23 results on '"Kawakami, Eiryo"'
Search Results
2. Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements
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Amariuta, Tiffany, Ishigaki, Kazuyoshi, Sugishita, Hiroki, Ohta, Tazro, Koido, Masaru, Dey, Kushal K., Matsuda, Koichi, Murakami, Yoshinori, Price, Alkes L., Kawakami, Eiryo, Terao, Chikashi, and Raychaudhuri, Soumya
- Abstract
Poor trans-ancestry portability of polygenic risk scores is a consequence of Eurocentric genetic studies and limited knowledge of shared causal variants. Leveraging regulatory annotations may improve portability by prioritizing functional over tagging variants. We constructed a resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 epigenetic datasets to predict binding patterns of 142 transcription factors across 245 cell types. We then partitioned the common SNP heritability of 111 genome-wide association study summary statistics of European (average n?˜?189,000) and East Asian (average n?˜?157,000) origin. IMPACT annotations captured consistent SNP heritability between populations, suggesting prioritization of shared functional variants. Variant prioritization using IMPACT resulted in increased trans-ancestry portability of polygenic risk scores from Europeans to East Asians across all 21 phenotypes analyzed (49.9% mean relative increase in R2). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data.
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- 2020
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3. Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity
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Tanaka, Shinya, Ise, Wataru, Inoue, Takeshi, Ito, Ayako, Ono, Chisato, Shima, Yoshihito, Sakakibara, Shuhei, Nakayama, Manabu, Fujii, Kentaro, Miura, Ikuo, Sharif, Jafar, Koseki, Haruhiko, Koni, Pandelakis A., Raman, Indu, Li, Quan-Zhen, Kubo, Masato, Fujiki, Katsunori, Nakato, Ryuichiro, Shirahige, Katsuhiko, Araki, Hiromitsu, Miura, Fumihito, Ito, Takashi, Kawakami, Eiryo, Baba, Yoshihiro, and Kurosaki, Tomohiro
- Abstract
A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten–eleven translocation (Tet) DNA demethylase family members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity.
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- 2020
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4. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases
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Ishigaki, Kazuyoshi, Akiyama, Masato, Kanai, Masahiro, Takahashi, Atsushi, Kawakami, Eiryo, Sugishita, Hiroki, Sakaue, Saori, Matoba, Nana, Low, Siew-Kee, Okada, Yukinori, Terao, Chikashi, Amariuta, Tiffany, Gazal, Steven, Kochi, Yuta, Horikoshi, Momoko, Suzuki, Ken, Ito, Kaoru, Koyama, Satoshi, Ozaki, Kouichi, Niida, Shumpei, Sakata, Yasushi, Sakata, Yasuhiko, Kohno, Takashi, Shiraishi, Kouya, Momozawa, Yukihide, Hirata, Makoto, Matsuda, Koichi, Ikeda, Masashi, Iwata, Nakao, Ikegawa, Shiro, Kou, Ikuyo, Tanaka, Toshihiro, Nakagawa, Hidewaki, Suzuki, Akari, Hirota, Tomomitsu, Tamari, Mayumi, Chayama, Kazuaki, Miki, Daiki, Mori, Masaki, Nagayama, Satoshi, Daigo, Yataro, Miki, Yoshio, Katagiri, Toyomasa, Ogawa, Osamu, Obara, Wataru, Ito, Hidemi, Yoshida, Teruhiko, Imoto, Issei, Takahashi, Takashi, Tanikawa, Chizu, Suzuki, Takao, Sinozaki, Nobuaki, Minami, Shiro, Yamaguchi, Hiroki, Asai, Satoshi, Takahashi, Yasuo, Yamaji, Ken, Takahashi, Kazuhisa, Fujioka, Tomoaki, Takata, Ryo, Yanai, Hideki, Masumoto, Akihide, Koretsune, Yukihiro, Kutsumi, Hiromu, Higashiyama, Masahiko, Murayama, Shigeo, Minegishi, Naoko, Suzuki, Kichiya, Tanno, Kozo, Shimizu, Atsushi, Yamaji, Taiki, Iwasaki, Motoki, Sawada, Norie, Uemura, Hirokazu, Tanaka, Keitaro, Naito, Mariko, Sasaki, Makoto, Wakai, Kenji, Tsugane, Shoichiro, Yamamoto, Masayuki, Yamamoto, Kazuhiko, Murakami, Yoshinori, Nakamura, Yusuke, Raychaudhuri, Soumya, Inazawa, Johji, Yamauchi, Toshimasa, Kadowaki, Takashi, Kubo, Michiaki, and Kamatani, Yoichiro
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The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P< 9.58 × 10−9). East Asian–specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2(associated with coronary artery disease) and p.V326A of POT1(associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
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- 2020
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5. Prediction of Change in Pelvic Tilt After Total Hip Arthroplasty Using Machine Learning.
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Fujii, Junpei, Aoyama, Shotaro, Tezuka, Taro, Kobayashi, Naomi, Kawakami, Eiryo, and Inaba, Yutaka
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A postoperative change in pelvic flexion following total hip arthroplasty (THA) is considered to be one of the causes of dislocation. This study aimed to predict the change of pelvic flexion after THA integrating preoperative and postoperative information with artificial intelligence. This study involved 415 hips which underwent primary THA. Pelvic flexion angle (PFA) is defined as the angle created by the anterior pelvic plane and the horizontal/vertical planes in the supine/standing positions, respectively. Changes in PFA from preoperative supine position to standing position at 5 years after THA were recorded and which were defined as a 5-year change in PFA. Machine learning analysis was performed to predict 5-year change in PFA less than −20° using demographic, blood biochemical, and radiographic data as explanatory variables. Decision trees were constructed based on the important predictors for 5-year change in PFA that can be handled by humans in clinical practice. Among several machine learning models, random forest showed the highest accuracy (area under the curve = 0.852). Lumbo-lordotic angle, femoral anteversion angle, body mass index, pelvic tilt, and sacral slope were most important random forest predictors. By integrating these preoperative predictors with those obtained 1 year after the surgery, we developed a clinically applicable decision tree model that can predict 5-year change in PFA with area under the curve = 0.914. A machine learning model to predict 5-year change in PFA after THA has been developed by integrating preoperative and postoperative patient information, which may have capabilities for preoperative planning of THA. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Non-negative tensor factorization workflow for time series biomedical data
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Tsuyuzaki, Koki, Yoshida, Naoki, Ishikawa, Tetsuo, Goshima, Yuki, and Kawakami, Eiryo
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Non-negative tensor factorization (NTF) enables the extraction of a small number of latent components from high-dimensional biomedical data. However, NTF requires many steps, which is a hurdle to implementation. Here, we provide a protocol for TensorLyCV, an easy to run and reproducible NTF analysis pipeline using Snakemake workflow management system and Docker container. Using vaccine adverse reaction data as an example, we describe steps for data processing, tensor decomposition, optimal rank parameter estimation, and visualization of factor matrices.
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- 2023
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7. Three-step transcriptional priming that drives the commitment of multipotent progenitors toward B cells
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Miyai, Tomohiro, Takano, Junichiro, Endo, Takaho A., Kawakami, Eiryo, Agata, Yasutoshi, Motomura, Yasutaka, Kubo, Masato, Kashima, Yukie, Suzuki, Yutaka, Kawamoto, Hiroshi, and Ikawa, Tomokatsu
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Miyai et al. used multipotent progenitors harboring a tamoxifen-inducible form of Id3—where virtually all cells became B cells within 6 d by withdrawing 4-OHT—to identify a three-step transcription factor network model during specification of multipotent progenitors toward the B-cell lineage.
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- 2018
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8. Leading role of TBP in the Establishment of Complexity in Eukaryotic Transcription Initiation Systems
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Kawakami, Eiryo, Adachi, Naruhiko, Senda, Toshiya, and Horikoshi, Masami
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While both archaeal and eukaryotic transcription initiation systems utilize TBP (TATA box-binding protein) and TFIIB (transcription factor IIB), eukaryotic systems include larger numbers of initiation factors. It remains uncertain how eukaryotic transcription initiation systems have evolved. Here, we investigate the evolutionary development of TBP and TFIIB, each of which has an intramolecular direct repeat, using two evolutionary indicators. Inter-repeat sequence dissimilarity (dDR, distance between direct repeats) indicates that the asymmetry of two repeats in TBP and TFIIB has gradually increased during evolution. Interspecies sequence diversity (PD, phylogenetic diversity) indicates that the resultant asymmetric structure, which is related to the ability to interact with multiple factors, diverged in archaeal TBP and archaeal/eukaryotic TFIIB during evolution. Our findings suggest that eukaryotic TBP initially acquired multiple Eukarya-specific interactors through asymmetric evolution of the two repeats. After the asymmetric TBP generated the complexity of the eukaryotic transcription initiation systems, its diversification halted and its asymmetric structure spread throughout eukaryotic species.
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- 2017
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9. Cbfβ2 deficiency preserves Langerhans cell precursors by lack of selective TGFβ receptor signaling
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Tenno, Mari, Shiroguchi, Katsuyuki, Muroi, Sawako, Kawakami, Eiryo, Koseki, Keita, Kryukov, Kirill, Imanishi, Tadashi, Ginhoux, Florent, and Taniuchi, Ichiro
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The mouse Langerhans cell (LC) network is established through the differentiation of embryonic LC precursors. BMP7 and TGFβ1 initiate cellular signaling that is essential for inducing LC differentiation and preserving LCs in a quiescent state, respectively. Here we show that loss of Cbfβ2, one of two RNA splice variants of the Cbfb gene, results in long-term persistence of embryonic LC precursors after their developmental arrest at the transition into the EpCAM+ stage. This phenotype is caused by selective loss of BMP7-mediated signaling essential for LC differentiation, whereas TGFβR signaling is intact, maintaining cells in a quiescent state. Transgenic Cbfβ2 expression at the neonatal stage, but not at the adult stage, restored differentiation from Cbfβ2-deficient LC precursors. Loss of developmental potential in skin-residential precursor cells was accompanied by diminished BMP7–BMPR1A signaling. Collectively, our results reveal an essential requirement for the Cbfβ2 variant in LC differentiation and provide novel insight into how the establishment and homeostasis of the LC network is regulated.
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- 2017
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10. Population-based Screening for Hereditary Colorectal Cancer Variants in Japan.
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Fujita, Masashi, Liu, Xiaoxi, Iwasaki, Yusuke, Terao, Chikashi, Mizukami, Keijiro, Kawakami, Eiryo, Takata, Sadaaki, Inai, Chihiro, Aoi, Tomomi, Mizukoshi, Misaki, Maejima, Kazuhiro, Hirata, Makoto, Murakami, Yoshinori, Kamatani, Yoichiro, Kubo, Michiaki, Akagi, Kiwamu, Matsuda, Koichi, Nakagawa, Hidewaki, and Momozawa, Yukihide
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Colorectal cancer (CRC) is one of the most common cancers in the world. A small proportion of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes. To better understand cancer risk, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations. We analyzed the coding regions of 27 cancer-predisposing genes in 12,503 unselected Japanese CRC patients and 23,705 controls by target sequencing and genome-wide SNP chip. Their clinical significance was assessed using ClinVar and the guidelines by ACMG/AMP. We identified 4,804 variants in the 27 genes and annotated them as pathogenic in 397 and benign variants in 941, of which 43.6% were novel. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant. The pathogenic variants of MSH2 (odds ratio (OR) = 18.1), MLH1 (OR = 8.6), MSH6 (OR = 4.9), APC (OR = 49.4), BRIP1 (OR=3.6), BRCA1 (OR = 2.6), BRCA2 (OR = 1.9), and TP53 (OR = 1.7) were significantly associated with CRC development in the Japanese population (P -values<0.01, FDR<0.05). These pathogenic variants were significantly associated with diagnosis age and personal/family history of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes, indicating hereditary cancers. This largest study of CRC heredity in Asia can contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2022
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11. Influenza Virus-Host Interactome Screen as a Platform for Antiviral Drug Development.
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Watanabe, Tokiko, Kawakami, Eiryo, Shoemaker, Jason E., Lopes, Tiago J.S., Matsuoka, Yukiko, Tomita, Yuriko, Kozuka-Hata, Hiroko, Gorai, Takeo, Kuwahara, Tomoko, Takeda, Eiji, Nagata, Atsushi, Takano, Ryo, Kiso, Maki, Yamashita, Makoto, Sakai-Tagawa, Yuko, Katsura, Hiroaki, Nonaka, Naoki, Fujii, Hiroko, Fujii, Ken, and Sugita, Yukihiko
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Summary Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and affect viral replication. After identifying over 1,000 host factors that coimmunoprecipitate with specific viral proteins, we generated a network of virus-host protein interactions based on the stage of the viral life cycle affected upon host factor downregulation. Using compounds that inhibit these host factors, we validated several proteins, notably Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets. Thus, virus-host interactome screens are powerful strategies to identify targetable host factors and guide antiviral drug development. [ABSTRACT FROM AUTHOR]
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- 2014
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12. Protocol to acquire time series data on adverse reactions following vaccination using a smartphone or web-based platform
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Yamao, Yasuo, Oami, Takehiko, Kawakami, Eiryo, and Nakada, Taka aki
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Data collection on adverse reactions in recipients after vaccination is vital to evaluate potential health issues, but health observation diaries are onerous for participants. Here, we present a protocol to collect time series information using a smartphone or web-based platform, thus eliminating the need for paperwork and data submission. We describe steps for setting up the platform using the Model-View-Controller web framework, uploading lists of recipients, sending notifications, and managing respondent data.
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- 2023
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13. Microbiota-Independent Spontaneous Dermatitis Associated with Increased Sebaceous Lipid Production in Tmem79-Deficient Mice
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Morimoto, Ari, Fukuda, Keitaro, Ito, Yoshihiro, Tahara, Umi, Sasaki, Takashi, Shiohama, Aiko, Kawasaki, Hiroshi, Kawakami, Eiryo, Naganuma, Tatsuro, Arita, Makoto, Sasaki, Hiroyuki, Koseki, Haruhiko, Matsui, Takeshi, and Amagai, Masayuki
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TMEM79is a predisposing gene for atopic dermatitis. Tmem79-deficient mice develop spontaneous dermatitis in a biphasic pattern. The first-phase dermatitis is unique because it occurs independent of microbiota status, whereas the second-phase dermatitis is microbiota dependent. In this study, we sought to identify the key factors mediating the development of first-phase dermatitis. Structural analysis showed that sebaceous gland hyperplasia started from first-phase dermatitis. Longitudinal RNA sequencing analysis revealed significant activation of fatty acid lipid metabolism pathways in first-phase dermatitis, whereas T helper 17‒based immune response genes were highly expressed in second-phase dermatitis. Quantitative RT-PCR analysis revealed that genes involved in fatty acid elongation and sebocyte differentiation were upregulated in first-phase dermatitis. The results of thin-layer chromatography supported these findings with an increased abundance of wax esters, cholesterol esters, and fatty alcohols in hair lipids. Further gas chromatography-tandem mass spectrometry analysis showed an increase in total fatty acid production, including that of elongated C20–24 saturated and C18–24 monounsaturated fatty acids. Collectively, these results suggest that aberrant production of sebaceous long-chain fatty acids is associated with microbiota-independent dermatitis. Further investigation of Tmem79-deficient mice may clarify the role of certain fatty acids in dermatitis.
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- 2022
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14. Development and validation of machine learning prediction model for post-rehabilitation functional outcome after intracerebral hemorrhage
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Sonobe, Shinya, Ishikawa, Tetsuo, Niizuma, Kuniyasu, Kawakami, Eiryo, Ueda, Takuya, Takaya, Eichi, Makoto Miyauchi, Carlos, Iwazaki, Junya, Kochi, Ryuzaburo, Endo, Toshiki, Shastry, Arun, Jagannatha, Vijayananda, Seth, Ajay, Nakagawa, Atsuhiro, Yoshida, Masahiro, and Tominaga, Teiji
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Predicting outcomes after intracerebral hemorrhage (ICH) may help improve patient outcomes. We developed and validated a machine learning prediction model for post-rehabilitation functional outcomes after ICH. Patient selection and explanatory variable settings were based on clinical significance. Functional outcomes were predicted using ternary classification.
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- 2022
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15. Publisher Correction: Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity
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Tanaka, Shinya, Ise, Wataru, Inoue, Takeshi, Ito, Ayako, Ono, Chisato, Shima, Yoshihito, Sakakibara, Shuhei, Nakayama, Manabu, Fujii, Kentaro, Miura, Ikuo, Sharif, Jafar, Koseki, Haruhiko, Koni, Pandelakis A., Raman, Indu, Li, Quan-Zhen, Kubo, Masato, Fujiki, Katsunori, Nakato, Ryuichiro, Shirahige, Katsuhiko, Araki, Hiromitsu, Miura, Fumihito, Ito, Takashi, Kawakami, Eiryo, Baba, Yoshihiro, and Kurosaki, Tomohiro
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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16. Seroprevalence of Pandemic 2009 (H1N1) Influenza A Virus among Schoolchildren and Their Parents in Tokyo, Japan
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Iwatsuki-Horimoto, Kiyoko, Horimoto, Taisuke, Tamura, Daisuke, Kiso, Maki, Kawakami, Eiryo, Hatakeyama, Shuji, Ebihara, Yasuhiro, Koibuchi, Tomohiko, Fujii, Takeshi, Takahashi, Kazuo, Shimojima, Masayuki, Sakai-Tagawa, Yuko, Ito, Mutsumi, Sakabe, Saori, Iwasa, Ayaka, Takahashi, Kei, Ishii, Takashi, Gorai, Takeo, Tsuji, Koichiro, Iwamoto, Aikichi, and Kawaoka, Yoshihiro
- Abstract
ABSTRACTSince its emergence, the 2009 pandemic H1N1 virus has spread rapidly throughout the world. Previously, we reported that most individuals born after 1920 do not have cross-reactive virus-neutralizing antibodies against pandemic (H1N1) 2009 virus, indicating that they were immunologically naïve to the pandemic virus prior to its emergence. This finding provided us with an excellent opportunity for a seroepidemiological investigation of the transmission mode of the pandemic virus in the community. To gain insight into its transmission within communities, we performed a serosurvey for pandemic virus infection with schoolchildren at an elementary school in Tokyo, Japan, and their parents. We observed a high prevalence of neutralizing antibodies to the pandemic virus in the children at this school, although the percentage of children positive for the neutralizing antibodies varied among classrooms. While a much lower prevalence was observed among parents, seropositivity of the parents correlated with that of their schoolchildren. Moreover, many adults appeared to have experienced asymptomatic infection with the pandemic virus. These data suggest that the pandemic virus was readily transmitted among schoolchildren in elementary schools and that it was also transmitted from schoolchildren to their parents.
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- 2011
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17. Staphylococcus cohniiis a potentially biotherapeutic skin commensal alleviating skin inflammation
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Ito, Yoshihiro, Sasaki, Takashi, Li, Youxian, Tanoue, Takeshi, Sugiura, Yuki, Skelly, Ashwin N., Suda, Wataru, Kawashima, Yusuke, Okahashi, Nobuyuki, Watanabe, Eiichiro, Horikawa, Hiroto, Shiohama, Aiko, Kurokawa, Rina, Kawakami, Eiryo, Iseki, Hachiro, Kawasaki, Hiroshi, Iwakura, Yoichiro, Shiota, Atsushi, Yu, Liansheng, Hisatsune, Junzo, Koseki, Haruhiko, Sugai, Motoyuki, Arita, Makoto, Ohara, Osamu, Matsui, Takeshi, Suematsu, Makoto, Hattori, Masahira, Atarashi, Koji, Amagai, Masayuki, and Honda, Kenya
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Host-microbe interactions orchestrate skin homeostasis, the dysregulation of which has been implicated in chronic inflammatory conditions such as atopic dermatitis and psoriasis. Here, we show that Staphylococcus cohniiis a skin commensal capable of beneficially inhibiting skin inflammation. We find that Tmem79−/−mice spontaneously develop interleukin-17 (IL-17)-producing T-cell-driven skin inflammation. Comparative skin microbiome analysis reveals that the disease activity index is negatively associated with S. cohnii. Inoculation with S. cohniistrains isolated from either mouse or human skin microbiota significantly prevents and ameliorates dermatitis in Tmem79−/−mice without affecting pathobiont burden. S. cohniicolonization is accompanied by activation of host glucocorticoid-related pathways and induction of anti-inflammatory genes in the skin and is therefore effective at suppressing inflammation in diverse pathobiont-independent dermatitis models, including chemically induced, type 17, and type 2 immune-driven models. As such, S. cohniistrains have great potential as effective live biotherapeutics for skin inflammation.
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- 2021
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18. The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation
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Kiuchi, Masahiro, Onodera, Atsushi, Kokubo, Kota, Ichikawa, Tomomi, Morimoto, Yuki, Kawakami, Eiryo, Takayama, Naoya, Eto, Koji, Koseki, Haruhiko, Hirahara, Kiyoshi, and Nakayama, Toshinori
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Different dynamics of gene expression are observed during cell differentiation. In T cells, genes that are turned on early or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that the Cxxc1 subunit of the Trithorax complex directs transcription of genes initially down-regulated by TCR stimulation but up-regulated again in a later phase. The late up-regulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1 deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T cell immune system via epigenetic control of a specific set of genes.
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- 2021
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19. Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal
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Inoue, Takeshi, Shinnakasu, Ryo, Kawai, Chie, Ise, Wataru, Kawakami, Eiryo, Sax, Nicolas, Oki, Toshihiko, Kitamura, Toshio, Yamashita, Kazuo, Fukuyama, Hidehiro, and Kurosaki, Tomohiro
- Abstract
A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate.
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- 2021
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20. Multiomics Investigation Revealing the Characteristics of HIV-1-Infected Cells In Vivo
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Aso, Hirofumi, Nagaoka, Shumpei, Kawakami, Eiryo, Ito, Jumpei, Islam, Saiful, Tan, Benjy Jek Yang, Nakaoka, Shinji, Ashizaki, Koichi, Shiroguchi, Katsuyuki, Suzuki, Yutaka, Satou, Yorifumi, Koyanagi, Yoshio, and Sato, Kei
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For eradication of HIV-1 infection, it is important to elucidate the detailed features and heterogeneity of HIV-1-infected cells in vivo. To reveal multiple characteristics of HIV-1-producing cells in vivo, we use a hematopoietic-stem-cell-transplanted humanized mouse model infected with GFP-encoding replication-competent HIV-1. We perform multiomics experiments using recently developed technology to identify the features of HIV-1-infected cells. Genome-wide HIV-1 integration-site analysis reveals that productive HIV-1 infection tends to occur in cells with viral integration into transcriptionally active genomic regions. Bulk transcriptome analysis reveals that a high level of viral mRNA is transcribed in HIV-1-infected cells. Moreover, single-cell transcriptome analysis shows the heterogeneity of HIV-1-infected cells, including CXCL13highcells and a subpopulation with low expression of interferon-stimulated genes, which can contribute to efficient viral spread in vivo. Our findings describe multiple characteristics of HIV-1-producing cells in vivo, which could provide clues for the development of an HIV-1 cure.
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- 2020
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21. Targeting Critical Kinases and Anti-Apoptotic Molecules Overcomes Steroid Resistance in Infant MLL-Rearranged Leukemia
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De Groot, Anne Pieta, Saito, Yoriko, Kawakami, Eiryo, Hashimoto, Mari, Aoki, Yuki, Ono, Rintaro, Ogahara, Ikuko, Fujiki, Saera, Kaneko, Akiko, Watanabe, Takashi, Takagi, Masatoshi, Tomizawa, Daisuke, Koh, Katsuyoshi, Eguchi, Mariko, Ishii, Eiichi, Ohara, Osamu, Shultz, Leonard, Mizutani, Shuki, and Ishikawa, Fumihiko
- Abstract
No relevant conflicts of interest to declare.
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- 2019
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22. Targeting Critical Kinases and Anti-Apoptotic Molecules Overcomes Steroid Resistance in Infant MLL-Rearranged Leukemia
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De Groot, Anne Pieta, Saito, Yoriko, Kawakami, Eiryo, Hashimoto, Mari, Aoki, Yuki, Ono, Rintaro, Ogahara, Ikuko, Fujiki, Saera, Kaneko, Akiko, Watanabe, Takashi, Takagi, Masatoshi, Tomizawa, Daisuke, Koh, Katsuyoshi, Eguchi, Mariko, Ishii, Eiichi, Ohara, Osamu, Shultz, Leonard, Mizutani, Shuki, and Ishikawa, Fumihiko
- Abstract
Acute lymphoblastic leukemia (ALL) with rearrangement of the mixed-lineage leukemia (MLL) gene frequently affects infants and is associated with a poor prognosis. Standard treatment protocol for infant MLL-rearranged ALL (MLL-ALL) includes glucocorticoids (GCs). However, resistance to GCs remains a major problem. Therefore, it is important to find new treatment strategies that overcome GC resistance in MLL-ALL.
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- 2019
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23. Network-Guided Discovery of Influenza Virus Replication Host Factors
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Ackerman, Emily E., Kawakami, Eiryo, Katoh, Manami, Watanabe, Tokiko, Watanabe, Shinji, Tomita, Yuriko, Lopes, Tiago J., Matsuoka, Yukiko, Kitano, Hiroaki, Shoemaker, Jason E., and Kawaoka, Yoshihiro
- Abstract
Integrating virus-host interactions with host protein-protein interactions, we have created a method using these established network practices to identify host factors (i.e., proteins) that are likely candidates for antiviral drug targeting. We demonstrate that interaction cascades between host proteins that directly interact with viral proteins and host factors that are important to influenza virus replication are enriched for signaling and immune processes. Additionally, we show that host proteins that interact with viral proteins are in network locations of power. Finally, we demonstrate a new network methodology to predict novel host factors and validate predictions with an siRNA screen. Our results show that integrating virus-host proteins interactions is useful in the identification of antiviral drug target candidates.
- Published
- 2018
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