Shigeo Koyasu

Keio University, Edo, Tōkyō, Japan

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Publications (219)1670.2 Total impact

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    ABSTRACT: Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.
    Nature immunology. 01/2015;
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    Kazuyo Moro, Shigeo Koyasu
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    ABSTRACT: Recent studies have identified novel lymphocyte subsets named innate lymphoid cells (ILCs) lacking antigen-specific receptors. ILCs are present in a wide variety of epithelial compartments and occupy an intermediate position between acquired immune cells and myeloid cells. ILCs are now classified into three groups: group 1 ILC, group 2 ILC, and group 3 ILC based on their cytokine production patterns that correspond to the helper T cell subsets Th1, Th2, and Th17, respectively. ILCs play important roles in protection against various invading microbes including multicellular parasites, and in the maintenance of homeostasis and repair of epithelial layers. Excessive activation of ILCs, however, leads to various inflammatory disease conditions. ILCs have thus attracted interests of many researchers in the fields of infectious immunity, inflammatory diseases, and allergic diseases. Because epithelial cells sense alterations in environmental cues, it is important to understand the functional interaction between epithelial cells, ILCs, and environmental factors such as commensal microbiota. We discuss in this review developmental pathways of ILCs, their functions, and contribution of commensal microbiota to the differentiation and function of ILCs.
    Seminars in Immunopathology 12/2014; · 6.48 Impact Factor
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    ABSTRACT: Recent years have witnessed the discovery of an unprecedented complexity in innate lymphocyte lineages, now collectively referred to as innate lymphoid cells (ILCs). ILCs are preferentially located at barrier surfaces and are important for protection against pathogens and for the maintenance of organ homeostasis. Inappropriate activation of ILCs has been linked to the pathogenesis of inflammatory and autoimmune disorders. Recent evidence suggests that ILCs can be grouped into two separate lineages, cytotoxic ILCs represented by conventional natural killer (cNK) cells and cytokine-producing helper-like ILCs (i.e., ILC1s, ILC2s, ILC3s). We will focus here on current work in humans and mice that has identified core transcriptional circuitry required for the commitment of lymphoid progenitors to the ILC lineage. The striking similarities in transcriptional control of ILC and T cell lineages reveal important insights into the evolution of transcriptional programs required to protect multicellular organisms against infections and to fortify barrier surfaces.
    Immunity 09/2014; 41(3):354-365. · 19.75 Impact Factor
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    ABSTRACT: Musculoskeletal infections, including surgical-site and implant-associated infections, often cause progressive inflammation and destroy areas of the soft tissue. Treating infections, especially those caused by multi-antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) remains a challenge. Although there are a few animal models that enable the quantitative evaluation of infection in soft tissues, these models are not always reproducible or sustainable. Here, we successfully established a real-time, in vivo, quantitative mouse model of soft-tissue infection in the superficial gluteus muscle (SGM) using bioluminescence imaging. A bioluminescent strain of MRSA was inoculated into the SGM of BALB/c adult male mice, followed by sequential measurement of bacterial photon intensity and serological and histological analyses of the mice. The mean photon intensity in the mice peaked immediately after inoculation and remained stable until day 28. The serum levels of interleukin-6, interleukin-1 and C-reactive protein at 12 hours after inoculation were significantly higher than those prior to inoculation, and the C-reactive protein remained significantly elevated until day 21. Histological analyses showed marked neutrophil infiltration and abscesses containing necrotic and fibrous tissues in the SGM. With this SGM mouse model, we successfully visualized and quantified stable bacterial growth over an extended period of time with bioluminescence imaging, which allowed us to monitor the process of infection without euthanizing the experimental animals. This model is applicable to in vivo evaluations of the long-term efficacy of novel antibiotics or antibacterial implants.
    PLoS ONE 09/2014; 9(9):e106367. · 3.53 Impact Factor
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    ABSTRACT: Allergic asthma is an inflammatory disease characterized by lung eosinophilia controlled by type 2 cytokines. Cysteine proteases are potent triggers of allergic inflammation by causing barrier disruption in lung epithelial cells inducing the elevation of interleukin-5 (IL-5) and IL-13 from natural helper (NH) cells, a member of ILC2s, which leads to lung eosinophilia. In this study, we found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens. Conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production. Resolution of eosinophilia was also observed in mice lacking IL-4 specifically in basophils, indicating that basophil-derived IL-4 enhanced expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in NH cells, thus attracting eosinophils. These results demonstrate that IL-4 from basophils has an important role in the NH-derived cytokine and chemokine expression, subsequently leading to protease allergen-induced airway inflammation.
    Immunity 05/2014; 40(5):758-71. · 19.75 Impact Factor
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    ABSTRACT: While the 2002–2003 outbreak of severe acute respiratory syndrome (SARS) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. The objective of the present work was to identify, using SARS coronavirus (SARS-CoV) mouse infection models, immune factors responsible for clearing of the virus. The elimination of pulmonary SARS-CoV infection required the activation of B cells by CD4+ T cells. Furthermore, passive immunization (post-infection) with homologous (murine) anti-SARS-CoV antiserum showed greater elimination efficacy against SARS-CoV than that with heterologous (rabbit) antiserum, despite the use of equivalent titers of neutralizing antibodies. This distinction was mediated by mouse phagocytic cells (monocyte-derived infiltrating macrophages and partially alveolar macrophages, but not neutrophils), as demonstrated both by adoptive transfer from donors and by immunological depletion of selected cell types. These results indicate that the cooperation of anti-SARS-CoV antibodies and phagocytic cells plays an important role in the elimination of SARS-CoV.
    Virology 04/2014; s 454–455:157–168. · 3.28 Impact Factor
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    ABSTRACT: Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.
    Nature 03/2014; 507(7493):455-61. · 42.35 Impact Factor
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    ABSTRACT: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.
    Nature 03/2014; 507(7493):462-70. · 42.35 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB291. · 11.25 Impact Factor
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    ABSTRACT: Ectodomain shedding (shedding) is a posttranslational modification mechanism, which liberates extracellular domains of membrane proteins through juxtamembrane processing. Because shedding alters cell characteristics in a rapid and irreversible manner, it must be strictly regulated. However, the regulatory mechanisms of shedding in response to environmental changes remain obscure. To evaluate the regulatory mechanisms of endogenous shedding, we previously developed a proteomic screening system to identify shedding targets. This system revealed a comprehensive picture of membrane proteins shed under defined conditions. In this study, we have improved the screening system to compare the shedding patterns in a mouse macrophage cell line treated with two different shedding inducers, lipopolysaccharide (LPS) and 12-O-tetradecanoylphorbol 13-acetate (TPA). We show here that LPS simultaneously activates the shedding of multiple membrane proteins. We further show that TPA specifically activates the shedding of αM/β2 integrin (Mac-1), which was not shed upon LPS-stimulation of macrophages. These results clearly demonstrate that the regulation of endogenous membrane protein shedding is both stimulus- and substrate-specific. The shedding targets reported to date play pivotal roles in a variety of biological phenomena, including the immunological response, cell growth, cell adhesion and cell movement. In addition, several disease-related membrane proteins are shedding targets. Thus, understanding the regulation of shedding is important for the elucidation of pathogenesis and the development of therapeutic strategies. We submit that a comprehensive characterization of endogenous shedding is indispensable for understanding the regulatory mechanisms of shedding, and thus have developed a proteomic screening system to identify shedding targets. In this study, using our screening system, we demonstrate that different extracellular stimuli activate different types of shedding, even in a single cell. Our results prove that this proteomic approach is quite effective for the elucidation of the regulatory mechanisms of shedding.
    Journal of proteomics 01/2014; · 5.07 Impact Factor
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    ABSTRACT: Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.
    Nature Communications 10/2013; 4:2675. · 10.74 Impact Factor
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    ABSTRACT: Natural helper (NH) cells, a member of Lin(-)IL-2R(+)IL-7R(+)IL-25R(+)IL-33R(+)GATA3(+) group 2 innate lymphoid cell subset, are characterized by the expression of transcription factors GATA3 and RORα and production of large amounts of Th2 cytokines such as IL-5, IL-6, and IL-13 upon IL-33 stimulation or a combination of IL-2 and IL-25. We have studied the signal transduction pathways critical for the cytokine expression and development of NH cell. Either stimulation with IL-33 or a combination of IL-2 and IL-25 induced p38 activation and phosphorylation of GATA3 in NH cells, and the phosphorylated form of GATA3 bound to the IL-5 and IL-13 promoters. All these events were blocked by SB203580, a p38 inhibitor. Inhibition of p38 also blocked IL-6 production. The mature NH cells lacking Gata3 were impaired in the proliferation and production of IL-5 and IL-13, but not IL-6, indicating that both p38 and GATA3 are critical for the proliferation and production of IL-5 and IL-13 and that the mechanisms downstream of p38 differ between IL-6 and IL-5/IL-13. In contrast, the NH cells lacking RORα showed no impairment in the proliferation and cytokine production, indicating that GATA3 but not RORα plays a pivotal role in the effector functions of mature NH cell. However, deletion of either GATA3 or RORα in hematopoietic stem cells severely blocked the development into NH cells. Our results demonstrate the important roles of p38 and GATA3 in NH cell functions.
    The Journal of Immunology 07/2013; 191(4). · 5.36 Impact Factor
  • Shigeo Koyasu, Kazuyo Moro
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    ABSTRACT: Natural helper (NH) cells are a newly identified innate lymphocyte population that responds to a combination of interleukin (IL)-2 and either IL-25 or IL-33 to produce large amounts of T helper cell type 2 (Th2) cytokines. NH cells have been identified in fat-associated lymphoid clusters (FALCs), produce Th2 cytokines constitutively without any stimulation, and support the self-renewal of B1 cells and IgA production by B cells. Large amounts of IL-5 and IL-13 produced upon helminth infection or in response to IL-33 can induce eosinophilia and goblet cell hyperplasia in the lung and intestine; these cytokines, which activate NH cells, play important roles in antihelminth immunity and allergic diseases such as asthma.
    Annals of the New York Academy of Sciences 04/2013; 1283(1):43-9. · 4.38 Impact Factor
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    ABSTRACT: TAK1, a member of MAPK kinase kinase (MAPKK-K) family, can activate JNK, p38 MAPK, and NF-κB signaling pathways. Although targeted gene disruption studies have demonstrated that TAK1 plays a critical role in T cell functions, precise functions of downstream mediators remain elusive. We used the chemical compound LL-Z1640-2, which preferentially suppressed MAPK activation but not NF-κB signal downstream of TAK1. LL-Z1640-2 blocked TCR-induced T cell proliferation and activation, confirming that a TAK1-mediated MAPK signal is essential for T cell activation. LL-Z1640-2 induced apoptosis of activated mouse splenic T cells in a caspase- and caspase-activated DNase-dependent manner. TAK1-JNK pathway, which is activated downstream of IL-2R, induced the phosphorylation of antiapoptotic protein Mcl1 in activated T cells, resulting in the stabilization of Mcl1 protein. Our data uncover that among signal transduction pathways downstream of TAK1, JNK mediates a survival program through Mcl1 stabilization downstream of IL-2R in activated T cells and that blockade of TAK1-JNK pathway can eliminate activated T cells by apoptosis.
    The Journal of Immunology 04/2013; · 5.36 Impact Factor
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    ABSTRACT: Interleukin (IL)-17-producing helper T (Th17) cells serve as a Th subset involved in epithelial cell- and neutrophil-mediated immune responses against extracellular microbes and in the development of various autoimmune diseases. The differentiation of Th17 cells is controlled by a number of intracellular signaling cascades and a complex network of transcription factors. Recently, it has been shown that PI3K, Akt, and mammalian target of rapamycin (mTOR) complexes, such as mTORC1 and mTORC2, also positively regulate Th17 differentiation both in vivo and in vitro via multiple mechanisms; here, we review the current knowledge regarding the mechanisms through which these molecules enhance Th17 differentiation.
    Annals of the New York Academy of Sciences 03/2013; 1280(1):30-4. · 4.38 Impact Factor
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    ABSTRACT: IL-17-producing T helper (Th17) cells comprise a distinct Th subset involved in epithelial cell- and neutrophil-mediated immune responses against extracellular microbes. At the same time, Th17 cells play significant roles in the development of autoimmune diseases including rheumatoid arthritis and multiple sclerosis. Since the identification of Th17 cells approximately a decade ago, the molecular mechanisms of their differentiation have been intensively studied and a number of signaling cascades and transcription factors have been shown to be involved. Here, we review the current knowledge regarding the function of Th17 cells in vivo as well as several key concepts for the molecular mechanisms of Th17 differentiation. We also discuss the emerging roles of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1 (HIF-1) in the differentiation of Th17 cells.
    Genes to Cells 02/2013; · 2.73 Impact Factor
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    ABSTRACT: Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
    Nature Reviews Immunology 01/2013; 13(2):145-9. · 33.84 Impact Factor
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    ABSTRACT: Class IA and IB phosphoinositide 3-kinases (PI3Ks) have been shown to regulate mast cell functions such as proliferation, development, survival and degranulation, but the functional redundancy between these two PI3K signaling pathways in mast cells remains unclear. Here, we have generated mice deficient in both class IA regulatory subunit p85α and class IB catalytic subunit p110γ, and show that p85α(-/-)p110γ(-/-) mice exhibit a more severe defect in mast cell development than single-knockout mice. In addition, the in vivo passive cutaneous anaphylaxis reaction of p85α(-/-)p110γ(-/-) mice was nearly completely abrogated, whereas single-knockout mice exhibit just marginal reduction. Pharmacological inactivation of Akt in wild-type bone marrow-derived mast cells (BMMCs) led to partial reduction of degranulation, while over-expression of a constitutively active Akt partially restored the impaired degranulation in p85α(-/-)p110γ(-/-) BMMCs. We also found that the extracellular signal-regulated kinase (ERK) signaling pathway was activated in a PI3K-dependent manner upon FcεRI stimulation and that simultaneous inhibition of Akt and ERK resulted in nearly complete blockade of FcεRI-induced degranulation. Our data provide evidence that Akt and ERK pathways play redundant roles in FcεRI-induced degranulation.
    International Immunology 11/2012; · 3.18 Impact Factor
  • Shigeo Koyasu
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    ABSTRACT: Natural helper (NH) cells are a newly identified innate lymphocyte population, which respond to a combination of interleukin (IL)-2 and IL-25 or IL-33 to produce large amounts of TH2 cytokines, most notably, IL-5 and IL-13. We identified NH cells in lymphoid clusters in adipose tissues, which we termed fat-associated lymphoid clusters. IL-5 and IL-13 produced by activated NH cells induce eosinophilia and goblet cell hyperplasia, respectively, and play an important role in anti-helminth immunity and allergic diseases, such as asthma. In addition, NH cells produce TH2 cytokines constitutively in the absence of stimulation and support the self-renewal of B1 cells and IgA production by B cells. After our identification of NH cells, other groups have also reported novel TH2 cytokine-producing cells, such as nuocytes, and innate helper type 2 cells. There are similarities and differences between these newly identified cell populations and NH cells. Multipotent progenitor cell type 2 (MPP) cells can differentiate to other myeloid cells, making this a distinct cell type from the others. MPP cells, nuocytes, and innate helper type 2 cells respond to IL-25 alone in vivo, whereas NH cells do not respond to IL-25 without IL-2, although they respond strongly to IL-33. Localization of NH cells in fat-associated lymphoid clusters is an intriguing difference compared with the other cell types, which are found in the lymph node and/or spleen. This article summarizes current information regarding the emerging field of TH2-type innate lymphocytes.
    Cornea 11/2012; 31 Suppl 1:S20-4. · 1.75 Impact Factor
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    ABSTRACT: Ubiquitously expressed D-type cyclins are required for hematopoiesis but are dispensable in other cell lineages. Furthermore, within different hematopoietic progenitor populations the D-type cyclins play nonredundant roles. The basis of this lineage and developmental specificity is unknown. In pro-B cells we demonstrate four distinct nuclear D-type cyclin compartments, including one cyclin D3 fraction associated with CDK4 and another phosphoinositide 3-kinase-regulated fraction not required for proliferation. A third fraction of cyclin D3 was associated with the nuclear matrix and repression of >200 genes including the variable (V) gene segments Igkv1-117, Iglv1, and Igh-VJ558. Consistent with different subnuclear compartments and functions, distinct domains of cyclin D3 mediated proliferation and Igk V gene segment repression. None of the cyclin D3 nuclear compartments overlapped with cyclin D2, which was distributed, unbound to CDK4, throughout the nucleus. Furthermore, compartmentalization of the cyclins appeared to be lineage restricted because in fibroblasts, cyclin D2 and cyclin D3 occupied a single nuclear compartment and neither bound CDK4 efficiently. These data suggest that subnuclear compartmentalization enables cyclin D3 to drive cell cycle progression and repress V gene accessibility, thereby ensuring coordination of proliferation with immunoglobulin recombination.
    Journal of Experimental Medicine 10/2012; · 13.91 Impact Factor

Publication Stats

11k Citations
1,670.20 Total Impact Points


  • 1997–2014
    • Keio University
      • Department of Microbiology and Immunology
      Edo, Tōkyō, Japan
  • 2012
    • Kansai Medical University
      • Institute of Biomedical Science
      Moriguchi, Ōsaka, Japan
  • 2011
    • Japan Science and Technology Agency (JST)
      Edo, Tōkyō, Japan
  • 2009
    • Nihon Medi - Physics
      Edo, Tōkyō, Japan
  • 1988–2005
    • Tokyo Metropolitan Institute of Medical Science
      Edo, Tōkyō, Japan
    • Tokyo Metropolitan Komagome Hospital
      Edo, Tōkyō, Japan
    • National Institute of Radiological Sciences
      Tiba, Chiba, Japan
  • 2001
    • National Institute of Arthritis and Musculoskeletal and Skin Diseases
      Maryland, United States
  • 2000
    • University of Toledo
      Toledo, Ohio, United States
    • Kyoto University
      • Department of Pediatrics
      Kyoto, Kyoto-fu, Japan
  • 1991–1997
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1990–1997
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 1978–1989
    • The University of Tokyo
      • Department of Biophysics and Biochemistry
      Tokyo, Tokyo-to, Japan