai, Koichi Watashi, Shingo Iwami
    Journal of Theoretical Biology 448 80 - 85 0022-5193 2018/07 [Refereed][Not invited]
  • Yueping Dong, Moitri Sen, Malay Banerjee, Yasuhiro Takeuchi, Shinji Nakaoka
    Nonlinear Dynamics 1 - 20 1573-269X 2018/06/25 [Refereed][Not invited]
    Abundances of bacterial species such as Escherichia coli in a given environment are partly regulated by predation by protozoa species. Interactions among prey and predator species are not simple since a prey species has acquired defense mechanism against predation. A variety of defense mechanisms are known, for instance, production of toxin as a negative feedback effect to suppress predator species. On the other hand, negative feedback effects can be generated by a predator species to the prey species. The resulting population dynamics under the presence of negative feedback effects would be significantly affected by the strength of feedback control and time delay which naturally occurs until negative feedback effects become effective. In this paper, we develop a mathematical model to investigate the interaction between Shiga-toxin producing Escherichia coli and Tetrahymena with delayed feedback controls by production of Shiga-toxin and recruitment of neutrophils. By applying the quasi-steady-state approximation, the proposed model is reduced to a Lotka–Volterra type predator–prey system with two discrete delays. By investigating the distribution of the roots of the characteristic equation, the local stability as well as Hopf-bifurcation are studied. We provide a clear classification framework to detect the possibility of Hopf-bifurcation when two delays are present. Numerical simulations are carried out to verify the analytical results. Our findings reveal that the instability regions of coexistence equilibrium in two delay parameters plane always enlarge with the increase in negative feedback control coefficients, and especially the feedback controls on Tetrahymena population play a dominant role in the destabilization of coexistence equilibrium. Besides, we observe some interesting phenomena such as peak-adding bifurcation, quasi-periodic oscillation and chaos.
  • Toju H, Peay KG, Yamamichi M, Narisawa K, Hiruma K, Naito K, Fukuda S, Ushio M, Nakaoka S, Onoda Y, Yoshida K, Schlaeppi K, Bai Y, Sugiura R, Ichihashi Y, Minamisawa K, Kiers ET
    Nature plants 4 (5) 247 - 257 2055-026X 2018/05 [Refereed][Not invited]
  • Mohamed Mahgoub, Jun-ichirou Yasunaga, Shingo Iwami, Shinji Nakaoka, Yoshiki Koizumi, Kazuya Shimura, Masao Matsuoka
    Proceedings of the National Academy of Sciences 115 (6) E1269 - E1278 0027-8424 2018/02/06 [Refereed][Not invited]
    Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1–encoded Tax is a critical transactivator of viral replication and a potent oncoprotein, but its significance in pathogenesis remains obscure due to its very low level of expression in vivo. Here, we show that Tax is expressed in a minor fraction of leukemic cells at any given time, and importantly, its expression spontaneously switches between on and off states. Live cell imaging revealed that the average duration of one episode of Tax expression is ∼19 hours. Knockdown of Tax rapidly induced apoptosis in most cells, indicating that Tax is critical for maintaining the population, even if its short-term expression is limited to a small subpopulation. Single-cell analysis and computational simulation suggest that transient Tax expression triggers antiapoptotic machinery, and this effect continues even after Tax expression is diminished; this activation of the antiapoptotic machinery is the critical event for maintaining the population. In addition, Tax is induced by various cytotoxic stresses and also promotes HTLV-1 replication. Thus, it seems that Tax protects infected cells from apoptosis and increases the chance of viral transmission at a critical moment. Keeping the expression of Tax minimal but inducible on demand is, therefore, a fundamental strategy of HTLV-1 to promote persistent infection and leukemogenesis.
  • Tomokazu Yamaguchi, Takashi Suzuki, Teruki Sato, Akinori Takahashi, Hiroyuki Watanabe, Ayumi Kadowaki, Miyuki Natsui, Hideaki Inagaki, Satoko Arakawa, Shinji Nakaoka, Yukio Koizumi, Shinsuke Seki, Shungo Adachi, Akira Fukao, Toshinobu Fujiwara, Tohru Natsume, Akinori Kimura, Masaaki Komatsu, Shigeomi Shimizu, Hiroshi Ito, Yutaka Suzuki, Josef M Penninger, Tadashi Yamamoto, Yumiko Imai, Keiji Kuba
    Science signaling 11 (516) 1945-0877 2018/02/06 [Refereed][Not invited]
    Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4-negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3-depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7, but not Atg5, increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3-depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death-promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis.
  • Eri Yamada, Shinji Nakaoka, Lukas Klein, Elisabeth Reith, Simon Langer, Kristina Hopfensperger, Shingo Iwami, Gideon Schreiber, Frank Kirchhoff, Yoshio Koyanagi, Daniel Sauter, Kei Sato
    Cell Host and Microbe 23 (1) 110 - 120.e7 1934-6069 2018/01/10 [Refereed][Not invited]
    The HIV-1-encoded accessory protein Vpu exerts several immunomodulatory functions, including counteraction of the host restriction factor tetherin, downmodulation of CD4, and inhibition of NF-κB activity to facilitate HIV-1 infection. However, the relative contribution of individual Vpu functions to HIV-1 infection in vivo remained unclear. Here, we used a humanized mouse model and HIV-1 strains with selective mutations in vpu to demonstrate that the anti-tetherin activity of Vpu is a prerequisite for efficient viral spread during the early phase of infection. Mathematical modeling and gain-of-function mutations in SIVcpz, the simian precursor of pandemic HIV-1, corroborate this finding. Blockage of interferon signaling combined with transcriptome analyses revealed that basal tetherin levels are sufficient to control viral replication. These results establish tetherin as a key effector of the intrinsic immune defense against HIV-1, and they demonstrate that Vpu-mediated tetherin antagonism is critical for efficient viral spread during the initial phase of HIV-1 replication. The HIV-1-encoded accessory protein Vpu exerts several functions. Using a humanized mouse model and HIV-1 Vpu mutant viruses, Yamada et al. demonstrate that Vpu-mediated antagonism of the interferon-induced antiviral protein tetherin is critical for efficient viral spread during the initial phase of HIV-1 replication in vivo.
  • Odo Diekmann, Mats Gyllenberg, J. A.J. Metz, Shinji Nakaoka, Andre M. de Roos
    Journal of Mathematical Biology 61 (2) 277 - 318 0303-6812 2017/07/01 [Refereed][Not invited]
    We consider the interaction between a general size-structured consumer population and an unstructured resource. We show that stability properties and bifurcation phenomena can be understood in terms of solutions of a system of two delay equations (a renewal equation for the consumer population birth rate coupled to a delay differential equation for the resource concentration). As many results for such systems are available (Diekmann et al. in SIAM J Math Anal 39:1023-1069, 2007), we can draw rigorous conclusions concerning dynamical behaviour from an analysis of a characteristic equation. We derive the characteristic equation for a fairly general class of population models, including those based on the Kooijman-Metz Daphnia model (Kooijman and Metz in Ecotox Env Saf 8:254-274, 1984 de Roos et al. in J Math Biol 28:609-643, 1990) and a model introduced by Gurney-Nisbet (Theor Popul Biol 28:150-180, 1985) and Jones et al. (J Math Anal Appl 135:354-368, 1988), and next obtain various ecological insights by analytical or numerical studies of special cases. © 2009 The Author(s).
  • Odo Diekmann, Mats Gyllenberg, J. A. J. Metz, Shinji Nakaoka, Andre M. de Roos
    JOURNAL OF MATHEMATICAL BIOLOGY 75 (1) 259 - 261 0303-6812 2017/07 [Refereed][Not invited]
  • Yusuke Ito, Azaria Remion, Alexandra Tauzin, Keisuke Ejima, Shinji Nakaoka, Yoh Iwasa, Shingo Iwami, Fabrizio Mammano
    SCIENTIFIC REPORTS 7 (1) 6559  2045-2322 2017/07 [Refereed][Not invited]
    HIV-1 accumulates changes in its genome through both recombination and mutation during the course of infection. For recombination to occur, a single cell must be infected by two HIV strains. These coinfection events were experimentally demonstrated to occur more frequently than would be expected for independent infection events and do not follow a random distribution. Previous mathematical modeling approaches demonstrated that differences in target cell susceptibility can explain the non-randomness, both in the context of direct cell-to-cell transmission, and in the context of free virus transmission (Q. Dang et al., Proc. Natl. Acad. Sci. USA 101:632-7, 2004: K. M. Law et al., Cell reports 15:2711-83, 2016). Here, we build on these notions and provide a more detailed and extensive quantitative framework. We developed a novel mathematical model explicitly considering the heterogeneity of target cells and analysed datasets of cell-free HIV-1 single and double infection experiments in cell culture. Particularly, in contrast to the previous studies, we took into account the different susceptibility of the target cells as a continuous distribution. Interestingly, we showed that the number of infection events per cell during cell-free HIV-1 infection follows a negative-binomial distribution, and our model reproduces these datasets.
  • Yusuke Nakano, Naoko Misawa, Guillermo Juarez-Fernandez, Miyu Moriwaki, Shinji Nakaoka, Takaaki Funo, Eri Yamada, Andrew Soper, Rokusuke Yoshikawa, Diako Ebrahimi, Yuuya Tachiki, Shingo Iwami, Reuben S. Harris, Yoshio Koyanagi, Kei Sato
    PLOS PATHOGENS 13 (5) e1006348  1553-7366 2017/05 [Refereed][Not invited]
    APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1.
  • Yusuke Nakano, Naoko Misawa, Guillermo Juarez-Fernandez, Miyu Moriwaki, Shinji Nakaoka, Takaaki Funo, Eri Yamada, Andrew Soper, Rokusuke Yoshikawa, Diako Ebrahimi, Yuuya Tachiki, Shingo Iwami, Reuben S. Harris, Yoshio Koyanagi, Kei Sato
    PLOS PATHOGENS 13 (5) e1006606  1553-7366 2017/05 [Refereed][Not invited]
    APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1.
  • Shoya Iwanami, Yusuke Kakizoe, Satoru Morita, Tomoyuki Miura, Shinji Nakaoka, Shingo Iwami
    THEORETICAL BIOLOGY AND MEDICAL MODELLING 14 (1) 9  1742-4682 2017/04 [Refereed][Not invited]
    Background: The host range of human immunodeficiency virus (HIV) is quite narrow. Therefore, analyzing HIV-1 pathogenesis in vivo has been limited owing to lack of appropriate animal model systems. To overcome this, chimeric simian and human immunodeficiency viruses (SHIVs) that encode HIV-1 Env and are infectious to macaques have been developed and used to investigate the pathogenicity of HIV-1 in vivo. So far, we have many SHIV strains that show different pathogenesis in macaque experiments. However, dynamic aspects of SHIV infection have not been well understood. To fully understand the dynamic properties of SHIVs, we focused on two representative strains-the highly pathogenic SHIV, SHIV-KS661, and the less pathogenic SHIV, SHIV-#64-and measured the time-course of experimental data in cell culture. Methods: We infected HSC-F with SHIV-KS661 and -#64 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for 9 days. The experiments were repeated at two different multiplicities of infection, and a previously developed mathematical model incorporating the infectious and non-infectious viruses was fitted to the full dataset of each strain simultaneously to characterize the infection dynamics of these two strains. Results and conclusions: We quantified virological indices including virus burst sizes and basic reproduction number of both SHIV-KS661 and -#64. Comparing the burst size of total and infectious viruses (viral RNA copies and TCID50, respectively), we found that there was a statistically significant difference between the infectious virus burst size of SHIV-KS661 and -#64, while there was no significant difference between the total virus burst size. Furthermore, our analyses showed that the fraction of infectious virus among the produced SHIV-KS661 viruses, which is defined as the infectious viral load (TCID50/ml) divided by the total viral load (RNA copies/ml), is more than 10-fold higher than that of SHIV-#64 during overall infection (i.e., for 9 days). Taken together, we conclude that the highly pathogenic SHIV produces infectious virions more effectively than the less pathogenic SHIV in cell culture.
  • Alexey Martyushev, Shinji Nakaoka, Kei Sato, Takeshi Noda, Shingo Iwami
    ANTIVIRAL RESEARCH 135 62 - 73 0166-3542 2016/11 [Refereed][Not invited]
    Ebola virus (EBOV) causes a severe, often fatal Ebola virus disease (EVD), for which no approved antivirals exist. Recently, some promising anti-EBOV drugs, which are experimentally potent in animal models, have been developed. However, because the quantitative dynamics of EBOV replication in humans is uncertain, it remains unclear how much antiviral suppression of viral replication affects EVD outcome in patients. Here, we developed a novel mathematical model to quantitatively analyse human viral load data obtained during the 2000/01 Uganda EBOV outbreak and evaluated the effects of different antivirals. We found that nucleoside analogue- and siRNA-based therapies are effective if a therapy with a >50% inhibition rate is initiated within a few days post-symptom-onset. In contrast, antibody-based therapy requires not only a higher inhibition rate but also an earlier administration, especially for otherwise fatal cases. Our results demonstrate that an appropriate choice of EBOV-specific drugs is required for effective EVD treatment. (C) 2016 Elsevier B.V. All rights reserved.
  • Shinji Nakaoka, Sota Kuwahara, Chang Hyeong Lee, Hyejin Jeon, Junho Lee, Yasuhiro Takeuchi, Yangjin Kim
    APPLIED SCIENCES-BASEL 6 (9) 2076-3417 2016/09 [Refereed][Not invited]
    The epidermal tissue is the outmost component of the skin that plays an important role as a first barrier system in preventing the invasion of various environmental agents, such as bacteria. Recent studies have identified the importance of microbial competition between harmful and beneficial bacteria and the diversity of the skin surface on our health. We develop mathematical models (M1 and M2 models) for the inflammation process using ordinary differential equations and delay differential equations. In this paper, we study microbial community dynamics via transcription factors, protease and extracellular cytokines. We investigate possible mechanisms to induce community composition shift and analyze the vigorous competition dynamics between harmful and beneficial bacteria through immune activities. We found that the activation of proteases from the transcription factor within a cell plays a significant role in the regulation of bacterial persistence in the M1 model. The competition model (M2) predicts that different cytokine clearance levels may lead to a harmful bacteria persisting system, a bad bacteria-free state and the co-existence of harmful and good bacterial populations in Type I dynamics, while a bi-stable system without co-existence is illustrated in the Type II dynamics. This illustrates a possible phenotypic switch among harmful and good bacterial populations in a microenvironment. We also found that large time delays in the activation of immune responses on the dynamics of those bacterial populations lead to the onset of oscillations in harmful bacteria and immune activities. The mathematical model suggests possible annihilation of time-delay-driven oscillations by therapeutic drugs.
  • Takuwa Yasuda, Toshiyuki Fukada, Keigo Nishida, Manabu Nakayama, Masashi Matsuda, Ikuo Miura, Teruki Dainichi, Shinji Fukuda, Kenji Kabashima, Shinji Nakaoka, Bum-Ho Bin, Masato Kubo, Hiroshi Ohno, Takanori Hasegawa, Osamu Ohara, Haruhiko Koseki, Shigeharu Wakana, Hisahiro Yoshida
    JOURNAL OF CLINICAL INVESTIGATION 126 (6) 2064 - 2076 0021-9738 2016/06 [Refereed][Not invited]
    Skin homeostasis is maintained by the continuous proliferation and differentiation of epidermal cells. The skin forms a strong but flexible barrier against microorganisms as well as physical and chemical insults; however, the physiological mechanisms that maintain this barrier are not fully understood. Here, we have described a mutant mouse that spontaneously develops pruritic dermatitis as the result of an initial defect in skin homeostasis that is followed by induction of a Th2-biased immune response. These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function. Accordingly, treatment with an ointment to maintain normal skin barrier function protected mutant mice from dermatitis onset. Pharmacological inhibition of JAK1 also delayed disease onset. Together, these findings indicate that JAK1-mediated signaling cascades in skin regulate the expression of proteases associated with the maintenance of skin barrier function and demonstrate that perturbation of these pathways can lead to the development of spontaneous pruritic dermatitis.
  • Eiryo Kawakami, Shinji Nakaoka, Tazro Ohta, Hiroaki Kitano
    NUCLEIC ACIDS RESEARCH 44 (11) 5010 - 5021 0305-1048 2016/06 [Refereed][Not invited]
    Predicting responsible transcription regulators on the basis of transcriptome data is one of the most promising computational approaches to understanding cellular processes and characteristics. Here, we present a novel method employing vast amounts of chromatin immunoprecipitation (ChIP) experimental data to address this issue. Global high-throughput ChIP data was collected to construct a comprehensive database, containing 8 578 738 binding interactions of 454 transcription regulators. To incorporate information about heterogeneous frequencies of transcription factor (TF)-binding events, we developed a flexible framework for gene set analysis employing the weighted t-test procedure, namely weighted parametric gene set analysis (wPGSA). Using transcriptome data as an input, wPGSA predicts the activities of transcription regulators responsible for observed gene expression. Validation of wPGSA with published transcriptome data, including that from over-expressed TFs, showed that the method can predict activities of various TFs, regardless of cell type and conditions, with results totally consistent with biological observations. We also applied wPGSA to other published transcriptome data and identified potential key regulators of cell reprogramming and influenza virus pathogenesis, generating compelling hypotheses regarding underlying regulatory mechanisms. This flexible framework will contribute to uncovering the dynamic and robust architectures of biological regulation, by incorporating high-throughput experimental data in the form of weights.
  • Daisuke Yoneoka, Eiko Saito, Shinji Nakaoka
    SCIENTIFIC REPORTS 6 26582  2045-2322 2016/05 [Refereed][Not invited]
    To optimally allocate health resources, policy planners require an indicator reflecting the inequality. Currently, health inequalities are frequently measured by area-based indices. However, methodologies for constructing the indices have been hampered by two difficulties: 1) incorporating the geographical relationship into the model and 2) selecting appropriate variables from the high-dimensional census data. Here, we constructed a new area-based health coverage index using the geographical information and a variable selection procedure with the example of gastric cancer. We also characterized the geographical distribution of health inequality in Japan. To construct the index, we proposed a methodology of a geographically weighted logistic lasso model. We adopted a geographical kernel and selected the optimal bandwidth and the regularization parameters by a two-stage algorithm. Sensitivity was checked by correlation to several cancer mortalities/screening rates. Lastly, we mapped the current distribution of health inequality in Japan and detected unique predictors at sampled locations. The interquartile range of the index was 0.0001 to 0.354 (mean: 0.178, SD: 0.109). The selections from 91 candidate variables in Japanese census data showed regional heterogeneities (median number of selected variables: 29). Our index was more correlated to cancer mortalities/screening rates than previous index and revealed several geographical clusters with unique predictors.
  • Hiroki Ikeda, Shinji Nakaoka, Rob J. de Boer, Satoru Morita, Naoko Misawa, Yoshio Koyanagi, Kazuyuki Aihara, Kei Sato, Shingo Iwami
    RETROVIROLOGY 13 23  1742-4690 2016/04 [Refereed][Not invited]
    Background: Tetherin is an intrinsic anti-viral factor impairing the release of nascent HIV-1 particles from infected cells. Vpu, an HIV-1 accessory protein, antagonizes the anti-viral action of tetherin. Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the anti-viral action of tetherin and the antagonizing action of Vpu against tetherin, it still remains unclear how Vpu affects the kinetics of HIV-1 replication in vivo. Results: To quantitatively assess the role of Vpu in viral replication in vivo, we analyzed time courses of experimental data with viral load and target cell levels in the peripheral blood of humanized mice infected with wild-type and vpu-deficient HIV-1. Our recently developed mathematical model describes the acute phase of this infection reasonably, and allowed us to estimate several parameters characterizing HIV-1 infection in mice. Using a technique of Bayesian parameter estimation, we estimate distributions of the basic reproduction number of wild-type and vpu-deficient HIV-1. This reveals that Vpu markedly increases the rate of viral replication in vivo. Conclusions: Combining experiments with mathematical modeling, we provide an estimate for the contribution of Vpu to viral replication in humanized mice.
  • Shinji Nakaoka, Shingo Iwami, Kei Sato
    JOURNAL OF MATHEMATICAL BIOLOGY 72 (4) 909 - 938 0303-6812 2016/03 [Refereed][Not invited]
    Human immunodeficiency virus (HIV) is a fast replicating ribonucleic acid virus, which can easily mutate in order to escape the effects of drug administration. Hence, understanding the basic mechanisms underlying HIV persistence in the body is essential in the development of new therapies that could eradicate HIV infection. Lymphoid tissues are the primary sites of HIV infection. Despite the recent progress in real-time monitoring technology, HIV infection dynamics in a whole body is unknown. Mathematical modeling and simulations provide speculations on global behavior of HIV infection in the lymphatic system. We propose a new mathematical model that describes the spread of HIV infection throughout the lymphoid tissue network. In order to represent the volume difference between lymphoid tissues, we propose the proportionality of several kinetic parameters to the lymphoid tissues' volume distribution. Under this assumption, we perform extensive numerical computations in order to simulate the spread of HIV infection in the lymphoid tissue network. Numerical computations simulate single drug treatments of an HIV infection. One of the important biological speculations derived from this study is a drug saturation effect generated by lymphoid network connection. This implies that a portion of reservoir lymphoid tissues to which drug is not sufficiently delivered would inhibit HIV eradication despite of extensive drug injection.
  • Naoki Nakada, Mizuho Nagata, Yasuhiro Takeuchi, Shinji Nakaoka
    SYMPOSIUM ON BIOMATHEMATICS (SYMOMATH 2015) 1723 0094-243X 2016 [Refereed][Not invited]
    The immune system has an ability to recognize tumor as non-self antigen, and initiates inflammatory response to eliminate tumor. A dendritic cell (DCs) population is one of immune cell subsets that specifically uptakes foreign antigen and then presents to T cells. Dendritic cell boost ex vivo is operated to enhance immune response against tumor that in general comes to fail due to several complex reasons. Although dendritic cell therapy has been operated in clinical trials by boosting tumor immune responses, less is known about dynamic behaviors generated by interactions among immune cell subsets and tumor cells. In this paper, we construct and analyze a mathematical model describing tumor killing by T cells activated by dendritic cells. A handling time representing a waiting time required for T cells to be activated during antigen presentation is incorporated in our model. Mathematical analyses imply that successful tumor elimination depends on the amount of T cells activated ex vivo when introduced. Moreover, numerical simulations imply that an immune escape basin in which tumor can escape from T cell responses increases when the handling time increases, indicating that efficient tumor elimination might result in immediate T cell inactivation due to rapid decline of antigenic stimulation.
  • Hiroshi Nishiura, Akira Endo, Masaya Saitoh, Ryo Kinoshita, Ryo Ueno, Shinji Nakaoka, Yuichiro Miyamatsu, Yueping Dong, Gerardo Chowell, Kenji Mizumoto
    BMJ OPEN 6 (2) e009936  2044-6055 2016 [Refereed][Not invited]
    Objectives: To investigate the heterogeneous transmission patterns of Middle East respiratory syndrome (MERS) in the Republic of Korea, with a particular focus on epidemiological characteristics of superspreaders. Design: Retrospective epidemiological analysis. Setting: Multiple healthcare facilities of secondary and tertiary care centres in an urban setting. Participants: A total of 185 laboratory-confirmed cases with partially known dates of illness onset and most likely sources of infection. Primary and secondary outcome measures: Superspreaders were identified using the transmission tree. The reproduction number, that is, the average number of secondary cases produced by a single primary case, was estimated as a function of time and according to different types of hosts. Results: A total of five superspreaders were identified. The reproduction number throughout the course of the outbreak was estimated at 1.0 due to reconstruction of the transmission tree, while the variance of secondary cases generated by a primary case was 52.1. All of the superspreaders involved in this outbreak appeared to have generated a substantial number of contacts in multiple healthcare facilities (association: p<0.01), generating on average 4.0 (0.0-8.6) and 28.6 (0.0-63.9) secondary cases among patients who visited multiple healthcare facilities and others. The time-dependent reproduction numbers declined substantially below the value of 1 on and after 13 June 2015. Conclusions: Superspreaders who visited multiple facilities drove the epidemic by generating a disproportionate number of secondary cases. Our findings underscore the need to limit the contacts in healthcare settings. Contact tracing efforts could assist early laboratory testing and diagnosis of suspected cases.
  • Mizuho Nagata, Yutaro Furuta, Yasuhiro Takeuchi, Shinji Nakaoka
    JAPAN JOURNAL OF INDUSTRIAL AND APPLIED MATHEMATICS 32 (3) 759 - 770 0916-7005 2015/11 [Refereed][Not invited]
    Recent clinical progresses indicate effectiveness of dendritic cell therapy against tumor. Targeting dendritic cells as a mean of enhancing tumor specific T cell responses requires efficient antigen presentation to boost adaptive immune responses. Exploration of tumor specific antigen is therefore the best practice for the development of novel immunotherapy against tumor. On the other hand, combinational enhancement of tumor specific immune response is a subsequent potential therapy on the basis of the discovery of tumor specific antigen. Although empirical applications of combinational immune boost such as dendritic boost of T cells or NKT cells are known, dynamical behaviors of immune response and tumor immune escape at the population level remain largely unknown. In the present paper, we construct a mathematical model representing dynamical behaviors of T cell tumor response under the support of dendritic cells. Mutual dependence of dendritic and T cells in activation and tumor elimination leads to bistability between tumor immune escape and immuno-suppressive states. Extensive numerical computations indicate the high opportunities of tumor immune escape despite the presence of high antigenic stimulation. These results can explain one of dynamical patterns of tumor immune escape.
  • Shingo Iwami, Junko S. Takeuchi, Shinji Nakaoka, Fabrizio Mammano, Francois Clavel, Hisashi Inaba, Tomoko Kobayashi, Naoko Misawa, Kazuyuki Aihara, Yoshio Koyanagi, Kei Sato
    ELIFE 4 2050-084X 2015/10 [Refereed][Not invited]
    Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation. Our analyses demonstrated that the cell-to-cell infection mode accounts for approximately 60% of viral infection, and this infection mode shortens the generation time of viruses by 0.9 times and increases the viral fitness by 3.9 times. Our results suggest that even a complete block of the cell-free infection would provide only a limited impact on HIV-1 spread.
  • Tago, K, Kikuchi, Y, Nakaoka, S, Katsuyama, C, Hayatsu, M
    Molecular Ecology 24 3766 - 3788 2015/07 [Refereed][Not invited]
  • Yusuke Kakizoe, Satoru Morita, Shinji Nakaoka, Yasuhiro Takeuchi, Kei Sato, Tomoyuki Miura, Catherine A. A. Beauchemin, Shingo Iwami
    JOURNAL OF THEORETICAL BIOLOGY 376 39 - 47 0022-5193 2015/07 [Refereed][Not invited]
    Conservation laws are among the most important properties of a physical system, but are not commonplace in biology. We derived a conservation law from the basic model for viral infections which consists in a small set of ordinary differential equations. We challenged the conservation law experimentally for the case of a virus infection in a cell culture. We found that the derived, conserved quantity remained almost constant throughout the infection period, implying that the derived conservation law holds in this biological system. We also suggest a potential use for the conservation law in evaluating the accuracy of experimental measurements. (C) 2015 Elsevier Ltd. All rights reserved.
  • Yusuke Kakizoe, Shinji Nakaoka, Catherine A. A. Beauchemin, Satoru Morita, Hiromi Mori, Tatsuhiko Igarashi, Kazuyuki Aihara, Tomoyuki Miura, Shingo Iwami
    SCIENTIFIC REPORTS 5 10371  2045-2322 2015/05 [Refereed][Not invited]
    The time elapsed between successful cell infection and the start of virus production is called the eclipse phase. Its duration is specific to each virus strain and, along with an effective virus production rate, plays a key role in infection kinetics. How the eclipse phase varies amongst cells infected with the same virus strain and therefore how best to mathematically represent its duration is not clear. Most mathematical models either neglect this phase or assume it is exponentially distributed, such that at least some if not all cells can produce virus immediately upon infection. Biologically, this is unrealistic (one must allow for the translation, transcription, export, etc. to take place), but could be appropriate if the duration of the eclipse phase is negligible on the time-scale of the infection. If it is not, however, ignoring this delay affects the accuracy of the mathematical model, its parameter estimates, and predictions. Here, we introduce a new approach, consisting in a carefully designed experiment and simple analytical expressions, to determine the duration and distribution of the eclipse phase in vitro. We find that the eclipse phase of SHIV-KS661 lasts on average one day and is consistent with an Erlang distribution.
  • Hiroki Ikeda, Shinji Nakaoka, Kei Sato, Naoko Misawa, Yoshio Koyanagi, Shingo Iwami
    Nonlinear Theory and Its Applications, IEICE 6 (1) 47 - 53 2185-4106 2015 [Refereed][Not invited]
  • Nakaoka Shinji
    IEICE NONLINEAR THEORY AND ITS APPLICATIONS 6 (1) 54 - 70 2185-4106 2015 [Refereed][Not invited]
  • Shinji Nakaoka, Hisashi Inaba
    MATHEMATICAL BIOSCIENCES AND ENGINEERING 11 (2) 363 - 384 1547-1063 2014/04 [Refereed][Not invited]
    Quantitative measurement for the timings of cell division and death with the application of mathematical models is a standard way to estimate kinetic parameters of cellular proliferation. On the basis of label-based measurement data, several quantitative mathematical models describing shortterm dynamics of transient cellular proliferation have been proposed and extensively studied. In the present paper, we show that existing mathematical models for cell population growth can be reformulated as a specific case of generation progression models, a variant of parity progression models developed in mathematical demography. Generation progression ratio (GER) is defined for a generation progression model as an expected ratio of population increase or decrease via cell division. We also apply a stochastic simulation algorithm which is capable of representing the population growth dynamics of transient amplifying cells for various inter-event time distributions of cell division and death. Demographic modeling and the application of stochastic simulation algorithm presented here can be used as a unified platform to systematically investigate the short term dynamics of cell population growth.
  • Hiroshi Nishiura, Keisuke Ejima, Kenji Mizumoto, Shinji Nakaoka, Hisashi Inaba, Seiya Imoto, Rui Yamaguchi, Masaya M. Saito
    THEORETICAL BIOLOGY AND MEDICAL MODELLING 11 (1) 5  1742-4682 2014/01 [Refereed][Not invited]
    Background: There has been a variation in published opinions toward the effectiveness of school closure which is implemented reactively when substantial influenza transmissions are seen at schools. Parameterizing an age-structured epidemic model using published estimates of the pandemic H1N1-2009 and accounting for the cost effectiveness, we examined if the timing and length of school closure could be optimized. Methods: Age-structured renewal equation was employed to describe the epidemic dynamics of an influenza pandemic. School closure was assumed to take place only once during the course of the pandemic, abruptly reducing child-to-child transmission for a fixed length of time and also influencing the transmission between children and adults. Public health effectiveness was measured by reduction in the cumulative incidence, and cost effectiveness was also examined by calculating the incremental cost effectiveness ratio and adopting a threshold of 1.0 x 10(7) Japanese Yen/life-year. Results: School closure at the epidemic peak appeared to yield the largest reduction in the final size, while the time of epidemic peak was shown to depend on the transmissibility. As the length of school closure was extended, we observed larger reduction in the cumulative incidence. Nevertheless, the cost effectiveness analysis showed that the cost of our school closure scenario with the parameters derived from H1N1-2009 was not justifiable. If the risk of death is three times or greater than that of H1N1-2009, the school closure could be regarded as cost effective. Conclusions: There is no fixed timing and duration of school closure that can be recommended as universal guideline for different types of influenza viruses. The effectiveness of school closure depends on the transmission dynamics of a particular influenza virus strain, especially the virulence (i.e. the infection fatality risk).
  • Shinji Nakaoka
    Methods in Molecular Biology 1195 269 - 283 1064-3745 2014 [Refereed][Not invited]
    Epidermal homeostasis is maintained by dynamic interactions among molecules and cells at different spatiotemporal scales. Mathematical modeling and simulation is expected to provide clear understanding and precise description of multiscaleness in tissue homeostasis under systems perspective. We introduce a stochastic process-based description of multiscale dynamics. Agent-based modeling as a framework of multiscale modeling to achieve consistent integration of definitive subsystems is proposed. A newly developed algorithm that particularly aims to perform stochastic simulations of cellular dynamical process is introduced. Finally we review applications of multiscale modeling and quantitative study to important aspects of epidermal and epithelial homeostasis. © 2014 Springer Science+Business Media New York.
  • Shinji Nakaoka, Kazuyuki Aihara
    JOURNAL OF MATHEMATICAL BIOLOGY 66 (4-5) 807 - 835 0303-6812 2013/03 [Refereed][Not invited]
    The epidermis is the outmost skin tissue. It operates as a first defense system to process inflammatory signals and responds by producing inflammatory mediators that promote the recruitment of immune cells. Various skin diseases such as atopic dermatitis occur as a result of the defect of proper skin barrier function and successive impaired inflammatory responses. The onset of such a skin disease links to the disturbed epidermal homeostasis regulated by appropriate self-renewal and differentiation of epidermal stem cells. The theory of physiologically structured population models provides a versatile framework to formulate mathematical models which describe the growth dynamics of a cell population such as the epidermis. In this paper, we develop an algorithm to implement stochastic simulation for a class of physiologically structured population models. We demonstrate that the developed algorithm is applicable to several cell population models and typical age-structured population models. On the basis of the developed algorithm, we investigate stochastic dynamics of skin cell populations and spread of inflammation. It is revealed that demographic stochasticity can bring considerable impact on the outcome of inflammation spread at the tissue level.
  • Shinji Nakaoka, Kazuyuki Aihara
    JOURNAL OF BIOLOGICAL DYNAMICS 6 (2) 836 - 854 1751-3758 2012 [Refereed][Not invited]
    Numerous haematological diseases occur due to dysfunctions during homeostasis processes of blood cell production. Haematopoietic stem cell transplantation (HSCT) is a therapeutic option for the treatment of haematological malignancy and congenital immunodeficiency. Today, HSCT is widely applied as an alternative method to bone marrow transplantation; however, HSCT can be a risky procedure because of potential side effects and complications after transplantations. Although an optimal regimen to achieve successful HSCT while maintaining quality of life is to be developed, even theoretical considerations such as the evaluations of successful engraftments and proposals of clinical management strategies have not been fully discussed yet. In this paper, we construct and investigate mathematical models that describe the kinetics of hematopoietic stem cell self-renewal and granulopoiesis under the influence of growth factors. Moreover, we derive theoretical conditions for successful HSCT, primarily on the basis of the idea that the basic reproduction number R-0 represents a threshold condition for a population to successfully grow in a given steady-state environment. Successful engraftment of transplanted haematopoietic stem cells (HSCs) is subsequently ensured by employing a concept of dynamical systems theory known as 'persistence'. On the basis of the implications from the modelling study, we discuss how the conditions derived for a successful HSCT are used to link to experimental studies.
  • Odo Diekmann, Mats Gyllenberg, J. A. J. Metz, Shinji Nakaoka, Andre M. de Roos
    JOURNAL OF MATHEMATICAL BIOLOGY 61 (2) 277 - 318 0303-6812 2010/08 [Refereed][Not invited]
    We consider the interaction between a general size-structured consumer population and an unstructured resource. We show that stability properties and bifurcation phenomena can be understood in terms of solutions of a system of two delay equations (a renewal equation for the consumer population birth rate coupled to a delay differential equation for the resource concentration). As many results for such systems are available (Diekmann et al. in SIAM J Math Anal 39:1023-1069, 2007), we can draw rigorous conclusions concerning dynamical behaviour from an analysis of a characteristic equation. We derive the characteristic equation for a fairly general class of population models, including those based on the Kooijman-Metz Daphnia model (Kooijman and Metz in Ecotox Env Saf 8:254-274, 1984; de Roos et al. in J Math Biol 28:609-643, 1990) and a model introduced by Gurney-Nisbet (Theor Popul Biol 28:150-180, 1985) and Jones et al. (J Math Anal Appl 135:354-368, 1988), and next obtain various ecological insights by analytical or numerical studies of special cases.
  • Odo Diekmann, Mats Gyllenberg, J. A.J. Metz, Shinji Nakaoka, André M. de Roos
    Journal of Mathematical Biology 75 (1) 259 - 261 0303-6812 2010/07/01 [Refereed][Not invited]
    In the original publication, the addresses of the authors Dr. J.A.J. Metz and Dr. S. Nakaoka were incorrectly published. The correct address list for the authors are: J.A.J. Metz: Institute of Biology and Institute of Mathematics, Leiden University, P.O. Box 9516, 2300RA Leiden, The Netherlands. S. Nakaoka: Graduate School of.
  • Shingo Iwami, Tomoyuki Miura, Shinji Nakaoka, Yasuhiro Takeuchi
    JOURNAL OF THEORETICAL BIOLOGY 260 (4) 490 - 501 0022-5193 2009/10 [Refereed][Not invited]
    Results of several studies show that some DC populations are susceptible to HIV. Modulation of DCs by HIV infection, in particular interference of the antigen-presenting function of DCs, is a key aspect in viral pathogenesis and contributes to viral evasion from immunity because the loss of the DC function engenders some impairment effects for a proliferation of CTL responses, which play an important role in the immune response to HIV. As described herein, we use a simple mathematical model to examine virus-immune dynamics over the course of HIV infection in the context of the immune impairment effects. A decrease of the DC number and function during the course of HIV-1 infection is observed. Therefore, we simply assumed that the immune impairment rate increases over the HIV infection. Under the assumption, four processes of the disease progression dynamics of our model are classifiable according to their virological properties. It is particularly interesting a typical disease progression presents a "risky threshold' and an "immunodeficiency threshold''. Regarding the former, the immune system might collapse when the impairment rate of HIV exceeds a threshold value (which corresponds to a transcritical bifurcation point). For the latter, the immune system always collapses when the impairment rate exceeds the value (which corresponds to a saddle-node bifurcation point). To test our theoretical framework, we investigate the existence and distribution of these thresholds in 10 patients. (C) 2009 Elsevier Ltd. All rights reserved.
  • Shinji Nakaoka, Wendi Wang, Yasuhiro Takeuchi
    JOURNAL OF THEORETICAL BIOLOGY 260 (1) 161 - 171 0022-5193 2009/09 [Refereed][Not invited]
    Behavioral changes of animal species can influence the consequence of population dynamics. One of the most remarkable behaviors of animal species is the aggregation by which species can reduce predation risk as a consequence of dilution or the other effects by forming a group. Empirical studies have demonstrated that an incompatibility exists in aggregation sincere source competition might become severe at the cost of reducing predation pressure from predatory species. Parental care by supplying the food consumed by adults to their juveniles would reduce the mortality of juvenile due to starvation, but it would reduce the reproduction rate at the same time. In this paper, we study a class of stage structured resource-consumer models to investigate the effect of behavioral changes on population dynamics. It is shown that under the presence of trade-off in parental care, moderate degrees of parental care will be favored as maximizing the equilibrium density of consumers. For consumer species having a long maturation period, consumer species might get benefit from dilution effects as a result of aggregation despite the elevated resource competition. Aggregation gives rise to two different outcomes in consumer extinction. Resource exhaustion as a consequence of over-exploitation can induce extinction of consumers due to Allee effects if aggregation strongly mediates juvenile survival. (C) 2009 Elsevier Ltd. All rights reserved.
  • Shingo Iwami, Yasuhiro Takeuchi, Xianning Liu, Shinji Nakaoka
    JOURNAL OF THEORETICAL BIOLOGY 259 (2) 219 - 228 0022-5193 2009/07 [Refereed][Not invited]
    Vaccination can be a useful tool for control of avian influenza outbreaks in poultry, but its use is reconsidered in most of the countries worldwide because of its negative effects on the disease control. One of the most important negative effects is the potential for emergence of vaccine-resistant viruses. Actually, in the vaccination program in China and Mexico, several vaccine-resistant strains were confirmed. Vaccine-resistant strains usually cause a loss of the protection effectiveness of vaccination. Therefore, a vaccination program that engenders the emergence of the resistant strain might promote the spread of the resistant strain and undermine the control of the infectious disease, even if the vaccination protects against the transmission of a vaccine-sensitive strain. We designed and analyzed a deterministic patch-structured model in heterogeneous areas (with or without vaccination) illustrating transmission of vaccine-sensitive and vaccine-resistant strains during a vaccination program. We found that the vaccination program can eradicate the vaccine-sensitive strain but lead to a prevalence of vaccine-resistant strain. Further, interestingly, the replacement of viral strain could occur in another area without vaccination through a migration of non-infectious individuals due to an illegal trade of poultry. It is also a novel result that only a complete eradication of both strains in vaccination area can achieve the complete eradication in another areas. Thus we can obtain deeper understanding of an effect of vaccination for better development of vaccination strategies to control avian influenza spread. (C) 2009 Elsevier Ltd. All rights reserved.
  • Yasuhiro Takeuchi, Wendi Wang, Shinji Nakaoka, Shingo Iwami
    BULLETIN OF MATHEMATICAL BIOLOGY 71 (4) 931 - 951 0092-8240 2009/05 [Refereed][Not invited]
    Two models are proposed to simulate population growth of species with mature stage and immature stage in which there are parental cares for immature. It is assumed that the protection of mature to their immature reduces mortality of immature at the cost of reduction of reproduction. Dynamical adaptation of parental care is incorporated into the models, one of which is described with the proportional transition rate from immature to mature (ODE model) and the other one is described with a transition rate from immature to mature according to a fixed age (DDE model). For the ODE model, it is shown that the adaptation of parental care enlarges the possibility of species survival in the sense that population is permanent under the influences of the adaptation, but becomes extinct in the absence of adaptation. It is proved that the outcome of the adaptation makes the population in an optimal state. It is also observed that there are parental care switches, from noncare strategy to care strategy, as the natural death rate of immature individuals increases. The analysis of the DDE model indicates that the adaptation also enlarges the opportunity of population persistence, but the stage delay has the tendency to hinder the movement of population evolution to the optimal state. It is found that the loss rate of immature in the absence of parental care can induce different patterns to disturb the adaptation of population to optimal state. However, it is shown that the adaptation of parental care approaches to the optimal state when parental care is required for the survival of the population, for example, when the loss rate of immature or competition among mature increases or the fecundity decreases.
  • Shingo Iwami, Shinji Nakaoka, Yasuhiro Takeuchi, Yoshiharu Miura, Tomoyuki Miura
    IMMUNOLOGY LETTERS 123 (2) 149 - 154 0165-2478 2009/04 [Refereed][Not invited]
    Longitudinal studies of patients infected with HIV-1 reveal a long and variable length of asymptomatic phase between infection and development of AIDS. Some HIV infected patients are still asymptomatic after 15 or more years of infection but some patients develop AIDS within 2 years. The mechanistic basis of the disease progression has remained obscure but many researchers have been trying to explain it. For example, the possible importance of viral diversity for the disease progression and the development of AIDS has been very well worked out in the early-1990s, especially by some important works of Martin A. Nowak. These studies can give an elegant explanation for a variability of asymptomatic phase. Here, a simple mathematical model was used to propose a new explanation for a variable length of asymptomatic phase. The main idea is that the immune impairment rate increases over the HIV infection. Our model suggested the existence of so-called "Risky threshold" and "Immunodeficiency threshold" on the impairment rate. The former implies that immune system may collapse when the impairment rate of HIV exceeds the threshold value. The latter implies that immune system always collapses when the impairment rate exceeds the value. We found that the length of asymptomatic phase is determined stochastically between these threshold values depending on the virological and immunological states. Furthermore, we investigated a distribution of the length of asymptomatic phase and a survival rate of the immune responses in one HIV patient. (C) 2009 Elsevier B.V. All rights reserved.
  • Chie Katsuyama, Shinji Nakaoka, Yasuhiro Takeuchi, Kanako Tago, Masahito Hayatsu, Kenji Kato
    JOURNAL OF THEORETICAL BIOLOGY 256 (4) 644 - 654 0022-5193 2009/02 [Refereed][Not invited]
    Interactions between microbial species, including competition and mutualism, influence the abundance and distribution of the related species. For example, metabolic cooperation among multiple bacteria plays a major role in the maintenance of consortia. This study aims to clarify how two bacterial species coexist in a syntrophic association involving the degradation of the pesticide fenitrothion. To elucidate essential mechanisms for maintaining a syntrophic association, we employed a mathematical model based on an experimental study, because experiment cannot elucidate various conditions for two bacterial coexistence. We isolated fenitrothion-degrading Sphingomonas sp. TFEE and its metabolite of 3-methyl-4-nitrophenol (3M4N)-degrading Burkholderia sp. MN1 from a fenitrothion-treated soil microcosm. Neither bacterium can completely degrade fenitrothion alone, but they can utilize the second intermediate, methylhydroquinone (MHQ). Burkholderia sp. MN1 excretes a portion of MHQ during the degradation of 3M4N, from which Sphingomonas sp. TFEE carries out degradation to obtain carbon and energy. Based on experimental findings, we developed mathematical models that represent the syntrophic association involving the two bacteria. We found that the two bacteria are characterized by the mutualistic degradation of fenitrothion. Dynamics of two bacteria are determined by the degree of cooperation between two bacteria (i.e., supply of 3M4N by Sphingomonas sp. TFEE and excretion of MHQ by Burkholderia sp. MN1) and the initial population sizes. The syntrophic association mediates the coexistence of the two bacteria under the possibility of resource competition for MHQ, and robustly facilitates the maintenance of ecosystem function in terms of degrading xenobiotics. Thus, the mathematical analysis and numerical computations based on the experiment indicate the key mechanisms for coexistence of Sphingomonas sp. TFEE and Burkholderia sp. MN1 in syntrophic association involving fenitrothion degradation. (c) 2008 Elsevier Ltd. All rights reserved.
  • Wendi Wang, Shinji Nakaoka, Yasuhiro Takeuchi
    JOURNAL OF THEORETICAL BIOLOGY 253 (1) 12 - 23 0022-5193 2008/07 [Refereed][Not invited]
    Parental care is incorporated into a prey-predator model in which immature predators are taken care of by their parents. It is assumed that adult predators confront the problem to stay home to protect offspring or to go out to forage. The global dynamics of the mathematical model is analyzed by means of analytical methods and numerical simulations. Conditions for the extinction of predator populations are established and the manners in which predators become extinct are revealed. Bifurcation analysis shows that the model admits changes from the extinction of predators to stable coexistence at a positive equilibrium point, and then to stage-structure induced oscillations. It is shown that optimal invest of adult predators can be achieved. (c) 2007 Elsevier Ltd. All rights reserved.
  • Shingo Iwami, Shinji Nakaoka, Yasuhiro Takeuchi
    MATHEMATICAL BIOSCIENCES AND ENGINEERING 5 (3) 457 - 476 1547-1063 2008/07 [Refereed][Not invited]
    We consider the effect of viral diversity on the human immune system with the frequency dependent proliferation rate of CTLs and the elimination rate of infected cells by CTLs. The model has very complex mathematical structures such as limit cycle, quasi-periodic attractors, chaotic attractors, and so on. To understand the complexity we investigate the global behavior of the model and demonstrate the existence and stability conditions of the equilibria. Further we give some theoretical considerations obtained by our mathematical model to HIV infection.
  • Shingo Iwami, Shinji Nakaoka, Yasuhiro Takeuchi
    THEORETICAL POPULATION BIOLOGY 73 (3) 332 - 341 0040-5809 2008/05 [Refereed][Not invited]
    We propose a new diversity threshold theory which states that the specific CTLs to the viral strain become inactivated (that is, some HIV strain can escape from its specific immune response) when the diversity of HIV strains exceeds some threshold number. We call this number "immune diversity threshold". Our theory can explain the inactivation of specific immune response and a limit of maximum immune diversity. We can conclude that the accumulation of viral diversity eventually leads to AIDS. (C) 2008 Elsevier Inc. All rights reserved.
  • Shinji Nakaoka, Yasuhiro Takeuchi
    Exploitative competition of two cross-feeding strains is studied. We found that two types of coexistence of two cross-feeding strains, type-I coexistence (cultivated type) and type-II coexistence (self-sufficiency type) are possible for microbial cross-feeding strains. In all cases of coexistence, trade-off in nutrient availability is required, However, trade-off is necessary but is not sufficient for the coexistence of two strains. Over-production of metabolite can induce competitive exclusion on one hand (cultivated regime) whereas do support the coexistence of two strain on the other hand (self-sufficiency regime). Coexistence of two strains is evaluated by invasibility and permanence criteria and numerical simulations.
  • Shingo Iwami, Shinji Nakaoka, Yasuhiro Takeuchi
    PHYSICA D-NONLINEAR PHENOMENA 223 (2) 222 - 228 0167-2789 2006/11 [Refereed][Not invited]
    In this paper, we consider the effect of viral diversity on the human immune system with frequency dependent rate of proliferation of CTLs (cytotoxic T-lymphocytes) and rate of elimination of infected cells by CTLs. We show that the interior equilibrium of our model can become unstable without viral diversity and we observe stable periodic orbits. Furthermore, our mathematical models suggest that viral diversity produces strange attractors. (c) 2006 Elsevier B.V. All rights reserved.
  • Wendi Wang, Yasuhiro Takeuchi, Yasuhisa Saito, Shinji Nakaoka
    JOURNAL OF THEORETICAL BIOLOGY 241 (3) 451 - 458 0022-5193 2006/08 [Refereed][Not invited]
    A stage structure is incorporated into a prey-predator model in which predators are split into immature predators and mature predators. It is assumed that immature predators are raised by their parents in the sense that they cannot catch the prey and their foods are provided by parents. Further, it is assumed that the maturation rate of immature predators is a function of the food availability for one immature individual. It is found that the model admits periodic solutions which are produced from the stage structure. Further, it is shown that two stability switches of positive equilibria may occur due to the transition rate incorporating the influence of nutrient, and that the enrichment of adult predators may lead to the catastrophe of the ecological system. (c) 2005 Elsevier Ltd. All rights reserved.
  • Shinji Nakaoka, Yasuhiro Takeuchi
    MATHEMATICAL BIOSCIENCES 201 (1-2) 157 - 171 0025-5564 2006/05 [Refereed][Not invited]
    Competition on a model with nutrient recycling is considered. The model is based on a chemostat-type equation which is used to study population dynamics of microorganisms. The model consists of four organisms competing for a limiting nutrient. Nutrient is supplied both from the in-flow of medium and a recycling with delay, the latter is generated from dead organisms by bacterial decomposition. This paper shows that the model undergoes a Hopf bifurcation through a critical value of time delay when the in-flow is small. Coexistence of four organisms competing for one limiting nutrient is indicated by numerical simulation results. (c) 2005 Elsevier Inc. All rights reserved.

Books etc


  • KITAGAWA Kousaku, NAKAOKA Shinji, ASAI Yusuke, AIHARA Kazuyuki, IWAMI Shingo  SEISAN KENKYU  69-  (3)  151  -153  2017  [Not refereed][Not invited]
    <p>A mathematical model of Hepatitis C Virus (HCV) dynamics with RNA replication under antiviral therapy was constructed by a set of partial differential equations (PDEs). In previous works, they solved the model as ordinary differential equations( ODEs) under the assumption of no de-novo infection and its analytical solution was used to describe the dynamics. However, the previous model by this approach has a limitation when it is applied to clinical data. Therefore, we developed a new mathematical model which is mathematically equivalent to PDE and compared the performance of our approach to the previous PDE model.</p>
  • KAKIZOE Yusuke, NAKAOKA Shinji, AIHARA Kazuyuki, IWAMI Shingo  SEISAN KENKYU  67-  (3)  275  -279  2015  [Not refereed][Not invited]
    Mathematical modeling has contributed to quantitative understanding of viral infections. The basic model,<b> </b><i>T'</i>(<i>t</i>)<i>=</i>-<i>βT</i>(<i>t</i>)<i>V</i>(<i>t</i>)<i>, I'</i>(<i>t</i>)<i>=βT</i>(<i>t</i>)<i>V</i>(<i>t</i>)-<i>δI</i>(<i>t</i>)<i> </i>and <i>V'</i>(<i>t</i>)<i>=pI</i>(<i>t</i>)-<i>cV</i>(<i>t</i>), has been analyzed which clinical or experimental data sets for many kinds of virus infections so far. However, in the basic model, we implicitly assume that punctual removal of cells and virions due to experimental sampling in cell cultures is described by an exponentially decay. However, the removal of cells and virions is performed instantaneously in viral infection experiments. Therefore, there might be differences among estimated parameters when we use the basic model or an explicit model including the punctual removal. Here, we constructed a hybrid dynamical model which describes the punctual removal by piecewise continuous function to the basic model. We analyzed time course of experimental data for SHIV-KS661 and SHIV-#64 infection <i>in vitro</i> by the basic model and the hybrid dynamical model, and compared the estimated parameters. Interestingly, we found that these two models give similar parameter estimations, and well capture the experimental virus infections. Our results provide a validation of the exponential decay assumption for the punctual removal in terms of parameter estimations.
  • NAKAOKA Shinji, AIHARA Kazuyuki  SEISAN KENKYU  65-  (3)  273  -280  2013  [Not refereed][Not invited]
    Helper T cells emerge from naive T cells via lineage commitment. Helper T cells play a pivotal role in adaptive immune response to remove antigen. Most of previous mathematical studies only consider either population dynamics of T cell clonal expansion or intracellular change of gene expression for transcription factors. In the present paper, on the other hand, we construct an individual based model which describes intra- and inter-cellular dynamics of T cell lineage commitment, and then carry out stochastic simulations to investigate how balance between two specific subsets is maintained. The method presented here can be effectively utilized to trace dynamics of a cell population such as immune cells which generically change their behavioral pattern during development.
  • NAKAOKA Shinji, AIHARA Kazuyuki  SEISAN KENKYU  63-  (3)  358  -369  2011  [Not refereed][Not invited]
    &nbsp;&nbsp;&nbsp; We review recent progress in mathematical study on hematopoietic stem cells. This review paper deals with theoretical investigations for two major issues on basic and clinical hematology: &ldquo;disorder of homeostasis in hematopoiesis&rdquo; and &ldquo;transplantation of hematopoietic stem cells&rdquo;. Several mathematical models are introduced to describe self-renewal and differentiation of hematopoietic stem cells. Finally, future potential applications of mathematical study to regenerative medicine and cancer treatment are discussed.<br>
  • NAKAOKA Shinji, TAKI Hisao, AIHARA Kazuyuki  SEISAN KENKYU  62-  (3)  235  -240  2010  [Not refereed][Not invited]
    In this review paper, we introduce recent progress in theoretical immunology, especially focusing on studies toward quantitative experiments for cell population growth and their mathematical models. We also show that, among mathematical models which have been independently developed by different authors, there exist similarities in terms of mathematical structure and underlying implicit assumptions.

Awards & Honors

  • 2009/09 日本数理生物学会 若手研究奨励賞
    受賞者: 中岡慎冶

Research Grants & Projects

Educational Activities

Teaching Experience

  • Inter-Graduate School Classes(General Subject):Inter-Disciplinary Sciences
    開講年度 : 2020
    課程区分 : 修士課程
    開講学部 : 大学院共通科目
    キーワード : データサイエンス,計算環境の再現性,計算環境の可搬性,推測統計,仮説検定,多変量解析,データ可視化
  • Soft Matter Design
    開講年度 : 2020
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : インフォマティクス, プログラミング, 確率統計, 機械学習, バイオインフォマティクス, ゲノムデータ
  • Bioinformation and Molecular Sciences
    開講年度 : 2020
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : インフォマティクス, プログラミング, 確率統計, 機械学習, バイオインフォマティクス, ゲノムデータ
  • Experimental Biological Science
    開講年度 : 2020
    課程区分 : 学士課程
    開講学部 : 理学部
    キーワード : 高分子機能学、実験技術、生命科学、物質科学、情報科学、融合科学
  • Exercise on Bioinformatics
    開講年度 : 2020
    課程区分 : 学士課程
    開講学部 : 理学部
    キーワード : 科学技術プログラミング、確率論、統計学、データ科学、バイオインフォマティクス、python, R

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