Researcher Profile and Settings

Master

Affiliation (Master)

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

Affiliation (Master)

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

researchmap

Profile and Settings

Affiliation

• Hokkaido University, Faculty of Advanced Life Science Division of Advanced Transdisciplinary Sciences

Degree

• Ph.D. of Science（Shizuoka University）

Profile and Settings

• Name (Japanese)

  Nakaoka

• Name (Kana)

  Shinji

• Name

  201401084616735532

Alternate Names

http://petadimension.org/
http://altair.sci.hokudai.ac.jp/infmcb/index-e.html

Affiliation

• Hokkaido University, Faculty of Advanced Life Science Division of Advanced Transdisciplinary Sciences

Achievement

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

Research Experience

• 2021/03 - Today Hokkaido University Faculty of Advanced Life Science Laboratory of mathematical biology Associate Professor
• 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

Education

• 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

Awards

• 2009/09 日本数理生物学会 若手研究奨励賞
   

  受賞者: 中岡慎冶

Published Papers

• Association between oral frailty and Prevotella percentage in the oral microbiota of community-dwelling older adults who participated in the CHEER Iwamizawa project, Japan.

  Chizuru Kimura, Kazuhito Miura, Yutaka Watanabe, Haruhisa Baba, Kimiya Ozaki, Akira Hasebe, Tokiyoshi Ayabe, Kiminori Nakamura, Shinji Nakaoka, Katsuhiko Ogasawara, Teppei Suzuki, Hiroshi Saito, Takashi Kimura, Akiko Tamakoshi, Yutaka Yamazaki

  Journal of oral rehabilitation 51 (9) 1721 - 1729 2024/06/08 

  BACKGROUND: Prevotella bacteria are associated with inherent diseases of the oral cavity, such as periodontal disease, and systemic diseases. Oral frailty (OF) has been associated with nursing necessity and death. However, the relationship between OF and oral microbiota has not been fully clarified. OBJECTIVE: This cross-sectional study investigated the association between OF and Prevotella percentage in the oral microbiota of community-dwelling older adults. METHODS: Oral bacteria species from saliva were identified in 208 community-dwelling older individuals aged ≥60 years in Japan. The proportion of Prevotella in the oral microbiota was classified into three tertile groups, and its relationship with each test item for OF (number of remaining teeth, masticatory performance, oral diadochokinesis, tongue pressure, difficulties eating tough foods, difficulties swallowing tea or soup, number of applicable OF judgement items, and existence of OF) was examined using ordinal logistic regression analysis. RESULTS: The Prevotella proportions were classified into lower, middle and upper groups, comprising 70, 69 and 69 participants, respectively. The three groups showed a significant relationship between the number of remaining teeth (odds ratio [OR]: 0.946, 95% confidence interval [CI]: 0.915-0.977), masticatory performance (OR: 0.897, 95% CI: 0.844-0.953), number of applicable OF judgement items (OR: 1.477, 95% CI: 1.14-1.915), and existence of OF (OR: 4.194, 95% CI: 1.519-11.576). CONCLUSION: The proportion of Prevotella in oral microbiota was high in individuals with OF. Among the older adults, the type of oral microbiota and systemic diseases may be related to the examination and management of oral function decline.
• Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation to analyze extracellular viral markers

  Kosaku Kitagawa, Kwang Su Kim, Masashi Iwamoto, Sanae Hayashi, Hyeongki Park, Takara Nishiyama, Naotoshi Nakamura, Yasuhisa Fujita, Shinji Nakaoka, Kazuyuki Aihara, Alan S. Perelson, Lena Allweiss, Maura Dandri, Koichi Watashi, Yasuhito Tanaka, Shingo Iwami

  PLOS Computational Biology 20 (3) e1011238 - e1011238 2024/03/11 

  Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.
• An energy landscape approach reveals the potential key bacteria contributing to the development of inflammatory bowel disease.

  Kaiyang Zhang, Shinji Nakaoka

  PloS one 19 (6) e0302151  2024 

  The dysbiosis of microbiota has been reported to be associated with numerous human pathophysiological processes, including inflammatory bowel disease (IBD). With advancements in high-throughput sequencing, various methods have been developed to study the alteration of microbiota in the development and progression of diseases. However, a suitable approach to assess the global stability of the microbiota in disease states through time-series microbiome data is yet to be established. In this study, we have introduced a novel Energy Landscape construction method, which incorporates the Latent Dirichlet Allocation (LDA) model and the pairwise Maximum Entropy (MaxEnt) model for their complementary advantages, and demonstrate its utility by applying it to an IBD time-series dataset. Through this approach, we obtained the microbial assemblages' energy profile of the whole microbiota under the IBD condition and uncovered the hidden stable stages of microbiota structure during the disease development with time-series microbiome data. The Bacteroides-dominated assemblages presenting in multiple stable states suggest the potential contribution of Bacteroides and interactions with other microbial genera, like Alistipes, and Faecalibacterium, to the development of IBD. Our proposed method provides a novel and insightful tool for understanding the alteration and stability of the microbiota under disease states and offers a more holistic view of the complex dynamics at play in microbiota-mediated diseases.
• Anti-HTLV-1 immunity combined with proviral load as predictive biomarkers for adult T-cell leukemia-lymphoma.

  Asami Yamada, Jun-Ichirou Yasunaga, Lihan Liang, Wenyi Zhang, Junya Sunagawa, Shinji Nakaoka, Shingo Iwami, Yasunori Kogure, Yuta Ito, Keisuke Kataoka, Masanori Nakagawa, Masako Iwanaga, Atae Utsunomiya, Ki-Ryang Koh, Toshiki Watanabe, Kisato Nosaka, Masao Matsuoka

  Cancer science 115 (1) 310 - 320 2023/11/10 

  Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV-1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV-1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV-1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV-1-infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti-Gag proteins to predict high risk group in HTLV-1 carriers. Consistent with this finding, anti-Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti-Gag CTLs for disease control. Our findings suggest that our strategy that combines anti-HTLV-1 antibodies and proviral load may be useful for prediction of the development of HTLV-1-associated diseases.
• Disentangling the growth curve of microbial culture

  Daiki Kumakura, Ryo Yamaguchi, Akane Hara, Shinji Nakaoka

  Journal of Theoretical Biology 573 111597 - 111597 0022-5193 2023/08 

  Many researchers have studied the population dynamics of microbe of microbes as a typical example of population dynamics. The Monod equation, which mainly focuses on the growth and stationary phases, is used when plotting a growth curve. However, the growth potential in the late stage of culture has been overlooked. Previous studies considered the direct degradation of products to the limiting substrate. In this study, we considered microbial growth during the stationary phase, which enables us to describe the dynamics precisely. The microbes were divided into two populations: one grew by consuming the limiting substrate and the other degraded the products by metabolism. According to the numerical analysis of our model, microbes may choose one of two strategies: one consumes substrates and expands quickly, and the other grows slowly while cleaning up the environment in which they thrive. Furthermore, we found three types of microbial growth depending on their ability to detect metabolite accumulation. Using experimentally measured data, this model can estimate the dynamics of cell density, the substrates, and the metabolites used. The model's disentangling of growth curves offers novel interpretive possibilities for culture system dynamics.
• Comparison of RNA-Seq analysis data between tracheal mite-infested and uninfested Japanese honey bees (Apis cerana japonica).

  Akihiko Suzuki, Masaki Kamakura, Takuya Shiramata, Shinji Nakaoka, Yoshiko Sakamoto

  BMC research notes 16 (1) 122 - 122 2023/06/26 

  OBJECTIVE: The purpose of this data set is to investigate differences in RNA-Seq transcriptome profiles between Acarapis woodi-infested and uninfested Japanese honey bees (Apis cerana japonica). The data set is strengthened by data collected from different body parts (head, thorax, and abdomen). The data set will support future studies of molecular biological changes in mite-infested honey bees. DATA DESCRIPTION: We collected 5 mite-infested and 5 uninfested A. cerana japonica workers from each of 3 different colonies (designated as A, B, and C). Workers were dissected into 3 body sites (i.e., heads, thoraces, and abdomen), and 5 of each body site were pooled together for RNA extraction, generating a total of 18 RNA-Seq samples (2 infection status × 3 colonies × 3 body sites). FASTQ data files of each sample that were generated by a DNBSEQ-G400 sequencer with the 2 × 100 bp paired-end sequencing protocol are available in the DDBJ Sequence Read Archive under accession number DRA015087 (RUN: DRR415616-DRR415633, BioProject: PRJDB14726, BioSample: SAMD00554139-SAMD00554156, Experiment: DRX401183-DRX401200). The data set is a fine-scale analysis of gene expression in the mite-infested A. cerana japonica workers because 18 RNA-Seq samples are separated by 3 body sites.
• 岩見沢市母子健康調査(SMILE Iwamizawa)における妊娠期から出産後の母体腸内細菌叢解析

  和泉 裕久, 両角 麻衣, 田畑 風華, 川上 智美, 武田 安弘, 宮地 一裕, 中村 公則, 綾部 時芳, 中岡 慎治, 相沢 智康, 中村 宝弘, 木村 尚史, 中村 幸志, 玉腰 暁子

  腸内細菌学雑誌 (公財)腸内細菌学会 37 (2) 122 - 122 1343-0882 2023/04
• 岩見沢市母子健康調査(SMILE Iwamizawa)における乳児の腸内細菌叢解析

  両角 麻衣, 和泉 裕久, 田畑 風華, 川上 智美, 武田 安弘, 宮地 一裕, 中村 公則, 綾部 時芳, 中岡 慎治, 相沢 智康, 中村 宝弘, 木村 尚史, 中村 幸志, 玉腰 暁子

  腸内細菌学雑誌 (公財)腸内細菌学会 37 (2) 123 - 123 1343-0882 2023/04
• Data mining for prediction and interpretation of bacterial population behavior in food

  Junpei Hosoe, Junya Sunagawa, Shinji Nakaoka, Shige Koseki, Kento Koyama

  Frontiers in Food Science and Technology 2 2022/12/15 

  Although bacterial population behavior has been investigated in a variety of foods in the past 40 years, it is difficult to obtain desired information from the mere juxtaposition of experimental data. We predicted the changes in the number of bacteria and visualize the effects of pH, a_w, and temperature using a data mining approach. Population growth and inactivation data on eight pathogenic and food spoilage bacteria under 5,025 environmental conditions were obtained from the ComBase database (www.combase.cc), including 15 food categories, and temperatures ranging from 0°C to 25°C. The eXtreme gradient boosting tree was used to predict population behavior. The root mean square error of the observed and predicted values was 1.23 log CFU/g. The data mining model extracted the growth inhibition for the investigated bacteria against a_w, temperature, and pH using the SHapley Additive eXplanations value. A data mining approach provides information concerning bacterial population behavior and how food ecosystems affect bacterial growth and inactivation.
• COVID-19-related stress, exercise, and oral health-related quality of life among community-dwelling older adults who participated in the CHEER Iwamizawa project, Japan.

  Kazuhito Miura, Yutaka Watanabe, Haruhisa Baba, Kimiya Ozaki, Takae Matsushita, Miyako Kondoh, Kazutaka Okada, Shinji Nakaoka, Katsuhiko Ogasawara, Teppei Suzuki, Hiroshi Saito, Takashi Kimura, Akiko Tamakoshi, Yutaka Yamazaki

  Scientific reports 12 (1) 20347 - 20347 2022/11/27 [Refereed][Not invited]
   

  This study examined the association between coronavirus disease 2019 (COVID-19)-related stress, exercise habits, and oral health-related quality of life (OHRQoL) in a sample of 215 community-dwelling older adults in Japan (57 men, 158 women; Mage = 74.2 years, SD = 6.0). Data were collected during wellness checkups in October 2020 and included participants' demographic characteristics, measures of instrumental activities of daily living and depressive tendencies, number of teeth, oral hypofunction, OHRQoL, COVID-19-related stress, and exercise habits. Four mutually exclusive groups were created, using the presence or absence of COVID-19-related stress and lack of exercise habits as risk factors for poor OHRQoL (no COVID-19-related stress and no lack of exercise, COVID-19-related stress only, lack of exercise habits only, and both COVID-19-related stress and lack of exercise habits). Poisson regression with robust standard errors provided the prevalence ratio for poor OHRQoL. The presence of both COVID-19-related stress and lack of exercise habits (adjusted prevalence ratio: 2.20, 95% CI: 1.31- 3.69) was associated with poor OHRQoL. The results indicate that COVID-19-related stress and exercise habits should be considered when designing oral health and public health initiatives.
• Evolving neural networks through bio-inspired parent selection in dynamic environments.

  Junya Sunagawa, Ryo Yamaguchi, Shinji Nakaoka

  Bio Systems 218 104686 - 104686 2022/05/04 

  Environmental variability often degrades the performance of algorithms designed to capture the global convergence of a given search space. Several approaches have been developed to challenge environmental uncertainty by incorporating biologically inspired notions, focusing on crossover, mutation, and selection. This study proposes a bio-inspired approach called NEAT-HD, which focuses on parent selection based on genetic similarity. The originality of the proposed approach rests on its use of a sigmoid function to accelerate species formation and contribute to population diversity. Experiments on two classic control tasks were performed to demonstrate the performance of the proposed method. The results show that NEAT-HD can dynamically adapt to its environment by forming hybrid individuals originating from genetically distinct parents. Additionally, an increase in diversity within the population was observed due to the formation of hybrids and novel individuals, which has never been observed before. Comparing two tasks, the characteristics of NEAT-HD were improved by appropriately setting the algorithm to include the distribution of genetic distance within the population. Our key finding is the inherent potential of newly formed individuals for robustness against dynamic environments.
• Analysis of the Pancreatic Cancer Microbiome Using Endoscopic Ultrasound-Guided Fine-Needle Aspiration-Derived Samples.

  Shintaro Nakano, Yasuyuki Kawamoto, Yoshito Komatsu, Rika Saito, Ken Ito, Takahiro Yamamura, Kazuaki Harada, Satoshi Yuki, Kazumichi Kawakubo, Ryo Sugiura, Shin Kato, Koji Hirata, Hajime Hirata, Masahito Nakajima, Ryutaro Furukawa, Yunosuke Takishin, Kousuke Nagai, Isao Yokota, Keisuke H Ota, Shinji Nakaoka, Masaki Kuwatani, Naoya Sakamoto

  Pancreas 51 (4) 351 - 357 2022/04/01 

  OBJECTIVES: Most previous studies have analyzed bacteria in tumors using resected pancreatic cancer (PC) tissues, because it is difficult to obtain tissue samples from unresectable advanced PC. We aimed to determine whether minimal tissue obtained by endoscopic ultrasound-guided fine-needle aspiration is useful for microbiome analysis. METHODS: Thirty PC and matched duodenal and stomach tissues (N = 90) were prospectively collected from 30 patients who underwent endoscopic ultrasound-guided fine-needle aspiration. Bacterial DNA was extracted, and 16S rRNA sequencing was performed. The primary outcome was the success rate of bacterial detection in tumors. Bacterial diversity and structure were investigated. RESULTS: The bacterial detection rates were 80%, 100%, and 97% in PC, gastric, and duodenal samples, respectively. Pancreatic cancer tissues showed a lower α-diversity and a significantly different microbial structure than stomach and duodenal tissues. Proteobacteria were more abundant, whereas Firmicutes, Bacteroidetes, and Fusobacteria were less abundant in PC tissues than in stomach and duodenal tissues. Acinetobacter was more abundant in PC tissues than in stomach and duodenal tissues, and Delftia was more frequently detected in resectable PC. CONCLUSIONS: Endoscopic ultrasound-guided fine-needle aspiration samples were valuable for PC microbiome analysis, revealing that the bacterial composition of PC is different from that of the stomach and duodenum.
• Antithetic effect of interferon-α on cell-free and cell-to-cell HIV-1 infection.

  Ryuichi Kumata, Shoya Iwanami, Katrina B Mar, Yusuke Kakizoe, Naoko Misawa, Shinji Nakaoka, Yoshio Koyanagi, Alan S Perelson, John W Schoggins, Shingo Iwami, Kei Sato

  PLoS computational biology 18 (4) e1010053  2022/04 

  In HIV-1-infected individuals, transmitted/founder (TF) virus contributes to establish new infection and expands during the acute phase of infection, while chronic control (CC) virus emerges during the chronic phase of infection. TF viruses are more resistant to interferon-alpha (IFN-α)-mediated antiviral effects than CC virus, however, its virological relevance in infected individuals remains unclear. Here we perform an experimental-mathematical investigation and reveal that IFN-α strongly inhibits cell-to-cell infection by CC virus but only weakly affects that by TF virus. Surprisingly, IFN-α enhances cell-free infection of HIV-1, particularly that of CC virus, in a virus-cell density-dependent manner. We further demonstrate that LY6E, an IFN-stimulated gene, can contribute to the density-dependent enhancement of cell-free HIV-1 infection. Altogether, our findings suggest that the major difference between TF and CC viruses can be explained by their resistance to IFN-α-mediated inhibition of cell-to-cell infection and their sensitivity to IFN-α-mediated enhancement of cell-free infection.
• Oral frailty and carriage of oral Candida in community-dwelling older adults (Check-up to discover Health with Energy for senior Residents in Iwamizawa; CHEER Iwamizawa).

  Haruhisa Baba, Yutaka Watanabe, Kazuhito Miura, Kimiya Ozaki, Takae Matsushita, Miyako Kondoh, Kazutaka Okada, Akira Hasebe, Tokiyoshi Ayabe, Kiminori Nakamura, Shinji Nakaoka, Katsuhiko Ogasawara, Teppei Suzuki, Hiroshi Saito, Takashi Kimura, Akiko Tamakoshi, Yutaka Yamazaki

  Gerodontology 39 (1) 49 - 58 2022/03 

  OBJECTIVE: To examine the association between oral frailty and oral Candida carriage as a general indicator of deteriorating oral function in older adults. BACKGROUND: Older adults exhibit an elevated risk of oral candidiasis caused by Candida. Although many studies have identified factors associated with oral Candida carriage, none have evaluated its relationship with oral function. MATERIALS AND METHODS: This study included 210 community-dwelling older adults aged ≥60 years who participated in wellness checks. Fungal flora expression in saliva samples was evaluated to identify oral C. albicans and C. glabrata. Participants were categorised by detection of neither strain (group 1), either one of the strains (group 2), or both strains (group 3). The relationship between oral Candida carriage and oral frailty was evaluated by multinomial logistic regression analysis. RESULTS: The participants included 58 men and 152 women with a mean age of 74.2 ± 6.1 years. A total of 88 (41.9%), 94 (44.8%) and 28 (13.3%) participants were assigned to groups 1, 2 and 3 respectively. In the multinomial logistic regression analysis, significant associations were observed between group 1 and group 2 for "Have you choked on your tea or soup recently?" and the number of applicable oral frailty items. Between group 1 and group 3, significant associations were observed for the number of remaining teeth, masticatory performance and the number of applicable oral frailty items. CONCLUSION: We obtained basic data useful for intervention studies aimed at verifying whether oral function management prevents deterioration of the oral bacterial flora.
• Chemical-Mediated Microbial Interactions Can Reduce the Effectiveness of Time-Series-Based Inference of Ecological Interaction Networks.

  Kenta Suzuki, Masato S Abe, Daiki Kumakura, Shinji Nakaoka, Fuki Fujiwara, Hirokuni Miyamoto, Teruno Nakaguma, Mashiro Okada, Kengo Sakurai, Shohei Shimizu, Hiroyoshi Iwata, Hiroshi Masuya, Naoto Nihei, Yasunori Ichihashi

  International journal of environmental research and public health 19 (3) 2022/01/22 

  Network-based assessments are important for disentangling complex microbial and microbial-host interactions and can provide the basis for microbial engineering. There is a growing recognition that chemical-mediated interactions are important for the coexistence of microbial species. However, so far, the methods used to infer microbial interactions have been validated with models assuming direct species-species interactions, such as generalized Lotka-Volterra models. Therefore, it is unclear how effective existing approaches are in detecting chemical-mediated interactions. In this paper, we used time series of simulated microbial dynamics to benchmark five major/state-of-the-art methods. We found that only two methods (CCM and LIMITS) were capable of detecting interactions. While LIMITS performed better than CCM, it was less robust to the presence of chemical-mediated interactions, and the presence of trophic competition was essential for the interactions to be detectable. We show that the existence of chemical-mediated interactions among microbial species poses a new challenge to overcome for the development of a network-based understanding of microbiomes and their interactions with hosts and the environment.
• Energy landscape analysis elucidates the multistability of ecological communities across environmental gradients

  Kenta Suzuki, Shinji Nakaoka, Shinji Fukuda, Hiroshi Masuya

  ECOLOGICAL MONOGRAPHS 91 (3) 0012-9615 2021/08 

  Compositional multistability is widely observed in multispecies ecological communities. Since differences in community composition often lead to differences in community function, understanding compositional multistability is essential to comprehend the role of biodiversity in maintaining ecosystems. In community assembly studies, it has long been recognized that the order and timing of species migration and extinction influence structure and function of communities. The study of multistability in ecology has focused on the change in dynamical stability across environmental gradients, and was developed mainly for low-dimensional systems. As a result, methodologies for studying the compositional stability of empirical multispecies communities are not well developed. Here, we show that models previously used in ecology can be analyzed from a new perspective, the energy landscape, to unveil compositional stability in observational data. To show that our method can be applicable to real-world ecological communities, we simulated assembly dynamics driven by population-level processes, and show that results were mostly robust to different simulation assumptions. Our method reliably captured the change in the overall compositional stability of multispecies communities over environmental change, and indicated a small fraction of community compositions that may be channels for transitions between stable states. When applied to murine gut microbiota, our method showed the presence of two alternative states whose relationship changes with age, and suggested mechanisms by which aging affects the compositional stability of the murine gut microbiota. Our method provides a practical tool to study the compositional stability of communities in a changing world, and will facilitate empirical studies that integrate the concept of multistability from different fields.
• Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials: A modeling study.

  Shoya Iwanami, Keisuke Ejima, Kwang Su Kim, Koji Noshita, Yasuhisa Fujita, Taiga Miyazaki, Shigeru Kohno, Yoshitsugu Miyazaki, Shimpei Morimoto, Shinji Nakaoka, Yoshiki Koizumi, Yusuke Asai, Kazuyuki Aihara, Koichi Watashi, Robin N Thompson, Kenji Shibuya, Katsuhito Fujiu, Alan S Perelson, Shingo Iwami, Takaji Wakita

  PLoS medicine 18 (7) e1003660  2021/07 

  BACKGROUND: Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials. METHODS AND FINDINGS: A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d-1 (95% CI: 1.06 to 1.27 d-1), 0.777 d-1 (0.716 to 0.838 d-1), and 0.450 d-1 (0.378 to 0.522 d-1) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. CONCLUSIONS: In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.
• Development of a rapid scabies immunodiagnostic assay based on transcriptomic analysis of Sarcoptes scabiei var. nyctereutis.

  Teruo Akuta, Daisuke Minegishi, Nobuhide Kido, Keitaro Imaizumi, Shinji Nakaoka, Shin-Ichiro Tachibana, Kenji Hikosaka, Fumi Hori, Masataka, Nakagawa, Chiaki Sakuma, Yuki Oouchi, Yu Nakajima, Sohei Tanaka, Tomoko Omiya, Kouki Morikaku, Minori Kawahara, Yoshifumi Tada, Hiroshi Tarui, Takafumi Ueda, Takane Kikuchi-Ueda, Yasuo Ono

  Scientific reports 11 (1) 6455 - 6455 2021/03/19 

  Scabies is a highly contagious skin disease caused by the mite Sarcoptes scabiei that affects many mammals. However, the sensitivity of traditional tests for scabies diagnosis in humans is less than 50%. To simplify the diagnosis of scabies, methods that are simple, sensitive, specific, and cost-effective are required. We developed an immunodiagnostic test based on S. scabiei var. nyctereutis RNA-seq data collected from Japanese raccoon dogs with sarcoptic mange. Three candidate antigens-a highly expressed hypothetical protein "QR98_0091190," another mite allergen known as "SMIPP-Cc," and an abundant "vitellogenin-like protein"-were evaluated by western-blot analysis. A lateral flow immunoassay, using specific antibodies against the vitellogenin-like protein, successfully detected scabies in the skin flakes of S. scabiei-infected raccoon dogs. This assay can potentially diagnose scabies more accurately in wildlife, as well as in humans.
• A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2.

  Kwang Su Kim, Keisuke Ejima, Shoya Iwanami, Yasuhisa Fujita, Hirofumi Ohashi, Yoshiki Koizumi, Yusuke Asai, Shinji Nakaoka, Koichi Watashi, Kazuyuki Aihara, Robin N Thompson, Ruian Ke, Alan S Perelson, Shingo Iwami

  PLoS biology 19 (3) e3001128  2021/03 

  The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2-3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.
• Early Dynamics of Chronic Myeloid Leukemia on Nilotinib Predicts Deep Molecular Response

  Yuji Okamoto, Mitsuhito Hirano, Kai Morino, Masashi K. Kajita, Shinji Nakaoka, Mayuko Tsuda, Kei-ji Sugimoto, Shigehisa Tamaki, Junichi Hisatake, Hisayuki Yokoyama, Tadahiko Igarashi, Atsushi Shinagawa, Takeaki Sugawara, Satoru Hara, Kazuhisa Fujikawa, Seiichi Shimizu, Toshiaki Yujiri, Hisashi Wakita, Kaichi Nishiwaki, Arinobu Tojo, Kazuyuki Aihara

  NPJ systems biology and applications 8 (1) 39 - 39 2021/02/17 

  Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase^1,2. ABL1-selective tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML^3–7. The ultimate goal of CML treatment is likely to be TKI-free maintenance of deep molecular response (DMR), which is defined by quantitative measurement of BCR-ABL1 transcripts on the international scale (IS)⁸, and durable DMR is a prerequisite to reach this goal⁹. Thus, an algorithm to enable the early prediction of DMR achievement on TKI therapy is quite valuable. Here, we show that our mathematical framework based on a clinical trial dataset¹⁰ can accurately predict the response to frontline nilotinib. We found that our simple dynamical model can predict nilotinib response by using two common laboratory findings (observation values): IS^11,12 and white blood cell (WBC) count. Furthermore, our proposed method identified patients who failed to achieve DMR with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs in clinical practice. Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. The goal of this treatment is the sequential achievement of deep molecular response (DMR). Tyrosine kinase inhibitors (TKIs) are effective in the reduction because they inhibit CML cell proliferation. However, because of individual differences in the TKI efficacy, some patients are unable to achieve DMR, so that early prediction of DMR reachability is necessary for personalized medicine. By combining time series analysis and mathematical modeling, we developed a mathematical method that accurately predicts patients who do not achieve DMR in the early stages of TKI administration. Our prediction method gives a basis of effective personalized treatments for CML patients.
• Exploring Similarity Between Embedding Dimension of Time-Series Data and Flows of an Ecological Population Model

  Daiki Kumakura, Shinji Nakaoka

  Springer Proceedings in Mathematics and Statistics 370 69 - 80 2194-1017 2021 

  Cancer cells interact with tissue cells in a complex manner. Immune cells had that initially participated in eliminating cancer cells are often educated to become assisting cancer growth. Identifying causal relationship of cellular interactions that mediate cancer progression is crucial to understand how cancer cells grow, evolve, and persist. A mathematical model that describes dynamics of cancer cell population is constructed based on a given causal relationship among model ingredients. Mathematical modeling has been employed to explain cancer progression patterns in terms of dynamical system.
• Dynamic Associations of Milk Components With the Infant Gut Microbiome and Fecal Metabolites in a Mother-Infant Model by Microbiome, NMR Metabolomic, and Time-Series Clustering Analyses.

  Yosuke Komatsu, Daiki Kumakura, Namiko Seto, Hirohisa Izumi, Yasuhiro Takeda, Yuki Ohnishi, Shinji Nakaoka, Tomoyasu Aizawa

  Frontiers in nutrition 8 813690 - 813690 2021 

  Background: The gut microbiome and fecal metabolites of breastfed infants changes during lactation, and are influenced by breast milk components. This study aimed to investigate dynamic associations of milk components with the infant gut microbiome and fecal metabolites throughout the lactation period in a mother-infant model. Methods: One month after delivery, breast milk and subsequent infant feces were collected in a pair for 5 months from a mother and an exclusively breastfed infant. Composition of the fecal microbiome was determined with 16S rRNA sequencing. Low-molecular-weight metabolites, including human milk oligosaccharides (HMOs), and antibacterial proteins were measured in feces and milk using 1H NMR metabolomics and enzyme-linked immunosorbent assays. The association of milk bioactive components with the infant gut microbiome and fecal metabolites was determined with Python clustering and correlation analyses. Results: The HMOs in milk did not fluctuate throughout the lactation period. However, they began to disappear in infant feces at the beginning of month 4. Notably, at this time-point, a bifidobacterium species switching (from B. breve to B. longum subsp. infantis) occurred, accompanied by fluctuations in several metabolites including acetate and butyrate in infant feces. Conclusions: Milk bioactive components, such as HMOs, might play different roles in the exclusively breastfed infants depending on the lactation period.
• Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element.

  Kwang Su Kim, Yusuke Yamamoto, Shinji Nakaoka, Keizo Tomonaga, Shingo Iwami, Tomoyuki Honda

  Journal of virology 94 (21) 2020/10/14 

  Endogenous retroviruses have demonstrated exaptation during long-term evolution with hosts, e.g., resulting in acquisition of antiviral effect on related extant viral infections. While empirical studies have found that an endogenous bornavirus-like element derived from viral nucleoprotein (itEBLN) in the ground squirrel genome shows antiviral effect on virus replication and de novo infection, the antiviral mechanism, dynamics, and quantitative effect of itEBLN remain unknown. In this study, we experimentally and theoretically investigated the dynamics of how an extant bornavirus, Borna disease virus 1 (BoDV-1), spreads and replicates in uninfected, BoDV-1-infected, and itEBLN-expressing cultured cells. Quantifying antiviral effect based on time course data sets, we found that the antiviral effects of itEBLN are estimated to be 75% and 34% on intercellular virus spread and intracellular virus replication, respectively. This discrepancy between intercellular virus spread and intracellular viral replication suggests that viral processes other than the replication of viral ribonucleoprotein complex (RNP) contributed to the suppression of virus spread in itEBLN-expressing cells. Because itEBLN binds to the BoDV-1 RNP, the suppression of viral RNP trafficking can be an attractive candidate explaining this discrepancy.IMPORTANCE Accumulating evidence suggests that some endogenous viral elements (EVEs), including endogenous retroviruses and endogenous nonretroviral virus elements, have acquired functions in the host as a result of long-term coevolution. Recently, an endogenous bornavirus-like element (itEBLN) found in the ground squirrel genome has been shown to have antiviral activity against exogenous bornavirus infection. In this study, we first quantified bornavirus spread in cultured cells and then calculated the antiviral activity of itEBLN on bornavirus infection. The calculated antiviral activity of itEBLN suggests its suppression of multiple processes in the viral life cycle. To our knowledge, this is the first study quantifying the antiviral activity of EVEs and speculating on a model of how some EVEs have acquired antiviral activity during host-virus arms races.
• Quantifying the antiviral effect of APOBEC3 on HIV-1 infection in humanized mouse model

  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]
   

  APOBEC3 proteins inhibit human immunodeficiency virus (HIV)-1 infection by independently impairing viral reverse transcription and inducing G-to-A mutations in viral DNA. An HIV-1-encoded protein, viral infectivity factor (Vif), can counteract these antiviral activities of APOBEC3 proteins. Although previous studies using in vitro cell culture systems have revealed the molecular mechanisms of the antiviral action of APOBEC3 proteins and their antagonism by Vif, it remains unclear how APOBEC3 proteins affect the kinetics of HIV-1 replication in vivo. Here we quantified the time-series of viral load datasets from humanized mice infected with HIV-1 variants in the presence of APOBEC3F, APOBEC3G, or both APOBEC3F/G using a simple mathematical model that accounted for inter-individual variability. Through experimental and mathematical investigation, we formulated and calculated the total antiviral activity of APOBEC3F and APOBEC3G based on the estimated initial growth rates of viral loads in vivo. Interestingly, we quantitatively demonstrated that compared with APOBEC3G, the antiviral activity of APOBEC3F was widely distributed but skewed toward lower activity, although their mean values were similar. We concluded that APOBEC3G markedly and robustly restricted the initial stages of viral growth in vivo. This is the first report to quantitatively elucidate how APOBEC3F and APOBEC3G differ in their anti-HIV-1 modes in vivo.
• Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma

  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]
   

  Virus proliferation involves gene replication inside infected cells and transmission to new target cells. Once positive-strand RNA virus has infected a cell, the viral genome serves as a template for copying ("stay-strategy") or is packaged into a progeny virion that will be released extracellularly ("leave-strategy"). The balance between genome replication and virion release determines virus production and transmission efficacy. The ensuing trade-off has not yet been well characterized. In this study, we use hepatitis C virus (HCV) as a model system to study the balance of the two strategies. Combining viral infection cell culture assays with mathematical modeling, we characterize the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral release characteristics. We found that 0.63% and 1.70% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial proliferation rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leave-strategy provides a higher level of initial transmission for Jc1-n, whereas, in contrast, the stay-strategy provides a higher initial proliferation rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses, which contributes to the efficient control of virus transmission. Ours is the first study to analyze the stay-leave trade-off during the viral life cycle and the significance of the replication-release switching mechanism for viral proliferation.
• Multiomics Investigation Revealing the Characteristics of HIV-1-Infected Cells In Vivo.

  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.
• 桑葉摂取によるα-defensinと腸内細菌叢の経時変化に対する統計解析

  子安 惟, 中岡 慎治, 菊池 摩仁, 中村 公則, 綾部 時芳

  腸内細菌学雑誌 (公財)腸内細菌学会 34 (2) 123 - 123 1343-0882 2020/04
• An information and statistical analysis pipeline for microbial metagenomic sequencing data

  Shinji Nakaoka, Keisuke H. Ota

  Handbook of Statistics 0169-7161 2020 

  Metagenomic sequencing produces massive collections of genomic reads in an unspecific manner, enabling profiling a given microbial community. Information processing of metagenomic data followed by data analysis and mining is indispensable to obtain proper interpretations and implications for a microbial community. A variety of data analysis and mining techniques have contributed to extract essential associations that constitute a microbial community. In the present chapter, brief overviews for popular methods are introduced to cover necessary procedures to analyze microbial metagenomic data.
• Information and Statistical Analysis Pipeline for High-Throughput RNA Sequencing Data.

  Shinji Nakaoka, Keita Matsuyama

  Methods in molecular biology (Clifton, N.J.) 2109 199 - 208 2020 

  Applications of RNA sequencing have been wide-spreading in various subfields of life science. Construction of information and statistical analysis pipeline is indispensable to process raw RNA sequencing (RNA-seq) data generated by next-generation sequencers in order to extract biological implications. In this chapter, we introduce a common pipeline for RNA-seq data. A collection of notes on related advanced topics will be useful when conducting information and statistical analysis in practice.
• A mathematical model for dynamics of soluble form of DNAM-1 as a biomarker for graft-versus-host disease.

  Yuki Goshima, Shinji Nakaoka, Kazuteru Ohashi, Hisashi Sakamaki, Kazuko Shibuya, Akira Shibuya

  PloS one 15 (2) e0228508  2020 

  DNAM-1 (CD226) is an activating immunoreceptor expressed on T cells and NK cells and involved in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously reported that a soluble form of DNAM-1 (sDNAM-1) is generated by shedding from activated T cells. Moreover, higher serum levels of sDNAM-1 in patients before allo-HSCT is a predictive biomarker for the development of aGVHD based on the retrospective univariate and multivariate analyses in allo-HSCT patients. However, it remains unclear how the serum levels of sDNAM-1 are regulated after allo-HSCT and whether they are associated with the development of aGVHD. Here, we constructed a mathematical model to assess the dynamics of sDNAM-1 after allo-HSCT by assuming that there are three types of sDNAM-1 (the first and the second were from alloreactive and non-alloreactive donor lymphocytes, respectively, and the third from recipient lymphocytes). Our mathematical model fitted well to the data set of sDNAM-1 in patients (n = 67) who had undergone allo-HSCT and suggest that the high proportion of the first type of sDNAM-1 to the total of the first and second types is associated with high risk of the development of severe aGVHD. Thus, sDNAM-1 after allo-HSCT can be a biomarker for the development of aGVHD.
• The Rules of Human T Cell Fate in vivo.

  Pedro Costa Del Amo, Bisrat Debebe, Milad Razavi-Mohseni, Shinji Nakaoka, Andrew Worth, Diana Wallace, Peter Beverley, Derek Macallan, Becca Asquith

  Frontiers in immunology 11 573 - 573 2020 

  The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells in vitro, lymphocyte fate is age-dependent and that younger cells (i.e., cells which have recently divided) are less likely to divide or die. Here we investigate whether the same rules determine human T cell fate in vivo. We combined data from in vivo stable isotope labeling in healthy humans with stochastic, agent-based mathematical modeling. We show firstly that the choice of model paradigm has a large impact on parameter estimates obtained using stable isotope labeling i.e., different models fitted to the same data can yield very different estimates of T cell lifespan. Secondly, we found no evidence in humans in vivo to support the model in which younger T cells are less likely to divide or die. This age-dependent model never provided the best description of isotope labeling; this was true for naïve and memory, CD4+ and CD8+ T cells. Furthermore, this age-dependent model also failed to predict an independent data set in which the link between division and death was explored using Annexin V and deuterated glucose. In contrast, the age-independent model provided the best description of both naïve and memory T cell dynamics and was also able to predict the independent dataset.
• Revealing uninfected and infected target cell dynamics from peripheral blood data in highly and less pathogenic simian/human immunodeficiency virus infected Rhesus macaque.

  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.
• T-Cell mediated adaptive immunity and antibody-dependent enhancement in secondary dengue infection.

  Sourav Kumar Sasmal, Yasuhiro Takeuchi, Shinji Nakaoka

  Journal of theoretical biology 470 50 - 63 2019/06/07 

  Dengue infection results in a significant number of deaths, mostly in the tropical and subtropical regions across the world. Yet, despite the seriousness of this disease, vaccine, and antiviral drugs that could be employed in dengue treatment remain elusive. The desire to establish the factors determining the disease severity and the growing need for efficient drugs has prompted extensive research interest in within-host viral dynamics. However, very few mathematical models of within-host dengue dynamics pertaining to secondary dengue infection with another serotype are presently available. To address this gap in the pertinent literature, in this work, a secondary dengue infection model with T-cell mediated adaptive immunity and antibody-dependent enhancement was developed by considering the memory cell and heterogeneous antibody as the main factor. In particular, the explicit role of cytokines is considered for both virus and infected cell clearance, along with both extrinsic and intrinsic mechanisms for antibody-dependent enhancement. In case of secondary dengue infection, both the virus and homogeneous antibody production are enhanced due to the influence of memory cells remaining from the previous (primary) dengue infection. Owing to the high model sensitivity, it was possible to establish that, among antibody-dependent enhancement mechanisms, the increased virus replication inside the infected cell, which increases the overall virus burst size, exerts the maximum effect on disease severity during secondary infection. Moreover, the role of initial memory cell concentrations and half-saturation constant in the secretion of memory cell in the disease severity was studied. The obtained results concur with the clinical observations and may be helpful in further research on antibody-dependent enhancements aimed at producing schemes relevant for the dengue vaccine design and development.
• Mathematical Analysis of a Transformed ODE from a PDE Multiscale Model of Hepatitis C Virus Infection

  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]
  
• Calculation of final size for vector-transmitted epidemic model.

  Yu Tsubouchi, Yasuhiro Takeuchi, Shinji Nakaoka

  Mathematical biosciences and engineering : MBE 16 (4) 2219 - 2232 2019/03/15 

  Calculation of final size of an epidemic model offers a useful estimation for the impact of an epidemic. Despite its usefulness, the majority of practical applications focuses on the classical Kermack McKendrick model for final size calculation. Estimation of final size for different types of epidemics such as vector-transmitted infection is a forthcoming target. In this paper, we derive an explicit form of a final size equation for a vector-transmitted epidemic model. Numerical calculation of a final size equation revealed the existence of a threshold curve which separates a region into two distinct bistable sub-regions if infection induced death is present. In other words, an epidemic outcome can be qualitatively different depending on the initial state of an epidemic.
• A mathematical model of multiple delayed feedback control system of the gut microbiota—Antibiotics injection controlled by measured metagenomic data

  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.
• Publisher Correction: Core microbiomes for sustainable agroecosystems.

  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 - 733 2018/09 [Refereed][Not invited]
   

  Owing to a technical error, this Perspective was originally published without its received and accepted dates; the dates "Received: 31 December 2017; Accepted: 23 March 2018" have now been included in all versions.
• A PDE multiscale model of hepatitis C virus infection can be transformed to a system of ODEs

  Kosaku Kitagawa, Shinji Nakaoka, Yusuke Asai, Koichi Watashi, Shingo Iwami

  Journal of Theoretical Biology 448 80 - 85 0022-5193 2018/07 [Refereed][Not invited]
  
• Delayed feedback induced complex dynamics in an Escherichia coli and Tetrahymena system

  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.
• Core microbiomes for sustainable agroecosystems.

  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]
   

  In an era of ecosystem degradation and climate change, maximizing microbial functions in agroecosystems has become a prerequisite for the future of global agriculture. However, managing species-rich communities of plant-associated microbiomes remains a major challenge. Here, we propose interdisciplinary research strategies to optimize microbiome functions in agroecosystems. Informatics now allows us to identify members and characteristics of 'core microbiomes', which may be deployed to organize otherwise uncontrollable dynamics of resident microbiomes. Integration of microfluidics, robotics and machine learning provides novel ways to capitalize on core microbiomes for increasing resource-efficiency and stress-resistance of agroecosystems.
• Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells

  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.
• The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function.

  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.
• Human-Specific Adaptations in Vpu Conferring Anti-tetherin Activity Are Critical for Efficient Early HIV-1 Replication In Vivo

  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.
• Erratum to: Daphnia revisited: local stability and bifurcation theory for physiologically structured population models explained by way of an example (Journal of Mathematical Biology, (2010), 61, 2, (277-318), 10.1007/s00285-009-0299-y)

  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).
• Daphnia revisited: local stability and bifurcation theory for physiologically structured population models explained by way of an example (vol 61, pg 277, 2010)

  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]
  
• Number of infection events per cell during HIV-1 cell-free infection

  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.
• HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation

  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.
• HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation

  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.
• A highly pathogenic simian/human immunodeficiency virus effectively produces infectious virions compared with a less pathogenic virus in cell culture

  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.
• Modelling Ebola virus dynamics: Implications for therapy

  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.
• Chronic Inflammation in the Epidermis: A Mathematical Model

  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.
• Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

  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.
• Weighted enrichment method for prediction of transcription regulators from transcriptome and global chromatin immunoprecipitation data

  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.
• New algorithm for constructing area-based index with geographical heterogeneities and variable selection: An application to gastric cancer screening

  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.
• Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model

  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.
• Dynamics of HIV infection in lymphoid tissue network

  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.
• Mathematical modeling and analysis of combinational immune boost for tumor elimination

  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.
• Identifying determinants of heterogeneous transmission dynamics of the Middle East respiratory syndrome (MERS) outbreak in the Republic of Korea, 2015: a retrospective epidemiological analysis

  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.
• Dynamical behavior of combinational immune boost against tumor

  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.
• Cell-to-cell infection by HIV contributes over half of virus infection

  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.
• Insecticide applications to soil contribute to the development of Burkholderia mediating insecticide resistance in stinkbugs.

  Tago, K, Kikuchi, Y, Nakaoka, S, Katsuyama, C, Hayatsu, M

  Molecular Ecology 24 (14) 3766 - 3788 0962-1083 2015/07 [Refereed][Not invited]
   

  Some soil Burkholderia strains are capable of degrading the organophosphorus insecticide, fenitrothion, and establish symbiosis with stinkbugs, making the host insects fenitrothion-resistant. However, the ecology of the symbiotic degrading Burkholderia adapting to fenitrothion in the free-living environment is unknown. We hypothesized that fenitrothion applications affect the dynamics of fenitrothion-degrading Burkholderia, thereby controlling the transmission of symbiotic degrading Burkholderia from the soil to stinkbugs. We investigated changes in the density and diversity of culturable Burkholderia (i.e. symbiotic and nonsymbiotic fenitrothion degraders and nondegraders) in fenitrothion-treated soil using microcosms. During the incubation with five applications of pesticide, the density of the degraders increased from less than the detection limit to around 10(6)/g of soil. The number of dominant species among the degraders declined with the increasing density of degraders; eventually, one species predominated. This process can be explained according to the competitive exclusion principle using V-max and K-m values for fenitrothion metabolism by the degraders. We performed a phylogenetic analysis of representative strains isolated from the microcosms and evaluated their ability to establish symbiosis with the stinkbug Riptortus pedestris. The strains that established symbiosis with R.pedestris were assigned to a cluster including symbionts commonly isolated from stinkbugs. The strains outside the cluster could not necessarily associate with the host. The degraders in the cluster predominated during the initial phase of degrader dynamics in the soil. Therefore, only a few applications of fenitrothion could allow symbiotic degraders to associate with their hosts and may cause the emergence of symbiont-mediated insecticide resistance.
• A conservation law for virus infection kinetics in vitro

  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.
• A method to determine the duration of the eclipse phase for in vitro infection with a highly pathogenic SHIV strain

  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.
• Effect of eclipse phase on quantifying viral dynamics of acute HIV-1 infection in humanized mouse model

  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]
  
• Mathematical analysis and classification of tumor immune dynamics in T cell transfer treatment

  Nakaoka Shinji

  IEICE NONLINEAR THEORY AND ITS APPLICATIONS 一般社団法人 電子情報通信学会 6 (1) 54 - 70 2185-4106 2015 [Refereed][Not invited]
   

  Immunotherapy for cancer is a forthcoming therapeutic option in cancer treatment. A variety of approaches, including adoptive cell transfer, adjuvant therapy, and monoclonal antibody therapy, are currently used as complementary or alternative cancer treatments. Since immunity against tumors is established as a result of complex interactions among tumors and immune cells, a theoretical framework to elucidate the dynamics of tumor killing by immune cells initiated by clinical intervention needs to be developed. We construct a simple mathematical model that describes the killing of tumors by T cells. We focus on a mathematical characterization of the effect of adoptive cell transfer therapy, the injection of a patient's own ex vivo activated T cells to initiate tumor immunity. On the basis of rigorous mathematical analyses and numerical computations, we provide biological interpretations for the possible outcomes of adoptive cell transfer under three different scenarios in terms of proliferation. In our modeling framework, adoptive cell transfer therapy can be understood as a driving force that potentially operates to shift the state of an immune response from inactive to active. On the other hand, our modeling framework suggests the possibility that a tumor can exploit a self-augmenting proliferation of T cells mediated by autocrine/paracrine signaling as an escape strategy from an immune response.
• DEMOGRAPHIC MODELING OF TRANSIENT AMPLIFYING CELL POPULATION GROWTH

  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.
• Cost-effective length and timing of school closure during an influenza pandemic depend on the severity

  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).
• Multiscale mathematical modeling and simulation of cellular dynamical process

  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.
• Stochastic simulation of structured skin cell population dynamics

  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.
• Mathematical study on kinetics of hematopoietic stem cells - theoretical conditions for successful transplantation

  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.
• Daphnia revisited: local stability and bifurcation theory for physiologically structured population models explained by way of an example

  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.
• Daphnia revisited: Local stability and bifurcation theory for physiologically structured population models explained by way of an example

  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.
• Immune impairment in HIV infection: Existence of risky and immunodeficiency thresholds

  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.
• Effect of parental care and aggregation on population dynamics

  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.
• A geographical spread of vaccine-resistance in avian influenza epidemics

  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.
• Dynamical Adaptation of Parental Care

  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.
• Immune impairment thresholds in HIV infection

  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.
• Complementary cooperation between two syntrophic bacteria in pesticide degradation

  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.
• Invest conflicts of adult predators

  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.
• Mathematical analysis of a HIV model with frequency dependence and viral diversity

  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.
• Viral diversity limits immune diversity in asymptomatic phase of 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.
• Two types of coexistence in cross-feeding microbial consortia

  Shinji Nakaoka, Yasuhiro Takeuchi

  COLLECTIVE DYNAMICS: TOPICS ON COMPETITION AND COOPERATION IN THE BIOSCIENCES 1028 233 - + 0094-243X 2008 [Refereed][Not invited]
   

  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.
• Frequency dependence and viral diversity imply chaos in an HIV model

  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.
• Prey-predator system with parental care for predators

  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.
• Competition in chemostat-type equations with two habitats

  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.

MISC

• Effect of shapes of activation functions on predictability in the echo state network (複雑コミュニケーションサイエンス)

  張 瀚天, 中岡 慎治, 安東 弘泰  電子情報通信学会技術研究報告 = IEICE technical report : 信学技報  119-  (157)  27  -30  2019/08/01
• 細菌群集データから相互作用ネットワークを推定する手法の活用 (複雑コミュニケーションサイエンス)

  中岡 慎治, 鈴木 憲幸, 竹内 康博  電子情報通信学会技術研究報告 = IEICE technical report : 信学技報  119-  (157)  23  -25  2019/08/01
• Quantification of Hepatitis B Virus infection dynamics in cell culture model

  Kakizoe Yusuke, Iwamoto Masashi, Nakaoka Shinji, Watashi Koichi, Iwami Shingo  RIMS Kokyuroku  (2087)  71  -76  2018/08
• Big-data analysis of allergy associations with gut microbiota

  HARA Akane, NAKAOKA Shinji, AIHARA Kazuyuki  SEISAN KENKYU  70-  (3)  141  -144  2018  

  Close association between intestinal microbiota and the immune system suggests possibility of developing a novel treatment method for allergy by modulating intestinal microbiota. Although time-series data with sufficient length are required for microbiota modulation, no such datasets are found which match the requirement. In this study, we apply and examine a new method to reconstruct a pseudo-temporal path of allergy development from non-time-series samples reflecting various individual states in the process of allergy development. We aim to refine this method to provide a data-driven intervention strategy for prevention of allergy.

• HIV-1侵入機構の定量化 (第13回生物数学の理論とその応用 : 連続および離散モデルのモデリングと解析)

  柿添 友輔, 中岡 慎治, 岩見 真吾  数理解析研究所講究録  (2043)  81  -86  2017/09
• マルチスケールモデルを用いたC型肝炎ウイルスの感染動態の記述 (第13回生物数学の理論とその応用 : 連続および離散モデルのモデリングと解析)

  北川 耕咲, 中岡 慎治, 浅井 雄介, 岩見 真吾  数理解析研究所講究録  (2043)  109  -115  2017/09
• New deprivation index for large scale cancer study with geographical heterogeneity

  YONEOKA Daisuke, SAITO Eiko, NAKAOKA Shinji  日本疫学会学術総会講演集(Web)  27th-  2017
• Comparison of two different formulations of multiscale models for HCV infection

  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>
• パッチ感染モデルを用いた基本・状態別再生産数の違いの検証 (実領域における常微分方程式の定性的研究)

  石塚 信行, 竹内 康博, 中岡 慎治  数理解析研究所講究録  (1993)  79  -84  2016/04
• 個体および集団ベースGillespieアルゴリズムの相互検証 (第11回生物数学の理論とその応用 : RIMS研究集会報告集)

  中岡 慎治  数理解析研究所講究録  (1937)  163  -170  2015/04
• Comparison of Numerical Simulation Methods for HIV Infection Dynamics Model in Lymphatic Network(Theory of Mathematical Models and Control for Infectious Diseases)

  NAKAOKA Shinji, IWAMI Shingo, SATO Kei  SYSTEMS, CONTROL AND INFORMATION  59-  (12)  452  -457  2015
• Quantification of viral infection dynamics with hybrid dynamical model

  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.
• 個体ベースのGillespieアルゴリズム解説 (第10回生物数学の理論とその応用 : RIMS研究集会報告集)

  中岡 慎治  数理解析研究所講究録  (1917)  21  -28  2014/09
• ディレイ方程式による短期細胞増殖過程の定式化 (第9回生物数学の理論とその応用 : RIMS研究集会報告集)

  中岡 慎治  数理解析研究所講究録  (1853)  19  -26  2013/10
• Mathematical modeling for the self-organization of cells

  KOJIMA Nobuhiko, OGATA Yuka, NAKAOKA Shinji, SAKAI Yasuyuki  SEISAN KENKYU  65-  (3)  337  -342  2013  

  In order to fabricate three-dimensionally reconstituted tissues, it is indispensable to use pattern formation of cells using interaction of mutual cells. However, it is unclear that what kind of mechanisms are included such self-organization. In this report, we aimed to establish a mathematical model that can emulate the behavior of cells computationally. This trial will be able to control and regulate the pattern formation.
• Simulation study of helper T cell growth and differentiation

  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.
• Mathematical modeling study on hematopoietic stem cells

  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>
• 細胞傷害性T細胞による感染細胞除去率の推定 (第6回生物数学の理論とその応用--RIMS研究集会報告集)

  中岡 慎治, 合原 一幸  数理解析研究所講究録  (1704)  40  -46  2010/08
• Mathematical modeling study on immune systems

  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.
• ポジティブフィードバックをもつ生物系モデルの解析 (関数方程式のダイナミクスと数理モデル--RIMS研究集会報告集)

  中岡 慎治  数理解析研究所講究録  (1637)  176  -188  2009/04
• 個体の成長を考慮した個体群モデルの解析

  中岡 慎治  盛岡応用数学小研究集会報告集  (2008)  30  -43  2009/03/01  

  本稿では，ステージ構造をもつ資源消賢者系のダイナミクスに対する数理解析の結果を紹介する．消費者の個体に年齢構造を考慮し，繁殖可能性の有無によってその個体を区別する方程式系が対象である．未成熟個休の死亡率に時間遅れを伴った密度依存効果を考慮し，それによってダイナミクスがどう影響されるかを明らかにする．消費者が存続できるような状況を数学的に表現する一様パーシステンス，Allee効果と呼ばれるメカニズムによる消費者の絶滅という2つのキーワードに基づき，消費者の存続性と絶滅可能性を議論した．
• Occurrence of periodic oscillations mediated by programmed proliferation of CTLs (Theory of Biomathematics and its Applications IV)

  Nakaoka Shinji  RIMS Kokyuroku  (1597)  19  -23  2008/05
• When do patients develop AIDS? (Theory of Biomathematics and its Applications IV)

  Iwami Shingo, Nakaoka Shinji, Takeuchi Yasuhiro  RIMS Kokyuroku  (1597)  24  -26  2008/05
• Mathematical study on sharing metabolism (Workshops on "Pattern Formation Problems in Dissipative Systems" and "Mathematical Modeling and Analysis for Nonlinear Phenomena")

  NAKAOKA Shinji, TAKEUCHI Yasuhiro  RIMS Kokyuroku Bessatsu  3-  193  -205  2007/11
• Steady state analysis for some delay equations(Functional Equations Based upon Phenomena)

  Nakaoka Shinji  RIMS Kokyuroku  1547-  34  -42  2007/04
• Oscillations induced by size-structured populations with saturating food dependent reproduction rate(Theory of Biomathematics and its Applications III)

  Nakaoka Shinji  RIMS Kokyuroku  1551-  93  -98  2007/04
• PA-40 Mathematical modeling and experimental analysis of syntrophic association in pesticide degradation(Symbiosis/Cell to cell interaction,Poster presentation A) :

  Katsuyama Chie, Nakaoka Shinji, Takeuchi Yasuhiro, Tago Kanako, Hayatsu Masahito, Kato Kenji  日本微生物生態学会講演要旨集  (23)  96  -96  2007
• Viral diversity in asymptomatic phase of HIV infection(Theory of Bio-Mathematics and Its Applications)

  Iwami Shingo, Nakaoka Shinji  RIMS Kokyuroku  1499-  37  -49  2006/07
• Two species, one feeding on the other (Biomathematics Kyoto Summer School)

  Nakaoka Shinji  RIMS Kokyuroku  1448-  67  -81  2005/09
• Necessary condition for the coexistence of species in a periodic chemostat (Functional Equations and Complex Systems)

  Nakaoka Shinji, Takeuchi Yasuhiro  RIMS Kokyuroku  1445-  46  -55  2005/07
• Balance Line in a Lotka-Volterra competition system (Theory of Bio-Mathematics and It's Applications)

  Nakaoka Shinji, Takeuchi Yasuhiro  RIMS Kokyuroku  1432-  23  -32  2005/05
• Stability Analysis for a physiological clock model with delayed negative feedback loop (Mathematical models and dynamics of functional equations)

  Nakaoka Shinji  RIMS Kokyuroku  1372-  51  -57  2004/04
• Local Asymptotic Stability for a Lotka-Volterra System with Distributed Delays (Functional Equations in Mathematical Models)

  Nakaoka Shinji, Hara Tadayuki, Matsunaga Hideaki  RIMS Kokyuroku  1309-  84  -91  2003/02

Books etc

• 進化のダイナミクス 生命の謎を解き明かす方程式

  Martin A. Nowak, 中岡 慎治, 巌佐 庸, 竹内 康博, 佐藤 一憲 
  共立出版 2008/02 (ISBN: 4320056655) 352

  

Research Projects

• Construction of state transition model based on energy landscape

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2021/07 -2024/03 

  Author : 中岡 慎治

   

  本年度では、細胞分化や発症の動的な遷移の軌跡を推定する手法の妥当性を検証するために必要なデータ解析を進め、結果として査読付研究論文を３編発表した。 研究論文 [1] では、授乳期における母子から5ヶ月間にわたって経時的に取得した腸内細菌叢データと代謝物の網羅的計測データ (NMRメタボロミクス) の時系列データ解析を行った。その結果、ビフィズス菌種の交代（Bifidobacterium breve から Bifidobacterium longum subsp. infantis）、糞便中の酢酸や酪酸などの代謝物も変動がみられることを明らかにした。
  研究論文 [2] では、複雑な微生物および微生物・宿主間の相互作用を推定するため、数理モデルのシミュレーションから得られた微生物動態の擬似的時系列データを用いて、微生物相互作用ネットワークを推定する５つの手法について比較検討した。本研究課題と関連して、相互作用を検出する手法候補の１つを提案した。その結果、提案手法の有用性を確認することができた。
  書籍のChapterとして寄稿した研究論文 [3] では、重要な疾患である発ガン過程に着目した解析を進めた。具体的には、ガン細胞がどのように増殖・進化して体内に存続するかを検討するため、ガン細胞集団の動態を記述した数理モデルをシミュレーションから得られたガン細胞動態の擬似的時系列データを用いて、細胞間相互作用を推定する手法の検討を行った。その結果、相互作用関係を推定する手法と発ガン進行パターンを記述した力学系の間に、興味深い関係性が得られることを見出した。
• Development of an integrated model for estimating emerging infectious diseases and a method for allocating medical resources by integrating mathematical science and healthcare administration

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2021/07 -2024/03 

  Author : 佐藤 大介, 中岡 慎治, 川上 英良, 吉村 健佑, 藤田 卓仙

   

  本研究は数理科学に基づくモデルを用いて新型コロナウイルス感染症の陽性者数および入院患者数等を推計し、公衆衛生学的介入やワクチン等による感染拡大防止政策が、どの対象や範囲に介入すれば最も効果的かつ医療需要に対する最適な医療資源を配置可能かを推計する数理モデルに基づく医療経済評価の手法を開発することである。 新型コロナウイルス感染症の陽性者数および入院患者数の把握は、感染拡大による急激な感染者増と都道府県および保健所設置市の人員不足や検査体制、情報収集方法の技術的課題等に加え、保健所が入力したデータは国の管理下に置かれ、入力した自治体が使用することが出来ず、研究利用として個票単位でのデータ収集が困難であった。そのため本研究では特定の都道府県に限定し、報道発表を通じて公表されている個票データを日別に集計することで、モデル分析に必要なデータを収集した。第６波以降はさらなる感染者数の増加により、公表資料においても集計値のみとされ個票でのデータ収集が不可能となった。これらの代替手法により、本年度においては第１波から第５波までの個票データをデータセットとして整理した。 いっぽうで、新型コロナウイルス感染症の陽性者等に関する情報の取り扱いに関する法的・倫理的課題（ELSI）については、特にIT技術を利用した感染症対策のELSI上の問題点についての課題を整理した。特にワクチン及び治療薬が存在しない段階の非製薬的介入（Nonpharmaceutical Interventions; NPIs）にIT技術を利活用する分類について、①隔離（措置入院、自宅療養、隔離）、②検疫（待機要請、停留）、③行動制限（緊急事態宣言、蔓延防止重点措置）、④リスク広報（政府公報）、⑤個人的防御（うがい、手洗い、マスク）の5類型を列挙し、公衆衛生上必要な個人情報を収集する場合の法的・倫理的課題を整理した。
• PHRを活用した機械学習モデルによる心血管病の重症化予防を目指した研究

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2021/04 -2024/03 

  Author : 横田 卓, 中岡 慎治, 中村 公則

   

  わが国は超高齢社会を迎え、心血管病の患者数は増加の一途を辿っており、早急に患者本人が主体的にセルフモニタリングを行い疾病予防に取り組む「患者中心の医療 (patient-centered care)」 を実現する必要に迫られている。心血管病の予防・治療の基本は食事・運動をはじめとする生活習慣の是正であるが、在宅で取得可能なパーソナル・ヘルス・レコード (PHR) の活用が必要不可欠である。さらにCOVID-19感染拡大をきっかけにオンライン診療が広く推奨されるようになり、とりわけ情報通信技術 (ICT) を活用したPHRのニーズが高まっている。そこで我々は、在宅で取得するPHRを活用し適切なセルフケアの実践を促すスマートフォン対応セルフケアサポートアプリを開発した。本研究の目的は、このアプリで収集する血圧・体重・体脂肪率・体温・酸素飽和度・塩分摂取量・身体活動量・睡眠時間などのバイタルサインや食事・運動内容、さらには便を用いた腸内フローラ解析データなどの多様なPHRを活用し、機械学習モデルを用いて、心血管病の重症化予測を行うとともに重症化予防のための個々に最適な食事・運動療法を提案することである。 臨床試験『スマートフォンアプリを活用した統合型高血圧セルフケアサポートシステムの有効性の検証 (AppCare-HT Study)』については、2022年3月までに目標症例数 (360名) に達したため、募集を終了し、現在12か月間のフォローアップを実施中である。また、心不全患者を対象にした臨床試験についても研究実施中で、順次データ解析を進めている。
• Emerging infectious diseases of bees in Japan: integrated risk assessment for conservation

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2020/04 -2023/03 

  Author : 坂本 佳子, 水谷 哲也, 宮崎 亮, 芳山 三喜雄, 池上 真木彦, 久本 峻平, 鎌倉 昌樹, 中岡 慎治

   

  国内に生息する野生ハナバチ 13 種を対象に DNA・RNA を抽出し、次世代シーケンサーを用いて網羅的解析を実施した。その結果、セイヨウミツバチ、ツツハナバチ、キムネクマバチより未知、あるいは国内未確認のウイルスを検出した。また、すでにミツバチの病原生物として知られる14種について、リアルタイムPCR検出システムを確立し、上記の野生ハナバチ13種における感染・寄生状況を調査した。 農薬が腸内細菌に及ぼす影響を評価するために、まずは、羽化直後のミツバチに均等・均質な腸内細菌叢を与え、14日間安定的に飼育する方法を確立した。当該飼育方法を用いて、ネオニコチノイド、フェニルピラゾール、有機リン、カーバメート、ピレスロイド等の殺虫剤、および殺菌剤、除草剤をそれぞれ2段階で濃度設定で投与し、セイヨウミツバチ3群の腸内細菌叢への影響を解析した。 3種のネオニコチノイド（イミダクロプリド、クロチアニジン、チアメトキサム）をミツバチに投与し、アカリンダニを付着させたところ、ミツバチがダニに気づくまでの時間が短縮し、かつダニを払い落とす行動（グルーミング）の回数が増加した。ネオニコチノイドがミツバチの過敏性を亢進させ、社会性免疫に影響を及ぼす可能性を示唆した。 ミツバチ伝染病の国内分布と近年のトレンドを把握するため、家畜伝染病である腐蛆病、届出伝染病であるバロア症、チョーク病、ノゼマ症、アカリンダニ症の国内発生届出件数データを農林水産省のサイトより入手し、月別・都道府県別で整備した。過去２０年間のトレンドをみたところ、腐蛆病やチョーク病発生は減少傾向にあるが、アカリンダニ症の拡大が見られた。バロア症は一時期減少したが近年増加傾向にあった。 ツツハナバチ属のドラフトゲノムを解析した。
• 包括的マルチオミクス解析によるウイルス感染ダイナミクスの時空間的理解

  文部科学省：基盤研究(B)

  Date (from‐to) : 2018 -2021 

  Author : 佐藤 佳
• Elucidate latent rules in disruption of biological system

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/07 -2019/03 

  Author : Kawakami Eiryo

   

  We reconstructed human and mouse gene regulatory network based on the enormous public ChIP-seq data. For sporadic and unequal time series data often obtained in medical/biological research, we introduced an algorithm that represent states of data as "landscape" based on multidimensional variables. Utilizing the method, we could stratify patient states and predict state transition of disease progression. We also applied machine learning for the accurate diagnostic and prognostic prediction for epithelial ovarian cancer based on preoperative blood test data. Hereafter, we would like to expand our research aiming at forecasting and preventing disease development by identifying presymptomatic disease state based on health check data and real-world measurement data obtained from various IoT devices.
• A quantitative model of new strategies for Japan's hyper-aging society

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/04 -2019/03 

  Author : GILMOUR Stuart

   

  This research developed a new model of population dynamics in Japan, and used this model to provide the first comprehensive assessment of major policies to adapt to the rapidly aging society. In this research I assessed two strategies for responding to aging in Japan: a) a strategy based on increasing births in the Japanese population; and b) a strategy based on increased migration. I assessed the impact of both of these strategies by the change in the old age dependency ratio (OADR) up to 50 years in the future. My research showed that neither increasing births nor increasing immigration will have any significant effect on the OADR in future. Even extreme strategies such as increasing the total fertility rate (TFR) to 3 births per woman, or increasing migration to the extent that over 30% of the Japanese population is foreign born, will have minimal effect on the OADR. This research concludes that it is too late for Japan to reverse its hyper-aging.
• Comprehensive Study of Disease Burden and Its Utilization by Prefecture in Japan

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/04 -2019/03 

  Author : SHIBUYA kenji

   

  This study is the first attempt in Japan to comprehensively analyze the burden of disease not at the national level but also at the prefectures, and apply it to concrete policy analysis. This year we expanded data collection, applied the latest statistical techniques, and improved methodologies. From 1990 to 2017, Japan's overall healthy life expectancy increased from 69.7 to 73.1 years. The top of present main cause of death is cerebrovascular disease and cardiovascular disease nationwide, and main cause of DALYs (Disability-adjusted life years) is back pain. Longevity leads to more disabilities (especially sensory and motor organs). In addition, the burden of degenerative diseases (Alzheimer's disease) is significant nationwide, and urgent measures are required.
• Theory for effective antiviral strategy based on multiscale mathematical modeling

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2015/07 -2019/03 

  Author : Iwami Shingo, NAKAOKA SHINJI

   

  In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect.
• 生命病態システムの数理モデリングとその個別化医療への応用のための数理的基盤の確立

  文部科学省：基盤研究(S)

  Date (from‐to) : 2015 -2019 

  Author : 合原 一幸
• mechanism of diversification of shiga toxin-encoding phage, from the ecological aspect

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/04 -2018/03 

  Author : Yoshitoshi Ogura, NAKAOKA shinji, ARIMIZU Yoko

   

  We constructed three Stx2 phage lysogenes of Escherichia coli K-12 and the lysogenes were infected to Dictyosteluim discoideum AX2. But growth of D. discoideum was not affected by the infection of the lysogens at all. Even original O157 strains were not toxic to D. discoideum. Furthermore, inconsistent with several previous studies, we found that infection of O157 strains was not toxic to Acanthamobae castellanii. It is thought that another model protist is required for this analysis. We also showed that the recent and repeated acquisition of the stx2 are occurred in multiple lineages of O26. This suggest the presence of selective pressure to accumulate Stx2 in E. coli O26 in environment. Protist that colonize in bovine intestine is thought to be one of the candidates of the selective pressure.
• 階層フィードバックを考慮したマルチスケール数理モデルと疾患力学系の解析

  文部科学省：基盤研究(C)

  Date (from‐to) : 2016 -2018 

  Author : 中岡 慎治
• 出芽酵母の人工進化系構築 ―生命の適応的機能創出をデザインする―

  文部科学省：基盤研究(C)

  Date (from‐to) : 2015 -2017 

  Author : 中岡 慎治
• Multiscale modeling and simulation study for immune inflammatory response at the skin tissue

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2013 -2015 

  Author : Nakaoka Shinji

   

  The purpose of the present research project is to construct multi-scale mathematical models representing disease progression. A particular focus of this study is to describe the progression of atopic dermatitis as a representative skin inflammatory disease. One of mathematical analyses conducted in this research project includes propagation of the inflammatory response at the epidermis tissue. Moreover, interactions amount protease activity and immune response was incorporated to investigate how chronic inflammation is maintained. The later of the project has been in preparation to submit a peer review journal. This work is done by an international collaboration. In addition, study on determining an appropriate numerical computation scheme was examined to develop an efficient and useful computation scheme to implement numerical simulations for multi-scale models. These achievements will be further improved to obtain clear understanding on multi-scale dynamics in disease progression.