69 results on '"Takai, J."'
Search Results
2. Involvement through photography
- Author
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Takai, J., primary
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- 2016
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3. The statistical geometry of transcriptome divergence in cell-type evolution and cancer
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Liang, C, Alam, I, Albanese, D, Altschuler, G, Andersson, R, Arakawa, T, Archer, J, Arner, E, Arner, P, Babina, M, Baillie, K, Bajic, V, Baker, S, Balic, A, Balwierz, P, Beckhouse, A, Bertin, N, Blake, Ja, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Burroughs, M, Califano, A, Cannistraci, C, Carbajo, D, Carninci, P, Chen, Yang, Chierici, M, Ciani, Y, Clevers, H, Dalla, Emiliano, Daub, C, Davis, C, De Hoon, M, De Lima Morais, D, Dermar, M, Diehl, A, Dimont, E, Dohl, T, Drabros, F, Edge, A, Edinger, M, Ekwall, K, Endoh, M, Enomoto, H, Fagiolini, M, Fairbairn, L, Fang, H, Farach Carson, Mc, Faulkner, G, Favorov, A, Fisher, M, Forrest, A, Francescatto, M, Freeman, T, Frith, M, Fujita, R, Fukuda, S, Furlanello, C, Furuno, M, Furusawa, J, Geijtenbeek, Tb, Gibson, A, Gingeras, T, Goldowithz, D, Gough, J, Guhl, S, Guler, R, Gustincich, Stefano, Ha, T, Haberle, V, Hamaguchi, M, Hara, M, Harbers, M, Harshbarger, J, Hasegawa, A, Hasegawa, Y, Hashimoto, T, Hayashizaki, Y, Herlyn, M, Heutink, P, Hide, W, Hitchens, K, Ho Sui, S, Hofmann, O, Hoof, I, Hori, F, Hume, D, Huminiecki, L, Iida, K, Ikawa, T, Ishizu, Y, Itoh, M, Jankovic, B, Jia, H, Jorgensen, M, Joshi, A, Jurman, G, Kaczkowski, B, Kai, C, Kaida, K, Kaiho, A, Kajiyama, K, Kanamori Katayama, M, Kasianov, A, Kasukawa, T, Katayama, S, Kato Ishikawa, S, Kawaguchi, S, Kawai, J, Kawaji, H, Kawamoto, H, Kawamura, Y, Kawashima, T, Kempfle, J, Kenna, T, Kere, J, Khachigian, L, Kitamura, T, Klinken, P, Knox, A, Kojima, M, Kojima, S, Kondo, N, Koseki, H, Koyasu, S, Krampitz, S, Kubosaki, A, Kulakovskiy, I, Kwon, At, Laros, J, Lassmann, T, Lenhard, B, Lennartsson, A, Li, K, Lilji, B, Lipovich, L, Lizio, M, Mackay Sim, A, Makeev, V, Manabe, R, Mar, J, Marchand, B, Mathelier, A, Medvedeva, Y, Meehan, Tf, Mejhert, N, Meynert, A, Mizuno, Y, Morikawa, H, Morimoto, M, Moro, K, Motakis, E, Motohashi, H, Mummery, C, Mungall, Cj, Murata, M, Nagao Sato, S, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nakazato, K, Ninomiya Fukuda, N, Nishiyori Sueki, H, Noma, S, Nozaki, T, Ogishima, S, Ohkura, N, Ohmiya, H, Ohno, H, Ohshima, M, Okada Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, D, Pain, A, Passier, R, Persson, H, Piazza, Silvano, Plessy, C, Pradhan Bhatt, S, Prendergast, J, Rackham, O, Ramilowski, J, Rashid, M, Ravasi, T, Rehli, M, Rizzu, P, Roncador, M, Roy, S, Rye, M, Saijyo, E, Sajantila, A, Saka, A, Sakaguchi, S, Sakai, M, Sandelin, A, Sato, H, Satoh, H, Suzana, S, Alka, S, Schaefer, U, Schmeier, S, Schmidl, C, Schneider, C, Schultes, Ea, Schulze Tanzil, G, Schwegmann, A, Semple, C, Sengstag, T, Severin, J, Sheng, G, Shimoji, H, Shimoni, Y, Shin, J, Simon, C, Sugiyama, D, Sugiyama, T, Summers, K, Suzuki, H, Suzuki, M, Suzuki, N, Swoboda, R, Hoen P, T, Tagami, M, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tatum, Z, Taylor, M, Thompson, M, Toyoda, H, Toyoda, T, Valen, E, Van De Wetering, M, Van Den Berg, L, Van Nimwegen, E, Verardo, R, Vijayan, D, Vitezic, M, Vorontzov, I, Wasserman, W, Watanabe, S, Wells, C, Winteringham, L, Wolvetang, E, Wood, Ej, Yamaguchi, Y, Yamamoto, M, Yoneda, M, Yonekura, Y, Yoshida, Shin'Ichirou, Young, R, Zabierowski, Se, Zhang, P, Zhao, X, Zucchelli, Silvia, Forrest, Ar, Wagner, Gp, Hubrecht Institute for Developmental Biology and Stem Cell Research, AII - Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology
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Cell type ,General Physics and Astronomy ,rna-seq data ,phylogenetic networks ,Biology ,ENCODE ,General Biochemistry, Genetics and Molecular Biology ,Divergence ,Transcriptome ,Models ,Settore BIO/13 - Biologia Applicata ,Neoplasms ,Humans ,Genetics ,Models, Statistical ,Multidisciplinary ,Statistical model ,General Chemistry ,Statistical ,Biological Evolution ,Body plan ,Tree structure ,Evolutionary biology ,Cancer cell - Abstract
In evolution, body plan complexity increases due to an increase in the number of individualized cell types. Yet, there is very little understanding of the mechanisms that produce this form of organismal complexity. One model for the origin of novel cell types is the sister cell-type model. According to this model, each cell type arises together with a sister cell type through specialization from an ancestral cell type. A key prediction of the sister cell-type model is that gene expression profiles of cell types exhibit tree structure. Here we present a statistical model for detecting tree structure in transcriptomic data and apply it to transcriptomes from ENCODE and FANTOM5. We show that transcriptomes of normal cells harbour substantial amounts of hierarchical structure. In contrast, cancer cell lines have less tree structure, suggesting that the emergence of cancer cells follows different principles from that of evolutionary cell-type origination.
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- 2015
4. Peace and Coexistence (III. Practice of Alternative Subjects)
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Hara, J., Sankoda, H., Takahashi, N., Noda, M., Takai, J., and Sato, Y.
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新教科 ,平和 ,ジェンダー ,共生 ,子どもの人権 ,環境問題 ,アンケート - Abstract
「共生と平和の科学」が、高2の後期に必修科目として開講されて3年になった。毎年生徒の集録を作成し、最後の授業で生徒に振り返りアンケートを実施している。我々はよりよい授業を目指して、過去2年の本紀要に報告してきたように授業研究を行ってきた。今回は3年間のまとめとして、生徒アンケートの年次比較を行い、我々の取り組みの成果と課題をまとめてみた。, 国立情報学研究所で電子化したコンテンツを使用している。
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- 2005
5. Peace and Coexistence (III. Practice of Elective Subjects and Alternative Subjects)
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Hara, J., Takahashi, N., Sankoda, H., and Takai, J.
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新教科 ,平和 ,自然破壊 ,ジェンダー ,児童労働 ,共生 ,子どもの人権 ,環境問題 ,男女平等 - Abstract
「共生と平和の科学」2年目の取り組みは、初年度の成果と課題を踏まえて次の2点を改めた。1点目は3つの軸を高校生が考えやすいようにより具体的にしたこと。2点目は、それぞれで異なっていた授業の流れを、合同授業を軸の要にして同様に組み立て、3つを結びつけて共通性を導きやすくしたこと、である。全16回の授業の流れと各授業のねらいを中心に、2年目の実践を報告する。, 国立情報学研究所で電子化したコンテンツを使用している。
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- 2004
6. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation
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Morikawa, H, Ohkura, N, Vandenbon, A, Itoh, M, Nagao Sato, S, Kawaji, H, Lassmann, T, Carninci, P, Hayashizaki, Y, Forrest, Ar, Standley, Dm, Date, H, Sakaguchi, S, FANTOM Consortium (Forrest AR, Rehli, M, Baillie, Jk, de Hoon MJ, Haberle, V, Kulakovskiy, Iv, Lizio, M, Andersson, R, Mungall, Cj, Meehan, Tf, Schmeier, S, Bertin, N, Jørgensen, M, Dimont, E, Arner, E, Schmidl, C, Schaefer, U, Medvedeva, Ya, Plessy, C, Vitezic, M, Severin, J, Semple, Ca, Ishizu, Y, Francescatto, M, Alam, I, Albanese, D, Altschuler, Gm, Archer, Ja, Arner, P, Babina, M, Baker, S, Balwierz, Pj, Beckhouse, Ag, Pradhan Bhatt, S, Blake, Ja, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Burroughs, Am, Califano, A, Cannistraci, Cv, Carbajo, D, Chen, Y, Chierici, M, Ciani, Y, Clevers, Hc, Dalla, E, Davis, Ca, Deplancke, B, Detmar, M, Diehl, Ad, Dohi, T, Drabløs, F, Edge, As, Edinger, M, Ekwall, K, Endoh, M, Enomoto, H, Fagiolini, M, Fairbairn, L, Fang, H, Farach Carson MC, Faulkner, Gj, Favorov, Av, Fisher, Me, Frith, Mc, Fujita, R, Fukuda, S, Furlanello, C, Furuno, M, Furusawa, J, Geijtenbeek, Tb, Gibson, A, Gingeras, T, Goldowitz, D, Gough, J, Guhl, S, Guler, R, Gustincich, Stefano, Ha, Tj, Hamaguchi, M, Hara, M, Harbers, M, Harshbarger, J, Hasegawa, A, Hasegawa, Y, Hashimoto, T, Herlyn, M, Hitchens, Kj, Ho Sui SJ, Hofmann, Om, Hoof, I, Hori, F, Huminiecki, L, Iida, K, Ikawa, T, Jankovic, Br, Jia, H, Joshi, A, Jurman, G, Kaczkowski, B, Kai, C, Kaida, K, Kaiho, A, Kajiyama, K, Kanamori Katayama, M, Kasianov, As, Kasukawa, T, Katayama, S, Kato, S, Kawaguchi, S, Kawamoto, H, Kawamura, Yi, Kawashima, T, Kempfle, Js, Kenna, Tj, Kere, J, Khachigian, Lm, Kitamura, T, Klinken, Sp, Knox, Aj, Kojima, M, Kojima, S, Kondo, N, Koseki, H, Koyasu, S, Krampitz, S, Kubosaki, A, Kwon, At, Laros, Jf, Lee, W, Lennartsson, A, Li, K, Lilje, B, Lipovich, L, Mackay Sim, A, Manabe, R, Mar, Jc, Marchand, B, Mathelier, A, Mejhert, N, Meynert, A, Mizuno, Y, Morais, Da, Morimoto, M, Moro, K, Motakis, E, Motohashi, H, Mummery, Cl, Murata, M, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nakazato, K, van Nimwegen, E, Ninomiya, N, Nishiyori, H, Noma, S, Nozaki, T, Ogishima, S, Ohmiya, H, Ohno, H, Ohshima, M, Okada Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, Da, Pain, A, Passier, R, Patrikakis, M, Persson, H, Piazza, S, Prendergast, Jg, Rackham, Oj, Ramilowski, Ja, Rashid, M, Ravasi, T, Rizzu, P, Roncador, M, Roy, S, Rye, Mb, Saijyo, E, Sajantila, A, Saka, A, Sakai, M, Sato, H, Satoh, H, Savvi, S, Saxena, A, Schneider, C, Schultes, Ea, Schulze Tanzil GG, Schwegmann, A, Sengstag, T, Sheng, G, Shimoji, H, Shimoni, Y, Shin, Jw, Simon, C, Sugiyama, D, Sugiyama, T, Suzuki, M, Swoboda, Rk, 't Hoen PA, Tagami, M, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tatum, Z, Thompson, M, Toyoda, H, Toyoda, T, Valen, E, van de Wetering, M, van den Berg LM, Verardo, R, Vijayan, D, Vorontsov, Ie, Wasserman, Ww, Watanabe, S, Wells, Ca, Winteringham, Ln, Wolvetang, E, Wood, Ej, Yamaguchi, Y, Yamamoto, M, Yoneda, M, Yonekura, Y, Yoshida, S, Zabierowski, Se, Zhang, Pg, Zhao, X, Zucchelli, S, Summers, Km, Suzuki, H, Daub, Co, Kawai, J, Heutink, P, Hide, W, Freeman, Tc, Lenhard, B, Bajic, Vb, Taylor, Ms, Makeev, Vj, Sandelin, A, Hume, Da, Hayashizaki, Y., AII - Amsterdam institute for Infection and Immunity, Infectious diseases, Experimental Immunology, and Hubrecht Institute for Developmental Biology and Stem Cell Research
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Transcription, Genetic ,Regulatory T cell ,T-Lymphocytes ,Down-Regulation ,chemical and pharmacologic phenomena ,Biology ,Inbred C57BL ,T-Lymphocytes, Regulatory ,Epigenesis, Genetic ,Mice ,Genetic ,Settore BIO/13 - Biologia Applicata ,medicine ,Transcriptional regulation ,Animals ,Epigenetics ,Gene ,Inbred BALB C ,Genetics ,Regulation of gene expression ,Mice, Inbred BALB C ,Multidisciplinary ,Binding Sites ,FOXP3 ,hemic and immune systems ,Forkhead Transcription Factors ,DNA Methylation ,Biological Sciences ,Regulatory ,Cap analysis gene expression ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Gene Expression Regulation ,DNA methylation ,Transcription ,Epigenesis - Abstract
Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression.
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- 2014
7. Anthropomorphic Robot Hand "Gifu Hand III" and Real Time Control System
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Mouri, T., primary, Kawasaki, H., additional, Yoshikawa, K., additional, Takai, J., additional, and Ito, S., additional
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- 2002
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8. The Japanese journal of ergonomics
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Watanabe, T., primary, Omori, M., additional, Takada, H., additional, Takai, J., additional, Takayanagi, Y., additional, Miyao, M., additional, Ishihara, S., additional, Moyoshi, M., additional, Ohtani, A., additional, Fujikake, K., additional, Miyoshi, M., additional, Mukai, M., additional, and Kansaku, H., additional
- Published
- 2001
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9. The Japanese journal of ergonomics
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Omori, M., primary, Watanabe, T., additional, Takada, H., additional, Takai, J., additional, Takayanagi, Y., additional, Miyao, M., additional, Ishihara, S., additional, Moyoshi, M., additional, Ohtani, A., additional, Fujikake, K., additional, Miyoshi, M., additional, Mukai, M., additional, and Kansaku, H., additional
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- 2001
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10. ChemInform Abstract: Decomposition and Formation of Triazine Series Compounds. Part 13. Thermal Behavior and Characterization of Some 2-Oxazolidinone Derivatives
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SHIMASAKI, C., primary, HAYASE, S., additional, MURAI, A., additional, TAKAI, J., additional, TSUKURIMICHI, E., additional, and YOSHIMURA, T., additional
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- 1990
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11. Effect of Cyclamate Sodium, Saccharin Sodium and Stevioside on Arginine-Induced Insulin and Glucagon Secretion in the Isolated Perfused Rat Pancreas
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Usami, M., primary, Seino, Y., additional, Takai, J., additional, Nakahara, H., additional, Seino, S., additional, Ikeda, M., additional, and Imura, H., additional
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- 1980
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12. Development of a multifingered robotic human upper limb as an inverse haptic interface
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Mrad, C., primary, Kawasaki, H., additional, Takai, J., additional, Tanaka, Y., additional, and Mouri, T., additional
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13. Control of multi-fingered haptic interface opposite to human hand
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Kawasaki, H., primary, Takai, J., additional, Tanaka, Y., additional, Mrad, C., additional, and Mouri, T., additional
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14. Control of multi-fingered haptic interface opposite to human hand.
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Kawasaki, H., Takai, J., Tanaka, Y., Mrad, C., and Mouri, T.
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- 2003
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15. Development of a multifingered robotic human upper limb as an inverse haptic interface.
- Author
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Mrad, C., Kawasaki, H., Takai, J., Tanaka, Y., and Mouri, T.
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- 2002
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16. Enamine Catalysis for the Direct Asymmetric Hydroxyamination.
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Kano, T., Ueda, M., Takai, J., and Maruoka, K.
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- 2006
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17. Adjustment Patterns of International Students in Japan
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Tanaka, T., Takai, J., Kohyama, T., and Fujihara, T.
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- 1994
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18. Training Effects on the Divergent Thinking Attitudes of Japanese Managers
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Basadur, M., Wakabayashi, M., and Takai, J.
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- 1992
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19. Operational research to inform post-validation surveillance of lymphatic filariasis in Tonga study protocol: History of lymphatic filariasis elimination, rational, objectives, and design.
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Lawford H, Tukia ', Takai J, Sheridan S, and Lau CL
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- Humans, Tonga epidemiology, Population Surveillance methods, Male, Female, Wuchereria bancrofti, Child, Elephantiasis, Filarial epidemiology, Elephantiasis, Filarial transmission, Elephantiasis, Filarial prevention & control, Disease Eradication methods
- Abstract
Background: Lymphatic filariasis (LF), a mosquito-borne helminth infection, is an important cause of chronic disability globally. The World Health Organization has validated eight Pacific Island countries as having eliminated lymphatic filariasis (LF) as a public health problem, but there are limited data to support an evidence-based approach to post-validation surveillance (PVS). Tonga was validated as having eliminated LF in 2017 but no surveillance has been conducted since 2015. This paper describes a protocol for an operational research project investigating different PVS methods in Tonga to provide an evidence base for national and regional PVS strategies., Methods: Programmatic baseline surveys and Transmission Assessment Surveys conducted between 2000-2015 were reviewed to identify historically 'high-risk' and 'low-risk' schools and communities. 'High-risk' were those with LF antigen (Ag)-positive individuals recorded in more than one survey, whilst 'low-risk' were those with no recorded Ag-positives. The outcome measure for ongoing LF transmission will be Ag-positivity, diagnosed using Alere™ Filariasis Test Strips. A targeted study will be conducted in May-July 2024 including: (i) high and low-risk schools and communities, (ii) boarding schools, and (iii) patients attending a chronic-disease clinic. We estimate a total sample size of 2,010 participants., Conclusions: Our methodology for targeted surveillance of suspected 'high-risk' populations using historical survey data can be adopted by countries when designing their PVS strategies. The results of this study will allow us to understand the current status of LF in Tonga and will be used to develop the next phase of activities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lawford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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20. Perturbed collagen metabolism underlies lymphatic recanalization failure in Gata2 heterozygous deficient mice.
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Watanabe-Asaka T, Hayashi M, Harada T, Uemura S, Takai J, Nakamura Y, Moriguchi T, and Kawai Y
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- Animals, Mice, Lymphatic Vessels metabolism, Lymphatic Vessels pathology, Mice, Knockout, Haploinsufficiency, GATA2 Deficiency metabolism, GATA2 Deficiency genetics, Mice, Inbred C57BL, GATA2 Transcription Factor metabolism, GATA2 Transcription Factor genetics, Lymphedema metabolism, Lymphedema genetics, Lymphedema pathology, Heterozygote, Collagen metabolism
- Abstract
Lymphedema has become a global health issue following the growing number of cancer surgeries. Curative or supportive therapeutics have long been awaited for this refractory condition. Transcription factor GATA2 is crucial in lymphatic development and maintenance, as GATA2 haploinsufficient disease often manifests as lymphedema. We recently demonstrated that Gata2 heterozygous deficient mice displayed delayed lymphatic recanalization upon lymph node resection. However, whether GATA2 contributes to lymphatic regeneration by functioning in the damaged lymph vessels' microenvironment remains explored. In this study, our integrated analysis demonstrated that dermal collagen fibers were more densely accumulated in the Gata2 heterozygous deficient mice. The collagen metabolism-related transcriptome was perturbed, and collagen matrix contractile activity was aberrantly increased in Gata2 heterozygous embryonic fibroblasts. Notably, soluble collagen placement ameliorated delayed lymphatic recanalization, presumably by modulating the stiffness of the extracellular matrix around the resection site of Gata2 heterozygous deficient mice. Our results provide valuable insights into mechanisms underlying GATA2-haploinsufficiency-mediated lymphedema and shed light on potential therapeutic avenues for this intractable disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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21. Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide.
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Xu X, Fukuda T, Takai J, Morii S, Sun Y, Liu J, Ohno S, Isaji T, Yamaguchi Y, Nakano M, Moriguchi T, and Gu J
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- Animals, Humans, Mice, Cytokine Receptor gp130, Fucosyltransferases genetics, Fucosyltransferases metabolism, Interleukin-6 genetics, Neuroinflammatory Diseases, RNA, Messenger, Fucose pharmacology, Fucose metabolism, Inflammation drug therapy, Inflammation metabolism, Lipopolysaccharides toxicity
- Abstract
α1,6-Fucosyltransferase (Fut8) catalyzes the transfer of fucose to the innermost GlcNAc residue of N-glycan to form core fucosylation. Our previous studies showed that lipopolysaccharide (LPS) treatment highly induced neuroinflammation in Fut8 homozygous KO (Fut8
-/- ) or heterozygous KO (Fut8+/- ) mice, compared with the WT (Fut8+/+ ) mice. To understand the underlying mechanism, we utilized a sensitive inflammation-monitoring mouse system that contains the human interleukin-6 (hIL6) bacterial artificial chromosome transgene modified with luciferase (Luc) reporter cassette. We successfully detected LPS-induced neuroinflammation in the central nervous system by exploiting this bacterial artificial chromosome transgenic monitoring system. Then we examined the effects of l-fucose on neuroinflammation in the Fut8+/- mice. The lectin blot and mass spectrometry analysis showed that l-fucose preadministration increased the core fucosylation levels in the Fut8+/- mice. Notably, exogenous l-fucose attenuated the LPS-induced IL-6 mRNA and Luc mRNA expression in the cerebral tissues, confirmed using the hIL6-Luc bioluminescence imaging system. The activation of microglial cells, which provoke neuroinflammatory responses upon LPS stimulation, was inhibited by l-fucose preadministration. l-Fucose also suppressed the downstream intracellular signaling of IL-6, such as the phosphorylation levels of JAK2 (Janus kinase 2), Akt (protein kinase B), and STAT3 (signal transducer and activator of transcription 3). l-Fucose administration increased gp130 core fucosylation levels and decreased the association of gp130 with the IL-6 receptor in Fut8+/- mice, which was further confirmed in BV-2 cells. These results indicate that l-fucose administration ameliorates the LPS-induced neuroinflammation in the Fut8+/- mice, suggesting that core fucosylation plays a vital role in anti-inflammation and that l-fucose is a potential prophylactic compound against neuroinflammation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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22. The Il6 -39 kb enhancer containing clustered GATA2- and PU.1-binding sites is essential for Il6 expression in murine mast cells.
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Ohmori S, Takai J, Uemura S, Otsuki A, Mori T, Ohneda K, and Moriguchi T
- Abstract
Mast cells serve as a first-line defense of innate immunity. Interleukin-6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in mast cells plays a crucial role in antibacterial protection. The zinc finger transcription factor GATA2 cooperatively functions with the ETS family transcription factor PU.1 in multiple mast cell activities. However, the regulatory landscape directed by GATA2 and PU.1 under inflammation remains elusive. We herein showed that a large proportion of GATA2-binding peaks were closely located with PU.1-binding peaks in distal cis -regulatory regions of inflammatory cytokine genes in mast cells. Notably, GATA2 and PU.1 played crucial roles in promoting LPS-mediated inflammatory cytokine production. Genetic ablation of GATA2-PU.1-clustered binding sites at the Il6 -39 kb region revealed its central role in LPS-induced Il6 expression in mast cells. We demonstrate a novel collaborative activity of GATA2 and PU.1 in cytokine induction upon inflammatory stimuli via the GATA2-PU.1 overlapping sites in the distal cis -regulatory regions., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2022.)
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- 2022
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23. Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells.
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Fejes Z, Pócsi M, Takai J, Erdei J, Tóth A, Balogh E, Rusznyák Á, Fenyvesi F, Nagy A, Kappelmayer J, Jeney V, and Nagy B Jr
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- C-Reactive Protein cerebrospinal fluid, C-Reactive Protein metabolism, Case-Control Studies, Cerebral Hemorrhage complications, Cerebral Hemorrhage congenital, Cerebral Hemorrhage metabolism, Choroid Plexus pathology, Cohort Studies, Cytokines cerebrospinal fluid, Cytokines metabolism, Epithelial Cells metabolism, Epithelial Cells pathology, Female, Heme metabolism, Hemoglobins metabolism, Humans, Hungary, Infant, Newborn, Infant, Premature, Intercellular Adhesion Molecule-1 cerebrospinal fluid, Intercellular Adhesion Molecule-1 metabolism, Male, Systemic Inflammatory Response Syndrome congenital, Systemic Inflammatory Response Syndrome etiology, Systemic Inflammatory Response Syndrome metabolism, Vascular Cell Adhesion Molecule-1 cerebrospinal fluid, Vascular Cell Adhesion Molecule-1 metabolism, Cerebral Hemorrhage pathology, Choroid Plexus metabolism, Systemic Inflammatory Response Syndrome pathology
- Abstract
Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0-60 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v / v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-κB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41-60. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-κB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.
- Published
- 2021
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24. Gata2 heterozygous mutant mice exhibit reduced inflammatory responses and impaired bacterial clearance.
- Author
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Takai J, Shimada T, Nakamura T, Engel JD, and Moriguchi T
- Abstract
Infectious diseases continually pose global medical challenges. The transcription factor GATA2 establishes gene networks and defines cellular identity in hematopoietic stem/progenitor cells and in progeny committed to specific lineages. GATA2-haploinsufficient patients exhibit a spectrum of immunodeficiencies associated with bacterial, viral, and fungal infections. Despite accumulating clinical knowledge of the consequences of GATA2 haploinsufficiency in humans, it is unclear how GATA2 haploinsufficiency compromises host anti-infectious defenses. To address this issue, we examined Gata2 -heterozygous mutant ( G2
Het ) mice as a model for human GATA2 haploinsufficiency. In vivo inflammation imaging and cytokine multiplex analysis demonstrated that G2Het mice had attenuated inflammatory responses with reduced levels of inflammatory cytokines, particularly IFN-γ, IL-12p40, and IL-17A, during lipopolysaccharide-induced acute inflammation. Consequently, bacterial clearance was significantly impaired in G2Het mice after cecal ligation and puncture-induced polymicrobial peritonitis. These results provide direct molecular insights into GATA2-directed host defenses and the pathogenic mechanisms underlying observed immunodeficiencies in GATA2-haploinsufficient patients., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)- Published
- 2021
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25. GATA2 participates in the recanalization of lymphatic vessels after surgical lymph node extirpation.
- Author
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Watanabe-Asaka T, Hayashi M, Uemura S, Takai J, Suzuki A, Moriguchi T, and Kawai Y
- Subjects
- Animals, GATA2 Transcription Factor genetics, GATA3 Transcription Factor genetics, GATA3 Transcription Factor metabolism, Heterozygote, Lymphatic Vessels physiology, Lymphedema etiology, Mice, Postoperative Complications etiology, Regeneration, GATA2 Transcription Factor metabolism, Lymph Node Excision adverse effects, Lymphatic Vessels metabolism, Lymphedema metabolism, Postoperative Complications metabolism
- Abstract
Lymphatic recanalization failure after lymphadenectomy constitutes a major risk of lymphedema in cancer surgery. It has been reported that GATA2, a zinc finger transcription factor, is expressed in lymphatic endothelial cells and is involved in the development of fetal lymphatic vessels. GATA3, another member of the GATA family of transcription factors, is required for the differentiation of lymphoid tissue inducer (LTi) cells and is essential for lymph node formation. However, how GATA2 and GATA3 function in recanalization after the surgical extirpation of lymphatic vessels has not been elucidated. Employing a new model of lymphatic recanalization, we examined the lymphatic reconnection process in Gata2 heterozygous deficient (Gata2
+/- ) and Gata3 heterozygous deficient (Gata3+/- ) mice. We found that lymphatic recanalization was significantly impaired in Gata2+/- mice, while Gata3+/- mice rarely showed such abnormalities. Notably, the perturbed lymphatic recanalization in the Gata2+/- mice was partially restored by crossing with the Gata3+/- mice. Our results demonstrate for the first time that GATA2 participates in the regeneration of damaged lymphatic vessels and the unexpected suppressive activity of GATA3 against lymphatic recanalization processes., (© 2021 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)- Published
- 2021
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26. Elevated Pro-Inflammatory Cell-Free MicroRNA Levels in Cerebrospinal Fluid of Premature Infants after Intraventricular Hemorrhage.
- Author
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Fejes Z, Erdei J, Pócsi M, Takai J, Jeney V, Nagy A, Varga A, Bácsi A, Bognár L, Novák L, Kappelmayer J, and Nagy B Jr
- Subjects
- Biomarkers cerebrospinal fluid, Cell Line, Circulating MicroRNA, Female, Humans, Infant, Infant, Newborn, Male, Cerebral Hemorrhage cerebrospinal fluid, Infant, Newborn, Diseases cerebrospinal fluid, Infant, Premature cerebrospinal fluid
- Abstract
Intraventricular hemorrhage (IVH) represents a high risk of neonatal mortality and later neurodevelopmental impairment in prematurity. IVH is accompanied with inflammation, hemolysis, and extracellular hemoglobin (Hb) oxidation. However, microRNA (miRNA) expression in cerebrospinal fluid (CSF) of preterm infants with IVH has been unknown. Therefore, in the present study, candidate pro-inflammatory cell-free miRNAs were analyzed in CSF samples from 47 preterm infants with grade III or IV IVH vs. clinical controls ( n = 14). miRNAs were quantified by RT-qPCR, normalized to "spike-in" cel-miR-39. Oxidized Hb and total heme levels were determined by spectrophotometry as well as IL-8, VCAM-1, ICAM-1, and E-selectin concentrations by ELISA. To reveal the origin of the investigated miRNAs, controlled hemolysis experiments were performed in vitro; in addition, human choroid plexus epithelial cell (HCPEpiC) cultures were treated with metHb, ferrylHb, heme, or TNF-α to replicate IVH-triggered cellular conditions. Levels of miR-223, miR-155, miR-181b, and miR-126 as well as Hb metabolites along with IL-8 were elevated in CSF after the onset of IVH vs. controls. Significant correlations were observed among the miRNAs, oxidized Hb forms, and the soluble adhesion molecules. During the post-IVH follow-up, attenuated expression of miRNAs and protein biomarkers in CSF was observed upon elimination of Hb metabolites. These miRNAs remained unaffected by a series of artificially induced hemolysis, which excluded red blood cells as their origin, while stimulation of HCPEpiCs with oxidized Hb fractions and heme resulted in increased extracellular miRNA levels in the cell culture supernatant. Overall, the hemorrhage-induced CSF miRNAs reflected inflammatory conditions as potential biomarkers in preterm IVH.
- Published
- 2020
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27. Histamine and histidine decarboxylase: Immunomodulatory functions and regulatory mechanisms.
- Author
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Moriguchi T and Takai J
- Subjects
- Animals, Chromosomes, Artificial, Bacterial, Gene Expression Regulation, Enzymologic immunology, Histamine physiology, Histidine Decarboxylase genetics, Histones metabolism, Methylation, Mice, Mice, Transgenic, Myeloid Cells metabolism, Sepsis metabolism, Histamine metabolism, Histidine Decarboxylase metabolism, Receptors, Histamine metabolism, Sepsis immunology
- Abstract
Histamine is a bioactive monoamine that is synthesized by the enzymatic activity of histidine decarboxylase (HDC) in basophils, mast cells, gastric enterochromaffin-like (ECL) cells and histaminergic neuronal cells. Upon a series of cellular stimuli, these cells release stored histamine, which elicits allergies, inflammation, and gastric acid secretion and regulates neuronal activity. Recent studies have shown that certain other types of myeloid lineage cells also produce histamine with HDC induction under various pathogenic stimuli. Histamine has been shown to play a series of pathophysiological roles by modulating immune and inflammatory responses in a number of disease conditions, whereas the mechanistic aspects underlying induced HDC expression remain elusive. In the present review, we summarize the current understanding of the regulatory mechanism of Hdc gene expression and the roles played by histamine in physiological contexts as well as pathogenic processes. We also introduce a newly developed histaminergic cell-monitoring transgenic mouse line (Hdc-BAC-GFP) that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals., (© 2020 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)
- Published
- 2020
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28. Lipopolysaccharide-induced expansion of histidine decarboxylase-expressing Ly6G + myeloid cells identified by exploiting histidine decarboxylase BAC-GFP transgenic mice.
- Author
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Takai J, Ohtsu H, Sato A, Uemura S, Fujimura T, Yamamoto M, and Moriguchi T
- Subjects
- Animals, Hematopoiesis drug effects, Histamine biosynthesis, Lung cytology, Lung drug effects, Lung metabolism, Mice, Mice, Transgenic, Myeloid Cells cytology, Chromosomes, Artificial, Bacterial genetics, Gene Expression Regulation, Enzymologic drug effects, Green Fluorescent Proteins genetics, Histidine Decarboxylase metabolism, Lipopolysaccharides pharmacology, Myeloid Cells drug effects, Myeloid Cells metabolism
- Abstract
Histamine is a biogenic amine that is chiefly produced in mast cells and basophils and elicits an allergic response upon stimulation. Histidine decarboxylase (HDC) is a unique enzyme that catalyzes the synthesis of histamine. Therefore, the spatiotemporally specific Hdc gene expression profile could represent the localization of histamine-producing cells under various pathophysiological conditions. Although the bioactivity of histamine is well defined, the regulatory mechanism of Hdc gene expression and the distribution of histamine-producing cell populations in various disease contexts remains unexplored. To address these issues, we generated a histidine decarboxylase BAC (bacterial artificial chromosome) DNA-directed GFP reporter transgenic mouse employing a 293-kb BAC clone containing the entire Hdc gene locus and extended flanking sequences (Hdc-GFP). We found that the GFP expression pattern in the Hdc-GFP mice faithfully recapitulated that of conventional histamine-producing cells and that the GFP expression level mirrored the increased Hdc expression in lipopolysaccharide (LPS)-induced septic lungs. Notably, a CD11b
+ Ly6G+ Ly6Clow myeloid cell population accumulated in the lung during sepsis, and most of these cells expressed high levels of GFP and indeed contain histamine. This study reveals the accumulation of a histamine-producing myeloid cell population during sepsis, which likely participates in the immune process of sepsis.- Published
- 2019
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29. Spiral ganglion cell degeneration-induced deafness as a consequence of reduced GATA factor activity.
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Hoshino T, Terunuma T, Takai J, Uemura S, Nakamura Y, Hamada M, Takahashi S, Yamamoto M, Engel JD, and Moriguchi T
- Subjects
- Animals, Apoptosis genetics, Cell Count, Cochlea metabolism, Cochlea pathology, Deafness metabolism, Deafness physiopathology, Disease Models, Animal, GATA Transcription Factors genetics, Gene Expression, Genes, Reporter, Immunohistochemistry, Mice, Mice, Knockout, Mice, Transgenic, Mutation, Sensory Receptor Cells metabolism, Sensory Receptor Cells pathology, Spiral Ganglion pathology, Deafness etiology, GATA Transcription Factors metabolism, Spiral Ganglion metabolism
- Abstract
Zinc-finger transcription factors GATA2 and GATA3 are both expressed in the developing inner ear, although their overlapping versus distinct activities in adult definitive inner ear are not well understood. We show here that GATA2 and GATA3 are co-expressed in cochlear spiral ganglion cells and redundantly function in the maintenance of spiral ganglion cells and auditory neural circuitry. Notably, Gata2 and Gata3 compound heterozygous mutant mice had a diminished number of spiral ganglion cells due to enhanced apoptosis, which resulted in progressive hearing loss. The decrease in spiral ganglion cellularity was associated with lowered expression of neurotrophin receptor TrkC that is an essential factor for spiral ganglion cell survival. We further show that Gata2 null mutants that additionally bear a Gata2 YAC (yeast artificial chromosome) that counteracts the lethal hematopoietic deficiency due to complete Gata2 loss nonetheless failed to complement the deficiency in neonatal spiral ganglion neurons. Furthermore, cochlea-specific Gata2 deletion mice also had fewer spiral ganglion cells and resultant hearing impairment. These results show that GATA2 and GATA3 redundantly function to maintain spiral ganglion cells and hearing. We propose possible mechanisms underlying hearing loss in human GATA2- or GATA3-related genetic disorders., (© 2019 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)
- Published
- 2019
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30. Patients with Asthma Prescribed Once-Daily Fluticasone Furoate/Vilanterol or Twice-Daily Fluticasone Propionate/Salmeterol as Maintenance Treatment: Analysis from a Claims Database.
- Author
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Atsuta R, Takai J, Mukai I, Kobayashi A, Ishii T, and Svedsater H
- Abstract
Introduction: There is a paucity of data describing prescribing patterns and adherence to therapy of inhaled corticosteroids (ICS) in combination with long-acting β
2 -agonists (LABA) in the Japanese population in clinical practice., Methods: This was a non-interventional, retrospective, cohort study of patients who were prescribed medication for asthma, using data from the Japan Medical Data Center Claims Database. Data from patients aged ≥ 15 years with a prescription of asthma drugs between December 2014 and October 2015 (Day 0, the index date when asthma medication was initiated) were analysed in 12-month pre-index and post-index periods. Part 1 focused on baseline characteristics and epidemiological outcomes in the pre- and post-index period in the overall asthma population, whereas comparing medication adherence [number of prescribed days per year and proportion of days covered (PDC)] between ICS/LABA-naïve patients treated with once-daily fluticasone furoate/vilanterol (FF/VI) and twice-daily fluticasone propionate/salmeterol (FP/SAL) was the primary endpoint in Part 2., Results: Of the available patient data (N = 2,953,652), 28,699 patients were identified as having asthma. ICS/LABA was the main asthma treatment prescribed; 11,167 (38.9%) patients were continuous ICS/LABA users. In ICS/LABA-naïve asthma patients, treatment with once-daily FF/VI was associated with higher medication adherence compared with twice-daily FP/SAL; mean [standard deviation (SD)] number of prescribed days per year was 97.8 (115.9) for FF/VI versus 80.5 (92.7) for FP/SAL (p = 0.04), mean (SD) PDC was 26.7% (31.5) for FF/VI versus 21.9% (24.8) for FP/SAL (p = 0.04). FF/VI was also associated with a lower rate of treatment discontinuation and no difference in use of short-acting beta2 -agonists or oral corticosteroids compared with FP/SAL., Conclusions: ICS/LABA was the major prescribed asthma treatment in Japan. Medication adherence was greater with FF/VI, which may indicate that patients are more likely to adhere to once-daily FF/VI versus twice-daily FP/SAL., Funding: This study was funded by GSK (study sponsor)., Study Registration: GSK Study No. 207264, GSK Study Register site: https://www.gsk-clinicalstudyregister.com/search/?search_terms=207264 .- Published
- 2018
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31. A Gata3 3' Distal Otic Vesicle Enhancer Directs Inner Ear-Specific Gata3 Expression.
- Author
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Moriguchi T, Hoshino T, Rao A, Yu L, Takai J, Uemura S, Ise K, Nakamura Y, Lim KC, Shimizu R, Yamamoto M, and Engel JD
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Mice, Transgenic, Ear, Inner growth & development, GATA3 Transcription Factor genetics, Gene Expression Regulation, Developmental genetics, Regulatory Sequences, Nucleic Acid genetics
- Abstract
Transcription factor GATA3 plays vital roles in inner ear development, while regulatory mechanisms controlling its inner ear-specific expression are undefined. We demonstrate that a cis -regulatory element lying 571 kb 3' to the Gata3 gene directs inner ear-specific Gata3 expression, which we refer to as the Gata3 otic vesicle enhancer (OVE). In transgenic murine embryos, a 1.5-kb OVE-directed lacZ reporter (Tg
OVE-LacZ ) exhibited robust lacZ expression specifically in the otic vesicle (OV), an inner ear primordial tissue, and its derivative semicircular canal. To further define the regulatory activity of this OVE, we generated Cre transgenic mice in which Cre expression was directed by a 246-bp core sequence within the OVE element (TgcoreOVE-Cre ). TgcoreOVE-Cre successfully marked the OV-derived inner ear tissues, including cochlea, semicircular canal and spiral ganglion, when crossed with ROSA26 lacZ reporter mice. Furthermore, Gata3 conditionally mutant mice, when crossed with the TgcoreOVE-Cre , showed hypoplasia throughout the inner ear tissues. These results demonstrate that OVE has a sufficient regulatory activity to direct Gata3 expression specifically in the otic vesicle and semicircular canal and that Gata3 expression driven by the OVE is crucial for normal inner ear development., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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32. Effects of relational uncertainty in heightening national identification and reactive approach motivation of Japanese.
- Author
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Terashima Y and Takai J
- Subjects
- Adult, Asian People, Female, Humans, Male, Motivation, Young Adult, Uncertainty
- Abstract
This study investigated whether relational uncertainty poses uncertainty threat, which causes compensatory behaviours among Japanese. We hypothesised that Japanese, as collectivists, would perceive relational uncertainty to pose uncertainty threat. In two experiments, we manipulated relational uncertainty, and confirmed that participants exhibited compensatory reactions to reduce aversive feelings due to it. In Study 1, we conducted direct comparison between relational uncertainty, independent self-uncertainty and control conditions. The results revealed that participants who were instructed to imagine events pertaining to relational uncertainty heightened national identification as compensation than did participants in the control condition, but independent self-uncertainty did not provoke such effects. In Study 2, we again manipulated relational uncertainty; however, we also manipulated participants' individualism-collectivism cultural orientation through priming, and the analyses yielded a significant interaction effect between these variables. Relational uncertainty evoked reactive approach motivation, a cause for compensatory behaviours, among participants primed with collectivism, but not for individualism. It was concluded that the effect of uncertainty on compensatory behaviour is influenced by cultural priming, and that relational uncertainty is important to Japanese., (© 2017 International Union of Psychological Science.)
- Published
- 2018
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33. FANTOM5 CAGE profiles of human and mouse samples.
- Author
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Noguchi S, Arakawa T, Fukuda S, Furuno M, Hasegawa A, Hori F, Ishikawa-Kato S, Kaida K, Kaiho A, Kanamori-Katayama M, Kawashima T, Kojima M, Kubosaki A, Manabe RI, Murata M, Nagao-Sato S, Nakazato K, Ninomiya N, Nishiyori-Sueki H, Noma S, Saijyo E, Saka A, Sakai M, Simon C, Suzuki N, Tagami M, Watanabe S, Yoshida S, Arner P, Axton RA, Babina M, Baillie JK, Barnett TC, Beckhouse AG, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Carlisle AJ, Clevers HC, Davis CA, Detmar M, Dohi T, Edge ASB, Edinger M, Ehrlund A, Ekwall K, Endoh M, Enomoto H, Eslami A, Fagiolini M, Fairbairn L, Farach-Carson MC, Faulkner GJ, Ferrai C, Fisher ME, Forrester LM, Fujita R, Furusawa JI, Geijtenbeek TB, Gingeras T, Goldowitz D, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Hasegawa Y, Herlyn M, Heutink P, Hitchens KJ, Hume DA, Ikawa T, Ishizu Y, Kai C, Kawamoto H, Kawamura YI, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klein S, Klinken SP, Knox AJ, Kojima S, Koseki H, Koyasu S, Lee W, Lennartsson A, Mackay-Sim A, Mejhert N, Mizuno Y, Morikawa H, Morimoto M, Moro K, Morris KJ, Motohashi H, Mummery CL, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nozaki T, Ogishima S, Ohkura N, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Passier R, Patrikakis M, Pombo A, Pradhan-Bhatt S, Qin XY, Rehli M, Rizzu P, Roy S, Sajantila A, Sakaguchi S, Sato H, Satoh H, Savvi S, Saxena A, Schmidl C, Schneider C, Schulze-Tanzil GG, Schwegmann A, Sheng G, Shin JW, Sugiyama D, Sugiyama T, Summers KM, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tomoiu A, Toyoda H, van de Wetering M, van den Berg LM, Verardo R, Vijayan D, Wells CA, Winteringham LN, Wolvetang E, Yamaguchi Y, Yamamoto M, Yanagi-Mizuochi C, Yoneda M, Yonekura Y, Zhang PG, Zucchelli S, Abugessaisa I, Arner E, Harshbarger J, Kondo A, Lassmann T, Lizio M, Sahin S, Sengstag T, Severin J, Shimoji H, Suzuki M, Suzuki H, Kawai J, Kondo N, Itoh M, Daub CO, Kasukawa T, Kawaji H, Carninci P, Forrest ARR, and Hayashizaki Y
- Subjects
- Animals, Gene Expression Regulation, Humans, Mice, Promoter Regions, Genetic, Species Specificity, Gene Expression Profiling, Genome
- Abstract
In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
- Published
- 2017
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34. Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis.
- Author
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Yu L, Takai J, Otsuki A, Katsuoka F, Suzuki M, Katayama S, Nezu M, Engel JD, Moriguchi T, and Yamamoto M
- Subjects
- Animals, Apoptosis genetics, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Lineage, Colony-Forming Units Assay, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases metabolism, Embryo, Mammalian metabolism, Erythroid Cells cytology, Erythroid Cells metabolism, Gene Expression Profiling, Gene Expression Regulation, Haploidy, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Homeostasis genetics, Integrases metabolism, Liver embryology, Liver metabolism, Mice, Transgenic, Models, Biological, Survival Analysis, Cell Differentiation genetics, DNA Methylation genetics, Erythropoiesis genetics, GATA1 Transcription Factor genetics
- Abstract
GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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35. Cultural Difference in Conflict Management Strategies of Children and Its Development: Comparing 3- and 5-Year-Olds Across China, Japan, and Korea.
- Author
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Maruyama H, Ujiie T, Takai J, Takahama Y, Sakagami H, Shibayama M, Fukumoto M, Ninomiya K, Hyang Ah P, Feng X, Takatsuji C, Hirose M, Kudo R, Shima Y, Nakayama R, Hamaie N, Zhang F, and Moriizumi S
- Abstract
Research Findings: The purpose of this study was to examine differences in the development of conflict management strategies, focusing on 3- and 5-year-olds, through a comparison of 3 neighboring Asian cultures, those of China ( n = 114), Japan ( n = 98), and Korea ( n = 90). The dual concern model of conflict management was adopted to probe which strategy children would prefer to use in 2 hypothetical conflict situations. Results indicated that, first, for disagreement, 3-year-olds in the 3 countries equally preferred the dominating strategy. For competition for resources, 3-year-olds differed in their strategy preference across all cultures. Second, the observed strategy preference of 3- to 5-year-old children in this study was more or less different from that of older schoolchildren, regardless of culture. Practice or Policy: These findings suggest the significance of the context, the complexity of the phenomenon of the development of cultural differences, and the significance of cohort sampling.
- Published
- 2015
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36. Whole-Body In Vivo Monitoring of Inflammatory Diseases Exploiting Human Interleukin 6-Luciferase Transgenic Mice.
- Author
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Hayashi M, Takai J, Yu L, Motohashi H, Moriguchi T, and Yamamoto M
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Brain immunology, Brain metabolism, Cells, Cultured, Dermatitis, Atopic drug therapy, Dermatitis, Atopic immunology, Dermatitis, Atopic metabolism, Dexamethasone pharmacology, Dexamethasone therapeutic use, Drug Evaluation, Preclinical, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Genes, Reporter, Humans, Interleukin-6 biosynthesis, Lipopolysaccharides pharmacology, Luciferases, Firefly biosynthesis, Luciferases, Firefly genetics, Macrophages immunology, Macrophages metabolism, Mice, Transgenic, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Organ Specificity, Sepsis immunology, Sepsis metabolism, Interleukin-6 genetics, Whole Body Imaging
- Abstract
Chronic inflammation underlies the pathological progression of various diseases, and thus many efforts have been made to quantitatively evaluate the inflammatory status of the diseases. In this study, we generated a highly sensitive inflammation-monitoring mouse system using a bacterial artificial chromosome (BAC) clone containing extended flanking sequences of the human interleukin 6 gene (hIL6) locus, in which the luciferase (Luc) reporter gene is integrated (hIL6-BAC-Luc). We successfully monitored lipopolysaccharide-induced systemic inflammation in various tissues of the hIL6-BAC-Luc mice using an in vivo bioluminescence imaging system. When two chronic inflammatory disease models, i.e., a genetic model of atopic dermatitis and a model of experimental autoimmune encephalomyelitis (EAE), were applied to the hIL6-BAC-Luc mice, luciferase bioluminescence was specifically detected in the atopic skin lesion and central nervous system, respectively. Moreover, the Luc activities correlated well with the disease severity. Nrf2 is a master transcription factor that regulates antioxidative and detoxification enzyme genes. Upon EAE induction, the Nrf2-deficient mice crossed with the hIL6-BAC-Luc mice exhibited enhanced neurological symptoms concomitantly with robust luciferase luminescence in the neuronal tissue. Thus, whole-body in vivo monitoring using the hIL6-BAC-Luc transgenic system (WIM-6 system) provides a new and powerful diagnostic tool for real-time in vivo monitoring of inflammatory status in multiple different disease models., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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37. THE EFFECT OF INTIMACY AND STATUS DISCREPANCY ON SALIENT AND NON-SALIENT CONFLICT STRATEGIES OF JAPANESE.
- Author
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Nakatsugawa S and Takai J
- Subjects
- Adolescent, Female, Humans, Japan, Male, Sex Factors, Students psychology, Surveys and Questionnaires, Workplace psychology, Conflict, Psychological, Interpersonal Relations
- Abstract
It has been claimed that Japanese people prefer passive forms of conflict strategies to preserve interpersonal harmony. This study aimed to identify some conditions in which such passive strategies are used. The effects of target intimacy and status discrepancy on the intent and use of salient and non-salient conflict strategies were examined, along with respondent sex differences. Questionnaires were collected from 205 Japanese university students. Results indicated that women were more likely to have non-salient intents than men and that intimacy affected considerateness intent but not avoidance intent. Active non-salient strategy was affected by status while passive non-salient strategy was affected by intimacy. Overall, target characteristics proved to be a strong factor in the intents and strategies employed in conflict situations of Japanese.
- Published
- 2015
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38. The Human GATA1 Gene Retains a 5' Insulator That Maintains Chromosomal Architecture and GATA1 Expression Levels in Splenic Erythroblasts.
- Author
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Moriguchi T, Yu L, Takai J, Hayashi M, Satoh H, Suzuki M, Ohneda K, and Yamamoto M
- Subjects
- Animals, Binding Sites, CCCTC-Binding Factor, Cells, Cultured, Chromatin physiology, Chromosomes, Artificial, Bacterial genetics, GATA1 Transcription Factor chemistry, GATA1 Transcription Factor metabolism, Genetic Vectors genetics, Humans, K562 Cells, Mice, Mice, Transgenic, Repressor Proteins metabolism, Spleen metabolism, Chromosomes genetics, Erythroblasts metabolism, GATA1 Transcription Factor genetics, Insulator Elements, Spleen cytology
- Abstract
GATA1 is a key transcription factor for erythropoiesis. GATA1 gene expression is strictly regulated at the transcriptional level. While the regulatory mechanisms governing mouse Gata1 (mGata1) gene expression have been studied extensively, how expression of the human GATA1 (hGATA1) gene is regulated remains to be elucidated. To address this issue, we generated hGATA1 bacterial artificial chromosome (BAC) transgenic mouse lines harboring a 183-kb hGATA1 locus covering the hGATA1 exons and distal flanking sequences. Transgenic hGATA1 expression coincides with endogenous mGata1 expression and fully rescues hematopoietic deficiency in mGata1 knockdown mice. The transgene exhibited copy number-dependent and integration position-independent expression of hGATA1, indicating the presence of chromatin insulator activity within the transgene. We found a novel insulator element at 29 kb 5' to the hGATA1 gene and refer to this element as the 5' CCCTC-binding factor (CTCF) site. Substitution mutation of the 5' CTCF site in the hGATA1 BAC disrupted the chromatin architecture and led to a reduction of hGATA1 expression in splenic erythroblasts under conditions of stress erythropoiesis. Our results demonstrate that expression of the hGATA1 gene is regulated through the chromatin architecture organized by 5' CTCF site-mediated intrachromosomal interactions in the hGATA1 locus., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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39. Progenitor stage-specific activity of a cis-acting double GATA motif for Gata1 gene expression.
- Author
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Moriguchi T, Suzuki M, Yu L, Takai J, Ohneda K, and Yamamoto M
- Subjects
- Alleles, Amino Acid Motifs, Animals, Cell Separation, Chromatin Immunoprecipitation, Chromosomes, Artificial, Bacterial, Erythropoiesis, Female, Flow Cytometry, GATA2 Transcription Factor metabolism, Gene Deletion, Genes, Reporter, Green Fluorescent Proteins metabolism, Homeostasis, Introns, Male, Mice, Mice, Transgenic, Mutation, Protein Binding, Erythroblasts cytology, GATA1 Transcription Factor metabolism, Gene Expression Regulation, Hematopoietic Stem Cells cytology
- Abstract
GATA1 is a master regulator of erythropoiesis, expression of which is regulated by multiple discrete cis-acting elements. In this study, we examine the activity of a promoter-proximal double GATA (dbGATA) motif, using a Gata1 bacterial artificial chromosome (BAC)-transgenic green fluorescent protein (GFP) reporter (G1BAC-GFP) mouse system. Deletion of the dbGATA motif led to significant reductions in GFP expression in hematopoietic progenitors, while GFP expression was maintained in erythroblasts. Consistently, in mice with a germ line deletion of the dbGATA motif (Gata1(ΔdbGATA) mice), GATA1 expression in progenitors was significantly decreased. The suppressed GATA1 expression was associated with a compensatory increase in GATA2 levels in progenitors. When we crossed Gata1(ΔdbGATA) mice with Gata2 hypomorphic mutant mice (Gata2(fGN/fGN) mice), the Gata1(ΔdbGATA)::Gata2(fGN/fGN) compound mutant mice succumbed to a significant decrease in the progenitor population, whereas both groups of single mutant mice maintained progenitors and survived to adulthood, indicating the functional redundancy between GATA1 and GATA2 in progenitors. Meanwhile, the effects of the dbGATA site deletion on Gata1 expression were subtle in erythroblasts, which showed increased GATA1 binding and enhanced accumulation of active histone marks around the 1st-intron GATA motif of the ΔdbGATA locus. These results thus reveal a novel role of the dbGATA motif in the maintenance of Gata1 expression in hematopoietic progenitors and a functional compensation between the dbGATA site and the 1st-intron GATA motif in erythroblasts., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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40. Enhancement of stability and activity of siRNA by terminal substitution with serinol nucleic acid (SNA).
- Author
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Kamiya Y, Takai J, Ito H, Murayama K, Kashida H, and Asanuma H
- Subjects
- Nucleic Acids chemistry, Propanolamines chemistry, Propylene Glycols chemistry, RNA Stability, RNA, Small Interfering chemistry, RNA, Small Interfering metabolism
- Abstract
RNA interference (RNAi ), sequence-specific gene silencing triggered by double-stranded, small interfering RNA (siRNA), has become a facile and effective tool for biological research and holds potential for therapeutic applications. However, the application of siRNA is hindered by susceptibility to nucleases and off-target effects. In this study, we introduced artificial nucleotides, serinol nucleic acid (SNA), with an acyclic scaffold, at the termini of siRNA strands. Our aim was appropriately to accommodate the antisense strand in an RNA-induced silencing complex (RISC) by inhibiting sense-strand incorporation and thus improve resistance to nuclease-mediated degradation. Substitution of SNA into siRNA at both termini of the sense strand and at the 3' terminus of the antisense strand improved antisense strand selectivity remarkably in the formation of RISC, RNAi activity, and nuclease resistance., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2014
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41. GATA2 regulates body water homeostasis through maintaining aquaporin 2 expression in renal collecting ducts.
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Yu L, Moriguchi T, Souma T, Takai J, Satoh H, Morito N, Engel JD, and Yamamoto M
- Subjects
- Animals, Cell Line, GATA2 Transcription Factor genetics, GATA3 Transcription Factor metabolism, Green Fluorescent Proteins biosynthesis, Homeostasis physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Osmolar Concentration, Promoter Regions, Genetic, Urine physiology, Aquaporin 2 genetics, Body Water metabolism, GATA2 Transcription Factor physiology, Gene Expression Regulation, Kidney Medulla metabolism, Kidney Tubules, Collecting metabolism
- Abstract
The transcription factor GATA2 plays pivotal roles in early renal development, but its distribution and physiological functions in adult kidney are largely unknown. We examined the GATA2 expression pattern in the adult kidney by tracing green fluorescent protein (GFP) fluorescence in Gata2(GFP/+) mice that recapitulate endogenous GATA2 expression and found a robust GFP expression specifically in the renal medulla. Upon purification of the GFP-positive cells, we found that collecting duct (CD)-specific markers, including aquaporin 2 (Aqp2), an important channel for water reabsorption from urine, were abundantly expressed. To address the physiological function of GATA2 in the CD cells, we generated renal tubular cell-specific Gata2-deficient mice (Gata2-CKO) by crossing Gata2 floxed mice with inducible Pax8-Cre mice. We found that the Gata2-CKO mice showed a significant decrease in Aqp2 expression. The Gata2-CKO mice exhibited high 24-h urine volume and low urine osmolality, two important signs of diabetes insipidus. We introduced biotin-tagged GATA2 into a mouse CD-derived cell line and conducted chromatin pulldown assays, which revealed direct GATA2 binding to conserved GATA motifs in the Aqp2 promoter region. A luciferase reporter assay using an Aqp2 promoter-reporter showed that GATA2 trans activates Aqp2 through the GATA motifs. These results demonstrate that GATA2 regulates the Aqp2 gene expression in CD cells and contributes to the maintenance of the body water homeostasis.
- Published
- 2014
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42. A promoter-level mammalian expression atlas.
- Author
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Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jørgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JA, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drabløs F, Edge AS, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furino M, Furusawa J, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Ho Sui SJ, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov AS, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JF, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-Sim A, Manabe R, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, de Lima Morais DA, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Noma S, Noazaki T, Ogishima S, Ohkura N, Ohimiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Pain A, Passier R, Patrikakis M, Persson H, Piazza S, Prendergast JG, Rackham OJ, Ramilowski JA, Rashid M, Ravasi T, Rizzu P, Roncador M, Roy S, Rye MB, Saijyo E, Sajantila A, Saka A, Sakaguchi S, Sakai M, Sato H, Savvi S, Saxena A, Schneider C, Schultes EA, Schulze-Tanzil GG, Schwegmann A, Sengstag T, Sheng G, Shimoji H, Shimoni Y, Shin JW, Simon C, Sugiyama D, Sugiyama T, Suzuki M, Suzuki N, Swoboda RK, 't Hoen PA, Tagami M, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tatum Z, Thompson M, Toyodo H, Toyoda T, Valen E, van de Wetering M, van den Berg LM, Verado R, Vijayan D, Vorontsov IE, Wasserman WW, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Wood EJ, Yamaguchi Y, Yamamoto M, Yoneda M, Yonekura Y, Yoshida S, Zabierowski SE, Zhang PG, Zhao X, Zucchelli S, Summers KM, Suzuki H, Daub CO, Kawai J, Heutink P, Hide W, Freeman TC, Lenhard B, Bajic VB, Taylor MS, Makeev VJ, Sandelin A, Hume DA, Carninci P, and Hayashizaki Y
- Subjects
- Animals, Cell Line, Cells, Cultured, Cluster Analysis, Conserved Sequence genetics, Gene Expression Regulation genetics, Gene Regulatory Networks genetics, Genes, Essential genetics, Genome genetics, Humans, Mice, Open Reading Frames genetics, Organ Specificity, RNA, Messenger analysis, RNA, Messenger genetics, Transcription Factors metabolism, Transcription Initiation Site, Transcription, Genetic genetics, Atlases as Topic, Molecular Sequence Annotation, Promoter Regions, Genetic genetics, Transcriptome genetics
- 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.
- Published
- 2014
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43. The Gata1 5' region harbors distinct cis-regulatory modules that direct gene activation in erythroid cells and gene inactivation in HSCs.
- Author
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Takai J, Moriguchi T, Suzuki M, Yu L, Ohneda K, and Yamamoto M
- Subjects
- Animals, Cell Lineage, Cells, Cultured metabolism, Chromosomes, Artificial, Bacterial, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation genetics, Enhancer Elements, Genetic genetics, Erythropoiesis genetics, GATA1 Transcription Factor physiology, GATA2 Transcription Factor metabolism, Gene Silencing, Genes, Reporter, Genes, Synthetic, Liver cytology, Liver embryology, Megakaryocytes metabolism, Mice, Mice, Transgenic, Nucleotide Motifs genetics, Sequence Deletion, Transcriptional Activation genetics, Erythroid Cells metabolism, GATA1 Transcription Factor genetics, Gene Expression Regulation, Developmental genetics, Hematopoietic Stem Cells metabolism, Regulatory Sequences, Nucleic Acid genetics
- Abstract
GATA1 is a master regulator of hematopoietic differentiation, but Gata1 expression is inactivated in hematopoietic stem cells (HSCs). Using a bacterial artificial chromosome containing the Gata1 gene modified with green fluorescent protein (GFP) reporter, we explored the function of the 3.7-kb Gata1 upstream region (GdC region) that harbors 3 core cis-elements: Gata1 hematopoietic enhancer, double GATA-motif, and CACCC-motif. Transgenic GFP expression directed by the Gata1-BAC faithfully recapitulated the endogenous Gata1 expression pattern. However, deletion of the GdC-region eliminated reporter expression in all hematopoietic cells. To test whether the combination of the core cis-elements represents the regulatory function of the GdC-region, we replaced the region with a 659-bp minigene that linked the three cis-elements (MG-GFP). The GFP reporter expression directed by the MG-GFP BAC fully recapitulated the erythroid-megakaryocytic Gata1 expression. However, the GFP expression was aberrantly increased in the HSCs and was associated with decreases in DNA methylation and abundant GATA2 binding to the transgenic MG-GFP allele. The 3.2-kb sequences interspaced between the Gata1 hematopoietic enhancer and the double GATA-motif were able to recruit DNA methyltransferase 1, thereby exerting a cis-repressive function in the HSC-like cell line. These results indicate that the 3.2-kb interspacing sequences inactivate Gata1 by maintaining DNA-methylation in the HSCs.
- Published
- 2013
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44. GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation.
- Author
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Suzuki M, Kobayashi-Osaki M, Tsutsumi S, Pan X, Ohmori S, Takai J, Moriguchi T, Ohneda O, Ohneda K, Shimizu R, Kanki Y, Kodama T, Aburatani H, and Yamamoto M
- Subjects
- Animals, Binding Sites, Cell Differentiation, Erythroid Cells metabolism, GATA1 Transcription Factor metabolism, GATA2 Transcription Factor metabolism, Gene Expression Regulation, Developmental, Hematopoietic Stem Cells metabolism, Mice, Mice, Transgenic, Erythroid Cells cytology, Erythropoiesis physiology, GATA1 Transcription Factor genetics, GATA2 Transcription Factor genetics, Hematopoietic Stem Cells cytology
- Abstract
Transcription factor GATA2 is highly expressed in hematopoietic stem cells and progenitors, whereas its expression declines after erythroid commitment of progenitors. In contrast, the start of GATA1 expression coincides with the erythroid commitment and increases along with the erythroid differentiation. We refer this dynamic transition of GATA factor expression to as the 'GATA factor switching'. Here, we examined contribution of the GATA factor switching to the erythroid differentiation. In Gata1-knockdown embryos that concomitantly express Gata2-GFP reporter, high-level expression of GFP reporter was detected in accumulated immature hematopoietic cells with impaired differentiation, demonstrating that GATA1 represses Gata2 gene expression in hematopoietic progenitors in vivo. We have conducted chromatin immunoprecipitation (ChIP) on microarray analyses of GATA2 and GATA1, and results indicate that the GATA1-binding sites widely overlap with the sites pre-occupied by GATA2 before the GATA1 expression. Importantly, erythroid genes harboring GATA boxes bound by both GATA1 and GATA2 tend to be expressed in immature erythroid cells, whereas those harboring GATA boxes to which GATA1 binds highly but GATA2 binds only weakly are important for the mature erythroid cell function. Our results thus support the contention that preceding binding of GATA2 helps the following binding of GATA1 and thereby secures smooth expression of the transient-phase genes., (© 2013 The Authors Genes to Cells © 2013 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.)
- Published
- 2013
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45. Laminar shear stress upregulates endothelial Ca²⁺-activated K⁺ channels KCa2.3 and KCa3.1 via a Ca²⁺/calmodulin-dependent protein kinase kinase/Akt/p300 cascade.
- Author
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Takai J, Santu A, Zheng H, Koh SD, Ohta M, Filimban LM, Lemaître V, Teraoka R, Jo H, and Miura H
- Subjects
- Adaptation, Physiological, Calcium-Calmodulin-Dependent Protein Kinase Kinase antagonists & inhibitors, Cells, Cultured, Endothelial Cells drug effects, Enzyme Activation, Hemodynamics, Humans, Intermediate-Conductance Calcium-Activated Potassium Channels genetics, Membrane Potentials, Phosphorylation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, RNA, Messenger metabolism, Small-Conductance Calcium-Activated Potassium Channels genetics, Stress, Mechanical, Time Factors, Up-Regulation, Calcium-Calmodulin-Dependent Protein Kinase Kinase metabolism, E1A-Associated p300 Protein metabolism, Endothelial Cells enzymology, Intermediate-Conductance Calcium-Activated Potassium Channels metabolism, Mechanotransduction, Cellular drug effects, Proto-Oncogene Proteins c-akt metabolism, Small-Conductance Calcium-Activated Potassium Channels metabolism
- Abstract
In endothelial cells (ECs), Ca²⁺-activated K⁺ channels KCa2.3 and KCa3.1 play a crucial role in the regulation of arterial tone via producing NO and endothelium-derived hyperpolarizing factors. Since a rise in intracellular Ca²⁺ levels and activation of p300 histone acetyltransferase are early EC responses to laminar shear stress (LS) for the transcriptional activation of genes, we examined the role of Ca²⁺/calmodulin-dependent kinase kinase (CaMKK), the most upstream element of a Ca²⁺/calmodulin-kinase cascade, and p300 in LS-dependent regulation of KCa2.3 and KCa3.1 in ECs. Exposure to LS (15 dyn/cm²) for 24 h markedly increased KCa2.3 and KCa3.1 mRNA expression in cultured human coronary artery ECs (3.2 ± 0.4 and 45 ± 10 fold increase, respectively; P < 0.05 vs. static condition; n = 8-30), whereas oscillatory shear (OS; ± 5 dyn/cm² × 1 Hz) moderately increased KCa3.1 but did not affect KCa2.3. Expression of KCa2.1 and KCa2.2 was suppressed under both LS and OS conditions, whereas KCa1.1 was slightly elevated in LS and unchanged in OS. Inhibition of CaMKK attenuated LS-induced increases in the expression and channel activity of KCa2.3 and KCa3.1, and in phosphorylation of Akt (Ser473) and p300 (Ser1834). Inhibition of Akt abolished the upregulation of these channels by diminishing p300 phosphorylation. Consistently, disruption of the interaction of p300 with transcription factors eliminated the induction of these channels. Thus a CaMKK/Akt/p300 cascade plays an important role in LS-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes.
- Published
- 2013
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46. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis.
- Author
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Satoh H, Moriguchi T, Takai J, Ebina M, and Yamamoto M
- Subjects
- Adenocarcinoma chemically induced, Adenocarcinoma immunology, Adenocarcinoma pathology, Animals, Base Sequence, Cytochrome P-450 CYP2E1 genetics, Cytochrome P-450 CYP2E1 metabolism, DNA Mutational Analysis, Lung enzymology, Lung pathology, Lung Neoplasms chemically induced, Lung Neoplasms immunology, Lung Neoplasms pathology, Mice, Mice, Inbred ICR, Mice, Knockout, Mice, Nude, Mutation, Myeloid Cells immunology, NF-E2-Related Factor 2 genetics, Neoplasm Transplantation, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins p21(ras) genetics, Signal Transduction, Transcriptional Activation, Transcriptome, Tumor Burden, Tumor Escape, Urethane, Adenocarcinoma metabolism, Cell Transformation, Neoplastic metabolism, Lung Neoplasms metabolism, NF-E2-Related Factor 2 metabolism, Proto-Oncogene Proteins p21(ras) metabolism
- Abstract
Nrf2 (Nfe2l2) governs cellular defenses against oxidative and electrophilic stresses and protects against chemical carcinogenesis. However, many cancers have been found to accumulate NRF2 protein, raising questions of precisely how Nrf2 contributes to carcinogenesis. In this report, we explored such questions in an established urethane-induced multistep model of lung carcinogenesis. Consistent with earlier observations, Nrf2-deficient (Nrf2(-/-)) mice exhibited a relative increase in tumor foci by 8 weeks after urethane administration. However, after 16 weeks, we observed a relative reduction in the number of tumors with more malignant characteristics in Nrf2(-/-) mice. Furthermore, all Nrf2(+/+) tumors harbored activated mutations in Kras, whereas Nrf2(-/-) tumors were rarely associated with similar Kras mutations. Overall, our results established that Nrf2 has two roles during carcinogenesis, one of which is preventive during tumor initiation and the second that promotes malignant progression. These findings establish Nrf2 inhibitors as rational tools to prevent malignant progression in lung cancer, whereas Nrf2 activators are more suited for lung cancer prevention., (©2013 AACR.)
- Published
- 2013
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47. The intermediate conductance calcium-activated potassium channel KCa3.1 regulates vascular smooth muscle cell proliferation via controlling calcium-dependent signaling.
- Author
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Bi D, Toyama K, Lemaître V, Takai J, Fan F, Jenkins DP, Wulff H, Gutterman DD, Park F, and Miura H
- Subjects
- Angiogenesis Inducing Agents pharmacology, Atherosclerosis drug therapy, Atherosclerosis genetics, Atherosclerosis metabolism, Becaplermin, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Calmodulin-Binding Proteins genetics, Calmodulin-Binding Proteins metabolism, Cells, Cultured, Cyclic AMP Response Element-Binding Protein genetics, Cyclic AMP Response Element-Binding Protein metabolism, Humans, Intermediate-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Intermediate-Conductance Calcium-Activated Potassium Channels genetics, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Microfilament Proteins genetics, Microfilament Proteins metabolism, Muscle, Smooth, Vascular cytology, Myocytes, Smooth Muscle cytology, Phosphorylation physiology, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-fos metabolism, Proto-Oncogene Proteins c-sis pharmacology, Calponins, Calcium Signaling physiology, Cell Proliferation, Intermediate-Conductance Calcium-Activated Potassium Channels metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism
- Abstract
The intermediate conductance calcium-activated potassium channel KCa3.1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis, and vascular remodeling. We examined the electrophysiological and transcriptional mechanisms by which KCa3.1 regulates vascular smooth muscle cell (VSMC) proliferation. Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca(2+) concentration ([Ca(2+)]i) and was enhanced by elevating [Ca(2+)]i. KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca(2+)]i and attenuating the expression of phosphorylated cAMP-response element-binding protein (CREB), c-Fos, and neuron-derived orphan receptor-1 (NOR-1). This antiproliferative effect was abolished by elevating [Ca(2+)]i. KCa3.1 overexpression induced VSMC proliferation, and potentiated PDGF-induced proliferation, by inducing CREB phosphorylation, c-Fos, and NOR-1. Pharmacological stimulation of KCa3.1 unexpectedly suppressed proliferation by abolishing the expression and activity of KCa3.1 and PDGF β-receptors and inhibiting the rise in [Ca(2+)]i. The stimulation also attenuated the levels of phosphorylated CREB, c-Fos, and cyclin expression. After KCa3.1 blockade, the characteristic round shape of VSMCs expressing high l-caldesmon and low calponin-1 (dedifferentiation state) was maintained, whereas KCa3.1 stimulation induced a spindle-shaped cellular appearance, with low l-caldesmon and high calponin-1. In conclusion, KCa3.1 plays an important role in VSMC proliferation via controlling Ca(2+)-dependent signaling pathways, and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis.
- Published
- 2013
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48. Regulation of GATA factor expression is distinct between erythroid and mast cell lineages.
- Author
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Ohmori S, Takai J, Ishijima Y, Suzuki M, Moriguchi T, Philipsen S, Yamamoto M, and Ohneda K
- Subjects
- Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Lineage, Cells, Cultured, Erythroid Cells cytology, GATA1 Transcription Factor metabolism, GATA2 Transcription Factor metabolism, Histones genetics, Histones metabolism, Male, Mast Cells cytology, Mice, Mice, Knockout, Protein Binding, RNA, Messenger genetics, Cell Differentiation, Erythroid Cells metabolism, GATA1 Transcription Factor genetics, GATA2 Transcription Factor genetics, Gene Expression Regulation, Developmental, Mast Cells metabolism
- Abstract
The zinc finger transcription factors GATA1 and GATA2 participate in mast cell development. Although the expression of these factors is regulated in a cell lineage-specific and differentiation stage-specific manner, their regulation during mast cell development has not been clarified. Here, we show that the GATA2 mRNA level was significantly increased while GATA1 was maintained at low levels during the differentiation of mast cells derived from mouse bone marrow (BMMCs). Unlike in erythroid cells, forced expression or small interfering RNA (siRNA)-mediated knockdown of GATA1 rarely affected GATA2 expression, and vice versa, in mast cells, indicating the absence of cross-regulation between Gata1 and Gata2 genes. Chromatin immunoprecipitation assays revealed that both GATA factors bound to most of the conserved GATA sites of Gata1 and Gata2 loci in BMMCs. However, the GATA1 hematopoietic enhancer (G1HE) of the Gata1 gene, which is essential for GATA1 expression in erythroid and megakaryocytic lineages, was bound only weakly by both GATA factors in BMMCs. Furthermore, transgenic-mouse reporter assays revealed that the G1HE is not essential for reporter expression in BMMCs and peritoneal mast cells. Collectively, these results demonstrate that the expression of GATA factors in mast cells is regulated in a manner quite distinct from that in erythroid cells.
- Published
- 2012
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49. UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice.
- Author
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Ainoya K, Moriguchi T, Ohmori S, Souma T, Takai J, Morita M, Chandler KJ, Mortlock DP, Shimizu R, Engel JD, Lim KC, and Yamamoto M
- Subjects
- Animals, GATA2 Transcription Factor metabolism, Mesoderm embryology, Mesoderm metabolism, Mice, Mutation, Urogenital Abnormalities, Vesico-Ureteral Reflux etiology, Vesico-Ureteral Reflux genetics, Bone Morphogenetic Protein 4 genetics, Bone Morphogenetic Protein 4 metabolism, Enhancer Elements, Genetic, GATA2 Transcription Factor genetics, Gene Expression Regulation, Developmental, Urogenital System embryology, Urogenital System metabolism
- Abstract
During renal development, the proper emergence of the ureteric bud (UB) from the Wolffian duct is essential for formation of the urinary system. Previously, we showed that expression of transcription factor GATA-2 in the urogenital primordium was demarcated anteroposteriorly into two domains that were regulated by separate enhancers. While GATA-2 expression in the caudal urogenital mesenchyme is controlled by the UG4 enhancer, its more-rostral expression is regulated by UG2. We found that anteriorly displaced budding led to obstructed megaureters in Gata2 hypomorphic mutant mice, possibly due to reduced expression of the downstream effector bone morphogenetic protein 4 (BMP4). Here, we report that UG4-driven, but not UG2-driven, GATA-2 expression in the urogenital mesenchyme significantly reverts the uropathy observed in the Gata2 hypomorphic mutant mice. Furthermore, the data show that transgenic rescue by GATA-2 reverses the rostral outgrowth of the UB. We also provide evidence for a GATA-2-BMP4 epistatic relationship by demonstrating that reporter gene expression from a Bmp4 bacterial artificial chromosome (BAC) transgene is altered in Gata2 hypomorphs; furthermore, UG4-directed BMP4 expression in the mutants leads to reduced incidence of megaureters. These results demonstrate that GATA-2 expression in the caudal urogenital mesenchyme as directed by the UG4 enhancer is crucial for proper development of the urinary tract and that its regulation of BMP4 expression is a critical aspect of this function.
- Published
- 2012
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50. Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells.
- Author
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Souma T, Abe M, Moriguchi T, Takai J, Yanagisawa-Miyazawa N, Shibata E, Akiyama Y, Toyohara T, Suzuki T, Tanemoto M, Abe T, Sato H, Yamamoto M, and Ito S
- Subjects
- Albumins pharmacology, Animals, Apoptosis drug effects, Cell Line, DNA Damage drug effects, Disease Models, Animal, Disease Progression, Female, Focal Adhesion Kinase 2 metabolism, Humans, Hydrogen-Ion Concentration, Kidney Diseases metabolism, Kidney Tubules, Proximal drug effects, Kidney Tubules, Proximal pathology, Male, Mice, Mice, Inbred C57BL, NADPH Oxidases metabolism, Oleic Acid pharmacology, Oxidative Stress drug effects, Oxygen metabolism, Proteinuria metabolism, Reactive Oxygen Species metabolism, Sodium Bicarbonate pharmacology, Kidney Diseases etiology, Kidney Diseases physiopathology, Kidney Tubules, Proximal physiopathology, Oxidative Stress physiology, Proteinuria complications, Proteinuria prevention & control, Sodium Bicarbonate therapeutic use
- Abstract
A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO(3)(-). It is unclear whether this luminal acidity affects proteinuria-induced progression of tubular cell damage. Here, we investigated the contribution of luminal acidity to superoxide (O(2)(·-)) production induced by oleic acid-bound albumin (OA-Alb) in proximal tubular cells. Acidic media significantly enhanced OA-Alb-induced O(2)(·-) production in the HK-2 proximal tubular cell line. Simultaneous treatment with both OA-Alb and acidic media led to phosphorylation of the intracellular pH sensor Pyk2. Highly phosphorylated Pyk2 associated with activation of Rac1, an essential subcomponent of NAD(P)H oxidase. Furthermore, knockdown of Pyk2 with siRNA attenuated the O(2)(·-) production induced by cotreatment with OA-Alb and acid. To assess whether luminal alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO(3) feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O(2)(·-)-induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease., (Copyright © 2011 by the American Society of Nephrology)
- Published
- 2011
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