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Kengo Kinoshita

Section

Graduate School of Information Sciences

Job title

Professor

Degree

博士（理学）（京都大学）
修士（理学）（京都大学）

researchmap

https://researchmap.jp/key

J-GLOBAL ID

201101045094807395

Research History 11

2019/04 - Present

東北大学高等研究機構来型医療創生センター（併任）　副センター長
2016/04 - Present

東北大学東北メディカル・メガバンク機構（併任）　副機構長
2012/04 - Present

東北大学東北メディカル・メガバンク機構ゲノム解析部門（併任）　教授
2009/10 - Present

東北大学大学院情報科学研究科　教授
2007/04 - 2009/09

東京大学医科学研究所附属ヒトゲノム解析センター　准教授（職名変更）
2004/10 - 2007/03

東京大学医科学研究所附属ヒトゲノム解析センター　助教授
2004/04 - 2004/09

大阪大学蛋白質研究所　特任研究員／客員助教授
2004/01 - 2004/03

大阪大学蛋白質研究所　産学官連携研究員／客員助教授
2001/04 - 2003/12

横浜市立大学大学院総合理学研究科　助手
2000/04 - 2001/03

理化学研究所ゲノム科学総合研究センター　リサーチアソシエイト
1999/04 - 2000/03

科学技術振興事業団　計算科学技術研究員

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Research Interests 30

蛋白質会合表面
非線型振動
組織特異的プロモーター
原子占有率
ホモ二量体
ゲノム配列解析
タンパク質立体構造
機能部位予測
会合表面間平均距離
振動緩和
結晶水
膜分子輸送複合体
タンパク質
ドッキング計算
カタユウレイボヤ
プロテオーム
立体構造-機能相関
ミオグロビン
会合空間体積
クリスタルパッキング
構造機能相関
タンパク質間相互作用
リガンド結合部位
静電ポテンシャル
分子表面
分子シミュレーション
立体構造
データベース
バイオインフォマティクス
蛋白質

Research Areas 3

Life sciences / Biophysics /
Life sciences / Systems genomics /
Life sciences / Genomics /

Awards 2

令和4年度科学技術分野の文部科学大臣表彰科学技術賞研究部門

2022/04　文部科学省　未来型医療実現を目指したゲノム情報基盤構築に関する研究
JSPS PRIZE

2012/02　Japan Society for the promotion of science　Prediction of Functions for the Genes with Unknown Functions Through Bioinformatics

Papers 260

Assessing Structural Classification Using <scp>AlphaFold2</scp> Models Through <scp>ECOD</scp>‐Based Comparative Analysis

Takeshi Kawabata, Kengo Kinoshita

Proteins: Structure, Function, and Bioinformatics　2025/04/19
Publisher: Wiley
DOI： 10.1002/prot.26828 　

ISSN： 0887-3585

eISSN： 1097-0134

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ABSTRACT Identifying homologous proteins is a fundamental task in structural bioinformatics. While AlphaFold2 has revolutionized protein structure prediction, the extent to which structure comparison of its models can reliably detect homologs remains unclear. In this study, we evaluate the feasibility of homology detection using AlphaFold2‐predicted structures through structural comparisons. We considered the classification of the ECOD database for experimental structures as the correct standard and obtained their corresponding predicted models from AlphaFoldDB. To ensure blind assessment, we divided the structures into test and train sets according to their release date. Predicted and experimental 3D structures in the test and train sets were compared using 3D structure comparisons (MATRAS, Dali, and Foldseek) and sequence comparisons (BLAST and HHsearch). The results were evaluated based on the homology annotations in the ECOD database. For top‐1 accuracy, the performance of structural comparisons was comparable to that of HHsearch. However, when considering metrics that included all structural pairs, including more remote homology, structural comparisons outperformed HHsearch. No significant differences were observed between comparisons of experimental versus experimental, predicted versus experimental, and predicted versus predicted structures with pLDDT (prediction confidence) values greater than 60. We also demonstrate that predicted protein structures, determined by NMR, had lower pLDDT values and contained fewer coils than their experimental counterparts. These findings highlight the potential of AlphaFold2 models in structural classification and suggest that 3D structural searches should be conducted not only against the PDB but also against AlphaFoldDB to identify more potential homologs.
Protein Data Bank Japan: Improved tools for sequence-oriented analysis of protein structures. International-journal

Gert-Jan Bekker, Chioko Nagao, Matsuyuki Shirota, Tsukasa Nakamura, Toshiaki Katayama, Daisuke Kihara, Kengo Kinoshita, Genji Kurisu

Protein science : a publication of the Protein Society　34　(3)　e70052　2025/03

DOI： 10.1002/pro.70052 　

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Protein Data Bank Japan (PDBj) is the Asian hub of three-dimensional macromolecular structure data, and a founding member of the worldwide Protein Data Bank. We have accepted, processed, and distributed experimentally determined biological macromolecular structures for over two decades. Although we collaborate with RCSB PDB and BMRB in the United States, PDBe and EMDB in Europe and recently PDBc in China for our data-in activities, we have developed our own unique services and tools for searching, exploring, visualizing and analyzing protein structures. We have recently introduced a new UniProt-integrated portal to provide users with a quick overview of their target protein and shows a recommended structure with integrated data from various internal and external resources. The portal page helps users identify known genomic variations of their protein of interest and provide insights into how these modifications might impact the structure, stability and dynamics of the protein. Furthermore, the portal page also helps users to select the optimal structure to use for further analysis. We have also introduced another service to explore proteins using experimental and computational approaches, which enables experimental structural biologists to increase their insight to help them to more efficiently design their experimental studies. With these new additions, we have enhanced our service portfolio to benefit both experimental and computational structural biologists in their search to interpret protein structures, their dynamics and function.
Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan. International-journal

Kinuko Ohneda, Yoichi Suzuki, Yohei Hamanaka, Shu Tadaka, Muneaki Shimada, Junko Hasegawa-Minato, Masanobu Takahashi, Nobuo Fuse, Fuji Nagami, Hiroshi Kawame, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Tomohiro Nakamura, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Shin-Ichi Kuriyama, Yoko Izumi, Ritsuko Shimizu, Mikako Tochigi, Tokiwa Motonari, Hideki Tokunaga, Atsuo Kikuchi, Atsushi Masamune, Yoko Aoki, Chikashi Ishioka, Takanori Ishida, Masayuki Yamamoto

Journal of human genetics　70　(3)　147-157　2025/03

DOI： 10.1038/s10038-024-01314-w 　

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Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants' understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.
Language Registration-Based Scoring System for Handwritten Logical Memory of Wechsler Memory Scale-Revised: Developed and Validated in the Tohoku Medical Megabank Project.

Naoko Mori, Shunji Mugikura, Atsushi Hozawa, Makiko Taira, Hiroaki Hashizume, Atsushi Sekiguchi, Mitsunari Abe, Michiyo Kasai, Tomo Saito, Kengo Kinoshita, Nobuo Fuse, Shinichi Kuriyama, Masayuki Yamamoto

The Tohoku journal of experimental medicine　2025/01/16

DOI： 10.1620/tjem.2025.J006 　
Deep learning-based histopathological assessment of tubulo-interstitial injury in chronic kidney diseases. International-journal

Nonoka Suzuki, Kaname Kojima, Silvia Malvica, Kenshi Yamasaki, Yoichiro Chikamatsu, Yuji Oe, Tasuku Nagasawa, Ekyu Kondo, Satoru Sanada, Setsuya Aiba, Hiroshi Sato, Mariko Miyazaki, Sadayoshi Ito, Mitsuhiro Sato, Tetsuhiro Tanaka, Kengo Kinoshita, Yoshihide Asano, Avi Z Rosenberg, Koji Okamoto, Kosuke Shido

Communications medicine　5　(1)　3-3　2025/01/05

DOI： 10.1038/s43856-024-00708-3 　

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BACKGROUND: Chronic kidney disease (CKD) causes progressive and irreversible damage to the kidneys. Renal biopsies are essential for diagnosing the etiology and prognosis of CKD, while accurate quantification of tubulo-interstitial injuries from whole slide images (WSIs) of renal biopsy specimens is challenging with visual inspection alone. METHODS: We develop a deep learning-based method named DLRS to quantify interstitial fibrosis and inflammatory cell infiltration as tubulo-interstitial injury scores, from WSIs of renal biopsy specimens. DLRS segments WSIs into non-tissue areas, glomeruli, tubules, interstitium, and arteries, and detects interstitial nuclei. It then quantifies these tubulo-interstitial injury scores using the segmented tissues and detected nuclei. RESULTS: Applied to WSIs from 71 Japanese CKD patients with diabetic nephropathy or benign nephrosclerosis, DLRS-derived scores show concordance with nephrologists' evaluations. Notably, the DLRS-derived fibrosis score has a higher correlation with the estimated glomerular filtration rate (eGFR) at biopsy than scores from nephrologists' evaluations. Validated on WSIs from 28 Japanese tubulointerstitial nephritis patients and 49 European-ancestry patients with nephrosclerosis, DLRS-derived scores show a significant correlation with eGFR. In an expanded analysis of 238 Japanese CKD patients, including 167 from another hospital, deviations in eGFR from expected values based on DLRS-derived scores correlate with annual eGFR decline after biopsy. Inclusion of these deviations and DLRS-derived fibrosis scores improve predictions of the annual eGFR decline. CONCLUSIONS: DLRS-derived tubulo-interstitial injury scores are concordant with nephrologists' evaluations and correlated with eGFR across different populations and institutions. The effectiveness of DLRS-derived scores for predicting annual eGFR decline highlights the potential of DLRS as a predictor of renal prognosis.
Prevalence and Associations of Epiretinal Membrane by OCT in a Japanese Population-Based Cohort: Tohoku Medical Megabank Organization Eye Study. International-journal

Akihiko Shiraki, Atsushi Hirayama, Nobuo Fuse, Ryo Kawasaki, Satoko Fujimoto, Tomoyuki Okazaki, Susumu Sakimoto, Takatoshi Maeno, Makiko Taira, Tomo Saito, Tomohiro Nakamura, Soichi Ogishima, Atsushi Hozawa, Kengo Kinoshita, Masayuki Yamamoto, Kohji Nishida

Ophthalmology science　5　(4)　100752-100752　2025

DOI： 10.1016/j.xops.2025.100752 　

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PURPOSE: To examine the prevalence of epiretinal membrane (ERM) according to the OCT-based severity scales, and to describe associations focusing on the impact of smoking and axial length of the globe. DESIGN: Cross-sectional study. PARTICIPANTS: The baseline examination cohort comprised participants from the Tohoku Medical Megabank community cohort recruited from 2013 to 2017. METHODS: In total, 38 118 eyes of 19 486 participants were classified with ERM staging. The characteristics of ERM severity were analyzed, and the association between the prevalence of ERM and ocular and systemic parameters was investigated using logistic regression models. Cubic spline models were constructed to visualize the relationships with lifetime smoking exposure and axial lengths. Regarding ERM severity, the associations between stage 1 and stage 2 or more were analyzed with multivariate analysis. MAIN OUTCOME MEASURES: Epiretinal membrane prevalence at each stage determined via OCT and factors associated with ERM presence and severity. RESULTS: The prevalence of ERM was 2.3% per eye (3.6% per person), with a predominance at stage 1. The presence of severe ERM stages was higher in older individuals. The multivariate logistic analysis revealed that older age, female sex, and long axial length were associated with a higher prevalence of ERM. In a multivariate analysis stratified by sex, glaucoma was also identified as a significant factor associated with the prevalence of ERM in women. In the cubic spline model, no consistent trend was observed between smoking and ERM prevalence. However, a U-shaped relationship was indicated between axial length and ERM prevalence. Epiretinal membrane severity highlighted older age, alcohol consumption, and very long axial length as significantly associated compared with stage 1. CONCLUSIONS: Epiretinal membrane prevalence was significantly associated with older age, female sex, and long axial length. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Histological and genetic features and therapeutic responses of lung cancers explored via the global analysis of their metabolome profile

Daisuke Narita, Eiji Hishinuma, Risa Ebina-Shibuya, Eisaku Miyauchi, Naomi Matsukawa, Ikuko N. Motoike, Kengo Kinoshita, Seizo Koshiba, Yoko Tsukita, Hirotsugu Notsuda, Nozomu Kimura, Ryota Saito, Hisatoshi Sugiura

Lung Cancer　108082-108082　2025/01
Publisher: Elsevier BV
DOI： 10.1016/j.lungcan.2025.108082 　

ISSN： 0169-5002
Identification of risk loci for postpartum depression in a genome-wide association study. International-journal

Xue Li, Nagahide Takahashi, Akira Narita, Yukako Nakamura, Mika Sakurai-Yageta, Keiko Murakami, Mami Ishikuro, Taku Obara, Masahiro Kikuya, Fumihiko Ueno, Hirohito Metoki, Hisashi Ohseto, Ippei Takahashi, Tomohiro Nakamura, Noriko Warita, Tomoka Shoji, Zhiqian Yu, Chiaki Ono, Natsuko Kobayashi, Saya Kikuchi, Tasuku Matsuki, Fuji Nagami, Soichi Ogishima, Junichi Sugawara, Tetsuro Hoshiai, Masatoshi Saito, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Norio Ozaki, Gen Tamiya, Shinichi Kuriyama, Hiroaki Tomita

Psychiatry and clinical neurosciences　78　(11)　712-720　2024/11

DOI： 10.1111/pcn.13731 　

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AIM: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci. METHODS: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders. RESULTS: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10-8) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling. CONCLUSION: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis.
Next-generation sequencing analysis with a population-specific human reference genome.

Tomohisa Suzuki, Kota Ninomiya, Takamitsu Funayama, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Jun Takayama

Genes & genetic systems　99　2024/10/28

DOI： 10.1266/ggs.24-00112 　

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Next-generation sequencing (NGS) has become widely available and is routinely used in basic research and clinical practice. The reference genome sequence is an essential resource for NGS analysis, and several population-specific reference genomes have recently been constructed to provide a choice to deal with the vast genetic diversity of human samples. However, resources supporting population-specific references are insufficient, and it is burdensome to perform analysis using these reference genomes. Here, we constructed a set of resources to support NGS analysis using the Japanese reference genome, JG. We created resources for variant calling, variant-effect prediction, gene and repeat element annotations, read mappability, and RNA-seq analysis. We also provide a resource for reference coordinate conversion for further annotation enrichment. We then provide a variant calling protocol with JG. Our resources provide a guide to prepare sufficient resources for the use of population-specific reference genomes and can facilitate the migration of reference genomes.
Two-stage strategy using denoising autoencoders for robust reference-free genotype imputation with missing input genotypes. International-journal

Kaname Kojima, Shu Tadaka, Yasunobu Okamura, Kengo Kinoshita

Journal of human genetics　69　(10)　511-518　2024/10

DOI： 10.1038/s10038-024-01261-6 　

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Widely used genotype imputation methods are based on the Li and Stephens model, which assumes that new haplotypes can be represented by modifying existing haplotypes in a reference panel through mutations and recombinations. These methods use genotypes from SNP arrays as inputs to estimate haplotypes that align with the input genotypes by analyzing recombination patterns within a reference panel, and then infer unobserved variants. While these methods require reference panels in an identifiable form, their public use is limited due to privacy and consent concerns. One strategy to overcome these limitations is to use de-identified haplotype information, such as summary statistics or model parameters. Advances in deep learning (DL) offer the potential to develop imputation methods that use haplotype information in a reference-free manner by handling it as model parameters, while maintaining comparable imputation accuracy to methods based on the Li and Stephens model. Here, we provide a brief introduction to DL-based reference-free genotype imputation methods, including RNN-IMP, developed by our research group. We then evaluate the performance of RNN-IMP against widely-used Li and Stephens model-based imputation methods in terms of accuracy (R2), using the 1000 Genomes Project Phase 3 dataset and corresponding simulated Omni2.5 SNP genotype data. Although RNN-IMP is sensitive to missing values in input genotypes, we propose a two-stage imputation strategy: missing genotypes are first imputed using denoising autoencoders; RNN-IMP then processes these imputed genotypes. This approach restores the imputation accuracy that is degraded by missing values, enhancing the practical use of RNN-IMP.
Genetic Risk, Lifestyle Adherence, and Risk of Developing Hyperuricaemia in a Japanese Population. International-journal

Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Sayuri Tokioka, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Hisashi Ohseto, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Biobank Japan Project Koichi Matsuda, Yoko Izumi, Kengo Kinoshita, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

Rheumatology (Oxford, England)　2024/09/13

DOI： 10.1093/rheumatology/keae492 　

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OBJECTIVE: To investigate the inter-relationships among genetic risk, healthy lifestyle adherence, and hyperuricaemia susceptibility. METHODS: This prospective cohort study was conducted with 7,241 hyperuricaemia-free individuals aged ≥ 20 years from the Tohoku Medical Megabank Community-based cohort study. A comprehensive lifestyle score included body mass index, smoking, drinking, and physical activity, and a polygenic risk score (PRS) was constructed based on uric acid loci from a previous genome-wide association study meta-analysis. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and hyperuricaemia incidence and calculate the area under the receiver operating characteristic curve (AUROC). Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dl or a self-reported history of hyperuricaemia. RESULTS: Of the 7,241 adults (80.7% females; mean [SD] age: 57.7 [12.6] years), 217 (3.0%) developed hyperuricaemia during 3.5 years of follow-up. Genetic risk correlated with hyperuricaemia development (P for interaction = 0.287), and lifestyle risks were independently associated. Those with a high genetic risk and poor lifestyle had the highest risk (odds ratio: 5.34; 95% confidence interval [CI]: 2.61-12.10). Although not statistically significant, incorporating the PRS in the model with lifestyle information improved predictive ability (AUROC = 0.771, 95% CI: 0.736-0.806 for lifestyle; AUROC = 0.785, 95% CI: 0.751-0.819 for lifestyle and PRS; p = 0.07). CONCLUSION: : A healthy lifestyle to prevent hyperuricaemia, irrespective of genetic risk, may mitigate the genetic risk. Genetic risk may complement lifestyle factors in identifying individuals at a heightened hyperuricaemia risk.
Association of olfactory and cognitive function test scores with hippocampal and amygdalar grey matter volume: a cross-sectional study. International-journal

Shuichi Sato, Takao Imaeda, Shunji Mugikura, Naoko Mori, Masaki Takanashi, Kazumi Hayakawa, Tomo Saito, Makiko Taira, Akira Narita, Mana Kogure, Ippei Chiba, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Ryosuke Ishiwata, Tomohiro Nakamura, Ikuko N Motoike, Naoki Nakaya, Seizo Koshiba, Kengo Kinoshita, Shinichi Kuriyama, Soichi Ogishima, Fuji Nagami, Nobuo Fuse, Atsushi Hozawa

Scientific reports　14　(1)　19138-19138　2024/08/19

DOI： 10.1038/s41598-024-69726-4 　

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Few population-based studies including younger adults have examined the potential of olfactory function tests to capture the degree of atrophy in memory-associated brain regions, which cannot be adequately explained by cognitive function tests screening for cognitive impairment. This population-based study investigated associations between high-resolution olfactory test data with few odours and grey matter volumes (GMVs) of the left and right hippocampi, amygdala, parahippocampi, and olfactory cortex, while accounting for differences in cognitive decline, in 1444 participants (aged 31-91 years). Regression analyses included intracranial volume (ICV)-normalised GMVs of eight memory-related regions as objective variables and age, sex, education duration, smoking history, olfaction test score, and the Montreal Cognitive Assessment-Japanese version (MoCA-J) score as explanatory variables. Significant relationships were found between olfactory test scores and ICV-normalised GMVs of the left and right hippocampi and left amygdala (p = 0.020, 0.024, and 0.028, respectively), adjusting for the MoCA-J score. The olfactory test score was significantly related to the right amygdalar GMV (p = 0.020) in older adults (age ≥ 65 years). These associations remained significant after applying Benjamini-Hochberg multiple testing correction (false discovery rate < 0.1). Therefore, olfactory and cognitive function tests may efficiently capture the degree of atrophy in the hippocampi and amygdala, especially in older adults.
Functional significance of CYP2B6 gene rare allelic variants identified in Japanese individuals International-journal

Shuki Yamazaki, Eiji Hishinuma, Yuma Suzuki, Akiko Ueda, Caroline Kijogi, Tomoki Nakayoshi, Akifumi Oda, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Yu Sato, Masaki Kumondai, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka

Biochemical Pharmacology　229　116515-116515　2024/08
Publisher: Elsevier BV
DOI： 10.1016/j.bcp.2024.116515 　

ISSN： 0006-2952

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Cytochrome P450 2B6 (CYP2B6) catalyzes the metabolism of many drugs, including efavirenz and propofol. Genetic polymorphisms in CYP2B6 alter its enzymatic activity and substantially affect its pharmacokinetics. High-frequency variants, such as CYP2B6*6, are associated with the risk of developing side effects due to reduced CYP2B6 activity. However, the impact of rare alterations on enzyme function remains unknown, and some of these variants may significantly decrease the CYP2B6 activity. Therefore, in this study, we evaluated in vitro the functional alterations in 29 missense variants of the CYP2B6 gene identified in 8,380 Japanese individuals. Wild-type CYP2B6 and 29 rare CYP2B6 variants were transiently expressed in mammalian cells. The expression levels of variant CYP2B6 proteins in the microsomal fractions extracted from 293FT cells were assessed using western blotting and reduced-carbon monoxide difference spectroscopy, and a specific peak at 450 nm was detected in the wild-type and 19 variants. Furthermore, kinetic parameters were determined by assaying the reactions with efavirenz and propofol and quantifying the metabolite concentrations. We found that 12 variants had significantly lower or abolished enzymatic activity with both the substrates. In silico three-dimensional docking and molecular-dynamics simulations suggested that these functional changes were due to conformational changes in essential regions, such as the heme-binding site and ligand channels involved in transporting substrates to the active site. These findings have implications for predicting the plasma concentrations of CYP2B6 substrates and controlling their side effects.
Identifying critical age and gender-based metabolomic shifts in a Japanese population of the Tohoku Medical Megabank cohort. International-journal

Miyuki Sakurai, Ikuko N Motoike, Eiji Hishinuma, Yuichi Aoki, Shu Tadaka, Mana Kogure, Masatsugu Orui, Mami Ishikuro, Taku Obara, Naoki Nakaya, Kazuki Kumada, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

Scientific reports　14　(1)　15681-15681　2024/07/08

DOI： 10.1038/s41598-024-66180-0 　

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Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.
Genetic Risk, Healthy Lifestyle Adherence, and Risk of Developing Diabetes in the Japanese Population.

Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Koichi Matsuda, Yoko Izumi, Kengo Kinoshita, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

Journal of atherosclerosis and thrombosis　31　(12)　1717-1732　2024/06/22

DOI： 10.5551/jat.64906 　

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AIM: This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. METHODS: This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). RESULT: Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). CONCLUSION: Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.
PNPO–PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity International-journal

Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi

Nature Metabolism　6　(6)　1108-1127　2024/05/31
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s42255-024-01053-4 　

eISSN： 2522-5812

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Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.
The role of the STAS domain in SLC26A9 for chloride ion transporter function. International-journal

Satoshi Omori, Yuya Hanazono, Hafumi Nishi, Kengo Kinoshita

Biophysical journal　123　(12)　1751-1762　2024/05/21

DOI： 10.1016/j.bpj.2024.05.018 　

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The anion exchanger solute carrier family 26 (SLC26)A9, consisting of the transmembrane (TM) domain and the cytoplasmic STAS domain, plays an essential role in regulating chloride transport across cell membranes. Recent studies have indicated that C-terminal helices block the entrance of the putative ion transport pathway. However, the precise functions of the STAS domain and C-terminal helix, as well as the underlying molecular mechanisms governing the transport process, remain poorly understood. In this study, we performed molecular dynamics simulations of three distinct models of human SLC26A9, full-length, STAS domain removal (ΔSTAS), and C-terminus removal (ΔC), to investigate their conformational dynamics and ion-binding properties. Stable binding of ions to the binding sites was exclusively observed in the ΔC model in these simulations. Comparing the full-length and ΔC simulations, the ΔC model displayed enhanced motion of the STAS domain. Furthermore, comparing the ΔSTAS and ΔC simulations, the ΔSTAS simulation failed to exhibit stable ion bindings to the sites despite the absence of the C-terminus blocking the ion transmission pathway in both systems. These results suggest that the removal of the C-terminus not only unblocks the access of ions to the permeation pathway but also triggers STAS domain motion, gating the TM domain to promote ions' entry into their binding site. Further analysis revealed that the asymmetric motion of the STAS domain leads to the expansion of the ion permeation pathway within the TM domain, resulting in the stiffening of the flexible TM12 helix near the ion-binding site. This structural change in the TM12 helix stabilizes chloride ion binding, which is essential for SLC26A9's alternate-access mechanism. Overall, our study provides new insights into the molecular mechanisms of SLC26A9 transport and may pave the way for the development of novel treatments for diseases associated with dysregulated ion transport.
GWAS meta-analysis of kidney function traits in Japanese populations.

Asahi Hishida, Masahiro Nakatochi, Yoichi Sutoh, Shiori Nakano, Yukihide Momozawa, Akira Narita, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Kengo Kinoshita, Taiki Yamaji, Atsushi Goto, Mitsuhiko Noda, Norie Sawada, Hiroaki Ikezaki, Mako Nagayoshi, Megumi Hara, Sadao Suzuki, Teruhide Koyama, Chihaya Koriyama, Sakurako Katsuura-Kamano, Aya Kadota, Kiyonori Kuriki, Masayuki Yamamoto, Makoto Sasaki, Motoki Iwasaki, Keitaro Matsuo, Kenji Wakai

Journal of epidemiology　34　(11)　526-534　2024/04/06

DOI： 10.2188/jea.JE20230281 　

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BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.
Multi-Omics Profiling Reveals Phenotypic and Functional Heterogeneity of Neutrophils in COVID-19 International-journal

Lin Zhang, Hafumi Nishi, Kengo Kinoshita

International Journal of Molecular Sciences　25　(7)　3841-3841　2024/03/29
Publisher: MDPI AG
DOI： 10.3390/ijms25073841 　

eISSN： 1422-0067

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Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the functions of each subpopulation. We analyzed public single-cell RNA-seq, bulk RNA-seq, and proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis. We identified eight neutrophil subtypes: pro-neutrophil, pre-neutrophil, immature neutrophil, and five mature neutrophil subpopulations. The subtypes exhibited distinct features, including diverse activation signatures and multiple enriched pathways. The pro-neutrophil subtype was associated with severe and fatal disease, while the pre-neutrophil subtype was particularly abundant in mild/moderate disease. One of the mature neutrophil subtypes showed consistently large fractions in patients with different disease severity. Bulk RNA-seq dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of pro-neutrophils in severe COVID-19 patients. Cell–cell communication analysis revealed representative ligand–receptor interactions among the identified neutrophil subtypes. Further investigation into transcription factors and differential protein abundance revealed the regulatory network differences between healthy donors and patients with severe COVID-19. Overall, we demonstrated the complex interactions among heterogeneous neutrophil subtypes and other blood cell types during COVID-19 disease. Our work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.
Dietary habits and plasma lipid concentrations in a general Japanese population. International-journal

Mitsuharu Sato, Eiji Hishinuma, Naomi Matsukawa, Yoshiko Shima, Daisuke Saigusa, Ikuko N Motoike, Mana Kogure, Naoki Nakaya, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

Metabolomics : Official journal of the Metabolomic Society　20　(2)　34-34　2024/03/05

DOI： 10.1007/s11306-024-02087-1 　

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INTRODUCTION: Accumulating data on the associations between food consumption and lipid composition in the body is essential for understanding the effects of dietary habits on health. OBJECTIVES: As part of omics research in the Tohoku Medical Megabank Community-Based Cohort Study, this study sought to reveal the dietary impact on plasma lipid concentration in a Japanese population. METHODS: We conducted a correlation analysis of food consumption and plasma lipid concentrations measured using mass spectrometry, for 4032 participants in Miyagi Prefecture, Japan. RESULTS: Our analysis revealed 83 marked correlations between six food categories and the concentrations of plasma lipids in nine subclasses. Previously reported associations, including those between seafood consumption and omega-3 fatty acids, were validated, while those between dairy product consumption and odd-carbon-number fatty acids (odd-FAs) were validated for the first time in an Asian population. Further analysis suggested that dairy product consumption is associated with odd-FAs via sphingomyelin (SM), which suggests that SM is a carrier of odd-FAs. These results are important for understanding odd-FA metabolism with regards to dairy product consumption. CONCLUSION: This study provides insight into the dietary impact on plasma lipid concentration in a Japanese population.
Progress report of the Tohoku Medical Megabank Community-Based Cohort Study: Study profile of the repeated center-based survey during second period in Miyagi Prefecture.

Atsushi Hozawa, Kumi Nakaya, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Junichi Sugawara, Eiichi Kodama, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Naho Tsuchiya, Takumi Hirata, Akira Narita, Akito Tsuboi, Toru Tamahara, Akihito Otsuki, Maki Goto, Makiko Taira, Ritsuko Shimizu, Kichiya Suzuki, Taku Obara, Masahiro Kikuya, Hirohito Metoki, Mami Ishikuro, Inaho Danjoh, Soichi Ogishima, Satoshi Nagaie, Naoko Minegishi, Masahiro Hiratsuka, Kazuki Kumada, Ichiko Nishijima, Takahiro Nobukuni, Yumi Yamaguchi-Kabata, Fuji Nagami, Shigeo Kure, Nobuo Fuse, Kengo Kinoshita, Yoko Izumi, Shinichi Kuriyama, Masayuki Yamamoto

Journal of epidemiology　34　(9)　434-443　2024/02/24

DOI： 10.2188/jea.JE20230241 　

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BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period (2nd period survey) of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The 2nd period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the 2nd period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The 2nd period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the 2nd period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the 2nd period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSIONS: The 2nd period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.
Molecular pathological demonstration of an unusual angiosarcoma-like dedifferentiation pattern in hepatocellular carcinoma. International-journal

Keigo Murakami, Taito Itoh, Yasunobu Okamura, Kengo Kinoshita, Hideki Ota, Michiaki Unno, Takashi Kamei, Toru Furukawa

Pathology international　74　(3)　157-159　2024/02/06

DOI： 10.1111/pin.13412 　
高異型度PanIN/膵上皮内癌・小径膵癌の分子進化モデル(Molecular evolutionary model of early pancreatic cancer)

伊藤泰斗, 大森優子, 小野裕介, 高橋賢治, 岡村容伸, 木下賢吾, 正宗淳, 海野倫明, 水上裕輔, 古川徹

日本病理学会会誌　113　(1)　318-318　2024/02
Publisher: (一社)日本病理学会
ISSN： 0300-9181
高異型度PanIN/膵上皮内癌・小径膵癌の分子進化モデル(Molecular evolutionary model of early pancreatic cancer)

伊藤泰斗, 大森優子, 小野裕介, 高橋賢治, 岡村容伸, 木下賢吾, 正宗淳, 海野倫明, 水上裕輔, 古川徹

日本病理学会会誌　113　(1)　318-318　2024/02
Publisher: (一社)日本病理学会
ISSN： 0300-9181
Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people. International-journal

Yuriko N Koyanagi, Masahiro Nakatochi, Shinichi Namba, Isao Oze, Hadrien Charvat, Akira Narita, Takahisa Kawaguchi, Hiroaki Ikezaki, Asahi Hishida, Megumi Hara, Toshiro Takezaki, Teruhide Koyama, Yohko Nakamura, Sadao Suzuki, Sakurako Katsuura-Kamano, Kiyonori Kuriki, Yasuyuki Nakamura, Kenji Takeuchi, Atsushi Hozawa, Kengo Kinoshita, Yoichi Sutoh, Kozo Tanno, Atsushi Shimizu, Hidemi Ito, Yumiko Kasugai, Yukino Kawakatsu, Yukari Taniyama, Masahiro Tajika, Yasuhiro Shimizu, Etsuji Suzuki, Yasuyuki Hosono, Issei Imoto, Yasuharu Tabara, Meiko Takahashi, Kazuya Setoh, Koichi Matsuda, Shiori Nakano, Atsushi Goto, Ryoko Katagiri, Taiki Yamaji, Norie Sawada, Shoichiro Tsugane, Kenji Wakai, Masayuki Yamamoto, Makoto Sasaki, Fumihiko Matsuda, Yukinori Okada, Motoki Iwasaki, Paul Brennan, Keitaro Matsuo

Science advances　10　(4)　eade2780　2024/01/26

DOI： 10.1126/sciadv.ade2780 　

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An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.
Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal

Yu-Ichi Aoki, Keiko Taguchi, Hayato Anzawa, Junko Kawashima, Noriko Ishida, Akihito Otuki, Atsushi Hasegawa, Liam Baird, Takafumi Suzuki, Ikuko N Motoike, Kinuko Ohneda, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

Journal of biochemistry　175　(6)　611-627　2024/01/24

DOI： 10.1093/jb/mvae008 　

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Whole blood transcriptome analysis is a valuable approach in medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a dataset that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.
Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population. International-journal

Kei-Ichiro Inamori, Katsuya Nakamura, Fumi Shishido, Jia-Chen Hsu, Masakazu Nagafuku, Takahiro Nitta, Junji Ikeda, Hidekane Yoshimura, Minori Kodaira, Naomi Tsuchida, Naomichi Matsumoto, Satoshi Uemura, Shiho Ohno, Noriyoshi Manabe, Yoshiki Yamaguchi, Akira Togayachi, Kiyoko F Aoki-Kinoshita, Shoko Nishihara, Jun-Ichi Furukawa, Tadashi Kaname, Masahiko Nakamura, Takayoshi Shimohata, Shu Tadaka, Matsuyuki Shirota, Kengo Kinoshita, Yutaka Nakamura, Isao Ohno, Yoshiki Sekijima, Jin-Ichi Inokuchi

Frontiers in neuroscience　18　1437668-1437668　2024

DOI： 10.3389/fnins.2024.1437668 　

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Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurological disorders that are characterized by progressive spasticity and weakness in the lower limbs. SPG26 is a complicated form of HSP, which includes not only weakness in the lower limbs, but also cognitive impairment, developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy, and is caused by biallelic mutations in the B4GALNT1 (beta-1,4-N-acetylgalactosaminyltransferase 1) gene. The B4GALNT1 gene encodes ganglioside GM2/GD2 synthase (GM2S), which catalyzes the transfer of N-acetylgalactosamine to lactosylceramide, GM3, and GD3 to generate GA2, GM2, and GD2, respectively. The present study attempted to characterize a novel B4GALNT1 variant (NM_001478.5:c.937G>A p.Asp313Asn) detected in a patient with progressive multi-system neurodegeneration as well as deleterious variants found in the general population in Japan. Peripheral blood T cells from our patient lacked the ability for activation-induced ganglioside expression assessed by cell surface cholera toxin binding. Structural predictions suggested that the amino acid substitution, p.Asp313Asn, impaired binding to the donor substrate UDP-GalNAc. An in vitro enzyme assay demonstrated that the variant protein did not exhibit GM2S activity, leading to the diagnosis of HSP26. This is the first case diagnosed with SPG26 in Japan. We then extracted 10 novel missense variants of B4GALNT1 from the whole-genome reference panel jMorp (8.3KJPN) of the Tohoku medical megabank organization, which were predicted to be deleterious by Polyphen-2 and SIFT programs. We performed a functional evaluation of these variants and demonstrated that many showed perturbed subcellular localization. Five of these variants exhibited no or significantly decreased GM2S activity with less than 10% activity of the wild-type protein, indicating that they are carrier variants for HSP26. These results provide the basis for molecular analyses of B4GALNT1 variants present in the Japanese population and will help improve the molecular diagnosis of patients suspected of having HSP.
Identifying key genes in COPD risk via multiple population data integration and gene prioritization. International-journal

Afeefa Zainab, Hayato Anzawa, Kengo Kinoshita

PloS one　19　(11)　e0305803　2024

DOI： 10.1371/journal.pone.0305803 　

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Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease, making it a leading cause of death worldwide. Several genome-wide association studies (GWAS) have been conducted to identify loci associated with COPD. However, different ancestral genetic compositions for the same disease across various populations present challenges in studies involving multi-population data. In this study, we aimed to identify protein-coding genes associated with COPD by prioritizing genes for each population's GWAS data, and then combining these results instead of performing a common meta-GWAS due to significant sample differences in different population cohorts. Lung function measurements are often used as indicators for COPD risk prediction; therefore, we used lung function GWAS data from two populations, Japanese and European, and re-evaluated them using a multi-population gene prioritization approach. This study identified significant single nucleotide variants (SNPs) in both Japanese and European populations. The Japanese GWAS revealed nine significant SNPs and four lead SNPs in three genomic risk loci. In comparison, the European population showed five lead SNPs and 17 independent significant SNPs in 21 genomic risk loci. A comparative analysis of the results found 28 similar genes in the prioritized gene lists of both populations. We also performed a standard meta-analysis for comparison and identified 18 common genes in both populations. Our approach demonstrated that trans-ethnic linkage disequilibrium (LD) could detect some significant novel associations and genes that have yet to be reported or were missed in previous analyses. The study suggests that a gene prioritization approach for multi-population analysis using GWAS data may be a feasible method to identify new associations in data with genetic diversity across different populations. It also highlights the possibility of identifying generalized and population-specific treatment and diagnostic options.
遺伝要因、生活習慣の組み合わせと糖尿病発症の関連東北メディカル・メガバンク地域住民コホート調査

高瀬雅仁, 中谷直樹, 小暮真奈, 畑中里衣子, 中谷久美, 千葉一平, 中村智洋, 後岡広太郎, 土屋菜歩, 平田匠, 松田浩一, 栗山進一, 木下賢吾, 田宮元, 寳澤篤

Journal of Epidemiology　34　(Suppl.)　176-176　2024/01
Publisher: (一社)日本疫学会
ISSN： 0917-5040

eISSN： 1349-9092
Next-generation sequencing analysis with a population-specific human reference genome

Tomohisa Suzuki, Kota Ninomiya, Takamitsu Funayama, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Jun Takayama

Genes & Genetic Systems　2024
Publisher: Genetics Society of Japan
DOI： 10.1266/ggs.24-00112 　

ISSN： 1341-7568

eISSN： 1880-5779
Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS) Peer-reviewed

Sei Harada, Miho Iida, Naoko Miyagawa, Aya Hirata, Kazuyo Kuwabara, Minako Matsumoto, Tomonori Okamura, Shun Edagawa, Yoko Kawada, Atsuko Miyake, Ryota Toki, Miki Akiyama, Atsuki Kawai, Daisuke Sugiyama, Yasunori Sato, Ryo Takemura, Kota Fukai, Yoshiki Ishibashi, Suzuka Kato, Ayako Kurihara, Mizuki Sata, Takuma Shibuki, Ayano Takeuchi, Shun Kohsaka, Mitsuaki Sawano, Satoshi Shoji, Yoshikane Izawa, Masahiro Katsumata, Koichi Oki, Shinichi Takahashi, Tsubasa Takizawa, Hiroshi Maruya, Yuji Nishiwaki, Ryo Kawasaki, Akiyoshi Hirayama, Takamasa Ishikawa, Rintaro Saito, Asako Sato, Tomoyoshi Soga, Masahiro Sugimoto, Masaru Tomita, Shohei Komaki, Hideki Ohmomo, Kanako Ono, Yayoi Otsuka-Yamasaki, Atsushi Shimizu, Yoichi Sutoh, Atsushi Hozawa, Kengo Kinoshita, Seizo Koshiba, Kazuki Kumada

Journal of Epidemiology　34　(8)　393-401　2024/01

DOI： 10.2188/jea.je20230192 　

ISSN： 0917-5040 1349-9092

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The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.
Effects of NRF2 polymorphisms on safety and efficacy of bardoxolone methyl: subanalysis of TSUBAKI study Peer-reviewed

Kazuaki Ikejiri, Takafumi Suzuki, Satsuki Muto, Hirotaka Takama, Kengo Yamawaki, Tatsuya Miyazawa, Itaru Urakawa, Yuichi Aoki, Akihito Otsuki, Fumiki Katsuoka, Kengo Kinoshita, Masaomi Nangaku, Tadao Akizawa, Masayuki Yamamoto

Clinical and Experimental Nephrology　28　(3)　225-234　2023/11/14

DOI： 10.1007/s10157-023-02427-w 　

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BACKGROUND: In the TSUBAKI study, bardoxolone methyl significantly increased measured and estimated glomerular filtration rates (GFR) in patients with multiple forms of chronic kidney disease (CKD), including Japanese patients with type 2 diabetes and stage 3-4 CKD. Since bardoxolone methyl targets the nuclear factor erythroid 2-related factor 2 pathway, this exploratory analysis of the TSUBAKI study investigated the impact of the regulatory single nucleotide polymorphism, rs6721961, on the effects of bardoxolone methyl. METHODS: Japanese patients aged 20-79 years with type 2 diabetes and stage 3-4 CKD were randomized to bardoxolone methyl 5-15 mg/day (titrated as tolerated) or placebo for 16 weeks. Genotype frequency, clinical characteristics, renal function, and adverse events were primarily assessed. RESULTS: Of 104 patients (bardoxolone methyl n = 55, placebo n = 49); 57% were genotype C/C, 32% C/A and 12% A/A. The frequency of the A/A genotype was higher among patients with diabetic kidney disease than in the general Japanese population (~ 5%). Measured and estimated GFRs increased from baseline in all genotypes receiving bardoxolone methyl. There were no significant differences between genotypes for safety parameters, including blood pressure, bodyweight, and levels of B-type natriuretic peptide, or in the type and frequency of adverse events, suggesting that the efficacy and safety of bardoxolone methyl are unaffected by the rs6721961 polymorphism-617 (C→A) genotype. CONCLUSIONS: Our approach of combining genome analysis with clinical trials for an investigational drug provides important and useful clues for exploring the efficacy and safety of the drug. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02316821.
jMorp: Japanese Multi-Omics Reference Panel update report 2023. International-journal

Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　52　(D1)　D622-D632　2023/11/01

DOI： 10.1093/nar/gkad978 　

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Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.
Single-cell RNA-seq public data reveal the gene regulatory network landscape of respiratory epithelial and peripheral immune cells in COVID-19 patients International-journal

Lin Zhang, Hafumi Nishi, Kengo Kinoshita

Frontiers in Immunology　14　1194614-1194614　2023/10/23
Publisher: Frontiers Media SA
DOI： 10.3389/fimmu.2023.1194614 　

eISSN： 1664-3224

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Introduction Infection with SARS-CoV-2 leads to coronavirus disease 2019 (COVID-19), which can result in acute respiratory distress syndrome and multiple organ failure. However, its comprehensive influence on pathological immune responses in the respiratory epithelium and peripheral immune cells is not yet fully understood. Methods In this study, we analyzed multiple public scRNA-seq datasets of nasopharyngeal swabs and peripheral blood to investigate the gene regulatory networks (GRNs) of healthy individuals and COVID-19 patients with mild/moderate and severe disease, respectively. Cell-cell communication networks among cell types were also inferred. Finally, validations were conducted using bulk RNA-seq and proteome data. Results Similar and dissimilar regulons were identified within or between epithelial and immune cells during COVID-19 severity progression. The relative transcription factors (TFs) and their targets were used to construct GRNs among different infection sites and conditions. Between respiratory epithelial and peripheral immune cells, different TFs tended to be used to regulate the activity of a cell between healthy individuals and COVID-19 patients, although they had some TFs in common. For example, XBP1, FOS, STAT1, and STAT2 were activated in both the epithelial and immune cells of virus-infected individuals. In contrast, severe COVID-19 cases exhibited activation of CEBPD in peripheral immune cells, while CEBPB was exclusively activated in respiratory epithelial cells. Moreover, in patients with severe COVID-19, although some inflammatory genes, such as S100A8/A9, were found to be upregulated in both respiratory epithelial and peripheral immune cells, their relative regulators can differ in terms of cell types. The cell-cell communication analysis suggested that epidermal growth factor receptor signaling among epithelia contributes to mild/moderate disease, and chemokine signaling among immune cells contributes to severe disease. Conclusion This study identified cell type- and condition-specific regulons in a wide range of cell types from the initial infection site to the peripheral blood, and clarified the diverse mechanisms of maladaptive responses to SARS-CoV-2 infection.
Identification of predictive biomarkers for endometrial cancer diagnosis and treatment response monitoring using plasma metabolome profiling International-journal

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Yoshiko Shima, Bin Li, Ikuko N. Motoike, Yusuke Shibuya, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi

Cancer & Metabolism　11　(1)　16-16　2023/10/11
Publisher: Springer Science and Business Media LLC
DOI： 10.1186/s40170-023-00317-z 　

eISSN： 2049-3002

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Abstract Background Endometrial cancer (EMC) is the most common female genital tract malignancy with an increasing prevalence in many countries including Japan, a fact that renders early detection and treatment necessary to protect health and fertility. Although early detection and treatment are necessary to further improve the prognosis of women with endometrial cancer, biomarkers that accurately reflect the pathophysiology of EMC patients are still unclear. Therefore, it is clinically critical to identify biomarkers to assess diagnosis and treatment efficacy to facilitate appropriate treatment and development of new therapies for EMC. Methods In this study, wide-targeted plasma metabolome analysis was performed to identify biomarkers for EMC diagnosis and the prediction of treatment responses. The absolute quantification of 628 metabolites in plasma samples from 142 patients with EMC was performed using ultra-high-performance liquid chromatography with tandem mass spectrometry. Results The concentrations of 111 metabolites increased significantly, while the concentrations of 148 metabolites decreased significantly in patients with EMC compared to healthy controls. Specifically, LysoPC and TGs, including unsaturated fatty acids, were reduced in patients with stage IA EMC compared to healthy controls, indicating that these metabolic profiles could be used as early diagnostic markers of EMC. In contrast, blood levels of amino acids such as histidine and tryptophan decreased as the risk of recurrence increased and the stages of EMC advanced. Furthermore, a marked increase in total TG and a decrease in specific TGs and free fatty acids including polyunsaturated fatty acids levels were observed in patients with EMC. These results suggest that the polyunsaturated fatty acids in patients with EMC are crucial for disease progression. Conclusions Our data identified specific metabolite profiles that reflect the pathogenesis of EMC and showed that these metabolites correlate with the risk of recurrence and disease stage. Analysis of changes in plasma metabolite profiles could be applied for the early diagnosis and monitoring of the course of treatment of EMC patients.
Gene rearrangement and expression of PRKACA and PRKACB governs morpho-biology of pancreatobiliary oncocytic neoplasms International-journal

Taito Itoh, Yuko Omori, Mitsuru Seino, Katsuya Hirose, Fumiko Date, Yusuke Ono, Yusuke Mizukami, Shuichi Aoki, Masaharu Ishida, Masamichi Mizuma, Takanori Morikawa, Ryota Higuchi, Goro Honda, Yasunobu Okamura, Kengo Kinoshita, Michiaki Unno, Toru Furukawa

Modern Pathology　37　(1)　100358-100358　2023/10
Publisher: Elsevier BV
DOI： 10.1016/j.modpat.2023.100358 　

ISSN： 0893-3952

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Intraductal oncocytic papillary neoplasms (IOPNs) are distinct from intraductal papillary mucinous neoplasms based on characteristic morphologic and genetic features represented by fusion genes involving PRKACA or PRKACB (PRKACA/B). However, pancreatic and biliary tumors with partial oncocytic features are often encountered clinically, and their molecular features are yet to be clarified. This study included 80 intraductal papillary neoplasms: 32 tumors with mature IOPN morphology (typical), 28 with partial or subclonal oncocytic features (atypical), and 20 without oncocytic features (control). We analyzed PRKACA/B fusion genes, including ATP1B1::PRKACA, DNAJB1::PRKACA, and ATP1B1::PRKACB, by reverse-transcription PCR; mRNA expression of fusion genes and nonrearranged PRKACA/B genes by quantitative reverse-transcription PCR; mutations in KRAS, BRAF, and GNAS by targeted sequencing or droplet digital PCR; and the expression of cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunits α (PRKACA) and β (PRKACB), phosphorylated cAMP response element-binding protein, and aberrations of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry. PRKACA/B fusion genes were detected in 100% (32/32) of typical, 46% (13/28) of atypical, and 0% (0/20) of control (P < .05). Expression of PRKACA, PRKACB, and phosphorylated cAMP response element-binding protein was upregulated in neoplasms with PRKACA/B fusion genes (P < .05). mRNA expression of the PRKACA/B fusion genes and protein expression of PRKACA or PRKACB tended to be higher in typical than in atypical cases (mRNA, P = .002; protein expression, P = .054). In some atypical neoplasms with mixed subtypes, PRKACA/B fusion genes were superimposed exclusively on oncocytic components. Typical IOPNs harbored fewer KRAS and GNAS mutations than control samples and fewer alterations in p53 and STK11 than atypical samples (P < .05). In conclusion, PRKACA/B fusion genes not only are the characteristic drivers of IOPNs but also play a crucial role in the development of subclonal oncocytic neoplasms. Moreover, oncocytic morphology is strongly associated with upregulation of PRKACA/B, which may provide clues for potential therapeutic options.
Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8,380 Japanese Subjects and Assessment of Arachidonic Acid ω-Hydroxylation. International-journal

Yu Sato, Eiji Hishinuma, Shuki Yamazaki, Akiko Ueda, Masaki Kumondai, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Tomoki Nakayoshi, Akifumi Oda, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka

Drug metabolism and disposition: the biological fate of chemicals　51　(12)　1561-1568　2023/09/29

DOI： 10.1124/dmd.123.001389 　

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Cytochrome P450 4F2 (CYP4F2) is an enzyme that is involved in the metabolism of arachidonic acid (AA), vitamin E and K (VK), and xenobiotics including drugs. CYP4F2*3 polymorphism (rs2108622; c.1297G>A; p.Val433Met) has been associated with hypertension, ischemic stroke, and variation in the effectiveness of the anticoagulant drug warfarin. In this study, we characterized wild-type CYP4F2 and 28 CYP4F2 variants, including a Val433Met substitution, detected in 8,380 Japanese subjects. The CYP4F2 variants were heterologously expressed in 293FT cells to measure the concentrations of CYP4F2 variant holoenzymes using carbon monoxide-reduced difference spectroscopy, where the wild type and 18 holoenzyme variants showed a peak at 450 nm. Kinetic parameters (Vmax , S50 , and CL int as Vmax /S50 ) of AA ω-hydroxylation were determined for the wild type and 21 variants with enzyme activity. Compared to the wild type, two variants showed significantly decreased CL int values for AA ω-hydroxylation. The values for seven variants could not be determined because no enzymatic activity was detected at the highest substrate concentration used. Three-dimensional structural modeling was performed to determine the reason for reduced enzymatic activity of the CYP4F2 variants. Our findings contribute to a better understanding of CYP4F2 variant-associated diseases and possible future therapeutic strategies. Significance Statement CYP4F2 is involved in the metabolism of AA and VK, and CYP4F2*3 polymorphisms have been associated with hypertension and variation in the effectiveness of the anticoagulant drug warfarin. In this study, we present a functional analysis of 28 CYP4F2 variants identified in Japanese subjects, demonstrating that seven gene polymorphisms cause loss of CYP4F2 function, and propose structural changes that lead to altered function.
Association Between Olfactory Test Data with Multiple Levels of Odor Intensity and Suspected Cognitive Impairment: A Cross-Sectional Study. International-journal

Shuichi Sato, Takao Imaeda, Shunji Mugikura, Naoko Mori, Masaki Takanashi, Kazumi Hayakawa, Tomo Saito, Makiko Taira, Akira Narita, Mana Kogure, Ippei Chiba, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Ryosuke Ishiwata, Tomohiro Nakamura, Ikuko N Motoike, Naoki Nakaya, Seizo Koshiba, Kengo Kinoshita, Shinichi Kuriyama, Soichi Ogishima, Fuji Nagami, Nobuo Fuse, Atsushi Hozawa

Journal of Alzheimer's disease : JAD　95　(4)　1469-1480　2023/09/11

DOI： 10.3233/JAD-230318 　

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BACKGROUND: Olfactory function decline has recently been reported to be associated with a risk of cognitive impairment. Few population-based studies have included younger adults when examining the association between olfactory test data with multiple odor intensities and suspected cognitive impairment. OBJECTIVE: We investigated the association between high-resolution olfactory test data with fewer odors and suspected cognitive impairments. We also examined the differences between older and younger adults in this association. METHODS: The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered to 1,450 participants, with three odor-intensity-level olfactometry using six different odors. Logistic regressions to discriminate suspected cognitive impairment were conducted to examine the association, adjusted for age, sex, education duration, and smoking history. Data were collected from the Program by Tohoku University Tohoku Medical Megabank Organization, with an additional olfactory test conducted between 2019 and 2021. RESULTS: We generally observed that the lower the limit of distinguishable odor intensity was, the higher the MoCA-J score was. The combination of spearmint and stuffy socks contributed most to the distinction between suspected and unsuspected cognitive impairment. Furthermore, the association was significant in women aged 60-74 years (adjusted odds ratio 0.881, 95% confidence interval [0.790, 0.983], p = 0.024). CONCLUSIONS: The results indicate an association between the limit of distinguishable odor intensity and cognitive function. The olfactory test with multiple odor intensity levels using fewer odors may be applicable for the early detection of mild cognitive impairment, especially in older women aged 60-74 years.
Establishment of the early prediction models of low-birth-weight reveals influential genetic and environmental factors: a prospective cohort study. International-journal

Satoshi Mizuno, Satoshi Nagaie, Gen Tamiya, Shinichi Kuriyama, Taku Obara, Mami Ishikuro, Hiroshi Tanaka, Kengo Kinoshita, Junichi Sugawara, Masayuki Yamamoto, Nobuo Yaegashi, Soichi Ogishima

BMC pregnancy and childbirth　23　(1)　628-628　2023/08/31

DOI： 10.1186/s12884-023-05919-5 　

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BACKGROUND: Low birth weight (LBW) is a leading cause of neonatal morbidity and mortality, and increases various disease risks across life stages. Prediction models of LBW have been developed before, but have limitations including small sample sizes, absence of genetic factors and no stratification of neonate into preterm and term birth groups. In this study, we challenged the development of early prediction models of LBW based on environmental and genetic factors in preterm and term birth groups, and clarified influential variables for LBW prediction. METHODS: We selected 22,711 neonates, their 21,581 mothers and 8,593 fathers from the Tohoku Medical Megabank Project Birth and Three-Generation cohort study. To establish early prediction models of LBW for preterm birth and term birth groups, we trained AI-based models using genetic and environmental factors of lifestyles. We then clarified influential environmental and genetic factors for predicting LBW in the term and preterm groups. RESULTS: We identified 2,327 (10.22%) LBW neonates consisting of 1,077 preterm births and 1,248 term births. Our early prediction models archived the area under curve 0.96 and 0.95 for term LBW and preterm LBW models, respectively. We revealed that environmental factors regarding eating habits and genetic features related to fetal growth were influential for predicting LBW in the term LBW model. On the other hand, we identified that genomic features related to toll-like receptor regulations and infection reactions are influential genetic factors for prediction in the preterm LBW model. CONCLUSIONS: We developed precise early prediction models of LBW based on lifestyle factors in the term birth group and genetic factors in the preterm birth group. Because of its accuracy and generalisability, our prediction model could contribute to risk assessment of LBW in the early stage of pregnancy and control LBW risk in the term birth group. Our prediction model could also contribute to precise prediction of LBW based on genetic factors in the preterm birth group. We then identified parental genetic and maternal environmental factors during pregnancy influencing LBW prediction, which are major targets for understanding the LBW to address serious burdens on newborns' health throughout life.
Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus. International-journal

Han Ba Bui, Satoshi Watanabe, Norimichi Nomura, Kehong Liu, Tomoko Uemura, Michio Inoue, Akihisa Tsutsumi, Hiroyuki Fujita, Kengo Kinoshita, Yukinari Kato, So Iwata, Masahide Kikkawa, Kenji Inaba

Nature communications　14　(1)　4770-4770　2023/08/08

DOI： 10.1038/s41467-023-40521-5 　

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Zinc ions (Zn2+) are vital to most cells, with the intracellular concentrations of Zn2+ being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.2-3.1 Å-resolution cryo-EM structures of a Golgi-localized human Zn2+/H+ antiporter ZnT7 (hZnT7) in Zn2+-bound and unbound forms. Cryo-EM analyses show that hZnT7 exists as a dimer via tight interactions in both the cytosolic and transmembrane (TM) domains of two protomers, each of which contains a single Zn2+-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn2+ entry in the inward-facing conformation and widens the luminal cavity for Zn2+ release in the outward-facing conformation. An exceptionally long cytosolic histidine-rich loop characteristic of hZnT7 binds two Zn2+ ions, seemingly facilitating Zn2+ recruitment to the TM metal transport pathway. These structures permit mechanisms of hZnT7-mediated Zn2+ uptake into the Golgi to be proposed.
新生児臍帯血の網羅的エピゲノム解析による妊娠初期までの喫煙経験が次世代に及ぼす影響

美辺詩織, 小巻翔平, 大桃秀樹, 高嶋聰, 小野加奈子, 山崎弥生, 須藤洋一, 田高周, 水野聖士, 石黒真美, 工藤久智, 小原拓, 熊田和貴, 勝岡史城, 荻島創一, 木下賢吾, 菅原準一, 栗山進一, 清水厚志

DOHaD研究　11　(3)　37-37　2023/08
Publisher: (一社)日本DOHaD学会
ISSN： 2187-2562

eISSN： 2187-2597
C4S DB: Comprehensive Collection and Comparison for ChIP-Seq Database International-journal

Hayato Anzawa, Kengo Kinoshita

Journal of Molecular Biology　435　(14)　168157-168157　2023/07/24
Publisher: Elsevier {BV}
DOI： 10.1016/j.jmb.2023.168157 　

ISSN： 0022-2836

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Combining multiple binding profiles, such as transcription factors and histone modifications, is a crucial step in revealing the functions of complex biological systems. Although a massive amount of chromatin immunoprecipitation followed by sequencing (ChIP-seq) data is available, existing ChIP-seq databases or repositories focus on individual experiments, and it is difficult to elucidate orchestrated regulation by DNA-binding elements. We developed the Comprehensive Collection and Comparison for ChIP-Seq Database (C4S DB) to provide researchers with insights into the combination of DNA binding elements based on quality-assessed public ChIP-seq data. The C4S DB is based on >16,000 human ChIP-seq experiments and provides two main web interfaces to discover the relationships between ChIP-seq data. "Gene browser" illustrates the landscape of distributions of binding elements around a specified gene, and "global similarity," a hierarchical clustering heatmap based on a similarity between two ChIP-seq experiments, gives an overview of genome-wide relations of regulatory elements. These functions promote the identification or evaluation of both gene-specific and genome-wide colocalization or mutually exclusive localization. Modern web technologies allow users to search for and aggregate large-scale experimental data through interactive web interfaces with quick responses. The C4S DB is available at https://c4s.site.
Statistical Modeling of Subjective Sleep Quality

S. Choilek, A. Karashima, I. Motoike, N. Katayama, K. Kinoshita, M. Nakao

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference　2023　1-6　2023/07/01
Publisher: IEEE
DOI： 10.1109/EMBC40787.2023.10340638 　

eISSN： 2694-0604
Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background Peer-reviewed

Makiko Taira, Shunji Mugikura, Naoko Mori, Atsushi Hozawa, Tomo Saito, Tomohiro Nakamura, Hideyasu Kiyomoto, Tadao Kobayashi, Soichi Ogishima, Fuji Nagami, Akira Uruno, Ritsuko Shimizu, Tomoko Kobayashi, Jun Yasuda, Shigeo Kure, Miyuki Sakurai, Ikuko N. Motoike, Kazuki Kumada, Naoki Nakaya, Taku Obara, Kentaro Oba, Atsushi Sekiguchi, Benjamin Thyreau, Tatsushi Mutoh, Yuji Takano, Mitsunari Abe, Norihide Maikusa, Yasuko Tatewaki, Yasuyuki Taki, Nobuo Yaegashi, Hiroaki Tomita, Kengo Kinoshita, Shinichi Kuriyama, Nobuo Fuse, Masayuki Yamamoto

JMA Journal　6　(3)　246-264　2023/07
Publisher: Japan Medical Association
DOI： 10.31662/jmaj.2022-0220 　

ISSN： 2433-328X

eISSN： 2433-3298

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The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study (TMM Brain MRI Study) was established to collect multimodal information through neuroimaging and neuropsychological assessments to evaluate the cognitive function and mental health of residents who experienced the Great East Japan Earthquake (GEJE) and associated tsunami. The study also aimed to promote advances in personalized healthcare and medicine related to mental health and cognitive function among the general population. We recruited participants for the first (baseline) survey starting in July 2014, enrolling individuals who were participating in either the TMM Community-Based Cohort Study (TMM CommCohort Study) or the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). We collected multiple magnetic resonance imaging (MRI) sequences, including 3D T1-weighted sequences, magnetic resonance angiography (MRA), diffusion tensor imaging (DTI), pseudo-continuous arterial spin labeling (pCASL), and three-dimensional fluid-attenuated inversion recovery (FLAIR) sequences. To assess neuropsychological status, we used both questionnaire- and interview-based rating scales. The former assessments included the Tri-axial Coping Scale, Impact of Event Scale in Japanese, Profile of Mood States, and 15-item Depression, Anxiety, and Stress Scale, whereas the latter assessments included the Mini-Mental State Examination, Japanese version. A total of 12,164 individuals were recruited for the first (baseline) survey, including those unable to complete all assessments. In parallel, we returned the MRI results to the participants and subsequently shared the MRI data through the TMM Biobank. At present, the second (first follow-up) survey of the study started in October 2019 is underway. In this study, we established a large and comprehensive database that included robust neuroimaging data as well as psychological and cognitive assessment data. In combination with genomic and omics data already contained in the TMM Biobank database, these data could provide new insights into the relationships of pathological processes with neuropsychological disorders, including age-related cognitive impairment.
Identification of predictive biomarkers for diagnosis and radiation sensitivity of uterine cervical cancer using wide-targeted metabolomics. International-journal

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Bin Li, Ikuko N Motoike, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi

The journal of obstetrics and gynaecology research　49　(8)　2109-2117　2023/06/09

DOI： 10.1111/jog.15709 　

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AIM: Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer-specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide-targeted plasma metabolomics. METHODS: We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra-high-performance liquid chromatography with tandem mass spectrometry. RESULTS: The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non-susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment. CONCLUSIONS: Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy.
Identification of predictive biomarkers for diagnosis and radiation sensitivity of uterine cervical cancer using wide‐targeted metabolomics

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Bin Li, Ikuko N. Motoike, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi

Journal of Obstetrics and Gynaecology Research　2023/06/09
Publisher: Wiley
DOI： 10.1111/jog.15709 　

ISSN： 1341-8076

eISSN： 1447-0756
Salivary gland cancer organoids are valid for preclinical genotype-oriented medical precision trials. International-journal

Tomohiko Ishikawa, Takenori Ogawa, Masahiro Shiihara, Hajime Usubuchi, Yuko Omori, Katsuya Hirose, Taito Itoh, Takuya Yoshida, Ayako Nakanome, Akira Okoshi, Kenjiro Higashi, Ryo Ishii, Masahiro Rokugo, Shun Wakamori, Yasunobu Okamura, Kengo Kinoshita, Yukio Katori, Toru Furukawa

iScience　26　(5)　106695-106695　2023/05/19

DOI： 10.1016/j.isci.2023.106695 　

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Salivary gland cancers (SGCs) are heterogeneous tumors, and precision oncology represents a promising therapeutic approach; however, its impact on SGCs remains obscure. This study aimed to establish a translational model for testing molecular-targeted therapies by combining patient-derived organoids and genomic analyses of SGCs. We enrolled 29 patients, including 24 with SGCs and 5 with benign tumors. Resected tumors were subjected to organoid and monolayer cultures, as well as whole-exome sequencing. Organoid and monolayer cultures of SGCs were successfully established in 70.8% and 62.5% of cases, respectively. Organoids retained most histopathological and genetic profiles of their original tumors. In contrast, 40% of the monolayer-cultured cells did not harbor somatic mutations of their original tumors. The efficacy of molecular-targeted drugs tested on organoids depended on their oncogenic features. Organoids recapitulated the primary tumors and were useful for testing genotype-oriented molecular targeted therapy, which is valuable for precision medicine in patients with SGCs.
Relationship between age-related hearing loss and consumption of coffee and tea.

Gosuke Watarai, Jun Suzuki, Ikuko N Motoike, Miyuki Sakurai, Ryoukichi Ikeda, Tetsuaki Kawase, Kengo Kinoshita, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Masayuki Yamamoto, Yukio Katori

Geriatrics & gerontology international　23　(6)　453-456　2023/05/03

DOI： 10.1111/ggi.14589 　
日本人集団における食習慣と血漿中脂質濃度の関連解析

佐藤允治, 菱沼英史, 三枝大輔, 元池育子, 木下賢吾, 小柴生造

脂質生化学研究　65　291-292　2023/05
Publisher: 日本脂質生化学会
ISSN： 0285-1520
Investigating the association between glycaemic traits and colorectal cancer in the Japanese population using Mendelian randomisation. International-journal

Akiko Hanyuda, Atsushi Goto, Ryoko Katagiri, Yuriko N Koyanagi, Masahiro Nakatochi, Yoichi Sutoh, Shiori Nakano, Isao Oze, Hidemi Ito, Taiki Yamaji, Norie Sawada, Masao Iwagami, Aya Kadota, Teruhide Koyama, Sakurako Katsuura-Kamano, Hiroaki Ikezaki, Keitaro Tanaka, Toshiro Takezaki, Issei Imoto, Midori Suzuki, Yukihide Momozawa, Kenji Takeuchi, Akira Narita, Atsushi Hozawa, Kengo Kinoshita, Atsushi Shimizu, Kozo Tanno, Keitaro Matsuo, Shoichiro Tsugane, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Motoki Iwasaki

Scientific reports　13　(1)　7052-7052　2023/04/29

DOI： 10.1038/s41598-023-33966-7 　

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Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99-1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60-1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97-2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.
Prevalence, Associated Factors, and Inter-Eye Differences of Refractive Errors in a Population-Based Japanese Cohort: The Tohoku Medical Megabank Eye Study. International-journal

Atsuya Miki, Nobuo Fuse, Satoko Fujimoto, Makiko Taira, Tomo Saito, Tomoyuki Okazaki, Akihiko Shiraki, Shigeru Sato, Ryo Kawasaki, Tomohiro Nakamura, Kengo Kinoshita, Kohji Nishida, Masayuki Yamamoto

Ophthalmic epidemiology　31　(1)　1-9　2023/04/24

DOI： 10.1080/09286586.2023.2203226 　

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PURPOSE: To investigate the prevalence, associated factors, and inter-eye differences of myopia and astigmatism in an adult Japanese population-based cohort. METHODS: A total of 4282 participants from the Tohoku Medical Megabank Organization Eye Study (ToMMo Eye Study) underwent comprehensive ocular examinations as well as extensive physiological tests and a lifestyle questionnaire. The spherical equivalent (SE) and cylinder power were obtained as refractive parameters. The age- and gender-stratified prevalences of high myopia (SE < -5D), myopia (SE < -0.5D), hyperopia (SE > 0.5D), astigmatism (cylinder power < -0.5D), and anisometropia (SE difference >1D) were calculated. Multivariable analyses were performed to identify associated factors for refractive error (RE). Distribution and associated factors of the inter-eye difference in RE were also investigated. RESULTS: The age-adjusted prevalence of high myopia, myopia, hyperopia, astigmatism, and anisometropia was 15.9%, 63.5%, 14.7%, 51.1%, and 14.7%, respectively. Both myopia and high myopia were more prevalent in the younger age group, while astigmatism was more prevalent in the older age group. Age, education, blood pressure, intraocular pressure, and corneal thickness are significantly associated with myopic refraction. Age, gender, intraocular pressure, and corneal thickness are correlated with astigmatism. Older age was associated with against-the-rule astigmatism. Older age, myopia, and longer education showed a significant correlation with large inter-eye differences in SERE. CONCLUSIONS: This study demonstrated the high prevalence of myopia in young Japanese, which may be caused by a generational shift. This study also confirmed the influence of age and education on both the prevalence and inter-eye differences of RE.
Carbon nanotube recognition by human Siglec-14 provokes inflammation. International-journal

Shin-Ichiro Yamaguchi, Qilin Xie, Fumiya Ito, Kazuki Terao, Yoshinobu Kato, Miki Kuroiwa, Satoshi Omori, Hideo Taniura, Kengo Kinoshita, Takuya Takahashi, Shinya Toyokuni, Kota Kasahara, Masafumi Nakayama

Nature nanotechnology　18　(6)　628-636　2023/04/06

DOI： 10.1038/s41565-023-01363-w 　

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For the design and development of innovative carbon nanotube (CNT)-based tools and applications, an understanding of the molecular interactions between CNTs and biological systems is essential. In this study, a three-dimensional protein-structure-based in silico screen identified the paired immune receptors, sialic acid immunoglobulin-like binding lectin-5 (Siglec-5) and Siglec-14, as CNT-recognizing receptors. Molecular dynamics simulations showed the spatiotemporally stable association of aromatic residues on the extracellular loop of Siglec-5 with CNTs. Siglec-14 mediated spleen tyrosine kinase (Syk)-dependent phagocytosis of multiwalled CNTs and the subsequent secretion of interleukin-1β from human monocytes. Ectopic in vivo expression of human Siglec-14 on mouse alveolar macrophages resulted in enhanced recognition of multiwalled CNTs and exacerbated pulmonary inflammation. Furthermore, fostamatinib, a Syk inhibitor, blocked Siglec-14-mediated proinflammatory responses. These results indicate that Siglec-14 is a human activating receptor recognizing CNTs and that blockade of Siglec-14 and the Syk pathway may overcome CNT-induced inflammation.
Decreased β‐hydroxybutyrate and ketogenic amino acid levels in depressed human adults International-journal

Shiho Sato, Zhiqian Yu, Mai Sakai, Ikuko N. Motoike, Daisuke Saigusa, Ryo Hirayama, Yoshie Kikuchi, Takaaki Abe, Kengo Kinoshita, Seizo Koshiba, Hiroaki Tomita

European Journal of Neuroscience　57　(6)　1018-1032　2023/02/07
Publisher: Wiley
DOI： 10.1111/ejn.15931 　

ISSN： 0953-816X

eISSN： 1460-9568

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β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analysed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the prefrontal cortex at 6 h. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly decreased in the liver and PFC after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.
Association Between Glycemic Traits and Primary Open-Angle Glaucoma: A Mendelian Randomization Study in the Japanese Population. International-journal

Akiko Hanyuda, Atsushi Goto, Masahiro Nakatochi, Yoichi Sutoh, Akira Narita, Shiori Nakano, Ryoko Katagiri, Kenji Wakai, Naoyuki Takashima, Teruhide Koyama, Kokichi Arisawa, Issei Imoto, Yukihide Momozawa, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Kengo Kinoshita, Taiki Yamaji, Norie Sawada, Masao Iwagami, Kenya Yuki, Kazuo Tsubota, Kazuno Negishi, Keitaro Matsuo, Masayuki Yamamoto, Makoto Sasaki, Shoichiro Tsugane, Motoki Iwasaki

American journal of ophthalmology　245　193-201　2023/01

DOI： 10.1016/j.ajo.2022.09.004 　

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PURPOSE: A meta-analysis suggests a relationship between abnormal glucose metabolism and primary open-angle glaucoma (POAG); however, the causal association between them remains controversial. We therefore conducted a Mendelian randomization (MR) study to assess the causal association between genetically predicted glycemic traits and the risk of POAG. DESIGN: Two-sample MR design. METHODS: We examined the genetically predicted measures of fasting glucose, hemoglobin A1c (HbA1c), and fasting C-peptide, in relation to POAG. For the single nucleotide polymorphism (SNP)-exposure analyses, we meta-analyzed the study-level genome-wide associations of fasting glucose levels (n = 17,289; n of SNPs = 34), HbA1c (n = 52,802; n of SNPs = 43), and fasting C-peptide levels (n=1666; n of SNPs = 17) from the Japanese Consortium of Genetic Epidemiology studies. We used summary statistics from the BioBank Japan projects (n = 3980 POAG cases and 18,815 controls) for the SNP-outcome association. RESULTS: We observed no association of genetically predicted HbA1c and fasting C-peptide with POAG. The MR inverse-variance-weighted (IVW) odds ratios (ORs) were 1.44 (95% confidence interval [CI], 0.78-2.65; P = .25) for HbA1c (per 1% increment) and 0.92 (95% CI, 0.56-1.53; P = .76) for fasting C-peptide (per 2-fold increment). A significant association between fasting glucose (per 10 mg/dL-increment) and POAG was observed according to the MR IVW analysis (OR = 1.48 [95% CI, 1.10-1.79, P = .009]); however, sensitivity analyses, including MR-Egger and weighted-median methods, did not support this association (P > .10). CONCLUSIONS: We did not observe strong evidence to support the association between genetically predicted glycemic traits and POAG in the Japanese population.
A knowledge representation model for family relationship to three generation Peer-reviewed

Kazuro Shimokawa, Mami Ishikuro, Taku Obara, Hirohito Metoki, Satoshi Mizuno, Satoshi Nagaie, Masato Nagai, Chizuru Yamanaka, Hiroko Matsubara, Mayumi Kato, Yuki Sato, Soichi Ogishima, Takako Takai, Masahiro Kikuya, Atsushi Hozawa, Fuji Nagami, Shinichi Kuriyama, Takashi Suzuki, Kengo Kinoshita, Masayuki Yamamoto, Hiroshi Tanaka

Bioinformation　18　(12)　1166-1172　2022/12/31
Publisher: Biomedical Informatics
DOI： 10.6026/973206300181166 　

ISSN： 0973-8894

eISSN： 0973-2063

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A system for inputting and storing family information, named “BirThree Enrollment,” was developed to promote a birth and three-generation cohort study (BirThree Cohort Study). In this cohort study, it was necessary to satisfy many operational demands while constantly overwriting and changing input information. Complex kinship information must be quickly and accurately inputed and corrected, and information on those families not yet recruited must be retrieved. For these purposes, many devices are needed, from an input interface to the internal data structure. In the field of genetic statistics, a simple standard expressive form (describe father-child relation and mother-child relation) is used for describing family structure. However, this form doesn't have sufficient information. So we developed a new form in conducting the BirThree Cohort Study. Hence, we expanded the data structure, and constructed the Input control system. Family pedigree information is stored along with initial clinical information, and this enabled the input of all self-reported information to the data base. Operators are able to input this family information before the day is out. As a result, when recruitment is completed, family information will be completed concurrently. Therefore, operators can immediately know certain person's family structure. In this model data correction was improved dramatically, and the system was operated successfully. This study is the first report of the method for storing three generations of family data.
Plasma metabolic disturbances during pregnancy and postpartum in women with depression. International-journal

Zhiqian Yu, Naomi Matsukawa, Daisuke Saigusa, Ikuko N Motoike, Chiaki Ono, Yasunobu Okamura, Tomomi Onuma, Yuta Takahashi, Mai Sakai, Hisaaki Kudo, Taku Obara, Keiko Murakami, Matusyuki Shirota, Saya Kikuchi, Natsuko Kobayashi, Yoshie Kikuchi, Junichi Sugawara, Naoko Minegishi, Soichi Ogishima, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Shinichi Kuriyama, Seizo Koshiba, Hiroaki Tomita

iScience　25　(12)　105666-105666　2022/12/22

DOI： 10.1016/j.isci.2022.105666 　

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Examining plasma metabolic profiling during pregnancy and postpartum could help clinicians understand the risk factors for postpartum depression (PPD) development. This analysis targeted paired plasma metabolites in mid-late gestational and 1 month postpartum periods in women with (n = 209) or without (n = 222) PPD. Gas chromatogram-mass spectrometry was used to analyze plasma metabolites at these two time points. Among the 170 objected plasma metabolites, principal component analysis distinguished pregnancy and postpartum metabolites but failed to discriminate women with and without PPD. Compared to women without PPD, those with PPD exhibited 37 metabolites with disparate changes during pregnancy and the 1-month postpartum period and an enriched citrate cycle. Machine learning and multivariate statistical analysis identified two or three compounds that could be potential biomarkers for PPD prediction during pregnancy. Our findings suggest metabolic disturbances in women with depression and may help to elucidate metabolic processes associated with PPD development.
Sex-Specific Differences in the Transcriptome of the Human Dorsolateral Prefrontal Cortex in Schizophrenia. International-journal

Zhiqian Yu, Kazuko Ueno, Ryo Funayama, Mai Sakai, Naoki Nariai, Kaname Kojima, Yoshie Kikuchi, Xue Li, Chiaki Ono, Junpei Kanatani, Jiro Ono, Kazuya Iwamoto, Kenji Hashimoto, Kengo Kinoshita, Keiko Nakayama, Masao Nagasaki, Hiroaki Tomita

Molecular neurobiology　60　(2)　1083-1098　2022/11/22

DOI： 10.1007/s12035-022-03109-6 　

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Schizophrenia presents clinical and biological differences between males and females. This study investigated transcriptional profiles in the dorsolateral prefrontal cortex (DLPFC) using postmortem data from the largest RNA-sequencing (RNA-seq) database on schizophrenic cases and controls. Data for 154 male and 113 female controls and 160 male and 93 female schizophrenic cases were obtained from the CommonMind Consortium. In the RNA-seq database, the principal component analysis showed that sex effects were small in schizophrenia. After we analyzed the impact of sex-specific differences on gene expression, the female group showed more significantly changed genes compared with the male group. Based on the gene ontology analysis, the female sex-specific genes that changed were overrepresented in the mitochondrion, ATP (phosphocreatine and adenosine triphosphate)-, and metal ion-binding relevant biological processes. An ingenuity pathway analysis revealed that the differentially expressed genes related to schizophrenia in the female group were involved in midbrain dopaminergic and γ-aminobutyric acid (GABA)-ergic neurons and microglia. We used methylated DNA-binding domain-sequencing analyses and microarray to investigate the DNA methylation that potentially impacts the sex differences in gene transcription using a maternal immune activation (MIA) murine model. Among the sex-specific positional genes related to schizophrenia in the PFC of female offspring from MIA, the changes in the methylation and transcriptional expression of loci ACSBG1 were validated in the females with schizophrenia in independent postmortem samples by real-time PCR and pyrosequencing. Our results reveal potential genetic risks in the DLPFC for the sex-dependent prevalence and symptomology of schizophrenia.
Functional characterization of 12 dihydropyrimidinase allelic variants in Japanese individuals for the prediction of 5-fluorouracil treatment-related toxicity. International-journal

Eiji Hishinuma, Yoko Narita, Evelyn Marie Gutiérrez Rico, Akiko Ueda, Kai Obuchi, Yoshikazu Tanaka, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Nariyasu Mano, Tomoki Nakayoshi, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka

Drug metabolism and disposition: the biological fate of chemicals　51　(2)　165-173　2022/11/22

DOI： 10.1124/dmd.122.001045 　

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The drug 5-fluorouracil (5-FU) is the first-choice chemotherapeutic agent against advanced-stage cancers. However, 10-30% of treated patients experience grade 3-4 toxicity. The deficiency of dihydropyrimidinase (DHPase), which catalyzes the second step of the 5-FU degradation pathway, is correlated with the risk of developing toxicity. Thus, genetic polymorphisms within DPYS, the DHPase-encoding gene, could potentially serve as predictors of severe 5-FU-related toxicity. We identified 12 novel DPYS variants in 3,554 Japanese individuals, but the effects of these mutations on function remain unknown. In the current study, we performed in vitro enzymatic analyses of the 12 newly identified DHPase variants. Dihydrouracil or dihydro-5-FU hydrolytic ring-opening kinetic parameters, Km and Vmax , and intrinsic clearance (CLint = Vmax /Km ) of the wild-type DHPase and eight variants were measured. Five of these variants (R118Q, H295R, T418I, Y448H, and T513A) showed significantly reduced CLint compared with that in the wild-type. The parameters for the remaining four variants (V59F, D81H, T136M, and R490H) could not be determined as dihydrouracil and dihydro-5-FU hydrolytic ring-opening activity was undetectable. We also determined DHPase variant protein stability using cycloheximide and bortezomib. The mechanism underlying the observed changes in the kinetic parameters was clarified using blue-native polyacrylamide gel electrophoresis and three-dimensional structural modeling. The results suggested that the decrease or loss of DHPase enzymatic activity was due to reduced stability and oligomerization of DHPase variant proteins. Our findings support the use of DPYS polymorphisms as novel pharmacogenomic markers for predicting severe 5-FU-related toxicity in the Japanese population. Significance Statement DHPase contributes to the degradation of 5-fluorouracil, and genetic polymorphisms that cause decreased activity of DHPase can cause severe toxicity. In this study, we performed functional analysis of 12 DHPase variants in the Japanese population and identified 9 genetic polymorphisms that cause reduced DHPase function. In addition, we found that the ability to oligomerize and the conformation of the active site are important for the enzymatic activity of DHPase.
COXPRESdb v8: an animal gene coexpression database navigating from a global view to detailed investigations International-journal

Takeshi Obayashi, Shun Kodate, Himiko Hibara, Yuki Kagaya, Kengo Kinoshita

Nucleic Acids Research　51　(D1)　D80-D87　2022/11/09
Publisher: Oxford University Press (OUP)
DOI： 10.1093/nar/gkac983 　

ISSN： 0305-1048

eISSN： 1362-4962

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Abstract Gene coexpression is synchronization of gene expression across many cellular and environmental conditions and is widely used to infer the biological function of genes. Gene coexpression information is complex, comprising a complete graph of all genes in the genome, and requires appropriate visualization and analysis tools. Since its initial release in 2007, the animal gene expression database COXPRESdb (https://coxpresdb.jp) has been continuously improved by adding new gene coexpression data and analysis tools. Here, we report COXPRESdb version 8, which has been enhanced with new features for an overview, summary, and individual examination of coexpression relationships: CoexMap to display coexpression on a genome scale, pathway enrichment analysis to summarize the function of coexpressed genes, and CoexPub to bridges coexpression and existing knowledge. COXPRESdb also facilitates downstream analyses such as interspecies comparisons by integrating RNAseq and microarray coexpression data in a union-type gene coexpression. COXPRESdb strongly support users with the new coexpression data and enhanced functionality.
遺伝・生活習慣が日本人の血中代謝プロファイルに与える影響の解析

小柴生造, 元池育子, 井上仁, 菱沼英史, 青木裕一, 櫻井美由紀, 佐藤允治, 七谷圭, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　95回　1T17e-02　2022/11
Publisher: (公社)日本生化学会
Multiomics and artificial intelligence enabled peripheral blood-based prediction of amnestic mild cognitive impairment International-journal Peer-reviewed

Yota Tatara, Hiromi Yamazaki, Fumiki Katsuoka, Mitsuru Chiba, Daisuke Saigusa, Shuya Kasai, Tomohiro Nakamura, Jin Inoue, Yuichi Aoki, Miho Shoji, Ikuko Motoike, Yoshinori Tamada, Katsuhito Hashizume, Mikio Shoji, Kengo Kinoshita, Koichi Murashita, Shigeyuki Nakaji, Masayuki Yamamoto, Ken Itoh

Current Research in Translational Medicine　71　(1)　103367-103367　2022/10
Publisher: Elsevier BV
DOI： 10.1016/j.retram.2022.103367 　

ISSN： 2452-3186

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BACKGROUND: Since dementia is preventable with early interventions, biomarkers that assist in diagnosing early stages of dementia, such as mild cognitive impairment (MCI), are urgently needed. METHODS: Multiomics analysis of amnestic MCI (aMCI) peripheral blood (n = 25) was performed covering the transcriptome, microRNA, proteome, and metabolome. Validation analysis for microRNAs was conducted in an independent cohort (n = 12). Artificial intelligence was used to identify the most important features for predicting aMCI. FINDINGS: We found that hsa-miR-4455 is the best biomarker in all omics analyses. The diagnostic index taking a ratio of hsa-miR-4455 to hsa-let-7b-3p predicted aMCI patients against healthy subjects with 97% overall accuracy. An integrated review of multiomics data suggested that a subset of T cells and the GCN (general control nonderepressible) pathway are associated with aMCI. INTERPRETATION: The multiomics approach has enabled aMCI biomarkers with high specificity and illuminated the accompanying changes in peripheral blood. Future large-scale studies are necessary to validate candidate biomarkers for clinical use.
Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals. International-journal

Naomi Shiga, Yumi Yamaguchi-Kabata, Saori Igeta, Jun Yasuda, Shu Tadaka, Takamichi Minato, Zen Watanabe, Junko Kanno, Gen Tamiya, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Akiko Kondo, Masahito Tachibana, Masayuki Yamamoto, Nobuo Yaegashi, Junichi Sugawara

Human genome variation　9　(1)　34-34　2022/09/28

DOI： 10.1038/s41439-022-00213-w 　

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Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.
Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal

Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

Communications biology　5　(1)　991-991　2022/09/20

DOI： 10.1038/s42003-022-03953-1 　

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Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.
Selective Elimination of NRF2-Activated Cells by Competition with Neighboring Cells in the Esophageal Epithelium. International-journal

Wataru Hirose, Makoto Horiuchi, Donghan Li, Ikuko N Motoike, Lin Zhang, Hafumi Nishi, Yusuke Taniyama, Takashi Kamei, Mikiko Suzuki, Kengo Kinoshita, Fumiki Katsuoka, Keiko Taguchi, Masayuki Yamamoto

Cellular and molecular gastroenterology and hepatology　15　(1)　153-178　2022/09/14

DOI： 10.1016/j.jcmgh.2022.09.004 　

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BACKGROUND & AIMS: NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS: We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histological, quantitative reverse-transcription polymerase chain reaction (qRT‒PCR), single-cell RNA-sequencing (RNA-seq) and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS: KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS: Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.
患者由来がんオルガノイドの増殖と粘液分泌の特徴からみたIPMNの浸潤性表現型の立証(Characteristics of growth and mucus secretion of patient-derived organoids may substantiate invasive phenotypes of IPMN)

Shiihara Masahiro, Ishikawa Tomohiko, Yoshida Takuya, Omori Yuko, Hirose Katsuya, Morikawa Takanori, Nakagawa Kei, Mizuma Masamichi, Otsuka Hideo, Motoi Fuyuhiko, Unno Michiaki, Okamura Yasunobu, Kinoshita Kengo, Furukawa Toru

膵臓　37　(3)　A391-A392　2022/09
Publisher: (一社)日本膵臓学会
ISSN： 0913-0071

eISSN： 1881-2805
Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioral phenotype International-journal

Masayoshi Nagai, Kenji Iemura, Takako Kikkawa, Sharmin Naher, Satoko Hattori, Hideo Hagihara, Koh ichi Nagata, Hayato Anzawa, Risa Kugisaki, Hideki Wanibuchi, Takaya Abe, Kenichi Inoue, Kengo Kinoshita, Tsuyoshi Miyakawa, Noriko Osumi, Kozo Tanaka

Brain Communications　4　(5)　fcac220　2022/08/30
Publisher: Oxford University Press (OUP)
DOI： 10.1093/braincomms/fcac220 　

eISSN： 2632-1297

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Abstract CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore–microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1-/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1-/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioral test battery, adult CHAMP1 heterozygous-knockout mice showed mild memory defects, altered social interaction, and depression-like behaviors. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1-/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.
Blood lipids and the risk of colorectal cancer: Mendelian randomization analyses in the Japanese Consortium of Genetic Epidemiology studies. International-journal

Masao Iwagami, Atsushi Goto, Ryoko Katagiri, Yoichi Sutoh, Yuriko N Koyanagi, Masahiro Nakatochi, Shiori Nakano, Akiko Hanyuda, Akira Narita, Atsushi Shimizu, Kozo Tanno, Atsushi Hozawa, Kengo Kinoshita, Isao Oze, Hidemi Ito, Taiki Yamaji, Norie Sawada, Yohko Nakamura, Sho Nakamura, Kiyonori Kuriki, Sadao Suzuki, Asahi Hishida, Yumiko Kasugai, Issei Imoto, Midori Suzuki, Yukihide Momozawa, Kenji Takeuchi, Masayuki Yamamoto, Makoto Sasaki, Keitaro Matsuo, Shoichiro Tsugane, Kenji Wakai, Motoki Iwasaki

Cancer prevention research (Philadelphia, Pa.)　15　(12)　827-836　2022/08/30

DOI： 10.1158/1940-6207.CAPR-22-0146 　

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The associations between blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C), and colorectal cancer risk are controversial. We evaluated potential causal relationships between blood lipids and colorectal cancer risk. Using the baseline data from the Japanese Consortium of Genetic Epidemiology studies, we estimated the single-nucleotide polymorphism (SNP)-exposure associations (n=34,546 for TC, n=50,290 for HDL-C, n=51,307 for triglycerides, and n=30,305 for LDL-C). We also estimated the SNP-outcome associations in another Japanese dataset (n=7,936 colorectal cancer cases and n=38,042 controls). We conducted Mendelian randomization analyses for the association between each blood lipid type and the risk of colorectal cancer using an inverse variance-weighted method. The total variances explained by the selected SNPs in TC (68 SNPs), HDL-C (50 SNPs), log-transformed triglycerides (26 SNPs), and LDL-C (35 SNPs) were 7.0%, 10.0%, 6.2%, and 5.7%, respectively. The odds ratios for colorectal cancer were 1.15 (95% confidence interval 1.01-1.32) per 1 standard deviation (SD) (33.3 mg/dL) increase in TC, 1.11 (0.98-1.26) per 1 SD (15.4 mg/dL) increase in HDL-C, 1.06 (0.90-1.26) per 1 SD (0.5 log-mg/dL) increase in log-transformed triglycerides, and 1.17 (0.91-1.50) per 1 SD (29.6 mg/dL) increase in LDL-C. Sensitivity analyses consistently suggested the positive association between TC and colorectal cancer, whereas results of each lipid component were inconsistent. In conclusion, this large Mendelian randomization study of a Japanese population showed a potentially causal association between high TC and colorectal cancer risk, although the association between each lipid component and colorectal cancer remained inconclusive.
ATTED-II v11: A Plant Gene Coexpression Database Using a Sample Balancing Technique by Subagging of Principal Components.

Takeshi Obayashi, Himiko Hibara, Yuki Kagaya, Yuichi Aoki, Kengo Kinoshita

Plant & cell physiology　63　(6)　869-881　2022/06/15

DOI： 10.1093/pcp/pcac041 　

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ATTED-II (https://atted.jp) is a gene coexpression database for nine plant species based on publicly available RNAseq and microarray data. One of the challenges in constructing condition-independent coexpression data based on publicly available gene expression data is managing the inherent sampling bias. Here, we report ATTED-II version 11, wherein we adopted a coexpression calculation methodology to balance the samples using principal component analysis and ensemble calculation. This approach has two advantages. First, omitting principal components with low contribution rates reduces the main contributors of noise. Second, balancing large differences in contribution rates enables considering various sample conditions entirely. In addition, based on RNAseq- and microarray-based coexpression data, we provide species-representative, integrated coexpression information to enhance the efficiency of interspecies comparison of the coexpression data. These coexpression data are provided as a standardized z-score to facilitate integrated analysis with different data sources. We believe that with these improvements, ATTED-II is more valuable and powerful for supporting interspecies comparative studies and integrated analyses using heterogeneous data.
High levels of chromosomal instability facilitate the tumor growth and sphere formation. International-journal

Kenji Iemura, Hayato Anzawa, Ryo Funayama, Runa Iwakami, Keiko Nakayama, Kengo Kinoshita, Kozo Tanaka

Cancer science　113　(8)　2727-2737　2022/06/05

DOI： 10.1111/cas.15457 　

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Most cancer cells show chromosomal instability (CIN), a condition in which chromosome missegregation occurs at high rates. Growing evidence suggests that CIN is not just a consequence, but a driving force for oncogenic transformation, although the relationship between CIN and tumorigenesis has not been fully elucidated. Here we found that conventional two-dimensional (2D) culture of HeLa cells, a cervical cancer-derived cell line, is a heterogenous population containing cells with different CIN levels. Although cells with high CIN levels (high-CIN cells) grew slower than cells with low CIN levels (low-CIN cells) in 2D monolayer culture, they formed tumors in nude mice and larger spheres in three-dimensional (3D) culture, which is more representative of the in vivo environment. The duration of mitosis was longer in high-CIN cells, implicating their higher mitotic defects. Single cell genome sequencing revealed that high-CIN cells exhibit a higher karyotype heterogeneity compared with low-CIN cells. Intriguingly, the karyotype heterogeneity was reduced in the spheres formed by high-CIN cells, suggesting that cells with growth advantages were selected, although genomic copy number changes specific for spheres were not identified. When we examined gene expression profiles, genes related to K-ras signaling were upregulated, while those related to unfolded protein response were downregulated in high-CIN cells in 3D culture compared with 2D culture, suggesting the relevance of these genes for their survival. Our data suggest that although CIN is disadvantageous in monolayer culture, it promotes the selection of cells with growth advantages under in vivo environments, which may lead to tumorigenesis.
CEBPB is required for NRF2-mediated drug resistance in NRF2-activated non-small cell lung cancer cells International-journal

Keito Okazaki, Hayato Anzawa, Fumiki Katsuoka, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

The Journal of Biochemistry　171　(5)　567-578　2022/05/11
Publisher: Oxford University Press (OUP)
DOI： 10.1093/jb/mvac013 　

ISSN： 0021-924X

eISSN： 1756-2651

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Abstract NRF2 is a transcription activator that plays a key role in cytoprotection against oxidative stress. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental, as it drives their malignant progression. We previously found that CCAAT/enhancer-binding protein B (CEBPB) cooperates with NRF2 in NRF2-activated lung cancer and enhances tumour-initiating activity by promoting NOTCH3 expression. However, the general contribution of CEBPB in lung cancer is rather controversial, probably because the role of CEBPB depends on cooperating transcription factors in each cellular context. To understand how NRF2 shapes the function of CEBPB in NRF2-activated lung cancers and its biological consequence, we comprehensively explored NRF2-CEBPB–coregulated genes and found that genes involved in drug metabolism and detoxification were characteristically enriched. Indeed, CEBPB and NRF2 cooperatively contribute to the drug resistance. We also found that CEBPB is directly regulated by NRF2, which is likely to be advantageous for the coexpression and cooperative function of NRF2 and CEBPB. These results suggest that drug resistance of NRF2-activated lung cancers is achieved by the cooperative function of NRF2 and CEBPB.
A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants.

Kinuko Ohneda, Masahiro Hiratsuka, Hiroshi Kawame, Fuji Nagami, Yoichi Suzuki, Kichiya Suzuki, Akira Uruno, Mika Sakurai-Yageta, Yohei Hamanaka, Makiko Taira, Soichi Ogishima, Shinichi Kuriyama, Atsushi Hozawa, Hiroaki Tomita, Naoko Minegishi, Junichi Sugawara, Inaho Danjoh, Tomohiro Nakamura, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Shu Tadaka, Taku Obara, Eiji Hishimuma, Nariyasu Mano, Masaki Matsuura, Yuji Sato, Masateru Nakasone, Yohei Honkura, Jun Suzuki, Yukio Katori, Yoichi Kakuta, Atsushi Masamune, Yoko Aoki, Masaharu Nakayama, Shigeo Kure, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto

JMA journal　5　(2)　177-189　2022/04/15

DOI： 10.31662/jmaj.2021-0156 　

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Introduction: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. Methods: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. Results: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. Conclusions: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.
Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan International-journal

Nobuo Fuse, Miyuki Sakurai, Ikuko N. Motoike, Kaname Kojima, Takako Takai-Igarashi, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Akiko Miyazawa, Kei Homma, Keisuke Ido, Makiko Taira, Tomoko Kobayashi, Ritsuko Shimizu, Akira Uruno, Eiichi N. Kodama, Kichiya Suzuki, Yohei Hamanaka, Hiroaki Tomita, Junichi Sugawara, Yoichi Suzuki, Fuji Nagami, Soichi Ogishima, Fumiki Katsuoka, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Yaegashi, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto

Ophthalmology Science　2　(1)　100113-100113　2022/03
Publisher: Elsevier BV
DOI： 10.1016/j.xops.2022.100113 　

ISSN： 2666-9145

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PURPOSE: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data. DESIGN: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs). PARTICIPANTS: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined. METHODS: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis. MAIN OUTCOME MEASURES: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages. RESULTS: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci. CONCLUSIONS: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.
Current status and future perspectives of the evaluation of missense variants by using three-dimensional structures of proteins.

Matsuyuki Shirota, Kengo Kinoshita

Biophysics and physicobiology　19　e190023　2022

DOI： 10.2142/biophysico.bppb-v19.0023 　
メンデルのランダム化法による血中脂質と大腸がんの関係の検討

岩上将夫, 後藤温, 鈴木詩織, 片桐諒子, 羽入田明子, 山地太樹, 澤田典絵, 中杤昌弘, 若井建志, 須藤洋一, 清水厚志, 丹野高三, 木下賢吾, 寳澤篤, 伊藤秀美, 松尾恵太郎, 岩崎基, J-CGEグループ

Journal of Epidemiology　32　(Suppl.1)　155-155　2022/01
Publisher: (一社)日本疫学会
ISSN： 0917-5040

eISSN： 1349-9092
メンデルのランダム化法による糖代謝指標と大腸がんの関連解析

羽入田明子, 後藤温, 鈴木詩織, 片桐諒子, 岩上将夫, 山地太樹, 澤田典絵, 中杤昌弘, 若井建志, 須藤洋一, 清水厚志, 丹野高三, 木下賢吾, 寳澤篤, 伊藤秀美, 松尾恵太郎, 岩崎基

Journal of Epidemiology　32　(Suppl.1)　155-155　2022/01
Publisher: (一社)日本疫学会
ISSN： 0917-5040

eISSN： 1349-9092
Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population. International-journal

Eiji Hishinuma, Yoko Narita, Kai Obuchi, Akiko Ueda, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka

Frontiers in pharmacology　13　930470-930470　2022

DOI： 10.3389/fphar.2022.930470 　

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Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. In Caucasians, four DPYD risk variants are recognized to be responsible for interindividual variations in the development of 5-FU toxicity. However, these risk variants have not been identified in Asian populations. Recently, 41 DPYD allelic variants, including 15 novel single nucleotide variants, were identified in 3,554 Japanese individuals by analyzing their whole-genome sequences; however, the effects of these variants on DPD enzymatic activity remain unknown. In the present study, an in vitro analysis was performed on 41 DPD allelic variants and three DPD risk variants to elucidate the changes in enzymatic activity. Wild-type and 44 DPD-variant proteins were heterologously expressed in 293FT cells. DPD expression levels and dimerization of DPD were determined by immunoblotting after SDS-PAGE and blue native PAGE, respectively. The enzymatic activity of DPD was evaluated by quantification of dihydro-5-FU, a metabolite of 5-FU, using high-performance liquid chromatography-tandem mass spectrometry. Moreover, we used 3D simulation modeling to analyze the effect of amino acid substitutions on the conformation of DPD. Among the 41 DPD variants, seven exhibited drastically decreased intrinsic clearance (CL int ) compared to the wild-type protein. Moreover, R353C and G926V exhibited no enzymatic activity, and the band patterns observed in the immunoblots after blue native PAGE indicated that DPD dimerization is required for its enzymatic activity. Our data suggest that these variants may contribute to the significant inter-individual variability observed in the pharmacokinetics and pharmacodynamics of 5-FU. In our study, nine DPD variants exhibited drastically decreased or no enzymatic activity due to dimerization inhibition or conformational changes in each domain. Especially, the rare DPYD variants, although at very low frequencies, may serve as important pharmacogenomic markers associated with the severe 5-FU toxicity in Japanese population.
Public access to summary statistics for genome-wide association studies of body mass index, weight, and height among healthy Japanese individuals: the Japanese Consortium of Genetic Epidemiology studies.

Atsushi Goto, Shiori Suzuki, Ryoko Katagiri, Taiki Yamaji, Norie Sawada, Masahiro Nakatochi, Kenji Wakai, Atsushi Hozawa, Kengo Kinoshita, Kozo Tanno, Atsushi Shimizu, Hidemi Ito, Keitaro Matsuo, Motoki Iwasaki

Journal of epidemiology　32　(2)　115-116　2021/12/11

DOI： 10.2188/jea.JE20210459 　
dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project. International-journal

Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Akito Tsuboi, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Mika Sakurai, Satoshi Makino, Gen Tamiya, Yuichi Aoki, Ritsuko Shimizu, Ikuko N Motoike, Seizo Koshiba, Naoko Minegishi, Kazuki Kumada, Takahiro Nobukuni, Kichiya Suzuki, Inaho Danjoh, Fuji Nagami, Kozo Tanno, Hideki Ohmomo, Koichi Asahi, Atsushi Shimizu, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Teiji Tominaga, Shigeo Kure, Nobuo Yaegashi, Kengo Kinoshita, Makoto Sasaki, Hiroshi Tanaka, Masayuki Yamamoto

Human genome variation　8　(1)　44-44　2021/12/10

DOI： 10.1038/s41439-021-00175-5 　

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To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.
Publisher Correction: Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers (Nature Communications, (2020), 11, 1, (5911), 10.1038/s41467-020-19593-0)

Keito Okazaki, Hayato Anzawa, Zun Liu, Nao Ota, Hiroshi Kitamura, Yoshiaki Onodera, Md Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Shu Tadaka, Ikuko Motoike, Mika Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

Nature Communications　12　(1)　2021/12/01

DOI： 10.1038/s41467-021-20927-9 　

eISSN： 2041-1723
Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator. International-journal

Mitsuhiro Yamada, Ikuko N Motoike, Kaname Kojima, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Fumiki Katsuoka, Shu Tadaka, Matsuyuki Shirota, Miyuki Sakurai, Tomohiro Nakamura, Yohei Hamanaka, Kichiya Suzuki, Junichi Sugawara, Soichi Ogishima, Akira Uruno, Eiichi N Kodama, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Ayumi Mitsune, Takashi Ohe, Kengo Kinoshita, Masakazu Ichinose, Hisatoshi Sugiura, Masayuki Yamamoto

Communications biology　4　(1)　1288-1288　2021/11/15

DOI： 10.1038/s42003-021-02813-8 　

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Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.
多層オミックスと機械学習による軽度認知障害の予測モデルの構築

多田羅洋太, 中村智洋, 千葉満, 三枝大輔, 山嵜博未, 勝岡史城, 葛西秋宅, 川瀬倫子, 本間リナ, 松田りら, 藤本哲太, 荘司美穂, 元池育子, 玉田嘉紀, 橋爪克仁, 東海林幹夫, 木下賢吾, 伊東健

Dementia Japan　35　(4)　660-660　2021/10
Publisher: (一社)日本認知症学会
ISSN： 1342-646X
Comparison of Kit-Based Metabolomics with Other Methodologies in a Large Cohort, towards Establishing Reference Values

Daisuke Saigusa, Eiji Hishinuma, Naomi Matsukawa, Masatomo Takahashi, Jin Inoue, Shu Tadaka, Ikuko N. Motoike, Atsushi Hozawa, Yoshihiro Izumi, Takeshi Bamba, Kengo Kinoshita, Kim Ekroos, Seizo Koshiba, Masayuki Yamamoto

Metabolites　11　(10)　652-652　2021/09/24
Publisher: MDPI AG
DOI： 10.3390/metabo11100652 　

eISSN： 2218-1989

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Metabolic profiling is an omics approach that can be used to observe phenotypic changes, making it particularly attractive for biomarker discovery. Although several candidate metabolites biomarkers for disease expression have been identified in recent clinical studies, the reference values of healthy subjects have not been established. In particular, the accuracy of concentrations measured by mass spectrometry (MS) is unclear. Therefore, comprehensive metabolic profiling in large-scale cohorts by MS to create a database with reference ranges is essential for evaluating the quality of the discovered biomarkers. In this study, we tested 8700 plasma samples by commercial kit-based metabolomics and separated them into two groups of 6159 and 2541 analyses based on the different ultra-high-performance tandem mass spectrometry (UHPLC-MS/MS) systems. We evaluated the quality of the quantified values of the detected metabolites from the reference materials in the group of 2541 compared with the quantified values from other platforms, such as nuclear magnetic resonance (NMR), supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) and UHPLC-Fourier transform mass spectrometry (FTMS). The values of the amino acids were highly correlated with the NMR results, and lipid species such as phosphatidylcholines and ceramides showed good correlation, while the values of triglycerides and cholesterol esters correlated less to the lipidomics analyses performed using SFC-MS/MS and UHPLC-FTMS. The evaluation of the quantified values by MS-based techniques is essential for metabolic profiling in a large-scale cohort.
Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation

Masaki Kumondai, Evelyn Gutiérrez Rico, Eiji Hishinuma, Yuya Nakanishi, Shuki Yamazaki, Akiko Ueda, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Daisuke Saigusa, Tomoki Nakayoshi, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka

Journal of Personalized Medicine　11　(8)　690-690　2021/07/22
Publisher: MDPI AG
DOI： 10.3390/jpm11080690 　

eISSN： 2075-4426

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Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin O-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants.
The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project. International-journal

Hiroshi Kawame, Akimune Fukushima, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Mika Sakurai-Yageta, Jun Yasuda, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Soichi Ogishima, Takako Takai, Shinichi Kuriyama, Atsushi Hozawa, Naoki Nakaya, Tomohiro Nakamura, Naoko Minegishi, Junichi Sugawara, Kichiya Suzuki, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Yayoi Aizawa, Tomoharu Tokutomi, Kayono Yamamoto, Kinuko Ohneda, Shigeo Kure, Yoko Aoki, Hideki Katagiri, Yasushi Ishigaki, Shojiro Sawada, Makoto Sasaki, Masayuki Yamamoto

Journal of human genetics　67　(1)　9-17　2021/07/08

DOI： 10.1038/s10038-021-00952-8 　

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Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.
Wide-Targeted Metabolome Analysis Identifies Potential Biomarkers for Prognosis Prediction of Epithelial Ovarian Cancer. International-journal

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Daisuke Saigusa, Bin Li, Kei Kudo, Keita Tsuji, Shogo Shigeta, Hideki Tokunaga, Kazuki Kumada, Keigo Komine, Hidekazu Shirota, Yuichi Aoki, Ikuko N Motoike, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto, Seizo Koshiba, Nobuo Yaegashi

Toxins　13　(7)　2021/06/30

DOI： 10.3390/toxins13070461 　

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Epithelial ovarian cancer (EOC) is a fatal gynecologic cancer, and its poor prognosis is mainly due to delayed diagnosis. Therefore, biomarker identification and prognosis prediction are crucial in EOC. Altered cell metabolism is a characteristic feature of cancers, and metabolomics reflects an individual's current phenotype. In particular, plasma metabolome analyses can be useful for biomarker identification. In this study, we analyzed 624 metabolites, including uremic toxins (UTx) in plasma derived from 80 patients with EOC using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Compared with the healthy control, we detected 77 significantly increased metabolites and 114 significantly decreased metabolites in EOC patients. Especially, decreased concentrations of lysophosphatidylcholines and phosphatidylcholines and increased concentrations of triglycerides were observed, indicating a metabolic profile characteristic of EOC patients. After calculating the parameters of each metabolic index, we found that higher ratios of kynurenine to tryptophan correlates with worse prognosis in EOC patients. Kynurenine, one of the UTx, can affect the prognosis of EOC. Our results demonstrated that plasma metabolome analysis is useful not only for the diagnosis of EOC, but also for predicting prognosis with the variation of UTx and evaluating response to chemotherapy.
Whole exome sequencing and establishment of an organoid culture of the carcinoma showing thymus-like differentiation (CASTLE) of the parotid gland. International-journal

Tomohiko Ishikawa, Takenori Ogawa, Ayako Nakanome, Yasunari Yamauchi, Hajime Usubuchi, Masahiro Shiihara, Takuya Yoshida, Yasunobu Okamura, Kengo Kinoshita, Yukio Katori, Toru Furukawa

Virchows Archiv : an international journal of pathology　478　(6)　1149-1159　2021/06

DOI： 10.1007/s00428-020-02981-8 　

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Carcinoma showing thymus-like differentiation (CASTLE) is a rare tumor, especially in the parotid gland. We encountered a CASTLE of the parotid gland and analyzed its clinicopathological features, as well as the genotype using whole exome sequencing (WES). Moreover, we successfully established an organoid culture cell line from the primary tumor tissue. The patient was a 23-year-old woman who underwent superficial parotidectomy with peripheral neck dissection, followed by radiotherapy. Pathologically, the resected specimen showed atypical epithelioid nests and trabeculae with squamous differentiation, separated by thick fibrous septa, accompanied by dense lymphocytes and plasma cell infiltration. Immunohistochemistry revealed that the tumor cells were positive for AE1/AE3, p40, p63, p16, CK5/6, and CD5, and the background lymphocytes were positive for CD5 and CD99. Based on these findings, the tumor was diagnosed as CASTLE. WES uncovered five nonsynonymous and splicing somatic mutations, namely, FREM2 p.Val861Phe, CLK3 p.Phe376Leu, DLGAP1 p.Lys294Asn, NOX1 p.Val165Met, and PSG9 c.430 + 4A > T. Organoid culture cells preserved the histopathological characteristics of the epithelioid component of CASTLE and harbored all five somatic mutations detected in the primary tumor. In conclusion, for the first time to the best of our knowledge, we successfully analyzed a comprehensive genotype and established an organoid culture cell line of a parotid gland CASTLE, which should serve for analyzing the nature of this rare tumor.
Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs. International-journal

Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

Journal of biochemistry　170　(3)　399-410　2021/05/13

DOI： 10.1093/jb/mvab060 　

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Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin >2.5-5% were >0.9 and >0.8, respectively, and >12 million markers were imputed with an INFO score >0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.
Subjective sleep quality, quantitative sleep features, and their associations dependent on demographic characteristics, habitual sleep–wake patterns, and distinction of weekdays/weekends

Siwalee Choilek, Akihiro Karashima, Ikuko Motoike, Norihiro Katayama, Kengo Kinoshita, Mitsuyuki Nakao

Sleep and Biological Rhythms　19　(4)　369-381　2021/05/09
Publisher: Springer Science and Business Media LLC
DOI： 10.1007/s41105-021-00326-9 　

ISSN： 1446-9235

eISSN： 1479-8425
Development of a system combining comprehensive genotyping and organoid cultures for identifying and testing genotype-oriented personalised medicine for pancreatobiliary cancers. International-journal

Masahiro Shiihara, Tomohiko Ishikawa, Yuriko Saiki, Yuko Omori, Katsuya Hirose, Shinichi Fukushige, Naoki Ikari, Ryota Higuchi, Masakazu Yamamoto, Takanori Morikawa, Kei Nakagawa, Hiroki Hayashi, Masamichi Mizuma, Hideo Ohtsuka, Fuyuhiko Motoi, Michiaki Unno, Yasunobu Okamura, Kengo Kinoshita, Toru Furukawa

European journal of cancer (Oxford, England : 1990)　148　239-250　2021/05

DOI： 10.1016/j.ejca.2021.01.047 　

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BACKGROUND: Pancreatobiliary cancer is a highly aggressive tumour with a dismal prognosis. Personalised medicine represents a promising and effective therapeutic approach for this intractable disease. In this study, we aimed to establish a system for identifying and testing genotype-oriented targeted drugs for pancreatobiliary cancers by combining exome sequencing and organoid culture of primary tumours. METHODS: Tumour cells isolated from resected tumours were subjected to organoid cultures based on published protocols with modifications. Exome sequencing was performed on the primary tumours. Histopathological and molecular features of the primary tumours were validated in the corresponding organoids. Genotype-oriented candidate targeted drugs were identified from exome sequencing, and their efficacies were tested in the organoids. RESULTS: Organoid cultures succeeded in 30 of 54 (55.6%) cases. Six primary cancers of the biliary tract and gall bladder were subjected to exome sequencing, which revealed a variety of somatic mutations of genes involved in signalling pathways, epigenetic modifiers, genome maintenance and metabolic enzymes. Most of the organoids of these 6 cases showed identical histopathological features and genomic aberrations as those of the primary tumours. Some of the aberrations were candidates for targeted therapies. Integrin-linked kinase (ILK) was one such candidate target, and an ILK inhibitor was confirmed to suppress proliferation of patient-derived organoids. CONCLUSIONS: By combining exome sequencing and organoid culture, our model enabled to identify genotype-oriented targets for personalised medicine and to test efficacies of candidate targeted drugs in the organoids. The current proof-of-concept approach could increase therapeutic opportunities for patients with pancreatobiliary cancers.
GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals. International-journal

Kosuke Shido, Kaname Kojima, Matsuyuki Shirota, Kenshi Yamasaki, Ikuko N Motoike, Atsushi Hozawa, Soichi Ogishima, Naoko Minegishi, Kozo Tanno, Fumiki Katsuoka, Gen Tamiya, Setsuya Aiba, Masayuki Yamamoto, Kengo Kinoshita

The Journal of investigative dermatology　141　(11)　2749-2752　2021/04/14

DOI： 10.1016/j.jid.2021.02.762 　
Body mass index and colorectal cancer risk: A Mendelian randomization study. International-journal

Shiori Suzuki, Atsushi Goto, Masahiro Nakatochi, Akira Narita, Taiki Yamaji, Norie Sawada, Ryoko Katagiri, Masao Iwagami, Akiko Hanyuda, Tsuyoshi Hachiya, Yoichi Sutoh, Isao Oze, Yuriko N Koyanagi, Yumiko Kasugai, Yukari Taniyama, Hidemi Ito, Hiroaki Ikezaki, Yuichiro Nishida, Takashi Tamura, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Etsuko Ozaki, Kiyonori Kuriki, Naoyuki Takashima, Kokichi Arisawa, Kenji Takeuchi, Kozo Tanno, Atsushi Shimizu, Gen Tamiya, Atsushi Hozawa, Kengo Kinoshita, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Keitaro Matsuo, Shoichiro Tsugane, Motoki Iwasaki

Cancer science　112　(4)　1579-1588　2021/04

DOI： 10.1111/cas.14824 　

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Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.
Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer's disease risk. International-journal

Daichi Shigemizu, Risa Mitsumori, Shintaro Akiyama, Akinori Miyashita, Takashi Morizono, Sayuri Higaki, Yuya Asanomi, Norikazu Hara, Gen Tamiya, Kengo Kinoshita, Takeshi Ikeuchi, Shumpei Niida, Kouichi Ozaki

Translational psychiatry　11　(1)　151-151　2021/03/03

DOI： 10.1038/s41398-021-01272-3 　

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Alzheimer's disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case-control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer's Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.
Functional Characterization of 40 CYP3A4 Variants by Assessing Midazolam 1'-Hydroxylation and Testosterone 6β-Hydroxylation. International-journal

Masaki Kumondai, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Daisuke Saigusa, Shu Tadaka, Kengo Kinoshita, Tomoki Nakayoshi, Akifumi Oda, Ai Abe, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka

Drug metabolism and disposition: the biological fate of chemicals　49　(3)　212-220　2021/03

DOI： 10.1124/dmd.120.000261 　

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CYP3A4 is among the most abundant liver and intestinal drug-metabolizing cytochrome P450 enzymes, contributing to the metabolism of more than 30% of clinically used drugs. Therefore, interindividual variability in CYP3A4 activity is a frequent cause of reduced drug efficacy and adverse effects. In this study, we characterized wild-type CYP3A4 and 40 CYP3A4 variants, including 11 new variants, detected among 4773 Japanese individuals by assessing CYP3A4 enzymatic activities for two representative substrates (midazolam and testosterone). The reduced carbon monoxide-difference spectra of wild-type CYP3A4 and 31 CYP3A4 variants produced with our established mammalian cell expression system were determined by measuring the increase in maximum absorption at 450 nm after carbon monoxide treatment. The kinetic parameters of midazolam and testosterone hydroxylation by wild-type CYP3A4 and 29 CYP3A4 variants (K m , k cat , and catalytic efficiency) were determined, and the causes of their kinetic differences were evaluated by three-dimensional structural modeling. Our findings offer insight into the mechanism underlying interindividual differences in CYP3A4-dependent drug metabolism. Moreover, our results provide guidance for improving drug administration protocols by considering the information on CYP3A4 genetic polymorphisms. SIGNIFICANCE STATEMENT: CYP3A4 metabolizes more than 30% of clinically used drugs. Interindividual differences in drug efficacy and adverse-effect rates have been linked to ethnicity-specific differences in CYP3A4 gene variants in Asian populations, including Japanese individuals, indicating the presence of CYP3A4 polymorphisms resulting in the increased expression of loss-of-function variants. This study detected alterations in CYP3A4 activity due to amino acid substitutions by assessing the enzymatic activities of coding variants for two representative CYP3A4 substrates.
Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation. International-journal

Satoshi Omori, Misato Tsugita, Yasuto Hoshikawa, Masanobu Morita, Fumiya Ito, Shin-Ichiro Yamaguchi, Qilin Xie, Osamu Noyori, Tomoya Yamaguchi, Ayato Takada, Tatsuya Saitoh, Shinya Toyokuni, Hisaya Akiba, Shigekazu Nagata, Kengo Kinoshita, Masafumi Nakayama

Cell reports　34　(6)　108734-108734　2021/02/09

DOI： 10.1016/j.celrep.2021.108734 　

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Macrophage recognition and phagocytosis of crystals is critical for the associated fibrosis and cancer. Of note, multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage NLRP3 inflammasome activation and cause asbestosis-like pathogenesis. However, it remains largely unknown how macrophages efficiently recognize MWCNTs on their cell surfaces. Here, we identify by a targeted screening of phagocyte receptors the phosphatidylserine receptors T cell immunoglobulin mucin 4 (Tim4) and Tim1 as the pattern-recognition receptors for carbon crystals. Docking simulation studies reveal spatiotemporally stable interfaces between aromatic residues in the extracellular IgV domain of Tim4 and one-dimensional carbon crystals. Further, CRISPR-Cas9-mediated deletion of Tim4 and Tim1 reveals that Tim4, but not Tim1, critically contributes to the recognition of MWCNTs by peritoneal macrophages and to granuloma development in a mouse model of direct mesothelium exposure to MWCNTs. These results suggest that Tim4 recognizes MWCNTs through aromatic interactions and mediates phagocytosis leading to granulomas.
Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals. International-journal

Masaki Kumondai, Akio Ito, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Tomoki Nakayoshi, Akifumi Oda, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka

Journal of personalized medicine　11　(2)　2021/02/02

DOI： 10.3390/jpm11020094 　

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Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype-phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.
Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis. International-journal

Akihito Otsuki, Yasunobu Okamura, Yuichi Aoki, Noriko Ishida, Kazuki Kumada, Naoko Minegishi, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

Molecular and cellular biology　41　(2)　2021/01/25

DOI： 10.1128/MCB.00472-20 　

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Our body responds to environmental stress by changing the expression levels of a series of cytoprotective enzymes/proteins through multilayered regulatory mechanisms, including the KEAP1-NRF2 system. While NRF2 upregulates the expression of many cytoprotective genes, there are fundamental limitations in short-read RNA sequencing (RNA-Seq), resulting in confusion regarding interpreting the effectiveness of cytoprotective gene induction at the transcript level. To precisely delineate isoform usage in the stress response, we conducted independent full-length transcriptome profiling (isoform sequencing; Iso-Seq) analyses of lymphoblastoid cells from three volunteers under normal and electrophilic stress-induced conditions. We first determined the first exon usage in KEAP1 and NFE2L2 (encoding NRF2) and found the presence of transcript diversity. We then examined changes in isoform usage of NRF2 target genes under stress conditions and identified a few isoforms dominantly expressed in the majority of NRF2 target genes. The expression levels of isoforms determined by Iso-Seq analyses showed striking differences from those determined by short-read RNA-Seq; the latter could be misleading concerning the abundance of transcripts. These results support that transcript usage is tightly regulated to produce functional proteins under electrophilic stress. Our present study strongly argues that there are important benefits that can be achieved by long-read transcriptome sequencing.
A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. International-journal

Hirofumi Zempo, Su-Jeong Kim, Noriyuki Fuku, Yuichiro Nishida, Yasuki Higaki, Junxiang Wan, Kelvin Yen, Brendan Miller, Roberto Vicinanza, Eri Miyamoto-Mikami, Hiroshi Kumagai, Hisashi Naito, Jialin Xiao, Hemal H Mehta, Changhan Lee, Megumi Hara, Yesha M Patel, Veronica W Setiawan, Timothy M Moore, Andrea L Hevener, Yoichi Sutoh, Atsushi Shimizu, Kaname Kojima, Kengo Kinoshita, Yasumichi Arai, Nobuyoshi Hirose, Seiji Maeda, Keitaro Tanaka, Pinchas Cohen

Aging　13　(2)　1692-1717　2021/01/19

DOI： 10.18632/aging.202529 　

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Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.
Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals. International-journal

Shinichi Nagaoka, Yumi Yamaguchi-Kabata, Naomi Shiga, Masahito Tachibana, Jun Yasuda, Shu Tadaka, Gen Tamiya, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Jun Murotsuki, Masayuki Yamamoto, Nobuo Yaegashi, Junichi Sugawara

Human genome variation　8　(1)　2-2　2021/01/15

DOI： 10.1038/s41439-020-00133-7 　

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Bone dysplasias are a group of rare hereditary diseases, with up to 436 disease types. Perinatal diagnosis is clinically important for adequate personalized management and counseling. There are no reports focused on pathogenic variants of bone dysplasias in the general population. In this study, we focused on autosomal recessive bone dysplasias. We identified pathogenic variants using whole-genome reference panel data from 3552 Japanese individuals. For the first time, we were able to estimate the carrier frequencies and the proportions of potential patients. For autosomal recessive bone dysplasias, we detected 198 pathogenic variants of 54 causative genes. We estimated the variant carrier frequencies and the proportions of potential patients with variants associated with four clinically important bone dysplasias: osteogenesis imperfecta (OI), hypophosphatasia (HPP), asphyxiating thoracic dysplasia (ATD), and Ellis-van Creveld syndrome (EvC). The proportions of potential patients with OI, ATD, and EvC based on pathogenic variants classified as "pathogenic" and "likely pathogenic" by InterVar were closer to the reported incidence rates in Japanese subjects. Furthermore, the proportions of potential patients with HPP variants classified as "pathogenic" and "likely pathogenic" in InterVar and "pathogenic" in ClinVar were closer to the reported incidence rates. For bone dysplasia, the findings of this study will provide a better understanding of the variant types and frequencies in the Japanese general population, and should be useful for clinical diagnosis, genetic counseling, and personalized medicine.
Facial UV photo imaging for skin pigmentation assessment using conditional generative adversarial networks. International-journal

Kaname Kojima, Kosuke Shido, Gen Tamiya, Kenshi Yamasaki, Kengo Kinoshita, Setsuya Aiba

Scientific reports　11　(1)　1213-1213　2021/01/13

DOI： 10.1038/s41598-020-79995-4 　

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Skin pigmentation is associated with skin damages and skin cancers, and ultraviolet (UV) photography is used as a minimally invasive mean for the assessment of pigmentation. Since UV photography equipment is not usually available in general practice, technologies emphasizing pigmentation in color photo images are desired for daily care. We propose a new method using conditional generative adversarial networks, named UV-photo Net, to generate synthetic UV images from color photo images. Evaluations using color and UV photo image pairs taken by a UV photography system demonstrated that pigment spots were well reproduced in synthetic UV images by UV-photo Net, and some of the reproduced pigment spots were difficult to be recognized in color photo images. In the pigment spot detection analysis, the rate of pigment spot areas in cheek regions for synthetic UV images was highly correlated with the rate for UV photo images (Pearson's correlation coefficient 0.92). We also demonstrated that UV-photo Net was effective for floating up pigment spots for photo images taken by a smartphone camera. UV-photo Net enables an easy assessment of pigmentation from color photo images and will promote self-care of skin damages and early signs of skin cancers for preventive medicine.
Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference. International-journal Peer-reviewed

Jun Takayama, Shu Tadaka, Kenji Yano, Fumiki Katsuoka, Chinatsu Gocho, Takamitsu Funayama, Satoshi Makino, Yasunobu Okamura, Atsuo Kikuchi, Sachiyo Sugimoto, Junko Kawashima, Akihito Otsuki, Mika Sakurai-Yageta, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto, Gen Tamiya

Nature communications　12　(1)　226-226　2021/01/11
Publisher: Cold Spring Harbor Laboratory
DOI： 10.1038/s41467-020-20146-8 　

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The complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using > 100× Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the Japanese major allele at most loci. We adopt JG1 as the reference for confirmatory exome re-analyses of seven rare-disease Japanese families and find that re-analysis using JG1 reduces total candidate variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genomes from a single population can aid genome analyses of that population.
jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. International-journal

Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　49　(D1)　D536-D544-544　2021/01/08

DOI： 10.1093/nar/gkaa1034 　

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In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.
Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2). International-journal

Hideki Tokunaga, Keita Iida, Atsushi Hozawa, Soichi Ogishima, Yoh Watanabe, Shogo Shigeta, Muneaki Shimada, Yumi Yamaguchi-Kabata, Shu Tadaka, Fumiki Katsuoka, Shin Ito, Kazuki Kumada, Yohei Hamanaka, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

PloS one　16　(1)　e0236907　2021

DOI： 10.1371/journal.pone.0236907 　

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Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.
Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia.

Yasuo Uchida, Tomoya Higuchi, Matsuyuki Shirota, Satoshi Kagami, Daisuke Saigusa, Seizo Koshiba, Jun Yasuda, Gen Tamiya, Shinichi Kuriyama, Kengo Kinoshita, Nobuo Yaegashi, Masayuki Yamamoto, Tetsuya Terasaki, Junichi Sugawara

Biological & pharmaceutical bulletin　44　(6)　804-815　2021

DOI： 10.1248/bpb.b20-01043 　

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The purpose of the present study was to identify a plasma protein biomarker able to predict pre-eclampsia (PE). Comprehensive quantitative proteomics using mass spectrometry with sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) was applied to plasma samples of 7 PE and 14 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE), and 11 proteins were selected as candidates potentially able to differentiate the two groups. Plasmas collected at gestational weeks 14-24 from 36 PE and 120 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE) were used to conduct selected reaction monitoring quantification analysis, optimize protein combinations and conduct internal validation, which consisted of 30 iterations of 10-fold cross-validation using multivariate logistic regression and receiver operating characteristic (ROC) analysis. The combination of afamin, fibronectin, and sex-hormone-binding globulin was selected as the best candidate. The 3-protein combination predictive model (predictive equation and cut-off value) generated using the internal validation subjects was successfully validated in another group of validation subjects (36 PE and 54 healthy (for PE subjects, plasma samples were taken before onset of PE)) and showed good predictive performance, with the area under the curve (AUC) 0.835 and odds ratio 13.43. In conclusion, we newly identified a 3-protein combination biomarker and established a predictive equation and cut-off value that can predict the onset of PE based on analysis of plasma samples collected during gestational weeks 14-24.
Genome-wide association studyによる日本人IgE値を規定する遺伝子群の同定

志藤光介, 小島要, 山崎研志, 木下賢吾, 相場節也

日本皮膚免疫アレルギー学会総会学術大会プログラム・抄録集　50回　188-188　2020/12
Publisher: (一社)日本皮膚免疫アレルギー学会
Combining MRI and genetic data in the Tohoku Medical Megabank Organization cohort study for innovative Alzheimer’s disease research

Makiko Taira, Nobuo Fuse, Shunji Mugikura, Kengo Kinoshita, Masayuki Yamamoto

Alzheimer's & Dementia　16　(S10)　2020/12
Publisher: Wiley
DOI： 10.1002/alz.045688 　

ISSN： 1552-5260

eISSN： 1552-5279
A novel circular ssDNA virus of the phylum Cressdnaviricota discovered in metagenomic data from otter clams (Lutraria rhynchaena). International-journal

Oanh T P Kim, Yuki Kagaya, Hoang S Tran, Ryuhei Minei, Trang T H Tran, Ha T T Duong, Binh T N Le, Lua T Dang, Kengo Kinoshita, Atsushi Ogura, Kei Yura

Archives of virology　165　(12)　2921-2926　2020/12

DOI： 10.1007/s00705-020-04819-9 　

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In this study, we present an analysis of metagenome sequences obtained from a filtrate of a siphon tissue homogenate of otter clams (Lutraria rhynchaena) with swollen-siphon disease. The viral signal was mined from the metagenomic data, and a novel circular ssDNA virus was identified. Genomic features and phylogenetic analysis showed that the virus belongs to the phylum Cressdnaviricota, which consists of viruses with circular, single-stranded DNA (ssDNA) genomes. Members of this phylum have been identified in various species and in environmental samples. The newly found virus is distantly related to the currently known members of the phylum Cressdnaviricota.
Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines. International-journal

Noriko Ishida, Yuichi Aoki, Fumiki Katsuoka, Ichiko Nishijima, Takahiro Nobukuni, Hayato Anzawa, Li Bin, Miyuki Tsuda, Kazuki Kumada, Hisaaki Kudo, Takahiro Terakawa, Akihito Otsuki, Kengo Kinoshita, Riu Yamashita, Naoko Minegishi, Masayuki Yamamoto

Free radical biology & medicine　161　71-83　2020/12

DOI： 10.1016/j.freeradbiomed.2020.09.023 　

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Human lymphoblastoid cell lines (LCLs) are valuable for the functional analyses of diseases. We have established more than 4200 LCLs as one of the resources of an integrated biobank. While oxidative and inflammatory stresses play critical roles in the onset and progression of various diseases, the responsiveness of LCLs, especially that of biobank-made LCLs, to these stresses has not been established. To address how LCLs respond to these stresses, in this study, we performed RNA sequencing of eleven human LCLs that were treated with an electrophile, diethyl maleate (DEM) and/or an inflammatory mediator, lipopolysaccharide (LPS). We found that over two thousand genes, including those regulated by a master regulator of the electrophilic/oxidative stress response, NRF2, were upregulated in LCLs treated with DEM, while approximately three hundred genes, including inflammation-related genes, were upregulated in LPS-treated LCLs. Of the LPS-induced genes, a subset of proinflammatory genes was repressed by DEM, supporting the notion that DEM suppresses the expression of proinflammatory genes through NRF2 activation. Conversely, a part of DEM-induced gene was repressed by LPS, suggesting reciprocal interference between electrophilic and inflammatory stress-mediated pathways. These data clearly demonstrate that LCLs maintain, by and large, responsive pathways against oxidative and inflammatory stresses and further endorse the usefulness of the LCL supply from the biobank.
Machine learning for effectively avoiding overfitting is a crucial strategy for the genetic prediction of polygenic psychiatric phenotypes Peer-reviewed

Yuta Takahashi, Masao Ueki, Gen Tamiya, Soichi Ogishima, Kengo Kinoshita, Atsushi Hozawa, Naoko Minegishi, Fuji Nagami, Kentaro Fukumoto, Kotaro Otsuka, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Makoto Sasaki, Kenji Sobue, Shigeo Kure, Masayuki Yamamoto, Hiroaki Tomita

Translational Psychiatry　10　(1)　2020/12
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s41398-020-00957-5 　

eISSN： 2158-3188
Improved metabolomic data-based prediction of depressive symptoms using nonlinear machine learning with feature selection Peer-reviewed

Yuta Takahashi, Masao Ueki, Makoto Yamada, Gen Tamiya, Ikuko N. Motoike, Daisuke Saigusa, Miyuki Sakurai, Fuji Nagami, Soichi Ogishima, Seizo Koshiba, Kengo Kinoshita, Masayuki Yamamoto, Hiroaki Tomita

Translational Psychiatry　10　(1)　2020/12/01

DOI： 10.1038/s41398-020-0831-9 　

eISSN： 2158-3188
Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers. International-journal

Keito Okazaki, Hayato Anzawa, Zun Liu, Nao Ota, Hiroshi Kitamura, Yoshiaki Onodera, Md Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Shu Tadaka, Ikuko Motoike, Mika Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi

Nature communications　11　(1)　5911-5911　2020/11/20

DOI： 10.1038/s41467-020-19593-0 　

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Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.
Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population. International-journal

Seizo Koshiba, Ikuko N Motoike, Daisuke Saigusa, Jin Inoue, Yuichi Aoki, Shu Tadaka, Matsuyuki Shirota, Fumiki Katsuoka, Gen Tamiya, Naoko Minegishi, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

Communications biology　3　(1)　662-662　2020/11/11

DOI： 10.1038/s42003-020-01383-5 　

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We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.
Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

Junichi Sugawara, Mami Ishikuro, Taku Obara, Tomomi Onuma, Keiko Murakami, Masahiro Kikuya, Fumihiko Ueno, Aoi Noda, Satoshi Mizuno, Tomoko Kobayashi, Yohei Hamanaka, Kichiya Suzuki, Eiichi Kodama, Naho Tsuchiya, Akira Uruno, Yoichi Suzuki, Osamu Tanabe, Hideyasu Kiyomoto, Akito Tsuboi, Atsushi Shimizu, Seizo Koshiba, Naoko Minegishi, Soichi Ogishima, Gen Tamiya, Hirohito Metoki, Atsushi Hozawa, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Shinichi Kuriyama, Masayuki Yamamoto

Journal of epidemiology　32　(2)　69-79　2020/10/10

DOI： 10.2188/jea.JE20200338 　

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BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.
Low birth weight and abnormal pre-pregnancy body mass index were at higher risk for hypertensive disorders of pregnancy. International-journal

Maiko Wagata, Mami Ishikuro, Taku Obara, Masato Nagai, Satoshi Mizuno, Naoki Nakaya, Tomohiro Nakamura, Takumi Hirata, Naho Tsuchiya, Hirohito Metoki, Soichi Ogishima, Atsushi Hozawa, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Shinichi Kuriyama, Junichi Sugawara

Pregnancy hypertension　22　119-125　2020/10

DOI： 10.1016/j.preghy.2020.08.001 　

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Low birth weight is known to be associated with hypertension, cardiovascular disease and hypertensive disorders of pregnancy (HDP); however, this association might vary by race/ethnicity. This study aimed to clarify the association between women's own birth weight and their subsequent risk for HDP in a Japanese population, in combination with pre-pregnancy body mass index (BMI). We conducted a cohort study as part of the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Miyagi, Japan. Our study's population included 4810 women. A multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (aOR) and the 95% confidence interval (CI) of the women's own birth weight for HDP, in the combination categories of birth weight and pre-pregnancy BMI. As a result, the group with a low birth weight of <2500 g had a significant association with HDP (the aOR, 1.50; 95% CI, 1.02-2.21). In the subtype analysis, the odds ratio for only preeclampsia was significantly increased in the low birth weight group (aOR, 3.37; 95% CI, 1.84-6.16). In the group with a low birth weight, the prevalence of HDP was higher in both the underweight and overweight groups. In conclusion, there was a significant association between low birth weight and subsequent HDP in Japanese women. Furthermore, a significant association with HDP was found for women born with a low birth weight who were underweight or overweight as adults. Maintaining a normal weight may be effective for preventing HDP even if a woman was born small.
A genotype imputation method for de-identified haplotype reference information by using recurrent neural network. International-journal

Kaname Kojima, Shu Tadaka, Fumiki Katsuoka, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

PLoS computational biology　16　(10)　e1008207　2020/10

DOI： 10.1371/journal.pcbi.1008207 　

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Genotype imputation estimates the genotypes of unobserved variants using the genotype data of other observed variants based on a collection of haplotypes for thousands of individuals, which is known as a haplotype reference panel. In general, more accurate imputation results were obtained using a larger size of haplotype reference panel. Most of the existing genotype imputation methods explicitly require the haplotype reference panel in precise form, but the accessibility of haplotype data is often limited, due to the requirement of agreements from the donors. Since de-identified information such as summary statistics or model parameters can be used publicly, imputation methods using de-identified haplotype reference information might be useful to enhance the quality of imputation results under the condition where the access of the haplotype data is limited. In this study, we proposed a novel imputation method that handles the reference panel as its model parameters by using bidirectional recurrent neural network (RNN). The model parameters are presented in the form of de-identified information from which the restoration of the genotype data at the individual-level is almost impossible. We demonstrated that the proposed method provides comparable imputation accuracy when compared with the existing imputation methods using haplotype datasets from the 1000 Genomes Project (1KGP) and the Haplotype Reference Consortium. We also considered a scenario where a subset of haplotypes is made available only in de-identified form for the haplotype reference panel. In the evaluation using the 1KGP dataset under the scenario, the imputation accuracy of the proposed method is much higher than that of the existing imputation methods. We therefore conclude that our RNN-based method is quite promising to further promote the data-sharing of sensitive genome data under the recent movement for the protection of individuals' privacy.
Theoretical characterisation of strand cross-correlation in ChIP-seq. International-journal

Hayato Anzawa, Hitoshi Yamagata, Kengo Kinoshita

BMC bioinformatics　21　(1)　417-417　2020/09/22

DOI： 10.1186/s12859-020-03729-6 　

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BACKGROUND: Strand cross-correlation profiles are used for both peak calling pre-analysis and quality control (QC) in chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis. Despite its potential for robust and accurate assessments of signal-to-noise ratio (S/N) because of its peak calling independence, it remains unclear what aspects of quality such strand cross-correlation profiles actually measure. RESULTS: We introduced a simple model to simulate the mapped read-density of ChIP-seq and then derived the theoretical maximum and minimum of cross-correlation coefficients between strands. The results suggest that the maximum coefficient of typical ChIP-seq samples is directly proportional to the number of total mapped reads and the square of the ratio of signal reads, and inversely proportional to the number of peaks and the length of read-enriched regions. Simulation analysis supported our results and evaluation using 790 ChIP-seq data obtained from the public database demonstrated high consistency between calculated cross-correlation coefficients and estimated coefficients based on the theoretical relations and peak calling results. In addition, we found that the mappability-bias-correction improved sensitivity, enabling differentiation of maximum coefficients from the noise level. Based on these insights, we proposed virtual S/N (VSN), a novel peak call-free metric for S/N assessment. We also developed PyMaSC, a tool to calculate strand cross-correlation and VSN efficiently. VSN achieved most consistent S/N estimation for various ChIP targets and sequencing read depths. Furthermore, we demonstrated that a combination of VSN and pre-existing peak calling results enable the estimation of the numbers of detectable peaks for posterior experiments and assess peak calling results. CONCLUSIONS: We present the first theoretical insights into the strand cross-correlation, and the results reveal the potential and the limitations of strand cross-correlation analysis. Our quality assessment framework using VSN provides peak call-independent QC and will help in the evaluation of peak call analysis in ChIP-seq experiments.
Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes in a 3,552 Japanese whole-genome sequence dataset (3.5KJPNv2) Peer-reviewed

Hideki Tokunaga, Keita Iida, Atsushi Hozawa, Soichi Ogishima, Yoh Watanabe, Shogo Shigeta, Muneaki Shimada, Yumi Yamaguchi-Kabata, Shu Tadaka, Fumiki Katsuoka, Shin Ito, Kazuki Kumada, Yohei Hamanaka, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda

2020/07/17
Publisher: Cold Spring Harbor Laboratory
DOI： 10.1101/2020.07.17.208454 　

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<title>Abstract</title>Identification of pathogenic germline variants yet no clinical evidence in <italic>BRCA</italic> genes has become important in patient care of hereditary breast and ovarian cancer syndrome (HBOC). Computational scoring and prospective cohort studies may help to identify such pathogenic variants. We annotated the variants in the <italic>BRCA1</italic> and <italic>BRCA2</italic> genes from a dataset of 3,552 whole-genome sequences obtained from members of the genome cohorts by Tohoku Medical Megabank Project (TMM) with the InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAF) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar are used for filtration criteria. Familial predispositions in cancers among the 35,000 TMM genome cohort participants are analyzed to verify the pathogenicity. Seven potentially pathogenic variants were newly identified. Carriers of these potential pathogenic variants and definite P and LP variants among participants of the TMM prospective cohort show a statistically significant preponderance in cancer onset in sisters in the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potential pathogenic variants in <italic>BRCA</italic> genes for Japanese population. These results will be helpful to follow up the carriers of variants of uncertain significance in the HBOC genes.
Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. International-journal

Yingsong Lin, Masahiro Nakatochi, Yasuyuki Hosono, Hidemi Ito, Yoichiro Kamatani, Akihito Inoko, Hiromi Sakamoto, Fumie Kinoshita, Yumiko Kobayashi, Hiroshi Ishii, Masato Ozaka, Takashi Sasaki, Masato Matsuyama, Naoki Sasahira, Manabu Morimoto, Satoshi Kobayashi, Taito Fukushima, Makoto Ueno, Shinichi Ohkawa, Naoto Egawa, Sawako Kuruma, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Masumi Okuda, Takako Osaki, Shigeru Kamiya, Chaochen Wang, Kazuo Hara, Yasuhiro Shimizu, Tatsuo Miyamoto, Yuko Hayashi, Hiromichi Ebi, Tomohiro Kohmoto, Issei Imoto, Yumiko Kasugai, Yoshinori Murakami, Masato Akiyama, Kazuyoshi Ishigaki, Koichi Matsuda, Makoto Hirata, Kazuaki Shimada, Takuji Okusaka, Takahisa Kawaguchi, Meiko Takahashi, Yoshiyuki Watanabe, Kiyonori Kuriki, Aya Kadota, Rieko Okada, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Atsushi Goto, Kengo Kinoshita, Nobuo Fuse, Fumiki Katsuoka, Atsushi Shimizu, Satoshi S Nishizuka, Kozo Tanno, Ken Suzuki, Yukinori Okada, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki, Herbert Yu, Jun Zhong, Laufey T Amundadottir, Yuichiro Doki, Hideshi Ishii, Hidetoshi Eguchi, David Bogumil, Christopher A Haiman, Loic Le Marchand, Masaki Mori, Harvey Risch, Veronica W Setiawan, Shoichiro Tsugane, Kenji Wakai, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo

Nature communications　11　(1)　3175-3175　2020/06/24

DOI： 10.1038/s41467-020-16711-w 　

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Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project.

Akito Tsuboi, Hiroyuki Matsui, Naru Shiraishi, Takahisa Murakami, Akihito Otsuki, Junko Kawashima, Tomomi Kiyama, Toru Tamahara, Maki Goto, Shihoko Koyama, Junichi Sugawara, Eiichi N Kodama, Hirohito Metoki, Atsushi Hozawa, Shinichi Kuriyama, Hiroaki Tomita, Masahiro Kikuya, Naoko Minegishi, Kichiya Suzuki, Seizo Koshiba, Gen Tamiya, Nobuo Fuse, Yuichi Aoki, Takako Takai-Igarashi, Soichi Ogishima, Tomohiro Nakamura, Mika Sakurai-Yageta, Fuji Nagami, Kengo Kinoshita, Shigeo Kure, Ritsuko Shimizu, Keiichi Sasaki, Masayuki Yamamoto

The Tohoku journal of experimental medicine　251　(2)　97-115　2020/06

DOI： 10.1620/tjem.251.97 　

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In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.
Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy International-journal Peer-reviewed

Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

Medical Mass Spectrometry　4　(1)　36-49　2020/04/16

DOI： 10.24508/mms.2020.06.001 　
Impacts of NRF2 activation in non-small-cell lung cancer cell lines on extracellular metabolites. International-journal Peer-reviewed

Daisuke Saigusa, Ikuko N Motoike, Sakae Saito, Michael Zorzi, Yuichi Aoki, Hiroshi Kitamura, Mikiko Suzuki, Fumiki Katsuoka, Hirofumi Ishii, Kengo Kinoshita, Hozumi Motohashi, Masayuki Yamamoto

Cancer science　111　(2)　667-678　2020/02

DOI： 10.1111/cas.14278 　

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Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T-Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G-Met and detailed transcriptome analyses. G-Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2-activated NSCLC.
Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. Peer-reviewed

Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiro Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

Journal of epidemiology　31　(1)　65-76　2020/01/11

DOI： 10.2188/jea.JE20190271 　

ISSN： 0917-5040

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BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.
Metagenome Sequences from the Environment of Diseased Otter Clams, Lutraria rhynchaena, from a Farm in Vietnam. International-journal

Yuki Kagaya, Ryuhei Minei, Ha T T Duong, Binh T N Le, Lua T Dang, Trang T H Tran, Hoa T Nguyen, Kengo Kinoshita, Kei Yura, Atsushi Ogura, Oanh T P Kim

Microbiology resource announcements　9　(2)　2020/01/09

DOI： 10.1128/MRA.01068-19 　

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Otter clam farming in Vietnam has recently encountered difficulties due to swollen-siphon disease. Here, we report the metagenome sequences of microorganisms extracted from the siphon tissue of infected otter clams. The data comprised bacterial and viral sequences which likely include those derived from the disease-causing agent.
Erratum: Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients (Haematologica (2019) (1967) DOI: 10.3324/haematol.2018.207241)

Minako Mori, Asuka Hira, Kenichi Yoshida, Hideki Muramatsu, Yusuke Okuno, Yuichi Shiraishi, Michiko Anmae, Jun Yasuda, Shu Tadaka, Kengo Kinoshita, Tomoo Osumi, Yasushi Noguchi, Souichi Adachi, Ryoji Kobayashi, Hiroshi Kawabata, Kohsuke Imai, Tomohiro Morio, Kazuo Tamura, Akifumi Takaori-Kondo, Masayuki Yamamoto, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa, Keitaro Matsuo, Hiromasa Yabe, Miharu Yabe, Minoru Takata

Haematologica　105　(4)　1166-1167　2020
Publisher: Ferrata Storti Foundation
DOI： 10.3324/haematol.2019.245720 　

ISSN： 1592-8721 0390-6078
Oral Microbiome Analysis in Prospective Genome Cohort Studies of the Tohoku Medical Megabank Project. International-journal

Sakae Saito, Yuichi Aoki, Toru Tamahara, Maki Goto, Hiroyuki Matsui, Junko Kawashima, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Yoichi Suzuki, Nobuo Fuse, Shigeo Kure, Riu Yamashita, Osamu Tanabe, Naoko Minegishi, Kengo Kinoshita, Akito Tsuboi, Ritsuko Shimizu, Masayuki Yamamoto

Frontiers in cellular and infection microbiology　10　604596-604596　2020

DOI： 10.3389/fcimb.2020.604596 　

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A baseline oral microbiome study of the Tohoku Medical Megabank Organization (TMM) was planned to characterize the profile of the oral microbiome in the Japanese population. The study also aimed to clarify risk factors for multifactorial diseases by integrated analysis of the oral microbiome and host genome/omics information. From 2013 to 2016, we collected three types of oral biospecimens, saliva, supragingival plaque, and tongue swab, from a total of 25,101 participants who had a dental examination in TMM. In this study, we used two independent cohorts; the Community-Based Cohort and Birth and Three-Generation Cohort as discovery and validation cohorts, respectively, and we selected participants examined by a single dentist. We found through the 16S ribosomal RNA gene sequencing analysis of 834 participants of the Community-Based Cohort Study that there are differences in the microbial composition and community structure between saliva and plaque. The species diversities in both saliva and plaque were increased in correlation with the severity of periodontal disease. These results were nicely reproduced in the analysis of 455 participants of the Birth and Three-Generation Cohort Study. In addition, strong positive and negative associations of microbial taxa in both plaque and saliva with periodontitis-associated biofilm formation were detected by co-occurrence network analysis. The classes Actinobacteria and Bacilli, including oral health-associated bacterial species, showed a positive correlation in saliva. These results revealed differences in microbial composition and community structure between saliva and plaque and a correlation between microbial species and the severity of periodontal disease. We expect that the large database of the oral microbiome in the TMM biobank will help in the discovery of novel targets for the treatment and prevention of oral diseases, as well as for the discovery of therapeutic and/or preventive targets of systemic diseases.
Consistency index of daily activity pattern and its correlations with subjective ratings of QOL Peer-reviewed

Ryota Amano, Akihiro Karashima, Ikuko Motoike, Norihiro Katayama, Kengo Kinoshita, Mitsuyuki Nakao

Sleep and Biological Rhythms　18　(4)　297-304　2020

DOI： 10.1007/s41105-020-00271-z 　

ISSN： 1446-9235

eISSN： 1479-8425
Construction of JRG (Japanese reference genome) with single-molecule real-time sequencing

Masao Nagasaki, Yoko Kuroki, Tomoko F. Shibata, Fumiki Katsuoka, Takahiro Mimori, Yosuke Kawai, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Yoichi Suzuki, Hiroshi Kawame, Fuji Nagami, Takako Takai-Igarashi, Soichi Ogishima, Kaname Kojima, Kazuharu Misawa, Osamu Tanabe, Nobuo Fuse, Hiroshi Tanaka, Nobuo Yaegashi, Kengo Kinoshita, Shiego Kure, Jun Yasuda, Masayuki Yamamoto

Human Genome Variation　6　2019/12/01

DOI： 10.1038/s41439-019-0057-7 　

eISSN： 2054-345X
Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. International-journal Peer-reviewed

Minako Mori, Asuka Hira, Kenichi Yoshida, Hideki Muramatsu, Yusuke Okuno, Yuichi Shiraishi, Michiko Anmae, Jun Yasuda, Shu Tadaka, Kengo Kinoshita, Tomoo Osumi, Yasushi Noguchi, Souichi Adachi, Ryoji Kobayashi, Hiroshi Kawabata, Kohsuke Imai, Tomohiro Morio, Kazuo Tamura, Akifumi Takaori-Kondo, Masayuki Yamamoto, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa, Keitaro Matsuo, Hiromasa Yabe, Miharu Yabe, Minoru Takata

Haematologica　104　(10)　1962-1973　2019/10

DOI： 10.3324/haematol.2018.207241 　

ISSN： 0390-6078

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Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.
Establishment of Integrated Biobank for Precision Medicine and Personalized Healthcare: The Tohoku Medical Megabank Project. Peer-reviewed

Fuse N, Sakurai-YagetaM, Katsuoka F, Danjoh I, Shimizu R, Tamiya G, Nagami F, Kawame H, Higuchi S, Kinoshita K, Kure S, Yamamoto M

JMA Journal　2　(2)　113-122　2019/09

DOI： 10.31662/jmaj.2019-0014. 　

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The Tohoku Medical Megabank (TMM) project was established to provide creative reconstruction of the Tohoku area that suffered from a huge earthquake and ensuing tsunami (the Great East Japan Earthquake, GEJE). TMM aims to establish two large-scale genome cohorts and an integrated biobank managing biospecimen and related information. It supports community medicine by establishing next-generation medical systems through a combination of the prospective genome cohort studies with a total of 150,000 participants and genomic medicine. The strategies for genome analyses in TMM are to develop an elaborate genome reference panel by means of high-fidelity Japanese whole-genome sequence, to design custom single nucleotide polymorphism (SNP) arrays based on the reference panel, and to obtain genotype data for all the TMM cohort participants subsequently. Disease-associated genomic information and omics data, including metabolomics and microbiome analysis, provide an essential platform for precision medicine and personalized healthcare (PHC). Ethical, legal, and social issues (ELSI) and education are important for implementing genomic medicine. The major considerations of ELSI regarding each participant of the cohort studies are the respect for the autonomy and the protection of privacies. Moreover, developing and provide human resources not only for the TMM project but also for the social implementation of precision medicine and PHC is required. We started a pilot study of the return of genomic results for familial hypercholesterolemia (FH) as a target disease. TMM aims to establish solid platforms that support precision medicine and PHC based on the genomic and omics information and environmental and lifestyle factors of the individuals, which is one of the most advanced medical care beyond the evidenced-based medicine in the near future.
Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): Rationale, Progress and Perspective. International-journal Peer-reviewed

Shinichi Kuriyama, Hirohito Metoki, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Masato Nagai, Hiroko Matsubara, Tomoko Kobayashi, Junichi Sugawara, Gen Tamiya, Atsushi Hozawa, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Mana Kogure, Takumi Hirata, Ichiro Tsuji, Fuji Nagami, Nobuo Fuse, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Yoichi Suzuki, Noriko Osumi, Keiko Nakayama, Kiyoshi Ito, Shinichi Egawa, Koichi Chida, Eiichi Kodama, Hideyasu Kiyomoto, Tadashi Ishii, Akito Tsuboi, Hiroaki Tomita, Yasuyuki Taki, Hiroshi Kawame, Kichiya Suzuki, Naoto Ishii, Soichi Ogishima, Satoshi Mizuno, Takako Takai-Igarashi, Naoko Minegishi, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Osamu Tanabe, Seizo Koshiba, Hiroaki Hashizume, Hozumi Motohashi, Teiji Tominaga, Sadayoshi Ito, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Jiro Hitomi, Makoto Sasaki, Kengo Kinoshita, Hiroshi Tanaka, Tadao Kobayashi, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

International journal of epidemiology　2019/08/25

DOI： 10.1093/ije/dyz169 　

ISSN： 0300-5771
Value of global metabolomics in association with diagnosis and clinicopathological factors of renal cell carcinoma. International-journal Peer-reviewed

Tomonori Sato, Yoshihide Kawasaki, Masamitsu Maekawa, Shinya Takasaki, Daisuke Saigusa, Hideki Ota, Shuichi Shimada, Shinichi Yamashita, Koji Mitsuzuka, Hiroaki Yamaguchi, Akihiro Ito, Kengo Kinoshita, Seizo Koshiba, Nariyasu Mano, Yoichi Arai

International journal of cancer　145　(2)　484-493　2019/07/15

DOI： 10.1002/ijc.32115 　

ISSN： 0020-7136

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Renal cell carcinoma (RCC) is a malignant tumor that currently lacks clinically useful biomarkers indicative of early diagnosis or disease status. RCC has commonly been diagnosed based on imaging results. Metabolomics offers a potential technology for discovering biomarkers and therapeutic targets by comprehensive screening of metabolites from patients with various cancers. We aimed to identify metabolites associated with early diagnosis and clinicopathological factors in RCC using global metabolomics (G-Met). Tumor and nontumor tissues were sampled from 20 cases of surgically resected clear cell RCC. G-Met was performed by liquid chromatography mass spectrometry and important metabolites specific to RCC were analyzed by multivariate statistical analysis for cancer diagnostic ability based on area under the curve (AUC) and clinicopathological factors (tumor volume, pathological T stage, Fuhrman grade, presence of coagulation necrosis and distant metastasis). We identified 58 metabolites showing significantly increased levels in tumor tissues, 34 of which showed potential early diagnostic ability (AUC >0.8), but 24 did not discriminate between tumor and nontumor tissues (AUC ≤0.8). We recognized 6 pathways from 9 metabolites with AUC >0.8 and 7 pathways from 10 metabolites with AUC ≤0.8 about malignant status. Clinicopathological factors involving malignant status correlated significantly with metabolites showing AUC ≤0.8 (p = 0.0279). The tricarboxylic acid cycle (TCA) cycle, TCA cycle intermediates, nucleotide sugar pathway and inositol pathway were characteristic pathways for the malignant status of RCC. In conclusion, our study found that metabolites and their pathways allowed discrimination between early diagnosis and malignant status in RCC according to our G-Met protocol.
A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing. International-journal Peer-reviewed

Takeshi Mizuguchi, Takeshi Suzuki, Chihiro Abe, Ayako Umemura, Katsushi Tokunaga, Yosuke Kawai, Minoru Nakamura, Masao Nagasaki, Kengo Kinoshita, Yasunobu Okamura, Satoko Miyatake, Noriko Miyake, Naomichi Matsumoto

Journal of human genetics　64　(5)　359-368　2019/05

DOI： 10.1038/s10038-019-0569-5 　

ISSN： 1434-5161

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We report a family with progressive myoclonic epilepsy who underwent whole-exome sequencing but was negative for pathogenic variants. Similar clinical courses of a devastating neurodegenerative phenotype of two affected siblings were highly suggestive of a genetic etiology, which indicates that the survey of genetic variation by whole-exome sequencing was not comprehensive. To investigate the presence of a variant that remained unrecognized by standard genetic testing, PacBio long-read sequencing was performed. Structural variant (SV) detection using low-coverage (6×) whole-genome sequencing called 17,165 SVs (7,216 deletions and 9,949 insertions). Our SV selection narrowed down potential candidates to only five SVs (two deletions and three insertions) on the genes tagged with autosomal recessive phenotypes. Among them, a 12.4-kb deletion involving the CLN6 gene was the top candidate because its homozygous abnormalities cause neuronal ceroid lipofuscinosis. This deletion included the initiation codon and was found in a GC-rich region containing multiple repetitive elements. These results indicate the presence of a causal variant in a difficult-to-sequence region and suggest that such variants that remain enigmatic after the application of current whole-exome sequencing technology could be uncovered by unbiased application of long-read whole-genome sequencing.
Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing Peer-reviewed

Takahiro Mimori, Jun Yasuda, Yoko Kuroki, Tomoko F. Shibata, Fumiki Katsuoka, Sakae Saito, Naoki Nariai, Akira Ono, Naomi Nakai-Inagaki, Kazuharu Misawa, Keiko Tateno, Yosuke Kawai, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Kichiya Suzuki, Kengo Kinoshita, Masao Nagasaki, Masayuki Yamamoto

The Pharmacogenomics Journal　19　(2)　136-146　2019/04/19
Publisher: Springer Nature
DOI： 10.1038/s41397-017-0010-4 　

ISSN： 1470-269X
Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. International-journal Peer-reviewed

Yamaguchi-Kabata Y, Yasuda J, Uruno A, Shimokawa K, Koshiba S, Suzuki Y, Fuse N, Kawame H, Tadaka S, Nagasaki M, Kojima K, Katsuoka F, Kumada K, Tanabe O, Tamiya G, Yaegashi N, Kinoshita K, Yamamoto M, Kure S, Tohoku Medical Megabank Project, Study Group

Human genetics　138　(4)　389-409　2019/04

DOI： 10.1007/s00439-019-01998-7 　

ISSN： 0340-6717

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Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.
Identification of genetic alterations in extramammary Paget disease using whole exome analysis. International-journal Peer-reviewed

Yukiko Kiniwa, Jun Yasuda, Sakae Saito, Rumiko Saito, Ikuko N Motoike, Inaho Danjoh, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto, Ryuhei Okuyama

Journal of dermatological science　94　(1)　229-235　2019/04

DOI： 10.1016/j.jdermsci.2019.03.006 　

ISSN： 0923-1811

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BACKGROUND: Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm, and the genomic alterations underlying its pathogenesis are unknown. OBJECTIVE: To identify tumor-specific genomic alterations in EMPD. METHODS: Exome analysis was performed in specimens from three EMPD patients, and target amplicon sequencing was done for genes frequently mutated in other adenocarcinomas. RESULTS: Exome analysis revealed recurrent somatic mutations in several genes, includingTP53, PIK3CA, and ERBB2. We identified additional candidate exons by searching the COSMIC database for exons that are frequently mutated in other adenocarcinomas. We obtained 19 exons in 12 genes as candidate exons, and performed target amplicon sequencing in samples obtained from EMPD patients. New somatic mutations in the TP53 gene were identified in six EMPD patients. Single nucleotide polymorphism analysis revealed multiple chromosomal alterations in three EMPD specimens, and two specimens exhibited amplification of chromosome 12p13 and losses of 3p21-24, 7q22 and 13q12-21. CONCLUSION: Our comprehensive genetic analysis identified novel genomic alterations, and will inform treatment options for EMPD.
Outlier detection for questionnaire data in biobanks. Peer-reviewed

Sakurai R, Ueki M, Makino S, Hozawa A, Kuriyama S, Takai-Igarashi T, Kinoshita K, Yamamoto M, Tamiya G

International journal of epidemiology　48　(4)　1305-1315　2019/03
Publisher: Oxford University Press (OUP)
DOI： 10.1093/ije/dyz012 　

ISSN： 0300-5771

eISSN： 1464-3685

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<title>Abstract</title> <sec> <title>Background</title> Biobanks increasingly collect, process and store omics with more conventional epidemiologic information necessitating considerable effort in data cleaning. An efficient outlier detection method that reduces manual labour is highly desirable. </sec> <sec> <title>Method</title> We develop an unsupervised machine-learning method for outlier detection, namely kurPCA, that uses principal component analysis combined with kurtosis to ascertain the existence of outliers. In addition, we propose a novel regression adjustment approach to improve detection, namely the regression adjustment for data by systematic missing patterns (RAMP). </sec> <sec> <title>Result</title> Application to epidemiological record data in a large-scale biobank (Tohoku Medical Megabank Organization, Japan) shows that a combination of kurPCA and RAMP effectively detects known errors or inconsistent patterns. </sec> <sec> <title>Conclusions</title> We confirm through the results of the simulation and the application that our methods showed good performance. The proposed methods are useful for many practical analysis scenarios. </sec>
Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy. International-journal Peer-reviewed

Junichi Sugawara, Daisuke Ochi, Riu Yamashita, Takafumi Yamauchi, Daisuke Saigusa, Maiko Wagata, Taku Obara, Mami Ishikuro, Yoshiki Tsunemoto, Yuki Harada, Tomoko Shibata, Takahiro Mimori, Junko Kawashima, Fumiki Katsuoka, Takako Igarashi-Takai, Soichi Ogishima, Hirohito Metoki, Hiroaki Hashizume, Nobuo Fuse, Naoko Minegishi, Seizo Koshiba, Osamu Tanabe, Shinichi Kuriyama, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Satoshi Hiyama, Masao Nagasaki

BMJ open　9　(2)　e025939　2019/02/19

DOI： 10.1136/bmjopen-2018-025939 　

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PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.
Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. International-journal Peer-reviewed

Jun Yasuda, Kengo Kinoshita, Fumiki Katsuoka, Inaho Danjoh, Mika Sakurai-Yageta, Ikuko N Motoike, Yoko Kuroki, Sakae Saito, Kaname Kojima, Matsuyuki Shirota, Daisuke Saigusa, Akihito Otsuki, Junko Kawashima, Yumi Yamaguchi-Kabata, Shu Tadaka, Yuichi Aoki, Takahiro Mimori, Kazuki Kumada, Jin Inoue, Satoshi Makino, Miho Kuriki, Nobuo Fuse, Seizo Koshiba, Osamu Tanabe, Masao Nagasaki, Gen Tamiya, Ritsuko Shimizu, Takako Takai-Igarashi, Soichi Ogishima, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Akito Tsuboi, Hideyasu Kiyomoto, Tadashi Ishii, Hiroaki Tomita, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroshi Kawame, Hiroshi Tanaka, Yasuyuki Taki, Nobuo Yaegashi, Shigeo Kure, Fuji Nagami, Kenjiro Kosaki, Yoichi Sutoh, Tsuyoshi Hachiya, Atsushi Shimizu, Makoto Sasaki, Masayuki Yamamoto

Journal of biochemistry　165　(2)　139-158　2019/02/01

DOI： 10.1093/jb/mvy096 　

ISSN： 0021-924X

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Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.
Relationship between Dynamics of Physiological Signals and Subjective Quality of Life and Its Lifestyle Dependency.

Ryota Amano, Akihiro Karashima, Ikuko N. Motoike, Norihiro Katayama, Kengo Kinoshita, Mitsuyuki Nakao

41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society(EMBC)　546-549　2019
Publisher: IEEE
DOI： 10.1109/EMBC.2019.8857083 　
3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. Peer-reviewed

Tadaka S, Katsuoka F, Ueki M, Kojima K, Makino S, Saito S, Otsuki A, Gocho C, Sakurai-Yageta M, Danjoh I, Motoike IN, Yamaguchi-Kabata Y, Shirota M, Koshiba S, Nagasaki M, Minegishi N, Hozawa A, Kuriyama S, Shimizu A, Yasuda J, Fuse N, Tohoku Medical Megabank Project, Study Group, Tamiya G, Yamamoto M, Kinoshita K

Human genome variation　6　(1)　28　2019
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s41439-019-0059-5 　

eISSN： 2054-345X
COXPRESdb v7: a gene coexpression database for 11 animal species supported by 23 coexpression platforms for technical evaluation and evolutionary inference. Peer-reviewed

Obayashi T, Kagaya Y, Aoki Y, Tadaka S, Kinoshita K

Nucleic acids research　47　(D1)　D55-D62　2019/01

DOI： 10.1093/nar/gky1155 　

ISSN： 0305-1048
Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2. Peer-reviewed

Kondo HX, Yoshida N, Shirota M, Kinoshita K

The journal of physical chemistry. B　122　(48)　10825-10833　2018/12

DOI： 10.1021/acs.jpcb.8b09446 　

ISSN： 1520-6106
Zn²⁺-Binding to the Voltage-Gated Proton Channel Hv1/VSOP. Peer-reviewed

Iwaki M, Takeshita K, Kondo HX, Kinoshita K, Okamura Y, Takano Y, Nakagawa A, Kandori H

The journal of physical chemistry. B　122　(39)　9076-9080　2018/09

DOI： 10.1021/acs.jpcb.8b04890 　

ISSN： 1520-6106
Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. International-journal Peer-reviewed

Jun Yasuda, Fumiki Katsuoka, Inaho Danjoh, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Sakae Saito, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N Motoike, Kazuki Kumada, Mika Sakurai-Yageta, Osamu Tanabe, Nobuo Fuse, Gen Tamiya, Koichiro Higasa, Fumihiko Matsuda, Nobufumi Yasuda, Motoki Iwasaki, Makoto Sasaki, Atsushi Shimizu, Kengo Kinoshita, Masayuki Yamamoto

BMC genomics　19　(1)　551-551　2018/07/24

DOI： 10.1186/s12864-018-4942-0 　

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BACKGROUND: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. RESULTS: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. CONCLUSIONS: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.
Matataki: an ultrafast mRNA quantification method for large-scale reanalysis of RNA-Seq data. Peer-reviewed

Okamura Y, Kinoshita K

BMC bioinformatics　19　(1)　266-9　2018/07

DOI： 10.1186/s12859-018-2279-y 　
De novo profile generation based on sequence context specificity with the long short-term memory network. Peer-reviewed

Yamada KD, Kinoshita K

BMC bioinformatics　19　(1)　272-11　2018/07

DOI： 10.1186/s12859-018-2284-1 　
Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. International-journal Peer-reviewed

Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　23　(6)　406-417　2018/06

DOI： 10.1111/gtc.12588 　

ISSN： 1356-9597

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Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.
Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell. Peer-reviewed

Ochiai K, Kondo H, Okamura Y, Shima H, Kurokochi Y, Kimura K, Funayama R, Nagashima T, Nakayama K, Yui K, Kinoshita K, Igarashi K

Blood advances　2　(8)　883-894　2018/04

DOI： 10.1182/bloodadvances.2017010413 　

ISSN： 2473-9529
ATTED-II in 2018: A Plant Coexpression Database Based on Investigation of the Statistical Property of the Mutual Rank Index. Peer-reviewed

Obayashi T, Aoki Y, Tadaka S, Kagaya Y, Kinoshita K

Plant & cell physiology　59　(2)　440　2018/02

DOI： 10.1093/pcp/pcx209 　

ISSN： 0032-0781
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. International-journal Peer-reviewed

Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

Journal of human genetics　63　(2)　213-230　2018/02

DOI： 10.1038/s10038-017-0347-1 　

ISSN： 1434-5161

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.
jMorp: Japanese Multi Omics Reference Panel. International-journal Peer-reviewed

Shu Tadaka, Daisuke Saigusa, Ikuko N Motoike, Jin Inoue, Yuichi Aoki, Matsuyuki Shirota, Seizo Koshiba, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　46　(D1)　D551-D557-D557　2018/01/04

DOI： 10.1093/nar/gkx978 　

ISSN： 0305-1048

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We developed jMorp, a new database containing metabolome and proteome data for plasma obtained from >5000 healthy Japanese volunteers from the Tohoku Medical Megabank Cohort Study, which is available at https://jmorp.megabank.tohoku.ac.jp. Metabolome data were measured by proton nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS), while proteome data were obtained by nanoLC-MS. We released the concentration distributions of 37 metabolites identified by NMR, distributions of peak intensities of 257 characterized metabolites by LC-MS, and observed frequencies of 256 abundant proteins. Additionally, correlation networks for the metabolites can be observed using an interactive network viewer. Compared with some existing databases, jMorp has some unique features: (i) Metabolome data were obtained using a single protocol in a single institute, ensuring that measurement biases were significantly minimized; (ii) The database contains large-scale data for healthy volunteers with various health records and genome data and (iii) Correlations between metabolites can be easily observed using the graphical viewer. Metabolites data are becoming important intermediate markers for evaluating the health states of humans, and thus jMorp is an outstanding resource for a wide range of researchers, particularly those in the fields of medical science, applied molecular biology, and biochemistry.
State-dependent HRV dynamics and their correlations with subjective sleep quality

AMANO RYOTA, KARASHIMA AKIHIRO, MOTOIKE IKUKO, KATAYAMA NORIHIRO, KINOSHITA KENGO, NAKAO MITSUYUKI

Transactions of Japanese Society for Medical and Biological Engineering　Annual56　(Abstract)　S331-S331　2018
Publisher: Japanese Society for Medical and Biological Engineering
DOI： 10.11239/jsmbe.annual56.s331 　

ISSN： 1347-443X

eISSN： 1881-4379

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Appropriate characterization of state-dependent Heart Rate Variability Dynamics (HRVD) has been explored.We analyzed the difference between state-dependent HRVD and the HRVD of Slow Wave Sleep (SWS: the deepest sleep), together with subjective sleep evaluation. The results showed that the subjective sleep evaluation differentiates the relationship between the state-dependent HRVD with reference to those in SWS. A future study will be further investigation of sleep quality and dynamics of cardiovascular control system.
ATTED-II in 2018: A Plant Coexpression Database Based on Investigation of the Statistical Property of the Mutual Rank Index. Peer-reviewed

Obayashi T, Aoki Y, Tadaka S, Kagaya Y, Kinoshita K

Plant & cell physiology　59　(1)　e3　2018/01

DOI： 10.1093/pcp/pcx191 　

ISSN： 0032-0781
遠隔セキュリティエリアからスーパーコンピュータへの接続サービス全国展開の事例

長瀬祥子, 中村直毅, 伊藤和哉, 葭葉純子, 齊藤智, 木下賢吾, 冨永悌二

医療情報学連合大会論文集　37回　538-540　2017/11
Publisher: (一社)日本医療情報学会
ISSN： 1347-8508

eISSN： 2433-698X
Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis Peer-reviewed

Risa Ebina-Shibuya, Mitsuyo Matsumoto, Makoto Kuwahara, Kyoung-Jin Jang, Manabu Sugai, Yoshiaki Ito, Ryo Funayama, Keiko Nakayama, Yuki Sato, Naoto Ishii, Yasunobu Okamura, Kengo Kinoshita, Kohei Kometani, Tomohiro Kurosaki, Akihiko Muto, Masakazu Ichinose, Masakatsu Yamashita, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　292　(44)　18098-18112　2017/11

DOI： 10.1074/jbc.M117.808535 　

ISSN： 0021-9258

eISSN： 1083-351X
New tools and functions in data-out activities at Protein Data Bank Japan (PDBj) Peer-reviewed

Akira R. Kinjo, Gert-Jan Bekker, Hiroshi Wako, Shigeru Endo, Yuko Tsuchiya, Hiromu Sato, Hafumi Nishi, Kengo Kinoshita, Hirofumi Suzuki, Takeshi Kawabata, Masashi Yokochi, Takeshi Iwata, Naohiro Kobayashi, Toshimichi Fujiwara, Genji Kurisu, Haruki Nakamura

Protein Science　27　(1)　95-102　2017/09
Publisher: Wiley
DOI： 10.1002/pro.3273 　

ISSN： 0961-8368
Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design Peer-reviewed

Takako Takai-Igarashi, Kengo Kinoshita, Masao Nagasaki, Soichi Ogishima, Naoki Nakamura, Sachiko Nagase, Satoshi Nagaie, Tomo Saito, Fuji Nagami, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroaki Hashizume, Shinichi Kuriyama, Atsushi Hozawa, Nobuo Yaegashi, Shigeo Kure, Gen Tamiya, Yoshio Kawaguchi, Hiroshi Tanaka, Masayuki Yamamoto

BMC MEDICAL INFORMATICS AND DECISION MAKING　17　(1)　100-12　2017/07

DOI： 10.1186/s12911-017-0494-5 　

ISSN： 1472-6947
Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies Peer-reviewed

Tsuyoshi Hachiya, Ryohei Furukawa, Yuh Shiwa, Hideki Ohmomo, Kanako Ono, Fumiki Katsuoka, Masao Nagasaki, Jun Yasuda, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Kozo Tanno, Mamoru Satoh, Ryujin Endo, Makoto Sasaki, Kiyomi Sakata, Seiichiro Kobayashi, Kuniaki Ogasawara, Jiro Hitomi, Kenji Sobue, Atsushi Shimizu

NPJ GENOMIC MEDICINE　2　11　2017/04

DOI： 10.1038/s41525-017-0016-5 　

ISSN： 2056-7944
SR-B1 Is a Silica Receptor that Mediates Canonical Inflammasome Activation Peer-reviewed

Misato Tsugita, Nobuyuki Morimoto, Manabu Tashiro, Kengo Kinoshita, Masafumi Nakayama

CELL REPORTS　18　(5)　1298-1311　2017/01

DOI： 10.1016/j.celrep.2017.01.004 　

ISSN： 2211-1247
NLDB: a database for 3D protein–ligand interactions in enzymatic reactions Peer-reviewed

Yoichi Murakami, Satoshi Omori, Kengo Kinoshita

Journal of Structural and Functional Genomics　17　(4)　101-110　2016/12/01
Publisher: Springer Netherland
DOI： 10.1007/s10969-016-9206-0 　

ISSN： 1570-0267 1345-711X
IBiSA_Tools: A Computational Toolkit for Ion-Binding State Analysis in Molecular Dynamics Trajectories of Ion Channels Peer-reviewed

Kota Kasahara, Kengo Kinoshita

PLOS ONE　11　(12)　e0167524　2016/12

DOI： 10.1371/journal.pone.0167524 　

ISSN： 1932-6203
VaProS: a database-integration approach for protein/genome information retrieval Peer-reviewed

Takashi Gojobori, Kazuho Ikeo, Yukie Katayama, Takeshi Kawabata, Akira R. Kinjo, Kengo Kinoshita, Yeondae Kwon, Ohsuke Migita, Hisashi Mizutani, Masafumi Muraoka, Koji Nagata, Satoshi Omori, Hideaki Sugawara, Daichi Yamada, Kei Yura

Journal of Structural and Functional Genomics　17　(4)　69-81　2016/12/01
Publisher: Springer Netherland
DOI： 10.1007/s10969-016-9211-3 　

ISSN： 1570-0267 1345-711X
NCMine: Core-peripheral based functional module detection using near-clique mining Peer-reviewed

Shu Tadaka, Kengo Kinoshita

BIOINFORMATICS　32　(22)　3454-3460　2016/11

DOI： 10.1093/bioinformatics/btw488 　

ISSN： 1367-4803

eISSN： 1460-2059
Landscape of protein-small ligand binding modes Peer-reviewed

Kota Kasahara, Kengo Kinoshita

PROTEIN SCIENCE　25　(9)　1659-1671　2016/09

DOI： 10.1002/pro.2971 　

ISSN： 0961-8368

eISSN： 1469-896X
The Tohoku Medical Megabank Project: Design and Mission Peer-reviewed

Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

JOURNAL OF EPIDEMIOLOGY　26　(9)　493-511　2016/09

DOI： 10.2188/jea.JE20150268 　

ISSN： 0917-5040
Discrepancies between human DNA, mRNA and protein reference sequences and their relation to single nucleotide variants in the human population Peer-reviewed

Matsuyuki Shirota, Kengo Kinoshita

DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION　2016　2016/09

DOI： 10.1093/database/baw124 　

ISSN： 1758-0463
The structural origin of metabolic quantitative diversity Peer-reviewed

Seizo Koshiba, Ikuko Motoike, Kaname Kojima, Takanori Hasegawa, Matsuyuki Shirota, Tomo Saito, Daisuke Saigusa, Inaho Danjoh, Fumiki Katsuoka, Soichi Ogishima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Miyuki Sakurai, Sachiko Hirano, Junichi Nakata, Hozumi Motohashi, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Yoichi Suzuki, Shigeo Kure, Nobuo Yaegashi, Osamu Tanabe, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

SCIENTIFIC REPORTS　6　31463　2016/08

DOI： 10.1038/srep31463 　

ISSN： 2045-2322
Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery Peer-reviewed

Daisuke Saigusa, Yasunobu Okamura, Ikuko N. Motoike, Yasutake Katoh, Yasuhiro Kurosawa, Reina Saijyo, Seizo Koshiba, Jun Yasuda, Hozumi Motohashi, Junichi Sugawara, Osamu Tanabe, Kengo Kinoshita, Masayuki Yamamoto

PLOS ONE　11　(8)　e0160555　2016/08

DOI： 10.1371/journal.pone.0160555 　

ISSN： 1932-6203
Structural basis for the membrane association of ankyrinG via palmitoylation Peer-reviewed

Yuichiro Fujiwara, Hiroko X. Kondo, Matsuyuki Shirota, Megumi Kobayashi, Kohei Takeshita, Atsushi Nakagawa, Yasushi Okamura, Kengo Kinoshita

SCIENTIFIC REPORTS　6　23981　2016/04

DOI： 10.1038/srep23981 　

ISSN： 2045-2322
Ion Concentration- and Voltage-Dependent Push and Pull Mechanisms of Potassium Channel Ion Conduction Peer-reviewed

Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

PLOS ONE　11　(3)　e0150716　2016/03

DOI： 10.1371/journal.pone.0150716 　

ISSN： 1932-6203
Distribution of single-nucleotide variants on protein-protein interaction sites and its relationship with minor allele frequency Peer-reviewed

Hafumi Nishi, Junichi Nakata, Kengo Kinoshita

PROTEIN SCIENCE　25　(2)　316-321　2016/02

DOI： 10.1002/pro.2845 　

ISSN： 0961-8368

eISSN： 1469-896X
Plasma Proteomics Study in the Tohoku Medical Megabank Organization

Shirota Matsuyuki, Katoh Yasutake, Ikuko Motoike, Kinoshita Kengo, Koshiba Seizo

Abstracts for Annual Meeting of Japanese Proteomics Society　2016　98-98　2016
Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)
DOI： 10.14889/jhupo.2016.0.98.0 　
ATTED-II in 2016: A Plant Coexpression Database Towards Lineage-Specific Coexpression Peer-reviewed

Yuichi Aoki, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Takeshi Obayashi

PLANT AND CELL PHYSIOLOGY　57　(1)　e5　2016/01

DOI： 10.1093/pcp/pcv165 　

ISSN： 0032-0781

eISSN： 1471-9053
ALCOdb: Gene Coexpression Database for Microalgae. Peer-reviewed

Yuichi Aoki, Yasunobu Okamura, Hiroyuki Ohta, Kengo Kinoshita, Takeshi Obayashi

Plant & cell physiology　57　(1)　e3　2016/01

DOI： 10.1093/pcp/pcv190 　

ISSN： 0032-0781

eISSN： 1471-9053
Structural characterization of single nucleotide variants at ligand binding sites and enzyme active sites of human proteins. Peer-reviewed

Kazunori D Yamada, Hafumi Nishi, Junichi Nakata, Kengo Kinoshita

Biophysics and physicobiology　13　157-163　2016

DOI： 10.2142/biophysico.13.0_157 　

ISSN： 2189-4779

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Functional sites on proteins play an important role in various molecular interactions and reactions between proteins and other molecules. Thus, mutations in functional sites can severely affect the overall phenotype. Progress of genome sequencing projects has yielded a wealth of information on single nucleotide variants (SNVs), especially those with less than 1% minor allele frequency (rare variants). To understand the functional influence of genetic variants at a protein level, we investigated the relationship between SNVs and protein functional sites in terms of minor allele frequency and the structural position of variants. As a result, we observed that SNVs were less abundant at ligand binding sites, which is consistent with a previous study on SNVs and protein interaction sites. Additionally, we found that non-rare variants tended to be located slightly apart from enzyme active sites. Examination of non-rare variants revealed that most of the mutations resulted in moderate changes of the physico-chemical properties of amino acids, suggesting the existence of functional constraints. In conclusion, this study shows that the mapping of genetic variants on protein structures could be a powerful approach to evaluate the functional impact of rare genetic variations.
Whole-genome Japanese Reference Panel and future directions Peer-reviewed

Masao Nagasaki, Jun Yasuda, Fumiki Katsuoka, Naoki Nariai, Kaname Kojima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Junji Yokozawa, Inaho Danjoh, Sakae Saito, Yukuto Sato, Takahiro Mimori, Kaoru Tsuda, Rumiko Saito, Pan Xiaoqing, Satoshi Nishikawa, Shin Ito, Yoko Kuroki, Osamu Tanabe, Nobuo Fuse, Shinichi Kuriyama, Hideyasu Kiyomoto, Atsushi Hozawa, Naoko Minegishi, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

GENES & GENETIC SYSTEMS　90　(6)　377-377　2015/12

ISSN： 1341-7568

eISSN： 1880-5779
Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals Peer-reviewed

Masao Nagasaki, Jun Yasuda, Fumiki Katsuoka, Naoki Nariai, Kaname Kojima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Junji Yokozawa, Inaho Danjoh, Sakae Saito, Yukuto Sato, Takahiro Mimori, Kaoru Tsuda, Rumiko Saito, Xiaoqing Pan, Satoshi Nishikawa, Shin Ito, Yoko Kuroki, Osamu Tanabe, Nobuo Fuse, Shinichi Kuriyama, Hideyasu Kiyomoto, Atsushi Hozawa, Naoko Minegishi, James Douglas Engel, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

NATURE COMMUNICATIONS　6　8018　2015/08

DOI： 10.1038/ncomms9018 　

ISSN： 2041-1723
Comparison of Gene Coexpression Profiles and Construction of Conserved Gene Networks to Find Functional Modules Peer-reviewed

Yasunobu Okamura, Takeshi Obayashi, Kengo Kinoshita

PLOS ONE　10　(7)　e0132039　2015/07

DOI： 10.1371/journal.pone.0132039 　

ISSN： 1932-6203
COXPRESdb in 2015: coexpression database for animal species by DNA-microarray and RNAseq-based expression data with multiple quality assessment systems Peer-reviewed

Yasunobu Okamura, Yuichi Aoki, Takeshi Obayashi, Shu Tadaka, Satoshi Ito, Takafumi Narise, Kengo Kinoshita

NUCLEIC ACIDS RESEARCH　43　(D1)　D82-D86　2015/01

DOI： 10.1093/nar/gku1163 　

ISSN： 0305-1048

eISSN： 1362-4962
Guanine nucleotide-binding protein 1 is one of the key molecules contributing to cancer cell radioresistance Peer-reviewed

Motoi Fukumoto, Tatsuya Amanuma, Yoshikazu Kuwahara, Tsutomu Shimura, Masatoshi Suzuki, Shiro Mori, Hiroyuki Kumamoto, Yohei Saito, Yasuhito Ohkubo, Zhenfeng Duan, Kenji Sano, Tomohiro Oguchi, Kazuyuki Kainuma, Shinichi Usami, Kengo Kinoshita, Inchul Lee, Manabu Fukumoto

CANCER SCIENCE　105　(10)　1351-1359　2014/10

DOI： 10.1111/cas.12489 　

ISSN： 1347-9032

eISSN： 1349-7006
Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population Peer-reviewed

Ikuko N. Motoike, Mitsuyo Matsumoto, Inaho Danjoh, Fumiki Katsuoka, Kaname Kojima, Naoki Nariai, Yukuto Sato, Yumi Yamaguchi-Kabata, Shin Ito, Hisaaki Kudo, Ichiko Nishijima, Satoshi Nishikawa, Xiaoqing Pan, Rumiko Saito, Sakae Saito, Tomo Saito, Matsuyuki Shirota, Kaoru Tsuda, Junji Yokozawa, Kazuhiko Igarashi, Naoko Minegishi, Osamu Tanabe, Nobuo Fuse, Masao Nagasaki, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

BMC GENOMICS　15　673　2014/08

DOI： 10.1186/1471-2164-15-673 　

ISSN： 1471-2164
Blind prediction of interfacial water positions in CAPRI Peer-reviewed

Marc F. Lensink, Iain H. Moal, Paul A. Bates, Panagiotis L. Kastritis, Adrien S. J. Melquiond, Ezgi Karaca, Christophe Schmitz, Marc van Dijk, Alexandre M. J. J. Bonvin, Miriam Eisenstein, Brian Jimenez-Garcia, Solene Grosdidier, Albert Solernou, Laura Perez-Cano, Chiara Pallara, Juan Fernandez-Recio, Jianqing Xu, Pravin Muthu, Krishna Praneeth Kilambi, Jeffrey J. Gray, Sergei Grudinin, Georgy Derevyanko, Julie C. Mitchell, John Wieting, Eiji Kanamori, Yuko Tsuchiya, Yoichi Murakami, Joy Sarmiento, Daron M. Standley, Matsuyuki Shirota, Kengo Kinoshita, Haruki Nakamura, Matthieu Chavent, David W. Ritchie, Hahnbeom Park, Junsu Ko, Hasup Lee, Chaok Seok, Yang Shen, Dima Kozakov, Sandor Vajda, Petras J. Kundrotas, Ilya A. Vakser, Brian G. Pierce, Howook Hwang, Thom Vreven, Zhiping Weng, Idit Buch, Efrat Farkash, Haim J. Wolfson, Martin Zacharias, Sanbo Qin, Huan-Xiang Zhou, Shen-You Huang, Xiaoqin Zou, Justyna A. Wojdyla, Colin Kleanthous, Shoshana J. Wodak

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　82　(4)　620-632　2014/04

DOI： 10.1002/prot.24439 　

ISSN： 0887-3585

eISSN： 1097-0134
3P030 A Study for the Structural and Physicochemical Properties of Sociable Ligand-Binding Sites in Proteins(01B. Protein: Structure & Function,Poster,The 52nd Annual Meeting of the Biophysical Society of Japan(BSJ2014))

Murakami Yoichi, Kinoshita Kengo

Seibutsu Butsuri　54　(1)　S253　2014
Publisher: The Biophysical Society of Japan General Incorporated Association
DOI： 10.2142/biophys.54.S253_6 　
ATTED-II in 2014: Evaluation of Gene Coexpression in Agriculturally Important Plants Peer-reviewed

Takeshi Obayashi, Yasunobu Okamura, Satoshi Ito, Shu Tadaka, Yuichi Aoki, Matsuyuki Shirota, Kengo Kinoshita

PLANT AND CELL PHYSIOLOGY　55　(1)　e6　2014/01

DOI： 10.1093/pcp/pct178 　

ISSN： 0032-0781

eISSN： 1471-9053
GIANT: pattern analysis of molecular interactions in 3D structures of protein-small ligand complexes Peer-reviewed

Kota Kasahara, Kengo Kinoshita

BMC BIOINFORMATICS　15　12-12　2014/01

DOI： 10.1186/1471-2105-15-12 　

ISSN： 1471-2105
Exhaustive comparison and classification of ligand-binding surfaces in proteins Peer-reviewed

Yoichi Murakami, Kengo Kinoshita, Akira R. Kinjo, Haruki Nakamura

PROTEIN SCIENCE　22　(10)　1379-1391　2013/10

DOI： 10.1002/pro.2329 　

ISSN： 0961-8368

eISSN： 1469-896X
[Molecular dynamics simulation, ion channel, dynamic structure, bioinformatics]. Peer-reviewed

Kasahara K, Shirota M, Kino-Shita K

Seikagaku. The Journal of Japanese Biochemical Society　85　(8)　656-662　2013/08

ISSN： 0037-1017
Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening Peer-reviewed

Takeshi Tenno, Natsuko Goda, Yoshitaka Umetsu, Motonori Ota, Kengo Kinoshita, Hidekazu Hiroaki

MOLECULES　18　(8)　9567-9581　2013/08

DOI： 10.3390/molecules18089567 　

ISSN： 1420-3049
Analyses of the general rule on residue pair frequencies in local amino acid sequences of soluble, ordered proteins Peer-reviewed

Matsuyuki Shirota, Kengo Kinoshita

PROTEIN SCIENCE　22　(6)　725-733　2013/06

DOI： 10.1002/pro.2255 　

ISSN： 0961-8368
Ion Concentration-Dependent Ion Conduction Mechanism of a Voltage-Sensitive Potassium Channel Peer-reviewed

Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

PLOS ONE　8　(2)　e56342　2013/02

DOI： 10.1371/journal.pone.0056342 　

ISSN： 1932-6203
Comprehensive Classification and Diversity Assessment of Atomic Contacts in Protein-Small Ligand Interactions Peer-reviewed

Kota Kasahara, Matsuyuki Shirota, Kengo Kinoshita

JOURNAL OF CHEMICAL INFORMATION AND MODELING　53　(1)　241-248　2013/01

DOI： 10.1021/ci300377f 　

ISSN： 1549-9596
COXPRESdb: a database of comparative gene coexpression networks of eleven species for mammals Peer-reviewed

Takeshi Obayashi, Yasunobu Okamura, Satoshi Ito, Shu Tadaka, Ikuko N. Motoike, Kengo Kinoshita

NUCLEIC ACIDS RESEARCH　41　(D1)　D1014-D1020　2013/01

DOI： 10.1093/nar/gks1014 　

ISSN： 0305-1048
Dynamic features of homodimer interfaces calculated by normal-mode analysis Peer-reviewed

Yuko Tsuchiya, Kengo Kinoshita, Shigeru Endo, Hiroshi Wako

PROTEIN SCIENCE　21　(10)　1503-1513　2012/10

DOI： 10.1002/pro.2140 　

ISSN： 0961-8368
Discrimination between biological interfaces and crystal-packing contacts

Yuko Tsuchiya, Haruki Nakamura, Kengo Kinoshita

Advances and Applications in Bioinformatics and Chemistry　5　(1)　99-113　2012

ISSN： 1178-6949
3PT131 Homology modeling and molecular dynamics study of proton permeation pathway in a channel protein(The 50th Annual Meeting of the Biophysical Society of Japan)

Chiba Susumu, Kasahara Kota, Shirota Matsuyuki, Kinoshita Kengo

Seibutsu Butsuri　52　S163　2012
Publisher: The Biophysical Society of Japan General Incorporated Association
DOI： 10.2142/biophys.52.S163_2 　
Prediction of protein-protein complex structures Peer-reviewed

Eiji Kanamori, Yoichi Murakami, Joy Sarmiento, Shide Uang, Daron M. Standley, Matsuyuki Shirota, Kengo Kinoshita, Yuko Tsucillya, Junicill Higo, Haruki Nakamura

Biomolecular Forms and Functions: A Celebration of 50 Years of the Ramachandran Map　160-172　2012/01/01
Publisher: World Scientific Publishing Co.
DOI： 10.1142/9789814449144_0013 　
NM23/nucleoside diphosphate kinase-A as a potent prognostic marker in invasive pancreatic ductal carcinoma identified by proteomic analysis of laser micro-dissected formalin-fixed paraffin-embedded tissue Peer-reviewed

Tatsuyuki Takadate, Tohru Onogawa, Kiyonaga Fujii, Fuyuhiko Motoi, Sayaka Mikami, Tetsuya Fukuda, Makoto Kihara, Takashi Suzuki, Taro Takemura, Takashi Minowa, Nobutaka Hanagata, Kengo Kinoshita, Takanori Morikawa, Keiichi Shirasaki, Toshiki Rikiyama, Yu Katayose, Shinichi Egawa, Toshihide Nishimura, Michiaki Unno

Clinical Proteomics　9　(1)　8　2012
Publisher: BioMed Central Ltd.
DOI： 10.1186/1559-0275-9-8 　

ISSN： 1559-0275 1542-6416

eISSN： 1559-0275
A novel biclustering approach with iterative optimization to analyze gene expression data Peer-reviewed

Sawannee Sutheeworapong, Motonori Ota, Hiroyuki Ohta, Kengo Kinoshita

Advances and Applications in Bioinformatics and Chemistry　5　(1)　23-59　2012

DOI： 10.2147/AABC.S32622 　

ISSN： 1178-6949
Community-Wide Assessment of Protein-Interface Modeling Suggests Improvements to Design Methodology Peer-reviewed

Sarel J. Fleishman, Timothy A. Whitehead, Eva-Maria Strauch, Jacob E. Corn, Sanbo Qin, Huan-Xiang Zhou, Julie C. Mitchell, Omar N. A. Demerdash, Mayuko Takeda-Shitaka, Genki Terashi, Iain H. Moal, Xiaofan Li, Paul A. Bates, Martin Zacharias, Hahnbeom Park, Jun-su Ko, Hasup Lee, Chaok Seok, Thomas Bourquard, Julie Bernauer, Anne Poupon, Jerome Aze, Seren Soner, Sefik Kerem Ovali, Pemra Ozbek, Nir Ben Tal, Turkan Haliloglu, Howook Hwang, Thom Vreven, Brian G. Pierce, Zhiping Weng, Laura Perez-Cano, Caries Pons, Juan Fernandez-Recio, Fan Jiang, Feng Yang, Xinqi Gong, Libin Cao, Xianjin Xu, Bin Liu, Panwen Wang, Chunhua Li, Cunxin Wang, Charles H. Robert, Mainak Guharoy, Shiyong Liu, Yangyu Huang, Lin Li, Dachuan Guo, Ying Chen, Yi Xiao, Nir London, Zohar Itzhaki, Ora Schueler-Furman, Yuval Inbar, Vladimir Potapov, Mati Cohen, Gideon Schreiber, Yuko Tsuchiya, Eiji Kanamori, Daron M. Standley, Haruki Nakamura, Kengo Kinoshita, Camden M. Driggers, Robert G. Hall, Jessica L. Morgan, Victor L. Hsu, Jian Zhan, Yuedong Yang, Yaoqi Zhou, Panagiotis L. Kastritis, Alexandre M. J. J. Bonvin, Weiyi Zhang, Carlos J. Camacho, Krishna P. Kilambi, Aroop Sircar, Jeffrey J. Gray, Masahito Ohue, Nobuyuki Uchikoga, Yuri Matsuzaki, Takashi Ishida, Yutaka Akiyama, Raed Khashan, Stephen Bush, Denis Fouches, Alexander Tropsha, Juan Esquivel-Rodriguez, Daisuke Kihara, P. Benjamin Stranges, Ron Jacak, Brian Kuhlman, Sheng-You Huang, Xiaoqin Zou, Shoshana J. Wodak, Joel Janin, David Baker

JOURNAL OF MOLECULAR BIOLOGY　414　(2)　289-302　2011/11

DOI： 10.1016/j.jmb.2011.09.031 　

ISSN： 0022-2836
Absolute quality evaluation of protein model structures using statistical potentials with respect to the native and reference states Peer-reviewed

Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　79　(5)　1550-1563　2011/05

DOI： 10.1002/prot.22982 　

ISSN： 0887-3585

eISSN： 1097-0134
ATTED-II Updates: Condition-Specific Gene Coexpression to Extend Coexpression Analyses and Applications to a Broad Range of Flowering Plants Peer-reviewed

Takeshi Obayashi, Kozo Nishida, Kota Kasahara, Kengo Kinoshita

PLANT AND CELL PHYSIOLOGY　52　(2)　213-219　2011/02

DOI： 10.1093/pcp/pcq203 　

ISSN： 0032-0781
Identification of novel transcription factors for catecholamine gene expression based upon the comprehensive analyses of transcripts in fetal pontine noradrenergic neurons using trasngenic mice expressing green fluorescent protein under the promoter of tyrosine hydroxylase Peer-reviewed

Haruka Yokohashi, Katsuya Uchida, Toshimitsu Fuse, Yasumasa Iwasaki, Kengo Kinoshita, Akira Okazaki, Gopal Das, Keisuke Sawada, Chiaki Tanaka, Hiroaki Tomita, Shinji Ohara, Kazuto Kobayashi, Keiichi Itoi

NEUROSCIENCE RESEARCH　71　E120-E120　2011
Publisher: ELSEVIER IRELAND LTD
DOI： 10.1016/j.neures.2011.07.514 　
SAHG, a comprehensive database of predicted structures of all human proteins Peer-reviewed

Chie Motono, Junichi Nakata, Ryotaro Koike, Kana Shimizu, Matsuyuki Shirota, Takayuki Amemiya, Kentaro Tomii, Nozomi Nagano, Naofumi Sakaya, Kiyotaka Misoo, Miwa Sato, Akinori Kidera, Hidekazu Hiroaki, Tsuyoshi Shirai, Kengo Kinoshita, Tamotsu Noguchi, Motonori Ota

NUCLEIC ACIDS RESEARCH　39　(Database issue)　D487-D493　2011/01

DOI： 10.1093/nar/gkq1057 　

ISSN： 0305-1048
COXPRESdb: a database to compare gene coexpression in seven model animals Peer-reviewed

Takeshi Obayashi, Kengo Kinoshita

NUCLEIC ACIDS RESEARCH　39　(Database issue)　D1016-D1022　2011/01

DOI： 10.1093/nar/gkq1147 　

ISSN： 0305-1048
Similarities and differences in the structure and function of 4.1G and 4.1R(135), two protein 4.1 paralogues expressed in erythroid cells Peer-reviewed

Wataru Nunomura, Kengo Kinoshita, Marilyn Parra, Philippe Gascard, Xiuli An, Narla Mohandas, Yuichi Takakuwa

BIOCHEMICAL JOURNAL　432　(2)　407-416　2010/12

DOI： 10.1042/BJ20100041 　

ISSN： 0264-6021
Domain distribution and intrinsic disorder in hubs in the human protein-protein interaction network Peer-reviewed

Ashwini Patil, Kengo Kinoshita, Haruki Nakamura

PROTEIN SCIENCE　19　(8)　1461-1468　2010/08

DOI： 10.1002/pro.425 　

ISSN： 0961-8368

eISSN： 1469-896X
Ligand-binding site prediction of proteins based on known fragment-fragment interactions Peer-reviewed

Kota Kasahara, Kengo Kinoshita, Toshihisa Takagi

BIOINFORMATICS　26　(12)　1493-1499　2010/06

DOI： 10.1093/bioinformatics/btq232 　

ISSN： 1367-4803

eISSN： 1460-2059
Coexpression landscape in ATTED-II: usage of gene list and gene network for various types of pathways Peer-reviewed

Takeshi Obayashi, Kengo Kinoshita

JOURNAL OF PLANT RESEARCH　123　(3)　311-319　2010/05

DOI： 10.1007/s10265-010-0333-6 　

ISSN： 0918-9440

eISSN： 1618-0860
Hub Promiscuity in Protein-Protein Interaction Networks Peer-reviewed

Ashwini Patil, Kengo Kinoshita, Haruki Nakamura

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES　11　(4)　1930-1943　2010/04

DOI： 10.3390/ijms11041930 　

ISSN： 1422-0067
Multi-dimensional correlations for gene coexpression and application to the large-scale data of Arabidopsis Peer-reviewed

Kengo Kinoshita, Takeshi Obayashi

BIOINFORMATICS　25　(20)　2677-2684　2009/10

DOI： 10.1093/bioinformatics/btp442 　

ISSN： 1367-4803
Rank of Correlation Coefficient as a Comparable Measure for Biological Significance of Gene Coexpression Peer-reviewed

Takeshi Obayashi, Kengo Kinoshita

DNA RESEARCH　16　(5)　249-260　2009/10

DOI： 10.1093/dnares/dsp016 　

ISSN： 1340-2838
Analyses on hydrophobicity and attractiveness of all-atom distance-dependent potentials Peer-reviewed

Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

PROTEIN SCIENCE　18　(9)　1906-1915　2009/09

DOI： 10.1002/pro.201 　

ISSN： 0961-8368
Development of new indices to evaluate protein-protein interfaces: Assembling space volume, assembling space distance, and global shape descriptor Peer-reviewed

Miki H. Maeda, Kengo Kinoshita

JOURNAL OF MOLECULAR GRAPHICS & MODELLING　27　(6)　706-711　2009/02

DOI： 10.1016/j.jmgm.2008.11.002 　

ISSN： 1093-3263
[Correlation between structure and function of peptidyl-prolyl isomerase] Peer-reviewed

Ikura T, Kinoshita K, Ito N

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　54　(2)　167-172　2009/02
Publisher: 2
ISSN： 0039-9450
Development of a new meta-score for protein structure prediction from seven all-atom distance dependent potentials using support vector regression.

Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

Genome informatics. International Conference on Genome Informatics　23　(1)　149-158　2009

DOI： 10.1142/9781848165632_0014 　

ISSN： 0919-9454
Classification of heterodimer interfaces using docking models and construction of scoring functions for the complex structure prediction. Peer-reviewed

Tsuchiya Y, Kanamori E, Nakamura H, Kinoshita K

Advances and applications in bioinformatics and chemistry : AABC　2　79-100　2009
PiSite: a database of protein interaction sites using multiple binding states in the PDB Peer-reviewed

Miho Higurashi, Takashi Ishida, Kengo Kinoshita

NUCLEIC ACIDS RESEARCH　37　(Database issue)　D360-D364　2009/01

DOI： 10.1093/nar/gkn659 　

ISSN： 0305-1048
ATTED-II provides coexpressed gene networks for Arabidopsis Peer-reviewed

Takeshi Obayashi, Shinpei Hayashi, Motoshi Saeki, Hiroyuki Ohta, Kengo Kinoshita

Nucleic Acids Research　37　(1)　D987-D991　2009
Publisher: Database issue
DOI： 10.1093/nar/gkn807 　

ISSN： 0305-1048 1362-4962
Effects of surface-to-volume ratio of proteins on hydrophilic residues: Decrease in occurrence and increase in buried fraction Peer-reviewed

Matsuyuki Shirota, Takashi Ishida, Kengo Kinoshita

PROTEIN SCIENCE　17　(9)　1596-1602　2008/09

DOI： 10.1110/ps.035592.108 　

ISSN： 0961-8368
Protein structure databases with new web services for structural biology and biomedical research Peer-reviewed

Daron M. Standley, Akira R. Kinjo, Kengo Kinoshita, Haruki Nakamura

BRIEFINGS IN BIOINFORMATICS　9　(4)　276-285　2008/07

DOI： 10.1093/bib/bbn015 　

ISSN： 1467-5463
Prediction of disordered regions in proteins based on the meta approach Peer-reviewed

Takashi Ishida, Kengo Kinoshita

BIOINFORMATICS　24　(11)　1344-1348　2008/06

DOI： 10.1093/bioinformatics/btn195 　

ISSN： 1367-4803
Weak correlation between sequence conservation in promoter regions and in protein-coding regions of human-mouse orthologous gene pairs Peer-reviewed

Hirokazu Chiba, Riu Yamashita, Kengo Kinoshita, Kenta Nakai

BMC GENOMICS　9　152　2008/04

DOI： 10.1186/1471-2164-9-152 　

ISSN： 1471-2164
A cavity with an appropriate size is the basis of the PPIase activity Peer-reviewed

Teikichi Ikura, Kengo Kinoshita, Nobutoshi Ito

PROTEIN ENGINEERING DESIGN & SELECTION　21　(2)　83-89　2008/02

DOI： 10.1093/protein/gzm087 　

ISSN： 1741-0126
A novel strategy to search conserved transcription factor binding sites among coexpressing genes in human.

Yosuke Hatanaka, Masao Nagasaki, Rui Yamaguchi, Takeshi Obayashi, Kazuyuki Numata, Andrè Fujita, Teppei Shimamura, Yoshinori Tamada, Seiya Imoto, Kengo Kinoshita, Kenta Nakai, Satoru Miyano

Genome informatics. International Conference on Genome Informatics　20　212-221　2008

DOI： 10.1142/9781848163003_0018 　

ISSN： 0919-9454
Discrimination between biological interfaces and crystal-packing contacts. Peer-reviewed

Tsuchiya Y, Nakamura H, Kinoshita K

Advances and applications in bioinformatics and chemistry : AABC　1　99-113　2008
COXPRESdb: A database of coexpressed gene networks in mammals Peer-reviewed

Takeshi Obayashi, Shinpei Hayashi, Masayuki Shibaoka, Motoshi Saeki, Hiroyuki Ohta, Kengo Kinoshita

Nucleic Acids Research　36　(1)　D77-D82　2008/01
Publisher: Database issue
DOI： 10.1093/nar/gkm840 　

ISSN： 0305-1048 1362-4962
Identification of transient hub proteins and the possible structural basis for their multiple interactions Peer-reviewed

Miho Higurashi, Takashi Ishida, Kengo Kinoshita

PROTEIN SCIENCE　17　(1)　72-78　2008/01

DOI： 10.1110/ps.073196308 　

ISSN： 0961-8368
Docking of proteins molecular surfaces, with evolutionary trace analysis Peer-reviewed

Eiji Kanamori, Yoichi Murakami, Yuko Tsuchiya, Daron M. Standley, Haruki Nakamura, Kengo Kinoshita

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　69　(4)　832-838　2007/12

DOI： 10.1002/prot.21737 　

ISSN： 0887-3585
PrDOS: prediction of disordered protein regions from amino acid sequence Peer-reviewed

Takashi Ishida, Kengo Kinoshita

NUCLEIC ACIDS RESEARCH　35　(Web Server issue)　W460-W464　2007/07

DOI： 10.1093/nar/gkm363 　

ISSN： 0305-1048
eF-seek: prediction of the functional sites of proteins by searching for similar electrostatic potential and molecular surface shape Peer-reviewed

Kengo Kinoshita, Yoichi Murakami, Haruki Nakamura

NUCLEIC ACIDS RESEARCH　35　(Web Server issue)　W398-W402　2007/07

DOI： 10.1093/nar/gkm351 　

ISSN： 0305-1048
Mutational analysis of block and facilitation of HERG current by A class III anti-arrhythmic agent, nifekalant Peer-reviewed

Yukio Hosaka, Miki Iwata, Narutoshi Kamiya, Mitsuhiko Yamada, Kengo Kinoshita, Yoshifumi Fukunishi, Kenji Tsujimae, Hiroshi Hibino, Yoshifusa Aizawa, Atsushi Inanobe, Haruki Nakamura, Yoshihisa Kurachi

CHANNELS　1　(3)　198-208　2007/05

ISSN： 1933-6950

eISSN： 1933-6969
Probabilistic alignment detects remote homology in a pair of protein sequences without homologous sequence information Peer-reviewed

Ryotaro Koike, Kengo Kinoshita, Akinori Kidera

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　66　(3)　655-663　2007/02

DOI： 10.1002/prot.21240 　

ISSN： 0887-3585
ATTED-II: a database of co-expressed genes and cis elements for identifying co-regulated gene groups in Arabidopsis Peer-reviewed

Takeshi Obayashi, Kengo Kinoshita, Kenta Nakai, Masayuki Shibaoka, Shinpei Hayashi, Motoshi Saeki, Daisuke Shibata, Kazuki Saito, Hiroyuki Ohta

NUCLEIC ACIDS RESEARCH　35　(Database issue)　D863-D869　2007/01

DOI： 10.1093/nar/gkl783 　

ISSN： 0305-1048
Analyses of homo-oligomer interfaces of proteins from the complementarity of molecular surface, electrostatic potential and hydrophobicity Peer-reviewed

Yuko Tsuchiya, Kengo Kinoshita, Haruki Nakamura

PROTEIN ENGINEERING DESIGN & SELECTION　19　(9)　421-429　2006/09

DOI： 10.1093/protein/gzl026 　

ISSN： 1741-0126
PreBI: prediction of biological interfaces of proteins in crystals Peer-reviewed

Yuko Tsuchiya, Kengo Kinoshita, Nobutoshi Ito, Haruki Nakamura

NUCLEIC ACIDS RESEARCH　34　(Web Server issue)　W320-W324　2006/07

DOI： 10.1093/nar/gkl267 　

ISSN： 0305-1048
Analysis of the three dimensional structure of the CXGXC motif in the CMGCC and CAGYC regions of alpha- and beta-subunits of human chorionic gonadotropin: Importance of glycine residue (G) in the motif Peer-reviewed

K Kinoshita, M Kusunoki, K Miyai

ENDOCRINE JOURNAL　53　(1)　51-58　2006/02

DOI： 10.1507/endocrj.53.51 　

ISSN： 0918-8959
DBTGR: a database of tunicate promoters and their regulatory elements Peer-reviewed

Nicolas Sierro, Takehiro Kusakabe, Keun-Joon Park, Riu Yamashita, Kengo Kinoshita, Kenta Nakai

NUCLEIC ACIDS RESEARCH　34　(Database issue)　D552-D555　2006/01

DOI： 10.1093/nar/gkj064 　

ISSN： 0305-1048
P-cats: prediction of catalytic residues in proteins from their tertiary structures Peer-reviewed

K Kinoshita, M Ota

BIOINFORMATICS　21　(17)　3570-3571　2005/09

DOI： 10.1093/bioinformatics/bti561 　

ISSN： 1367-4803
PreDs: a server for predicting dsDNA-binding site on protein molecular surfaces Peer-reviewed

Y Tsuchiya, K Kinoshita, H Nakamura

BIOINFORMATICS　21　(8)　1721-1723　2005/04

DOI： 10.1093/bioinformatics/bti232 　

ISSN： 1367-4803
Identification of the ligand binding sites on the molecular surface of proteins Peer-reviewed

K Kinoshita, H Nakamura

PROTEIN SCIENCE　14　(3)　711-718　2005/03

DOI： 10.1110/ps.041080105 　

ISSN： 0961-8368
Solution structure of the RWD domain of the mouse GCN2 protein Peer-reviewed

N Nameki, M Yoneyama, S Koshiba, N Tochio, M Inoue, E Seki, T Matsuda, Y Tomo, T Harada, K Saito, N Kobayashi, T Yabuki, M Aoki, E Nunokawa, N Matsuda, N Sakagami, T Terada, M Shirouzu, M Yoshida, H Hirota, T Osanai, A Tanaka, T Arakawa, P Carninci, J Kawai, Y Hayashizaki, K Kinoshita, P Guntert, T Kigawa, S Yokoyama

PROTEIN SCIENCE　13　(8)　2089-2100　2004/08

DOI： 10.1110/ps.04751804 　

ISSN： 0961-8368
Probabilistic description of protein alignments for sequences and structures Peer-reviewed

R Koike, K Kinoshita, A Kidera

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　56　(1)　157-166　2004/07

DOI： 10.1002/prot.20067 　

ISSN： 0887-3585
Structure-based prediction of DNA-binding sites on proteins using the empirical preference of electrostatic potential and the shape of molecular surfaces Peer-reviewed

Y Tsuchiya, K Kinoshita, H Nakamura

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　55　(4)　885-894　2004/06

DOI： 10.1002/prot.20111 　

ISSN： 0887-3585
eF-site and PDBjViewer: database and viewer for protein functional sites Peer-reviewed

K Kinoshita, H Nakamura

BIOINFORMATICS　20　(8)　1329-1330　2004/05

DOI： 10.1093/bioinformatics/bth073 　

ISSN： 1367-4803
Finding evolutionary relations beyond superfamilies: Fold-based superfamilies Peer-reviewed

K Matsuda, T Nishioka, K Kinoshita, T Kawabata, N Go

PROTEIN SCIENCE　12　(10)　2239-2251　2003/10

DOI： 10.1110/ps0383603 　

ISSN： 0961-8368
Identification of protein biochemical functions by similarity search using the molecular surface database eF-site Peer-reviewed

K Kinoshita, H Nakamura

PROTEIN SCIENCE　12　(8)　1589-1595　2003/08

DOI： 10.1110/ps.0368703 　

ISSN： 0961-8368
Crystal structure of the conserved protein TT1542 from Thermus thermophilus HB8 Peer-reviewed

N Handa, T Terada, Y Kamewari, H Hamana, JRH Tame, SY Park, K Kinoshita, M Ota, H Nakamura, S Kuramitsu, M Shirouzu, S Yokoyama

PROTEIN SCIENCE　12　(8)　1621-1632　2003/08

DOI： 10.1110/gad.03104003 　

ISSN： 0961-8368
Protein informatics towards function identification Peer-reviewed

K Kinoshita, H Nakamura

CURRENT OPINION IN STRUCTURAL BIOLOGY　13　(3)　396-400　2003/06

DOI： 10.1016/S0959-440X(03)00074-5 　

ISSN： 0959-440X
Prediction of catalytic residues in enzymes based on known tertiary structure, stability profile, and sequence conservation Peer-reviewed

M Ota, K Kinoshita, K Nishikawa

JOURNAL OF MOLECULAR BIOLOGY　327　(5)　1053-1064　2003/04

DOI： 10.1016/S0022-2836(03)00207-9 　

ISSN： 0022-2836
Ring and zipper formation is the key to understanding the structural variety in all-beta proteins Peer-reviewed

R Koike, K Kinoshita, A Kidera

FEBS LETTERS　533　(1-3)　9-13　2003/01

DOI： 10.1016/S0014-5793(02)03729-8 　

ISSN： 0014-5793

eISSN： 1873-3468
Key amino acid residues required for aryl migration catalysed by the cytochrome P450 2-hydroxyisoflavanone synthase Peer-reviewed

Y Sawada, K Kinoshita, T Akashi, T Aoki, S Ayabe

PLANT JOURNAL　31　(5)　555-564　2002/09

DOI： 10.1046/j.1365-313X.2002.01378.x 　

ISSN： 0960-7412
[Insight into the relation between protein structure and function] Peer-reviewed

Kengo Kinoshita

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　47　(8 Suppl)　1064-1070　2002/06
Publisher: 8 Suppl
ISSN： 0039-9450
Intramolecular interaction of SUR2 subtypes for intracellular ADP-induced differential control of K-ATP channels Peer-reviewed

K Matsushita, K Kinoshita, T Matsuoka, A Fujita, T Fujikado, Y Tano, H Nakamura, Y Kurachi

CIRCULATION RESEARCH　90　(5)　554-561　2002/03

DOI： 10.1161/01.RES.0000012666.42782.30 　

ISSN： 0009-7330
Analysis of Complementarity of Protein-DNA Interactions Using the Electrostatic Potential and the Molecular Surface Geometry

Tsuchiya Yuko, Kinoshita Kengo, Nakamura Haruki

GI　13　310-311　2002
Publisher: Japanese Society for Bioinformatics
DOI： 10.11234/gi1990.13.310 　

ISSN： 0919-9454
Identification of protein functions from a molecular surface database, eF-site Peer-reviewed

Kengo Kinoshita, Jun'ichi Furui, Haruki Nakamura

Journal of Structural and Functional Genomics　2　(1)　9-22　2002
Publisher: 1
DOI： 10.1023/A:1011318527094 　

ISSN： 1345-711X
スルフォニル尿素受容体第二ヌクレオチド結合ドメインの機能と構造モデル

松下賢治, 松岡哲郎, 藤田秋一, 木下賢吾, 中村春木, 倉智嘉久

生化学　73　(8)　1018-1018　2001/08
Publisher: (公社)日本生化学会
ISSN： 0037-1017
Analysis of Complementarity of Protein-Protein and Protein-DNA Interactions Using the Molecular Surface Database, eF-site

Kinoshita Kengo, Tsuchiya Yuko, Nakamura Haruki

GI　12　345-347　2001
Publisher: Japanese Society for Bioinformatics
DOI： 10.11234/gi1990.12.345 　

ISSN： 0919-9454
Two basic residues, Lys-107 and Lys-118, of RuvC resolvase are involved in critical contacts with the Holliday junction for its resolution Peer-reviewed

M Yoshikawa, H Iwasaki, K Kinoshita, H Shinagawa

GENES TO CELLS　5　(10)　803-813　2000/10

DOI： 10.1046/j.1365-2443.2000.00371.x 　

ISSN： 1356-9597
Comparison of Geometries and Properties of Protein Molecular Surface for Structure-Based Function Prediction

Kinoshita Kengo, Furui Jun'ichi, Nakamura Haruki

GI　11　428-429　2000
Publisher: Japanese Society for Bioinformatics
DOI： 10.11234/gi1990.11.428 　

ISSN： 0919-9454
Diversity of functions of proteins with internal symmetry in spatial arrangement of secondary structural elements Peer-reviewed

K Kinoshita, A Kidera, N Go

PROTEIN SCIENCE　8　(6)　1210-1217　1999/06

DOI： 10.1110/ps.8.6.1210 　

ISSN： 0961-8368
Structural motif of phosphate-binding site common to various protein superfamilies: all-against-all structural comparison of protein–mononucleotide complexes Peer-reviewed

Kengo Kinoshita, Keishi Sadanami, Akinori Kidera, Nobuhiro Go

Protein Engineering, Design and Selection　12　(1)　11-14　1999/01

DOI： 10.1093/protein/12.1.11 　

ISSN： 1741-0126

eISSN： 1741-0134

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Misc. 134

Author Correction: PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity. International-journal

Hiroki Sekine, Haruna Takeda, Norihiko Takeda, Akihiro Kishino, Hayato Anzawa, Takayuki Isagawa, Nao Ohta, Shohei Murakami, Hideya Iwaki, Nobufumi Kato, Shu Kimura, Zun Liu, Koichiro Kato, Fumiki Katsuoka, Masayuki Yamamoto, Fumihito Miura, Takashi Ito, Masatomo Takahashi, Yoshihiro Izumi, Hiroyuki Fujita, Hitoshi Yamagata, Takeshi Bamba, Takaaki Akaike, Norio Suzuki, Kengo Kinoshita, Hozumi Motohashi

Nature metabolism　6　(12)　2391-2391　2024/12

DOI： 10.1038/s42255-024-01183-9 　
Whole genome sequence-based association of cognitivedecline and retinal thickness in the Japanese population International-journal

Makiko Taira, Nobuo Fuse, Andrew J Saykin, Fuji Nagami, Kengo Kinoshita, Masayuki Yamamoto

Alzheimer's & dementia : the journal of the Alzheimer's Association　20 Suppl 1　e093405　2024/12

DOI： 10.1002/alz.093405 　

More details Close

BACKGROUND: Dementia is age-related with a significant genetic contribution, yet genome-wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole-genome sequencing (WGS) data in the Japanese population may reveal population-specific susceptibility loci for dementia. Retinal imaging with optical coherence tomography (OCT) is noninvasive, reproducible, and can detect thinning associated with progressive neurodegeneration. Association of population-specific genetic susceptibility loci with retinal thinning and cognitive decline may reveal novel aspects of dementia risk and pathophysiology. METHOD: Among participants with WGS data from the Tohoku Medical Megabank Organization (ToMMo) Ophthalmology Study ("ToMMo Eye Study"), individuals with adequate quality data on retinal nerve fiber layer and ganglion cell layer thickness from spectral-domain optical coherence tomography (SD-OCT) scans were selected. Since retinal thinning also occurs in glaucoma, we performed a GWAS using age, sex, and 10 principal components as covariates using SAGE1.2 to obtain a set of genes responsible for glaucoma and confirm that the genotyping was successful. We then attempted to identify susceptibility loci for cognitive decline by using (1) the Mini-Mental State Examination, Japanese version (MMSE-J), (2) the Montreal Cognitive Assessment, Japanese version (MoCA-J), and (3) the Mini-COG© (a simple screening for early detection of dementia, Japanese version) scores as associated factors, respectively. Furthermore, these validation results were also compared with those obtained from GWAS using imputation data performed on custom arrays (Japonica ArrayTM, v2 or NEO) for Japanese. RESULT: 84 significant (p < 5.0E-8) genome-wide susceptibility loci (hg38) of RNFL were detected on 14K WGS-based study (the top hit locus: Chr14, SIX6 gene, P = 4.50E-46). There were many genetic loci that have already been reported to be associated with glaucoma susceptibility, including the above locus. Among the results of GWAS for cognitive decline combining the three cognitive scores after normalization to z-scores, several loci have shown significant susceptibility in both of RNFL and cognitive rating scale. Some loci suggested more than a high or moderate effect of altering protein efficacy. CONCLUSION: We present an initial WGS-based genetic study of retinal thickness and cognitive decline in the Japanese population.
Functional characterization of 27 CYP2E1 variants identified in 8,380 Japanese indivisuals

大森悠生, 菱沼英史, 菱沼英史, 上田昭子, 山崎柊紀, 鈴木祐眞, 佐藤裕, 仲吉朝希, 小田彰史, 斎藤さかえ, 斎藤さかえ, 田高周, 木下賢吾, 木下賢吾, 木下賢吾, 平澤典保, 平澤典保, 平澤典保, 平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘

日本薬学会年会要旨集(Web)　144th　2024

ISSN： 0918-9823
人工呼吸器購入にあたり多角的に選定した過程と結果

黒澤和希, 佐羽内哲也, 西大路久美子, 田中正幸, 丹呉康典, 坂元楓, 諸橋貴史, 八木下賢吾, 川島陸歩

日本臨床工学技士会会誌　(82)　2024

ISSN： 1341-3171
Genome-wide association study of central corneal thickness in the cohort Study

布施昇男, 安澤隼人, 元池育子, 櫻井美由紀, 木下賢吾, 山本雅之

日本眼科学会雑誌　128　2024

ISSN： 0029-0203
神経変性症患者および一般住民に見出された新規B4GALNT1(GM2合成酵素)バリアントの機能解析

稲森啓一郎, 宍戸史, 許家甄, 永福正和, 新田昂大, 中村勝哉, 中村勝哉, 土田奈緒美, 池田淳司, 小平農, 栂谷内晶, 古川潤一, 山口芳樹, 木下聖子, 要匡, 中村豊, 大野勲, 中村雅彦, 下畑享良, 松本直通, 古庄知己, 古庄知己, 関島良樹, 木下賢吾, 西原祥子, 井ノ口仁一

脂質生化学研究　66　2024

ISSN： 0285-1520
日本人約6万人の血清総IgE値のGWAS並びにMHC関連解析

志藤光介, 志藤光介, 志藤光介, 小島要, 木下賢吾

アレルギー　73　(6/7)　2024

ISSN： 0021-4884
重症喘息患者を対象とした全血網羅的遺伝子発現解析;好中球活性化の関与

鈴木眞奈美, 山田充啓, 藤野直也, 吉良聡, 笠澄望, 元池育子, 元池育子, 上出庸介, 関谷潔史, 小林誠一, 佐藤輝幸, 松本周一郎, 小野祥直, 今野周一, 遠藤卓人, 玉田勉, 谷口正実, 勝岡史城, 木下賢吾, 杉浦久敏

アレルギー　73　(6/7)　2024

ISSN： 0021-4884
Functional characterization of 27 DPD variants identified in 8,380 Japanese individuals

寺内健人, 菱沼英史, 菱沼英史, 上田昭子, 小渕開, 前川正充, 前川正充, 佐藤裕, 齋藤さかえ, 齋藤さかえ, 田高周, 木下賢吾, 木下賢吾, 木下賢吾, 平澤典保, 平澤典保, 平澤典保, 平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘

日本薬学会年会要旨集(Web)　144th　2024

ISSN： 0918-9823
Functional analysis of novel variants of glycosyltransferases involved in ganglioside synthesis

稲森啓一郎, 宍戸史, 山口芳樹, 木下賢吾, 西原祥子, 井ノ口仁一

日本糖質学会年会要旨集　43rd　2024
血漿メタボローム解析を用いた婦人科癌におけるバイオマーカーの探索

菱沼英史, 菱沼英史, 島田宗昭, 島田宗昭, 島田宗昭, 松川直美, 萩原達也, 工藤敬, 渋谷祐介, 重田昌吾, 元池育子, 元池育子, 徳永英樹, 徳永英樹, 木下賢吾, 木下賢吾, 木下賢吾, 小柴生造, 小柴生造, 八重樫伸生, 八重樫伸生, 八重樫伸生

日本婦人科腫瘍学会学術講演会プログラム・抄録集(Web)　66th　2024
出生三世代コホートにおける7人家族のエピゲノム研究基盤構築

美辺詩織, 小巻翔平, 大桃秀樹, 高嶋聰, 小野加奈子, 山崎弥生, 須藤洋一, 田高周, 水野聖士, 石黒真美, 工藤久智, 小原拓, 熊田和貴, 勝岡史城, 荻島創一, 木下賢吾, 菅原準一, 栗山進一, 清水厚志

日本抗加齢医学会総会プログラム・抄録集　23回　252-252　2023/06
Publisher: (一社)日本抗加齢医学会
視覚特別援学校におけるSDGsの認知度調査

秋葉玲希, 中西孝幸, 木下歩, 小橋裕次郎, 萩原直樹, 森廣賢吾, 和田恒彦, 徳竹忠司, 浜田淳, 緒方昭広

筑波大学理療科教員養成施設紀要　8　(1)　2023

ISSN： 2423-9453
視覚障害者がSDGsボードゲームを操作する時の困難事項の抽出とその対策の検討

秋葉玲希, 中西孝幸, 木下歩, 小橋裕次郎, 萩原直樹, 森廣賢吾, 和田恒彦, 徳竹忠司, 浜田淳, 緒方昭広

筑波大学理療科教員養成施設紀要　8　(1)　2023

ISSN： 2423-9453
遺伝の基礎 11.ゲノムデータベース大規模ゲノムデータセット

鎌谷洋一郎, 河合洋介, 木下賢吾, 木下賢吾

日本医師会雑誌　152　2023

ISSN： 0021-4493
AlphaFoldDBの予測立体構造を用いた遠縁のホモログタンパク質の認識

川端猛, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　23rd (CD-ROM)　2023
Glycemic traits and POAG: Mendelian randomization study in a Japanese population

羽入田明子, 羽入田明子, 後藤温, 後藤温, 中杤昌弘, 若井建志, 清水厚志, 丹野高三, 木下賢吾, 寶澤篤, 伊藤秀美, 松尾恵太郎, 結城賢弥, 結城賢弥, 坪田一男, 坪田一男, 根岸一乃, 岩崎基

日本眼科学会雑誌　127　2023

ISSN： 0029-0203
Functional analysis of novel mutation and variants in the hereditary spastic paraplegia causative gene B4GALNT1

稲森啓一郎, 宍戸史, HSU Jia-Chen, 永福正和, 新田昂大, 中村勝哉, 中村勝哉, 土田奈緒美, 池田淳司, 小平農, 栂谷内晶, 古川潤一, 山口芳樹, 木下聖子, 要匡, 中村豊, 大野勲, 中村雅彦, 下畑享良, 松本直通, 古庄知己, 古庄知己, 関島良樹, 木下賢吾, 西原祥子, 井ノ口仁一

日本糖質学会年会要旨集　42nd　2023
ツイート頻度系列に基づく休息-活動リズムの大規模・グローバル解析

中尾光之, 中尾光之, 高橋容市, 辛島彰洋, 元池育子, 片山統裕, 木下賢吾, 木下賢吾, 乾健太郎, 乾健太郎

日本睡眠学会定期学術集会プログラム・抄録集　45th　2023
当院におけるカテーテルアブレーション業務の現状と課題

黒澤和希, 川島陸歩, 八木下賢吾, 坂元楓, 丹呉康典, 田中正幸, 西大路久美子, 佐羽内哲也

埼玉県臨床工学技士会会誌　45　2023
Inspection of metabolome-GWAS with metabolic pathway simulations

小舘俊, 小舘俊, 佐藤允治, 元池育子, 木下賢吾

日本分子生物学会年会プログラム・要旨集(Web)　46th　2023
海馬周辺の脳容積値と関連する血中メタボロームの探索

佐藤和, 藤原和樹, 長尾健児, 今泉明, 小柴生造, 佐藤允治, 元池育子, 木下賢吾, 山本雅之

Dementia Japan　37　(4)　2023

ISSN： 1342-646X
血中代謝プロファイルに遺伝・環境要因が与える影響の解析

小柴生造, 小柴生造, 元池育子, 元池育子, 菱沼英史, 菱沼英史, 青木裕一, 櫻井美由紀, 佐藤允治, 七谷圭, 七谷圭, 田高周, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

日本生化学会大会(Web)　96th　2023
遺伝性痙性対麻痺SPG26原因遺伝子B4GALNT1の新規変異およびバリアントの機能解析

稲森啓一郎, 宍戸史, 許家甄, 永福正和, 新田昂大, 中村勝哉, 中村勝哉, 土田奈緒美, 池田淳司, 小平農, 栂谷内晶, 古川潤一, 山口芳樹, 木下聖子, 要匡, 中村豊, 大野勲, 中村雅彦, 下畑享良, 松本直通, 古庄知己, 古庄知己, 関島良樹, 木下賢吾, 西原祥子, 井ノ口仁一

日本生化学会大会(Web)　96th　2023
Prospects for Structural Biology and Drug Development in the Post-AI Era

木下賢吾, 木下賢吾

CBI学会大会(CD-ROM)　2023　2023
東北メディカル・メガバンク計画におけるゲノム・オミックス参照パネルの構築

木下賢吾

日本人類遺伝学会大会(CD-ROM)　68th　2023
Functional characterization of CYP2B6 rare variants identified in 8,380 Japanese individuals

山崎柊紀, 菱沼英史, 菱沼英史, 上田昭子, 前川正充, 前川正充, 前川正充, 佐藤裕, 公文代將希, 眞野成康, 眞野成康, 仲吉朝希, 小田彰史, 齋藤さかえ, 齋藤さかえ, 田高周, 田高周, 木下賢吾, 木下賢吾, 木下賢吾, 平澤典保, 平澤典保, 平澤典保, 平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘

日本薬学会年会要旨集(Web)　143rd　2023

ISSN： 0918-9823
大規模ゲノム解析データを活用した日本人DPD活性予測パネルの構築

菱沼英史, 菱沼英史, 小渕開, 寺内健人, 上田昭子, 田高周, 齋藤さかえ, 前川正充, 木下賢吾, 平澤典保, 平塚真弘, 齋藤さかえ, 前川正充, 木下賢吾, 平澤典保, 平塚真弘, 平澤典保, 平塚真弘, 平塚真弘

日本薬学会東北支部大会講演要旨集　62nd　2023
Data-sharing by Data-visiting model. A proposal to realize data sharing of divergent, big and sensitive data

木下賢吾, 木下賢吾, 木下賢吾, 岡村容伸, 岡村容伸

実験医学　40　(6)　2022

ISSN： 0288-5514
患者由来IPMNオルガノイドとゲノム解析を用いた増殖形態の解明

椎原正尋, 石川智彦, 大森優子, 元井冬彦, 森川孝則, 中川圭, 林洋毅, 水間正道, 大塚英郎, 岡村容伸, 木下賢吾, 海野倫明, 古川徹

日本外科学会定期学術集会(Web)　122nd　2022
ゲノム情報の持つ可能性と東北大学での未来型医療への挑戦

木下賢吾, 木下賢吾

日本法科学技術学会誌　27　(Supplement)　2022

ISSN： 1880-1323
長鎖リードシークエンス技術を用いた日本人構造多型パネルJSV1の構築

大槻晃史, 大槻晃史, 岡村容伸, 岡村容伸, 勝岡史城, 勝岡史城, 木下賢吾, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

日本生化学会大会(Web)　95th　2022
Survey of Price Formation Factors of Rental Properties for Single Households in Sendai City.

溝井祥太, 西羽美, 木下賢吾

地理情報システム学会講演論文集(CD-ROM)　31　2022
東北メディカル・メガバンク計画におけるゲノム解析とデータの利活用

木下賢吾, 木下賢吾

日本人類遺伝学会大会(CD-ROM)　67th　2022
メンデルのランダム化法による血中脂質と大腸がんの関係の検討

岩上将夫, 後藤温, 鈴木詩織, 片桐諒子, 羽入田明子, 山地太樹, 澤田典絵, 中杤昌弘, 若井建志, 須藤洋一, 清水厚志, 丹野高三, 木下賢吾, 寳澤篤, 伊藤秀美, 松尾恵太郎, 岩崎基, J-CGEグループ

Journal of Epidemiology　32　(Suppl.1)　155-155　2022/01
Publisher: (一社)日本疫学会
ISSN： 0917-5040

eISSN： 1349-9092
メンデルのランダム化法による糖代謝指標と大腸がんの関連解析

羽入田明子, 後藤温, 鈴木詩織, 片桐諒子, 岩上将夫, 山地太樹, 澤田典絵, 中杤昌弘, 若井建志, 須藤洋一, 清水厚志, 丹野高三, 木下賢吾, 寳澤篤, 伊藤秀美, 松尾恵太郎, 岩崎基

Journal of Epidemiology　32　(Suppl.1)　155-155　2022/01
Publisher: (一社)日本疫学会
ISSN： 0917-5040

eISSN： 1349-9092
Protein Scientists Meet Genome Science:東北メディカル・メガバンク計画におけるタンパク質科学

山本雅之, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　21st　2021
Construction of infrastructure for medical bigdata analyses in large scale genome cohort studies

木下賢吾, 木下賢吾

実験医学　39　(7)　2021

ISSN： 0288-5514
Comprehensive extraction and analysis of the whole human glycan-related gene variant

西原祥子, 木下聖子, 栂谷内晶, 細田正恵, 伊藤和義, 山口芳樹, 真鍋法義, 大野詩歩, 稲森啓一郎, 井ノ口仁一, 灘中里美, 北川裕之, 城田松之, 木下賢吾

日本糖質学会年会要旨集　40th　2021
転写因子NRF2の持続的活性化によるエンハンサーリモデリングと腫瘍幹細胞性の増強

岡崎慶斗, 安澤隼人, 岡田克典, 鈴木貴, 木下賢吾, 関根弘樹, 本橋ほづみ

日本生化学会大会(Web)　94th　2021
東北メディカル・メガバンク計画におけるデータセキュリティと利活用促進での取り組み

木下賢吾, 木下賢吾

日本内視鏡外科学会総会(Web)　34th　2021
膵胆道癌オルガノイドの個別化医療モデルへの活用

椎原正尋, 椎原正尋, 樋口亮太, 岡村容伸, 木下賢吾, 山本雅一, 元井冬彦, 海野倫明, 古川徹

日本癌学会学術総会抄録集(Web)　80th　2021
Impact of sarcopenia on prognosis of elderly patients with DLBCL who received R-CHOP therapy

中村智幸, 太田賢吾, 楠本茂, 大橋一也, 河合秋美, 熊西亮介, 白神一秀, 大岩加奈, 鈴木智貴, 木下史緒理, 伊藤旭, 李政樹, 小松弘和, 芝本雄太, 飯田真介

日本血液学会学術集会抄録(Web)　83rd　2021
東北メディカル・メガバンク計画における大規模ゲノム解析とAI技術の活用

木下賢吾, 木下賢吾

日本人類遺伝学会大会(CD-ROM)　66th　2021
代謝プロファイルに影響を与える遺伝要因の網羅的解析

小柴生造, 小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 井上仁, 菱沼英史, 青木裕一, 青木裕一, 田高周, 田高周, 城田松之, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

日本生化学会大会(Web)　94th　2021
バイオバンク情報を活用した40種のCYP3A4バリアントにおける機能変化解析

平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘, 公文代將希, 公文代將希, GUTIERREZ Evelyn, 菱沼英史, 菱沼英史, 上田昭子, 齋藤さかえ, 齋藤さかえ, 三枝大輔, 三枝大輔, 田高周, 木下賢吾, 木下賢吾, 仲吉朝希, 小田彰史, 前川正充, 眞野成康, 平澤典保, 平澤典保, 平澤典保

日本人類遺伝学会大会プログラム・抄録集　66th (CD-ROM)　2021
Organoid培養とゲノム解析を用いた膵胆道癌の個別化医療システムの開発

椎原正尋, 碇直樹, 樋口亮太, 山本雅一, 森川孝則, 中川圭, 林洋毅, 水間正道, 大塚英郎, 元井冬彦, 元井冬彦, 海野倫明, 岡村容伸, 木下賢吾, 古川徹

日本外科学会定期学術集会(Web)　121st　2021
子宮体癌における血漿メタボローム解析によるバイオマーカーの探索

辻圭太, 島田宗昭, 菱沼英史, 重田昌吾, 李賓, 宮原周子, 土岐麻実, 工藤敬, 徳永英樹, 小柴生造, 木下賢吾, 山本雅之, 八重樫伸生

日本婦人科腫瘍学会雑誌　39　(1)　2021

ISSN： 1347-8559
がん代謝を標的とした卵巣癌におけるバイオマーカーの探索

工藤敬, 島田宗昭, 菱沼英史, 重田昌吾, 李賓, 宮原周子, 土岐麻実, 辻圭太, 徳永英樹, 小柴生造, 木下賢吾, 山本雅之, 八重樫伸生

日本婦人科腫瘍学会雑誌　39　(1)　2021

ISSN： 1347-8559
Applications of artificial intelligence in psychiatry.

米澤賢吾, 木下翔太郎, 岸本泰士郎

月刊脳神経内科　93　(6)　2020

ISSN： 2434-3285
日本人4776人の全ゲノム解析により同定された18種のCYP3A4遺伝子多型に由来するバリアント酵素の機能変化解析

公文代將希, GUTIERREZ Evelyn, 菱沼英史, 菱沼英史, 齋藤さかえ, 田高周, 木下賢吾, 前川正充, 前川正充, 三枝大輔, 三枝大輔, 仲吉朝希, 小田彰史, 平澤典保, 平澤典保, 平澤典保, 平塚真弘, 平塚真弘, 平塚真弘, 平塚真弘

臨床薬理　51　(Supplement)　2020

ISSN： 0388-1601
大規模ゲノムコホート調査におけるBRCA1/2遺伝子の病的バリアント保持者への遺伝情報回付に関する課題

濱中洋平, 石田孝宣, 布施昇男, 川目裕, 山口由美, 安田純, 多田寛, 宮下穣, 原田成美, 佐藤章子, 青木洋子, 長神風二, 八重樫伸生, 木下賢吾, 呉繁夫, 山本雅之

日本乳癌学会総会プログラム抄録集　27回　332-332　2019/07
Publisher: (一社)日本乳癌学会
網羅的構造解析による機能関連天然変性蛋白質の探索

大森聡, 西羽美, 木下賢吾

日本細胞生物学会大会(Web)　71st　2019
網羅的ヒトSLCトランスポーターデータベースCASLcDB

西羽美, 花園祐矢, 山田和範, 山形仁, 木下賢吾

日本分子生物学会年会プログラム・要旨集(Web)　42nd　2019
染色体整列因子CAMP(CHAMP1)欠損による知的障害発症メカニズムの解明

永井正義, 永井正義, 家村顕自, 服部聡子, 吉川貴子, 萩原英雄, 安澤隼人, 木下賢吾, 大隅典子, 宮川剛, 田中耕三

日本分子生物学会年会プログラム・要旨集(Web)　42nd　2019
Estimating frequency of pathogenic variants in a Japanese population by using the whole-genome reference panel of ToMMo

Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N. Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

HUMAN GENOMICS　12　2018/03

ISSN： 1473-9542

eISSN： 1479-7364
Structural Basis for the Membrane Association of Ankyrin

藤原祐一郎, 近藤寛子, 城田松之, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾

生物物理(Web)　58　(3)　2018

ISSN： 1347-4219
電位依存性カリウムチャネル変異体の電位依存的な不活性化機構の解析

近藤寛子, 城田松之, 城田松之, 城田松之, 鷹野優, 木下賢吾, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　18th　2018
ゲノム情報と連携した日本人多層オミックス参照パネルの意義

小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 城田松之, 城田松之, 青木裕一, 青木裕一, 田高周, 田高周, 斎藤智, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之

糖尿病(Web)　61　(Suppl)　2018

ISSN： 1881-588X
遠隔セキュリティルームからスーパーコンピュータへの接続サービスの展開事例

長瀬祥子, 中村直毅, 伊藤和哉, 葭葉純子, 齊藤智, 木下賢吾, 冨永悌二

医療情報学連合大会プログラム・抄録集　37th　310　2017/11
3次元Lattice構造の比較分類

加賀谷祐輝, 城田松之, 城田松之, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　17th　2017
低頻度一塩基多型のタンパク質立体構造を利用した機能アノテーションに向けて

城田松之, 木下賢吾, 木下賢吾, 木下賢吾

日本生化学会大会(Web)　90th　2017
天然変性領域の網羅的探索および機構解析

大森聡, 西羽美, 村上洋一, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　17th　2017
SR-B1はシリカ粒子認識およびインフラマソーム活性化に関与する

中山勝文, 継田美里, 森本展行, 木下賢吾, 木下賢吾

日本Cell Death学会学術集会プログラム抄録集　26th　2017
遺伝子共発現ネットワークにおけるタンパク質細胞内局在の影響

青木裕一, 青木裕一, 大林武, 木下賢吾, 木下賢吾

日本生化学会大会(Web)　90th　2017
VR技術を用いた生体分子の可視化システムの開発

佐藤広夢, 西羽美, 大森聡, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　17th　2017
電位依存性カリウムチャネル変異体の電位依存的な構造変化の解析

近藤寛子, 鷹野優, 木下賢吾, 木下賢吾, 木下賢吾

分子シミュレーション討論会講演要旨集　31st　2017
Play with 3D structure data of biomolecules - PDBj

Hirofumi Suzuki, Gert-Jan Bekker, Takahiro Kudo, Akira R. Kinjo, Kengo Kinoshita, Genji Kurisu, Haruki Nakamura

ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES　73　C579-C579　2017

DOI： 10.1107/S205327331708994X 　

ISSN： 2053-2733
遠隔セキュリティエリアからスーパーコンピュータへの接続サービス-全国展開の事例-

長瀬祥子, 長瀬祥子, 中村直毅, 中村直毅, 伊藤和哉, 葭葉純子, 齊藤智, 木下賢吾, 木下賢吾, 冨永悌二, 冨永悌二

医療情報学連合大会論文集(CD-ROM)　37th　2017

ISSN： 2433-698X
A study of dynamics of palmitoylated Ankyrin-G around a lipid bilayer by coarse-grained simulations Peer-reviewed

Kondo XH, Fujiwara Y, Shirota M, Kinoshita K

Journal of Physiological Sciences　67　(Supplement1)　S43　2017
マルチオミクスが解き明かす疾患生物学日本人多層オミックス参照パネルの拡張

小柴生造, 三枝大輔, 元池育子, 小島要, 城田松之, 齋藤智, 勝岡史城, 河合洋介, 山口由美, 田邉修, 長崎正郎, 安田純, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　89回　[1S05-5]　2016/09
Publisher: (公社)日本生化学会
ヒトゲノム一塩基変異のタンパク質構造からの理解:Exome6500とJPN1Kを例に

西羽美, 中田純一, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　16th　2016
薬物によるKir1.1チャネル選択的阻害の構造基盤

古谷和春, 半田健一郎, 村上洋一, 村上洋一, 木下賢吾, 倉智嘉久

日本薬理学会近畿部会プログラム・要旨集　129th　2016
日本人多層オミックス参照パネルの公開

小柴生造, 加藤恭丈, 三枝大輔, 元池育子, 城田松之, 斎藤智, 田邉修, 安田純, 木下賢吾, 山本雅之

日本生化学会大会(Web)　88th　4T21L-07(3P0816) (WEB ONLY)-07(3P0816)]　2015/12
Publisher: (公社)日本生化学会
LC‐MSによる大規模コホートメタボローム解析

三枝大輔, 加藤恭丈, 小柴生造, 元池育子, 荻島創一, 本橋ほづみ, 菅原準一, 中谷純, 寳澤篤, 峯岸直子, 木下賢吾, 田邉修, 山本雅之

日本農芸化学会大会講演要旨集(Web)　2015　4SY19-2 (WEB ONLY)　2015/03/05

ISSN： 2186-7976
電位依存性プロトンチャネルVSOPにおける亜鉛イオンの影響

近藤寛子, 近藤寛子, 城田松之, 城田松之, 城田松之, 米澤康滋, 米澤康滋, 鷹野優, 鷹野優, 木下賢吾, 木下賢吾, 木下賢吾, 木下賢吾

分子シミュレーション討論会講演要旨集　29th　2015
電位依存性プロトンチャネルVSOPにおける亜鉛イオンの役割についての計算機シミュレーション

近藤寛子, 城田松之, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　15th　2015
Plasma proteome analysis for a large-scale population-based cohort study

Katoh Yasutake, Koshiba Seizo, Igarashi Kazuhiko, Yamamoto Masayuki, Tanabe Osamu, Ebina Masayuki, Shirota Matsuyuki, Motoike Ikuko, Kinoshita Kengo, Kudo Hisaaki, Nobukuni Takahiro, Minegishi Naoko, Saigusa Daisuke

Abstracts for Annual Meeting of Japanese Proteomics Society　2015　(0)　62-62　2015
Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)
DOI： 10.14889/jhupo.2015.0.62.0 　
Effect of protein structure and genome sequence in variant analysis

Matsuyuki Shirota, Kengo Kinoshita

GENES & GENETIC SYSTEMS　89　(6)　292-292　2014/12

ISSN： 1341-7568

eISSN： 1880-5779
大規模住民コホート研究のためのLC‐MS/MS血漿プロテオーム解析の標準化

加藤恭丈, 蝦名真行, 城田松之, 木下賢吾, 五十嵐和彦, 田邉修, 山本雅之

日本生化学会大会(Web)　87th　3P-505 (WEB ONLY)-505]　2014/10
Publisher: (公社)日本生化学会
眼疾患と遺伝子緑内障のゲノム解析次世代医療・個別化医療に向けて

布施昇男, 清水愛, 木村雅恵, 高野良真, 石棟, 宮澤晃子, 国松志保, 劉孟林, 渡邉亮, 安田正幸, 横山悠, 檜森紀子, 津田聡, 山本耕太郎, 中澤徹, 安田純, 勝岡史城, 小島要, 成相直樹, 松本光代, 元池育子, 長崎正朗, 木下賢吾, 五十嵐和彦, 山本雅之, 新堀哲也, 青木洋子, 松原洋一, 舟山亮, 長嶋剛史, 中山啓子, 眞島行彦, 船山智代, 田中光一, 原田高幸, 阿部春樹, 福地健郎, 安田典子, 出田秀尚, 鄭暁東, 白石敦, 大橋裕一, 石田誠夫, 原岳, 金森章泰, 山田裕子, 中村誠, 酒井寛, Richards Julia E

日本眼科学会雑誌　118　(3)　216-240　2014/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
タンパク質機能解析に向けた立体構造情報の活用基盤の構築

木下賢吾, 木下賢吾, 木下賢吾, 村上洋一, 城田松之, 城田松之

日本農芸化学会大会講演要旨集(Web)　2014　2014

ISSN： 2186-7976
The standardization of parameters for plasma proteome samples in a large clinical cohort

Katoh Yasutake, Ebina Masayuki, Shirota Matsuyuki, Kinoshita Kengo, Igarashi Kazuhiko, Tanabe Osamu

Abstracts for Annual Meeting of Japanese Proteomics Society　2014　(0)　111-111　2014
Publisher: Japanese Proteomics Society (Japan Human Proteome Organisation)
DOI： 10.14889/jhupo.2014.0.111.0 　
遺伝子発現量データを利用した表現型の違いに影響を及ぼす遺伝子セットの検出方法の開発

土多隆雄, 大林武, 木下賢吾

研究報告バイオ情報学（BIO）　2013　(7)　1-2　2013/03/14

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マイクロアレイ解析では遺伝子単独の発現量変化に対して統計学的仮説検定を行うことで、表現型の違いに影響を及ぼす遺伝子を検出することが多い．しかし、実際には遺伝子は複数で相互に関わりあいながら機能することから、遺伝子単独ではなく複数の遺伝子による発現パターン変化にも着目する必要があるといえる．そこで、本研究では複数の遺伝子による発現パターン変化を検出する手法を新たに開発し、肺がんに関する遺伝子発現量データを用いて先行研究で提案されている手法との比較解析を行った．その結果、先行研究で提案されている手法では検出されない発現パターン変化を示す遺伝子ペアを検出することができた．
Identification of functional modules in protein networks by near-clique detection

2013　(4)　1-2　2013/03/14
Gene module detection from the conservation of gene coexpression patterns among species

2013　(5)　1-2　2013/03/14
タンパク質構造機能相関再考分子動力学シミュレーションによるタンパク質動的構造の解明:電位依存カリウムチャネルでの適用を例として

笠原浩太, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾

生化学　85　(8)　2013

ISSN： 0037-1017
低分子化合物との相互作用に必要なPDZドメインのアミノ酸残基の同定

天野剛志, 天野剛志, 合田名都子, 合田名都子, 岩谷奈央子, 木下賢吾, 木下賢吾, 木下賢吾, 太田元規, 太田元規, 廣明秀一, 廣明秀一

日本蛋白質科学会年会プログラム・要旨集　13th　2013
PDZドメイン-低分子化合物相互作用に重要なアミノ酸残基の同定

天野剛志, 合田名都子, 岩谷奈央子, 木下賢吾, 木下賢吾, 太田元規, 廣明秀一

Abstracts. Annual Meeting of the NMR Society of Japan　52nd　2013
乳癌における針生検と手術摘出標本の病理学的因子の比較-針生検の有用性と限界

山之内孝彰, 南恵樹, 崎村千香, 川上総子, 林田直美, 金高賢吾, 高槻光寿, 黒木保, 江口晋, 林徳真吉, 安部邦子, 木下直江

日本乳癌学会学術総会プログラム・抄録集　21st　2013
PDZドメイン-低分子化合物の相互作用解析

天野剛志, 合田名都子, 岩谷奈央子, 木下賢吾, 木下賢吾, 太田元規, 廣明秀一

日本分子生物学会年会プログラム・要旨集(Web)　36th　2013
Exploring the proton permeation pathway by using homology modeling and molecular dynamics simulation of the Hv1 proton channel

Matsuyuki Shirota, Susumu Chiba, Kota Kasahara, Kengo Kinoshita

JOURNAL OF PHYSIOLOGICAL SCIENCES　63　S55-S55　2013

ISSN： 1880-6546
Data-driven bioinformatics in the Biological Information Big bang

KINOSHITA kengo

IEICE technical report. Theoretical foundations of Computing　112　(272)　15-15　2012/10/24
Publisher: The Institute of Electronics, Information and Communication Engineers
Prediction of Protein-Protein Complex Structures Using a Docking Server, surFit

Eiji Kanamori, Yuko Tsuchiya, Yoichi Murakami, Joy Sarmiento, Shide Liang, Daron Standley, Matsuyuki Shirota, Kengo Kinoshita, Haruki Nakamura

PROTEIN SCIENCE　21　178-178　2012/08

ISSN： 0961-8368
公共の遺伝子発現データの二次利用

Obayashi T, Kinoshita K

Surgery Frontier　19　(2)　89-95　2012/06
Analysis of the Constraints on Amino Acid Pairs in Proteins

Matsuyuki Shirota, Kengo Kinoshita

IPSJ SIG technical reports　2012　(18)　1-2　2012/03/21
Publisher: Information Processing Society of Japan (IPSJ)
ISSN： 0919-6072

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Various constraints are imposed on amino acid sequences of native proteins in order to maintain their structures and functions. To clarify these constraints, we analyzed the propensities of amino acid pairs at particular sequence separations. As results, we found that identical amino acid pairs in local amino acid sequence occur more frequently than random in intrinsically disordered proteins, and that the occurrence of amino acid pairs are strongly dependent on the order of the two amino acids.
Comparative analysis of gene expression pattern between spieces

Yasunobu Okamura, Takeshi Obayashi, Kengo Kinoshita

IPSJ SIG technical reports　2012　(2)　1-2　2012/03/21
Publisher: Information Processing Society of Japan (IPSJ)
ISSN： 0919-6072

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Currently gene expression data by DNA microarray are increasing. We can construct coexpression gene families from similarity of gene expression patterns. To find core functions for living organisms and divergent function of each spices, we compared similarity of gene expression patterns. Here we found that ribosomal protein or other house keeping genes are well conserved between human and mouse and that genes involved in nervous system and signal transductions are divergent.
タンパク質におけるアミノ酸組成の偏りとアミノ酸配列の一様さ

城田松之, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　12th　2012
K⁺チャネルにおける溶液イオン濃度依存なイオン透過機構スイッチングに関する分子動力学的解析

笠原浩太, 城田松之, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　12th　2012
VSOPのNa⁺チャネルを用いたモデリングと分子シミュレーション

千葉奏, 城田松之, 笠原浩太, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　12th　2012
溶液NMR法によるタンパク質-低分子相互作用の検出~PDZドメイン結合リガンドの探索例

廣明秀一, 廣明秀一, 廣明秀一, 天野剛志, 天野剛志, 天野剛志, 合田名都子, 合田名都子, 合田名都子, 間瀬省吾, 里村香織, 古瀬幹夫, 木下賢吾, 木下賢吾, 太田元規, 太田元規

日本蛋白質科学会年会プログラム・要旨集　12th　2012
タンパク質-リガンド相互作用パターン解析ツールGIANTの開発

笠原浩太, 木下賢吾, 木下賢吾

日本薬学会年会要旨集　132nd　(4)　2012

ISSN： 0918-9823
Analysis of the Constraints on Amino Acid Pairs in Proteins

城田松之, 木下賢吾, 木下賢吾

情報処理学会研究報告(CD-ROM)　2011　(6)　2012

ISSN： 2186-2583
K₊チャネルにおける溶液イオン濃度依存なイオン透過機構スイッチングに関する分子動力学的解析

笠原浩太, 城田松之, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　12th　2012
タンパク質低分子結合部位の予測に向けた多様性の解析

木下賢吾

化学工学会秋季大会研究発表講演要旨集(CD-ROM)　44th　2012
蛋白質低分子複合体構造の解析による低分子結合部位の博物学

木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　12th　2012
PDZドメインに相互作用する低分子化合物の探索

天野剛志, 天野剛志, 合田名都子, 合田名都子, 岩谷奈央子, 木下賢吾, 木下賢吾, 木下賢吾, 太田元規, 太田元規, 廣明秀一, 廣明秀一

日本分子生物学会年会プログラム・要旨集(Web)　35th　2012
タンパク質-低分子リガンド間相互作用に関する網羅的パターン解析とデータベース開発

笠原浩太, 木下賢吾

日本薬学会年会要旨集　131st　(4)　2011

ISSN： 0918-9823
蛋白質立体構造における4体間相互作用の解析

城田松之, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　11th　2011
トランスポートソーム-生体膜輸送機構の全体像に迫る基礎,臨床,創薬応用研究の最新成果第4章残されたトランスポーターへのアプローチ 4 COXPRESdb: 共発現データに基づいた機能関連遺伝子の探索

大林武, 木下賢吾

遺伝子医学MOOK　(19)　2011

ISSN： 1349-2527
ヒトタンパク質構造データベースSAHGによるドラッガブルなPDZドメインの探索

天野剛志, 天野剛志, 合田名都子, 合田名都子, 岩谷奈央子, 岩谷奈央子, 廣明秀一, 廣明秀一, 木下賢吾, 木下賢吾, 木下賢吾, 太田元規, 太田元規

日本蛋白質科学会年会プログラム・要旨集　11th　2011
混合正規分布モデルに基づくタンパク質-低分子リガンド間相互作用の網羅的パターン解析

笠原浩太, 木下賢吾, 木下賢吾

日本蛋白質科学会年会プログラム・要旨集　11th　2011
ヒトゲノム構造・機能アノテーションデータベースSAHG:高等生物由来タンパク質の構造予測パイプラインの開発とヒト由来全タンパク質への適用

本野千恵, 中田淳一, 清水佳奈, 富井健太郎, 長野希美, 野口保, 廣明秀一, 雨宮崇之, 城田松之, 小池亮太郎, 白井剛, 木下賢吾, 太田元規

日本蛋白質科学会年会プログラム・要旨集　11th　2011
共発現情報から見る遺伝子機能ネットワーク

Obayashi T, Kinoshita K

KASEAA　49　(1)　48-56　2011
Publisher: Japan Society for Bioscience, Biotechnology, and Agrochemistry
DOI： 10.1271/kagakutoseibutsu.49.48 　

ISSN： 0453-073X
Hub Promiscuity in Protein-Protein Interaction Networks (vol 11, pg 1930, 2010)

Ashwini Patil, Kengo Kinoshita, Haruki Nakamura

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES　11　(8)　2791-2791　2010/08

DOI： 10.3390/ijms11082791 　

ISSN： 1422-0067
ヒトゲノム構造・機能アノテーションデータベースSAHG(Structural Atlas of Human Genome)の構築

本野千恵, 中田淳一, 清水佳奈, 富井健太郎, 長野希美, 野口保, 廣明秀一, 雨宮崇之, 城田松之, 小池亮太郎, 白井剛, 木下賢吾, 太田元規

日本蛋白質科学会年会プログラム・要旨集　10th　2010
Construction of CaMKII-interacting protein network obtained from affinity purified proteins in silico and its experimental verification

Takafumi Yamada, Akihiro Iwamatsu, Takeshi Obayashi, Kengo Kinoshita, Shunji Ohsako

NEUROSCIENCE RESEARCH　68　E345-E345　2010

DOI： 10.1016/j.neures.2010.07.1527 　

ISSN： 0168-0102
高等生物由来タンパク質の構造予測パイプラインの開発とヒト22番染色体への適用

本野千恵, 中田淳一, 富井健太郎, 清水佳奈, 小池亮太郎, 白井剛, 木下賢吾, 野口保, 太田元規

日本蛋白質科学会年会プログラム・要旨集　9th　2009
COXPRESdb: A DATABASE OF COEXPRESSED GENE NETWORKS FOR HUMAN, MOUSE AND RAT

Takeshi Obayashi, Kengo Kinoshita

JOURNAL OF PHYSIOLOGICAL SCIENCES　59　444-444　2009

ISSN： 1880-6546
Pattern recognition for Protein three-dimensional structures : Similarity search of protein folds, local atomic arrangements, and molecular surfaces

STANDLEY Daron M., KINJO Akira R., KINOSHITA Kengo, NAKAMURA Haruki

IPSJ SIG Notes　2008　(126)　101-102　2008/12/10
Publisher: Information Processing Society of Japan (IPSJ)
ISSN： 0919-6072
Development of a scoring method for predicting protein complex structures

Yuko Tsuchiya, Eiji Kanamori, Daron M. Standley, Haruki Nakamura, Kengo Kinoshita

ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES　64　C227-C227　2008

DOI： 10.1107/S0108767308092714 　

ISSN： 2053-2733
共発現データベースCOXPRESの構築と利用法

Obayashi T, Kinoshita K

Transportsome　4　16-20　2007/05
Analysis of facilitation of HERG current by a class III anti-arrhythmic agent, nifekalant

Miki Iwata, Yukio Hosaka, Narutoshi Kamiya, Kengo Kinoshita, Atsushi Inanobe, Haruki Nakamura, Yoshihisa Kurachi

JOURNAL OF PHARMACOLOGICAL SCIENCES　103　193P-193P　2007

ISSN： 1347-8613
Protein Informatics towards function identification: a practical version

Kengo KINOSHITA

41　5-8　2007
Publisher: 遺伝医学研究会
Protein Informatics Towards Function Identification

KINOSHITA Kengo

X-RAYS　47　(5)　341-347　2005/03
Publisher: The Crystallographic Society of Japan
DOI： 10.5940/jcrsj.47.341 　

ISSN： 0369-4585 1884-5576

More details Close

According to the progress of structural genomics projects, we have a large number of protein structures without any annotations. For the further understandings of biological systems from the view point of genome science, methods are now required to get some clues to identify the function of these"hypothetical"proteins. Here we would like to introduce several recent approaches based on protein informatics for the problem.
タンパク質の立体構造からの機能予測

木下賢吾

名古屋大学情報連携基盤センターニュース　4　(1)　47-55　2005
Publisher: 名古屋大学
ISSN： 1347-8982
Protein physical informatics based on structure

NAKAMURA Haruki, KAMIYA Narutoshi, HIGO Junichi, KINOSHITA Kengo

71　(12)　1474-1480　2002/12/10
Publisher: 応用物理学会
ISSN： 0369-8009
The C-terminal tails of sulfonylurea receptors control ADP-dependent activation of ATP-sensitive K(+)channels and its modulation by diazoxide

K Matsushita, T Matsuoka, Y Katayama, A Fujita, K Kinoshita, H Nakamura, Y Kurachi

BIOPHYSICAL JOURNAL　80　(1)　53A-53A　2001/01

ISSN： 0006-3495
Comparative study on the relationship between protein 3D structure and its function in fine-and coarse-grained representation of the structure.

Kinoshita K., Kidera A., Go N.

Biophysics　38　(2)　S44　1998/09/07
Publisher: The Biophysical Society of Japan General Incorporated Association
ISSN： 0582-4052
Comparison of Protein 3D Local Environments

Sadanami K., Kinoshita K., Kidera A., Go N.

Biophysics　38　(2)　S152　1998/09/07
Publisher: The Biophysical Society of Japan General Incorporated Association
ISSN： 0582-4052
Unit Structure of Proteins Emerged From Structural Comparison Stud

KINOSHITA K., KIDERA A., GO N.

Biophysics　37　S173　1997/10
Publisher: The Biophysical Society of Japan General Incorporated Association
ISSN： 0582-4052
To detect possible physicochemical constraints on protein fold patterns

KINOSHITA K., GO N.

Biophysics　37　S78　1997/10
Publisher: The Biophysical Society of Japan General Incorporated Association
ISSN： 0582-4052
Functional and structural similarities among ATP-related enzymes

NISHIOKA T., MATSUDA K., KINOSHITA K., GO N.

Biophysics　37　S18　1997/10
Publisher: The Biophysical Society of Japan General Incorporated Association
ISSN： 0582-4052
Classification of protein 3D structures

K Kinoshita, K Mizuguchi, N Go

PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY　65　PA203-PA203　1996

ISSN： 0079-6107

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Books and Other Publications 8

創薬研究のための相互作用解析パーフェクト : 低中分子・抗体創薬におけるスクリーニング戦略と実例、in silico解析、一歩進んだ分析技術まで

由良敬, 鈴木博文, 栗栖源嗣, 川端猛, 木下賢吾, 白井剛, 土方敦司, 田之倉優

羊土社　2021/12

ISBN: 9784758122566
実験医学増刊 Vol.39 No.7 日本人の疾患と健康のためのバイオバンクとデータベース活用法〜試料と情報の的確な探し方と使い方

木下賢吾

羊土社　2021/04/22

ISBN: 4758103941
バリアントデータ検索&活用 : 変異・多型情報を使いこなす達人レシピ

田高周, 木下賢吾

羊土社　2020/10

ISBN: 9784758122450
プレシジョン・メディシン〜ビッグデータの構築・分析から臨床応用・課題まで〜

木下賢吾

エヌ・ティー・エス　2018/10
実験医学増刊 Vol.35 No.17

木下賢吾

2017/10
計算と生命

柳田, 敏雄, 木下, 賢吾, 笠原, 浩太, 木寺, 詔紀, 林, 重彦, 江口, 至洋, 高木, 周 (流体工学)

岩波書店　2012/09

ISBN: 9784000113045
タンパク質の立体構造入門 : 基礎から構造バイオインフォマティクスへ

藤, 博幸, 太田, 元規, 川端, 猛, 木下, 賢吾, 白井, 剛, 諏訪, 牧子, 高田, 彰二, 高橋, 聡, 廣明, 秀一, 真柳, 浩太, 倭, 剛久, 由良, 敬

講談社　2010/12

ISBN: 9784061538818
Prediction of Molecular Interactions from 3D-Structures: From Small Ligands to Large Protein Complexes

Kengo Kinoshita, Hidetoshi Kono, Kei Yura

Prediction of Protein Structures, Functions, and Interactions　2008/12

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Presentations 108

jMorp: Japanese Multi Omics Reference Panel

田高周, 菱沼英史, 井上仁, 青木裕一, 岡村容伸, 川嶋順子, 大槻晃史, 田口恵子, 菅野貴成, 元池育子, 勝岡史城, 小柴生造, 木下賢吾

トーゴーの日2022　2022/10/05
一般住民バイオバンクの全ゲノム情報を活用したCYP2B6遺伝子多型バリアントの網羅的機能変化解析

平塚真弘, 渡邊卓嗣, 齋藤雄大, 菱沼英史, 公文代將希, 前川正充, 小田彰史, 齋藤さかえ, 三枝大輔, 田高周, 木下賢吾, 平澤典保

第42回日本臨床薬理学会学術総会
東北メディカル・メガバンク計画におけるデータセキュリティと利活用促進での取り組み

木下賢吾

第34回日本内視鏡外科学会総会　2021/12/04
SLC26A9トランスポーターの分子動力学シミュレーションが明らかにした、塩化物イオン輸送経路のゲート開閉運動における細胞質ドメインの役割

大森聡, 花園祐矢, 西羽美, 木下賢吾

第59回日本生物物理学会年会　2021/11/27
Comparative Scoring Power;Assessments of Protein-Liga;Docking Scoring Functions by Considering;Protein Functional Groups

Yovita Ardiyani, Hafumi Nishi, Kengo Kinoshita

2021/11/25
Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individual

Masahiro Hiratsuka, Masaki Kumondai, Akio Ito, Evelyn Marie, Gutierrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Tomoki Nakayoshi, Akifumi Oda, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa

2021/11/19
全ヒト糖鎖関連遺伝子Variantの網羅的抽出と解析

西原祥子, 木下聖子, 栂谷内晶, 細田正恵, 伊藤和義, 山口芳樹, 真鍋法義, 大野詩歩, 稲森啓一郎, 井ノ口仁一, 灘中里美, 北川裕之, 城田松之, 木下賢吾

第40回糖鎖学会　2021/10/29
バイオバンク情報を活用した40種のCYP3A4バリアントにおける機能変化解析

平塚真弘, 公文代將希, Evelyn Marie Gutierrez, 菱沼英史, 上田昭子, 齋藤さかえ, 三枝大輔, 田高周, 木下賢吾, 仲吉朝希, 小田彰史, 前川正充, 眞野成康, 平澤典保

日本人類遺伝学会第66回大会・第28回日本遺伝子診療学会大会
東北メディカル・メガバンク計画における大規模ゲノム解析とAI技術の活用

木下賢吾

日本人類遺伝学会第66回大会第28回日本遺伝子診療学会大会合同開催　2021/10/14
医療関連ビッグデータへの人工知能応用に向けた可能性と課題

木下賢吾

IEEE Sendai LMAG／Tokyo LMAG 共同主催講演会　2021/09/25
In silico および in vitro実験によるTim4受容体・カーボンナノチューブ結合様式の解明

謝祺琳, 大森聡, 笠原浩太, 山口慎一朗, 高橋卓也, 木下賢吾, 中山勝文

日本毒性学会学術年会
東北メディカル・メガバンク計画における蛋白質科学

山本雅之, 木下賢吾

第21回蛋白質科学会　2021/06/16
未来型医療創成センターの概要

木下賢吾

東北大学病院次世代医療開発セミナー　2021/03/29
人工知能応用 keynote講演

木下賢吾

日本超音波医学会第93回学術集会　2020/12/03
Genome-omics analyses in Tohoku Medical Megabank project toward the personalized medicine

Kengo Kinoshita

2020/07/07
ゲノム情報の持つ可能性と東北における大規模コホート研究

木下賢吾

第19回名古屋大学遺伝子実験施設公開セミナー　2019/12/19
核酸クロマトグラフィーストリップを利用したファーマコゲノミクス検査薬の開発

公文代將希, 伊藤暁生, 菱沼英史, 齋藤雄大, 石田典子, 峯岸直子, 齋藤さかえ, 木下賢吾, 山本雅之, 金子明, 平澤典保, 平塚真弘

臨床薬理　2019/11
個別化創薬の実現に向けた日本人大規模ゲノムコホートデータの活用

木下賢吾

2019/10/23
東北メディカル・メガバンク計画による未来型医療への挑戦

木下賢吾

BioJapan/再生医療JAPAN2019　2019/10/11
東北メディカル・メガバンク計画での大規模ゲノム解析

木下賢吾

第2回幹細胞情報学イニシアチブ研究会　2019/10/02
血漿メタボロームと頸動脈内膜中膜肥厚の関連

寳澤篤, 小柴生造, 平田匠, 中村智洋, 土屋菜歩, 成田暁, 小暮真奈, 元池育子, 三枝大輔, 峯岸直子, 栗山進一, 田宮元, 辻一郎, 木下賢吾, 呉繁夫

日本高血圧学会総会プログラム・抄録集　2019/10
Genome‐omics analyses in;Tohoku Medical Megabank;project toward;the realization of;ersonalized medicine

Kengo KInoshita

第5回日台AROワークショップ　2019/09/26
コホート調査における代謝プロファイルの経時変化の解析

小柴生造, 元池育子, 三枝大輔, 井上仁, 菱沼英史, 青木裕一, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　2019/09
未来型医療を目指した東北における大規模ゲノム解析の現状と今後

木下賢吾

第19回日本Men’s Health医学会　2019/07/13
ゲノム情報の持つ可能性と東北大学での未来型医療への挑戦

木下賢吾

次世代産業ナビゲータ第210回フォーラム　2019/07/09
大規模ゲノムコホート調査におけるBRCA1/2遺伝子の病的バリアント保持者への遺伝情報回付に関する課題

濱中洋平, 石田孝宣, 布施昇男, 川目裕, 山口由美, 安田純, 多田寛, 宮下穣, 原田成美, 佐藤章子, 青木洋子, 長神風二, 八重樫伸生, 木下賢吾, 呉繁夫, 山本雅之

日本乳癌学会総会プログラム抄録集　2019/07
メタボロームデータを用いた非線形変数選択機械学習によるうつ状態の予測

高橋雄太, 植木優夫, 山田誠, 田宮元, 元池育子, 三枝大輔, 櫻井美由紀, 長神風二, 小柴生造, 木下賢吾, 山本雅之, 富田博秋

精神神経学雑誌　2019/06
東北メディカル・メガバンク計画におけるゲノムオミックス解析戦略

木下賢吾

医薬基盤研セミナー　2019/05/17
Introduction to Tohoku Medical Megabank project

Kengo Kinoshita

GA4GH workshop　2019/03/18
東北メディカル・メガバンク計画・ゲノムオミックス解析の進捗

木下賢吾

AMEDバイオバンク交流会　2018/12/11
ゲノム変異・遺伝子発現量・タンパク質情報をつなぐ変異の遺伝子機能変化への影響推定

木下賢吾

BINDS報告会　2018/12/11
“ふつうの人”は科学で定義できるのか？

木下賢吾

未来館トークセッション　2018/10/27
Introduction to TMM and INGEM toward the next generation medicine

Kengo Kinoshita

Collaborative Seminar by Tohoku University and CEA, France Toward the Next Generation Medicine　2018/10/11
マクロファージによるシリカ粒子認識機構

中山勝文, 継田美里, 森本展行, 木下賢吾

日本免疫毒性学会学術年会　2018/09/18
Dynamic roles of intrinsically disordered regions of ligand binding proteins suggested by the comprehensive structural search

2018/09/15
メタボロームGWASによる日本人の代謝プロファイルの解析

小柴生造, 元池育子, 三枝大輔, 井上仁, 青木裕一, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　2018/09
大規模ゲノムオミックス解析時代の生命情報の現状と課題

木下賢吾

JST-CRDS俯瞰ワークショップ　2018/06/17
生命情報ビッグバン時代の生命情報解析の現状と課題

木下賢吾

ARLセミナー　2018/05/25
ゲノミクスを基盤とした生活習慣病解析最前線ゲノム情報と連携した日本人多層オミックス参照パネルの意義

小柴生造, 元池育子, 三枝大輔, 井上仁, 城田松之, 青木裕一, 田高周, 斎藤智, 木下賢吾, 山本雅之

糖尿病　2018/04
ToMMoにおけるゲノム・オミックス解析戦略

木下賢吾

いわて東北メディカルメガバンク機構講演会　2018/03/05
低頻度一塩基多型のタンパク質立体構造を利用した機能アノテーションに向けて

木下賢吾

生命科学系学会合同年次大会　2017/12/07
高精度日本人多層オミックス参照パネルの提供

小柴生造, 元池育子, 三枝大輔, 井上仁, 城田松之, 斎藤智, 木下賢吾, 山本雅之

生命科学系学会合同年次大会　2017/12
大規模ゲノム・オミックス解析に向けたスーパーコンピュータシステムに必要な要件

木下賢吾

Japan Lustre User Group (JLUG) 2017　2017/11/02
A Challenge to Understand Functional Impacts of Rare Variants Using Protein Strucral Information

Kengo Kinoshita

2nd Karolinska-Tohoku Joint Symposium on Medical Sciences　2017/10/04
バイオインフォマティクス（生命情報学）の現状と今後の課題

木下賢吾

第6回生命医薬情報学連合大会　2017/09/28
PDBjを利用したデータベース構築の事例紹介

城田松之, 木下賢吾

第6回生命医薬情報学連合大会　2017/09/27
Comprehensive search and mechanism analysis of intrinsically disordered region of ligand binding proteins

2017/09/19
ゲノム変異・遺伝子発現量・蛋白質情報をつなぐ試み

木下賢吾

平成29年度創薬等先端技術支援基盤プラットフォーム(BINDS)公開シンポジウム　2017/08/30
Comprehensive analyses of human single nucleotide variants on membrane transporters

2017/06/22
VR技術を用いた生体分子の可視化システムの開発

佐藤広夢, 西羽美, 大森聡, 木下賢吾

第17回日本蛋白質科学会年会　2017/06/21
5. Bioinfo Comics: NGS関連知識の普及を目指した解析工程の漫画化

小舘俊, 木下賢吾

NGS現場の会第五回研究会　2017/05/22
Genome and Omics Analyses in the Tohoku Medical Megabank Project

Kengo Kinoshita

Tohoku Forum for Creativity　2017/05/18
Strategy of genome-omics analyses in Tohoku Medical Megabank Project

Kinoshita K

The 2017 Japan-NIH Joint Symposium on Advances in Biomedical Research and Disease　2017/02/16
ゲノム情報の理解に向けたタンパク質立体構造情報の活用

木下賢吾

創薬等支援基盤プラットフォーム事業公開シンポジウム　2016/12/07
ヒトゲノム変異の影響評価に対する生命情報科学的アプローチ

木下賢吾

第39回日本分子生物学会シンポジウム　2016/12/01
ゲノム解析と生化学

木下賢吾

第89回日本生化学会　2016/09/26
天然リガンドデータベースの構築とタンパク質低分子相互作用解析への応用

木下賢吾

農芸化学会シンポジウム　2016/03/28
転写因子による細胞分化・増殖抑制転写因子IRF4が支配する胚中心B細胞および形質細胞分化誘導の遺伝子発現ネットワーク

落合恭子, 近藤晴香, 岡村容伸, 木下賢吾, 五十嵐和彦

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　2015/12
身近な例で学ぶバイオインフォマティクス

木下賢吾

生命医薬情報学連合大会2015年大会特別講演　2015/10/29
機能未知遺伝子の分子機能・細胞機能の推定

木下賢吾

創薬等支援基盤プラットフォーム事業講演会　2015/09/25
Prediction of the biological and biochemical functions of uncharacterized genes

木下賢吾

日本バイオインフォマティクス学会北海道地域部会セミナー　2015/08/21
Prediction of biological and biochemical functions of uncharacterized genes

Kengo Kinoshita

Data Science in Life Science and Engineering Collaboration and Symposium　2015/07/30
分子階層でのシミュレーション基盤技術研究

木下賢吾

新学術領域研究「多階層生態生命機能学」最終成果報告会　2015/03/04
リガンド結合部位周辺に見られる多型情報の検索

木下賢吾

構造生命科学データクラウド講習会　2015/02/03
ゲノム情報解析の現状と課題

木下賢吾

次世代PGSフォーラム設立記念シンポジウム　2014/12/04
Prediction of the biological and biochemical functions of uncharacterized genes

Kenogo Kinoshita

2014 Bilateral Workshop between Tohoku University & National Tsing Hua University　2014/11/21
タンパク質機能解析に向けた立体構造情報の活用基盤の構築

木下賢吾

第５２回日本生物物理学会　2014/09/19
変異解析におけるタンパク質立体構造とゲノムの論理

城田松之, 木下賢吾

遺伝学会第８５回大会　2014/09/19
ゲノム解析による個別化予防に向けた情報科学の挑戦

木下賢吾

生体医工学会大会　2014/06/04
大規模ゲノム解析研究に必要なスパコン環境の構築

木下賢吾

バイオスーパーコンピューティング東北2014　2014/06/02
タンパク質機能解析に向けた立体構造情報の活用基盤の構築

木下賢吾

日本農芸化学会2014年度大会　2014/03/30
2P072 Analysis of the ion permeation mechanism of Kv1.2 using the molecular dynamics simulations of a single point mutant(01D. Protein: Function,Poster,The 52nd Annual Meeting of the Biophysical Society of Japan(BSJ2014))

Kondo Hiroko X., Shirota Matsuyuki, Kasahara Kota, Saito Toshiyuki, Kinoshita Kengo

Seibutsu Butsuri　2014
2SCP-02 From Personal Genome to Personal Proteins: Connection between the Reference sequences of genomic DNA and Proteins(Prediction and analysis of protein functions from structural bioinformatics,Symposium,The 52th Annual Meeting of the Biophysical Society of Japan(BSJ2014))

Kengo Kinoshita

Seibutsu Butsuri　2014
生命科学ビッグデータへの情報科学の挑戦

木下賢吾

東北大学電気・情報東京フォーラム2013　2013/11/21
生命情報科学の現状と今後の課題

木下賢吾

創薬等支援技術基盤プラットフォーム公開シンポジウム　2013/09/24
新蛋白質の時代 : ゲノムと表現型の架け橋としての蛋白質

木下賢吾

生物物理　2013/07/25
In-Silico Approach to Predict the Biological and Biochemical Functions of Uncharacterized Genes

Kengo Kinoshita

NIH-Tohoku University-JSPS Symposium　2013/05/09
東北メディカルメガバンクへの誘い

木下賢吾

情報処理学会第33回バイオ情報学研究会　2013/03/21
ヒト生命情報統合解析とその情報基盤

木下賢吾

大阪大学蛋白質研究所セミナー　2013/03/08
タンパク質による低分子認識多様性に見られる生物と物理の接点

木下賢吾

第138回加齢研集談会　2012/06/30
蛋白質低分子複合体構造の解析による低分子結合部位の博物学

木下賢吾

第12回蛋白質科学会年会　2012/06/22
K+チャネルにおける溶液イオン濃度依存なイオン透過機構スイッチングに関する分子動力学的解析

笠原浩太, 城田松之, 木下賢吾

第12回蛋白質科学会年会　2012/06/21
生命情報ビッグバン時代に必要な情報科学的基盤

木下賢吾

東北大学情報科学研究科シンポジウム「実世界ビッグデータへの情報科学の挑戦」　2012/04/26
Seeing in silico is believing? An informal introduction to Bioinformatics

Kengo Kinoshita

Network Medicine Winter Camp 2012　2012/02/04
3E1046 Optimization of protein model structures according to statistical potentials with different reference states(Proteins:Structure,Oral Presentation)

Shirota Matsuyuki, Kinoshita Kengo

Seibutsu Butsuri　2012
生命科学と数学の連携例と今後の課題

木下賢吾

東北大学情報科学研究科数学・数理科学と諸科学・産業との連携研究ワークショップ：広がってゆく数学「数学をコアとするスマートイノベーションの探索」　2011/11/29
COXPRESdb: a gene coexpression database for 7 animal species

大林武, 木下賢吾

東北大学加齢医学研究所創立70周年記念国際シンポジウム　2011/11/28
Seeing in silico is believing, Brief introduction and some recent topics in bioinformatics

Kengo Kinoshita

The 12th, RIES-Hokudai International Symposium　2011/11/22
COXPRESdb, A database of gene coexpression in seven model animals

Kengo Kinoshita

CBI/JSBi　2011/11/08
ハブタンパク質の構造的基盤

木下賢吾

学際ライフサイエンスシンポジウム　2011/11/01
Illuminating the background and capabilities of statistical potentials of protein structures

M Shirota, K Kinoshita

The 11th KIAS Conference on Protein Structure and Function　2011/10
遺伝子の機能推定

木下賢吾

生物物理学会夏の学校　2011/08/27
Universal patterns of protein-ligand interactions: Gaussian mixture model analyses on 3D structure of proteins in Protein Data Bank

Kasahara, K Kinoshita

ISMB　2011/07/18
遺伝子の機能推定法の開発

木下賢吾

生物物理学会東北支部会　2011/06/17
東北大学の震災状況報告

木下賢吾

第11回日本蛋白質科学会年会　2011/06/07
遺伝子共発現を利用した機能関連遺伝子の同定法

木下賢吾

日本薬学会第131年会（東日本大震災のため中止、年会は成立）　2011/03/29
遺伝子機能推定のバイオインフォマティクス

木下賢吾

東北大学ワークショップ「数学の展開—諸分野との連携を探る」　2010/11/26
バイオインフォマティクスによる遺伝子機能推定

木下賢吾

東北大学加齢研セミナー　2010/07/27
Function prediction of uncharacterized genes and proteins

Kengo Kinoshita

Bio- and Nano-Electronics,
バイオインフォマティクスによる遺伝子機能推定入門

木下賢吾

Network Medicine GCOE セミナー　2010/02/16
Multi-dimensional correlations for gene coexpression and application to the large-scale data of Arabidopsis,

Kengo Kinoshita

Bioinformatics beyond omics data analyses
Web services for function prediction of proteins

Kengo Kinoshita

Bioinfo2009
機能未知タンパク質の機能推定法の開発

木下賢吾

第82回日本生化学大会
Classification of hetero-dimer interfaces and development of multiple scoring functions for complex structure predictions of proteins

Kengo Kinoshita

International symposium on muti-scale dynamics of protein complex formation and function
類似性検索による遺伝子機能推定法の開発

木下賢吾

アルゴリズム研究会　2009/05/11
A new multi-dimensional index for gene coexpression and application to the large-scale data of Arabidopsis

Kengo Kinoshita

The 1299th Biological Symposium at National Institute of Genetics　2009/03/31
COXPRESdb: gene coexpression database for Human, mouse and rat,

Kengo Kinoshita

XXXVI International congress of Physiological Sciences　2009/07/27
Structural properties of hub proteins in interaction networks and its implications on interaction promiscuity

A Patil, K Kinoshita, H Nakamura, K Nakai

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Industrial Property Rights 3

データ処理装置、データ処理方法、データ処理プログラム及び記録媒体

木下賢吾

特許第4401650号

Property Type: Patent
三次元構造データベースから特定のリガンドが結合した生体高分子を検索する検索方法、検索装置、検索プログラム及び記録媒体

木下賢吾

Property Type: Patent
データ処理装置、データ処理方法、データ処理プログラム及び記録媒体

木下賢吾

Property Type: Patent

Research Projects 24

International research using big data for lifestyle disease, brain aging and genetic background

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2023/04/01 - 2026/03/31
Elucidation of the mechanism of intractability of pancreatobiliary cancers using patients-derived organoids

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2022/04/01 - 2026/03/31
Elucidation of the mechanism of intractability of pancreatobiliary cancers using patients-derived organoids

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2022/04/01 - 2026/03/31
脳血管のゲノム解析と血流解析の統合による脳血管障害発症に至る軌跡の解明と診療応用を目指す研究

大島まり, 太田信, 安西眸, 二宮利治, 松田文彦, 猪原匡史, 松田浩一, 木下賢吾, 鄭銀強, 小林匡治, 小林啓之, 中冨浩文, 下山隆, 曽根原究人

Offer Organization: AMED

System: ゲノム研究を創薬等出口に繋げる研究開発プログラム

Institution: 東京大学

2024/01 - 2026/03
Development of Adverse Events-free Local Anesthetics in Cryo-EM Structural Determination of Sodium Channels

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Research (Exploratory)

Institution: Tohoku University

2021/07/09 - 2024/03/31
Feasibility study of an evaluation of the impact of rare variants on gene expression

Kinoshita Kengo

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Exploratory Research

Institution: Tohoku University

2016/04/01 - 2019/03/31

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The effect of mutations on expression levels is still largely unknown and very challenging. To begin with, the large-scale analysis of expression level data was carried out focusing on A 562 and K 549 cells as a pretreatment for the collection of basic data and the full-scale analysis. We also collected and analyzed ChIP-seq data in the public database for the analysis of transcription factor binding sites. In conducting these analyses, we were able to develop our own analysis methods, such as accurate library length estimation for Matataki and ChIP-seq. In the future, while utilizing the elemental methods developed in this research project, they will be deployed to a wider variety of cells and will not lead to the development of methods for the impact analysis of mutations in non-coding regions.
Epigenetic mechanisms in schizophrenia by immune activation during pregnancy

YU ZHIQIAN, TOMITA HIROAKI, NAGASAKI MASAO, NAKAYAMA KEIKO, HASHIMOTO KENJI, IWAMOTO KAZUYA, KINOSHITA KENGO

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2016/04/01 - 2019/03/31

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Gender differences in susceptibility to schizophrenia have been a hotly debated research issue for decades. Epidemiological evidence has shown that female offspring exposed to maternal infection during pregnancy are significantly more susceptible to developing schizophrenia. From an analysis of the offspring of poly I:C-treated pregnant mice we show that only female offspring of poly I:C-treated dams express schizophrenia-linked behavioral changes, profound genome-wide DNA hypermethylation profiles in the prefrontal cortices and postmortem prefrontal cortices of female patients with schizophrenia.
Inflammatory responses to crystals and nanoparticles

Nakayama Masafumi, Kinoshita Kengo

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2016/04/01 - 2019/03/31

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The inhalation of silica dust is associated with fibrosis and lung cancer, which are triggered by macrophage inflammatory responses; however, how macrophages recognize silica remains largely unknown. Here we identify by functional expression cloning the class B scavenger receptor SR-B1 as a silica receptor. Genetic deletion of SR-B1 and masking of SR-B1 by monoclonal antibodies showed that SR-B1-mediated recognition of silica is associated with caspase-1-mediated inflammatory responses in mouse macrophages and human peripheral blood monocytes. Furthermore, SR-B1 was involved in silica-induced pulmonary inflammation in mice. These results indicate that SR-B1 is a silica receptor associated with canonical inflammasome activation.
Analysis of cell-cell communication using comparison of gene co-expression for different tissues

Obayashi Takeshi, Kinoshita Kengo

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (B)

Institution: Tohoku University

2015/04/01 - 2018/03/31

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Cell functions are composed of the individual functions of many genes. Gene network analysis is widely used to estimate the functional combination of genes. Similarly with protein-protein interaction network analysis, gene co-expression network analysis, which is a similarity of gene expression profiles, is widely used as network analysis. In this study, I have developed a methodology to compare and integrate multiple gene co-expression networks among multiple tissues of a model plant, Arabidopsis. The results based on the new methodologies in this study were available in a plant co-expression database, ATTED-II [ http://atted.jp/ ].
Construction of analyses basis for understanding rare variants using protein structural information

Kinoshita Kengo, SHIRAI TSUYOSHI, OHTA MOTONORI

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2015/04/01 - 2018/03/31

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We could construct the proposed systems as planned, which can map genetic variations onto protein structures, and the results are available through the web site called snvmap. For the purpose, we generated model structures of human proteins, if they are not available in PDB. By using the mapping results, we performed statistical analyses and found some interesting rare variations related with the metabolism of oseltamivir, an anti-virus drug, which specific for east Asian populations.
Design Theory of Probabilistic Computational Models for Community Detections based on Non-Additive Volume and Entropy

TANAKA Kazuyuki, KINOSHITA KENGO, Hsu Chiou-Ting, Furtlehner Cyril, Zdeboraba Lenka, Ricci-Tersenghi Federico, Welling Max, Zhang Pan

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2013/04/01 - 2017/03/31

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We have proposed a new algorithm to detect the community structure in a network that utilizes both the network structure and vertex attribute data. The problem addressed this paper is the detection of the community structure from the information of both the network structure and the vertex attribute data. The detection of the community structure in our method is achieved by using belief propagation and an EM algorithm. We numerically verified the performance of our method using computer-generated networks and real world networks. Actually, a part of our research results and aspects in complex networks are expanded to the traffic data reconstruction problem and on-demand color calibration system to track pedestrians across non overlapping fields of fixed camera view. Moreover, we have proposed a new quantum annealing method to achieve the optimization of modularity in community detection problems.
Establishment of Integrative Multi-level Systems Biology and its Applications

KURACHI YOSHIHISA, INOUE Ryuji, YAMASHITA Fumiyoshi, SUZUKI Hiroshi, KITANO Hiroaki, OHTSUKI Sumio, AMANO Akira, KINOSHITA Kengo, HARI Yoshiyuki, MAKITA Naomasa, ISHIKAWA Yoshihiro, HONJO Haruo, NAKAZAWA Kazuo, OKUNO Yasushi, KUSUHARA Hiroyuki, KAGECHIKA Hiroyuki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Institution: Osaka University

2010/04/01 - 2016/03/31
Development and analyses of integrated networks for cellular function predictions

KENGO Kinoshita

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2012/04/01 - 2015/03/31

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We have more than several thousands of whole genome sequences of many divergent species, but more than half of the genes on the genomes are still uncharacterized. It is almost impossible to determine all functions of all genes by experimental procedure, and thus some computational approaches to infer some possible functions of the uncharacterized genes. In this study, we have constructed integrated networks by using RNA-seq based co-expression networks and high throughput protein-protein interaction data, and developed a method to compare the integrated networks among the species. We also developed a new clustering method and applied it to infer the cellular function of uncharacterized genes.
Development of new simulation methods at the molecular layer

KENGO Kinoshita

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Institution: Tohoku University

2010/04/01 - 2015/03/31

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Systems-biology approaches often suffer from the description of molecular details, because atomic details are too much to be considered with whole systems at the same time. As a result, it becomes hard to consider molecular interactions with drugs and to evaluate the effect of genomic variations due to the individual differences. To overcome the difficulty, we have developed a few methods to consider the interaction between molecular level and an upper level of the different biological layers. More specifically, we develop a method of model building for channel proteins, a method to analyze long-time molecular dynamics simulation results, and a method to simulate the mutant proteins to evaluate the molecular function differences.
Structural Interactome Studies from Computational and Bioinformatics Approaches

NAKAMURA Haruki, KINOSHITA Kengjo, HIGO Junichi, KAMIYA Narutoshi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Osaka University

2008 - 2010

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For structural interactome study, which investigates the protein-protein interaction network based on their tertiary structures, we have constructed several different kinds of databases and made informatics analyses by identifying and predicting the interfaces, so that complex structural models have been predicted. In addition, for the intrinsically denatured proteins, we have successfully reproduced and analyzed their coupled folding and binding procedures as the stable states in the free energy landscapes from computational studies.
Construction and analyses of interaction network for transportsomeusing structural information

KINOSHITA Kengo, NAKAMURA Haruki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research on Priority Areas

Institution: The University of Tokyo

2005 - 2009

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Construction of interaction network of protein is a first step toward the understanding of complex biological systems. Usually, the network is made from nodes and edges representing proteins and interactions, respectively. However, the abstract representation prevents us from analyzing the biological systems in molecular levels. Therefore, in this project, we have developed a method to construct the interaction networks based on gene coexpression, and also develop a method to predict the protein complex structures.
蛋白質の立体構造に基づく分子会合表面特性の解析

前田美紀, 木下賢吾

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 萌芽研究

Institution: 独立行政法人農業生物資源研究所

2005 - 2007

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前年度までのシステムを用いて多数の蛋白質インターフェースを解析したところ、会合領域の形状による結果の不確実性が判明したため、インターフェース領域を新たに定義した。この改良法を用いて再度天然蛋白質におけるサブユニット間インターフェースを解析したところ、空間体積/会合表面積比はほぼ1.4A付近に分布することが判明した。この値は、「天然蛋白質らしさ」を表す指標の1つとして利用できると考えられる。会合表面積の大きさと、空間体積/会合表面積比のすれの大きさをもとにして、実際のクリスタルパッキングを含む複数の結晶構造に対して計算を行い、結果を比較したところ、同一結晶内の天然インターフェースに比較してクリスタルパッキングと判定できるものは会合表面積が小さく、また空間体積/会合表面積比の値が1.4からのずれが大きい傾向があることが判った。本解析方法の一部として採用したQHULLプログラムについて、サーバ内の組み込みについての開発者の了承が得られたことから、前年度までに作成した蛋白質サブユニット間空間体積を計算するプログラム群(溶媒接触表面積計算プログラム、多面体空間内の空隙体稽計算プログラム)と併せ、単一の入力ファイルから全ての計算が連続的に動作するように改良した。さらにこのシステムをWEBプラットフォームからの入力およびWEBページとしての出力機能を付加した解析サーバとして構築した(現在、「13.備考」欄に示したURLから利用可能)。解析サーバ構築時に新たに会合空間内の原子占有率を計算できる機能、同空間内に存在する結晶水を判定する機能を付加した。
Construction of a computational model for the transcriptional regulatory regions in Ciona intestinalis and its experimental verification

NAKAI Kenta, KUSAKABE Takehiro, YAMASHITA Riu

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: The University of Tokyo

2005 - 2006

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Transcriptional regulation is the first level of regulation of gene expression and is therefore a major topic in computational biology. For the studies of DNA regions that specify tissue-specific gene expression, we chose tunicates as our main model organisms and constructed a database of transcription in tunicates (esp. Ciona intestinalis): DBTGR (http: //dbtgr.hgc.jp/). Then, we introduced a Markov chain-based promoter structure model that uses both shared motifs and shared features from an input set of promoter sequences to predict candidate genes with similar expression. The model uses positional preference, order, and orientation of motifs. The trained model is used to score a genomic set of promoter sequences: high-scoring promoters are assumed to have a structure similar to the input sequences and are thus expected to drive similar expression patterns. We applied our model on two datasets in Caenorhabditis elegans and in Ciona intestinalis. Both computational and experimental verifications indicate that this model is capable of predicting candidate promoters driving similar expression patterns as the input-regulatory sequences. This model can be useful for finding promising candidate genes for wet-lab experiments and for increasing our understanding of transcriptional regulation
構造プロテオミクスに基づく蛋白質間相互作用の解析と予測

中村春木, 木下賢吾, 塩生くらら

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 特定領域研究

Institution: 大阪大学

2005 - 2005

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種々の蛋白質間相互作用データを収集して相同性があるホモログを同定しドメイン情報を加えたデータベース(HINT db)さらに充実し、インターネットでアクセスできるWeb pageを公開した。また、それを基にした相互作用の評価サイト(Hit Predict)を公開した。さらに、これらデータベースを利用して、蛋白質間相互作用ネットワークにおけるハブ蛋白質の構造的特徴を解析した。その結果、小さな蛋白質では多くの荷電残基をもつこと、大きな蛋白質ではループではなくNaturally disordered regionが統計的に有意に多く観測されることを見出し、論文に発表した。蛋白質相互作用部位の推定のために進化トレース法(ET法)の利用を行い、まずET法専用のサーバを構築し、インターネット上に公開した。次に、モンテカルロ法とGA法を利用したドッキング・シミュレーション・プログラムをほぼ完成させ、CAPRIに提出された問題とシグナル伝達系の蛋白質間相互作用の系に応用し、ET法による相互作用情報を加えた解析によって、多くの場合に良好なドッキング結果を得た。また、CAPRIに3回参加した。さらに、flexible loopの構造アンサンブル予測を精度良く行うため、統計物理学的な自由エネルギー地形をForce-biased McMD法によって描き、GB/SA法による溶媒効果を比較的正確に取り込んだ上で、ループ構造を予測する手法を確立した。この手法をいくつかの蛋白質のループに応用し、特にDHFR(ジヒドロ葉酸還元酵素)のリガンド・フリーのランダムなループ構造から出発して、リガンド結合状態のループ構造を見出し、リガンド(葉酸)とのドッキング計算によってinduced fittingが起こるシステムにも応用できることを示した
蛋白質分子表面の形状と物性の類似性検索による機能予測法の開発

木下賢吾

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 若手研究(B)

2003 - 2005

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今年度は高分子リガンド(タンパク質)を主な対象とした機能予測法の開発を行ってきた。この目的のためにまず、蛋白質相互作用面データベースの構築が必要であるが、X線結晶解析による複合体構造では、生理条件下の構造をとらえたものと、クリスタルパッキングによるアーティファクトが混在している。これらの特徴を捉え、自動的に生物学的に重要な相互作用面を同定する手法を開発するために、最初に生物学的な相互作用によって形成されている重複のない374ホモ相互作用面を、SCOPデータベースを用いて同定した。その後、特徴を抽出するために、これらの相互作用面を形成する2蛋白質間の回転対称に従って、ダイマー型、サイクリックオリゴマー型、巻き付き型の3タイプに分類した。さらにダイマー型に関しては、対称軸に対する相互作用面の広がり方向から、並行型、垂直型、均等型に分類を行った。そして、5タイプの型ごとに相互作用面における物性(静電ポテンシャル、疎水性度)と形状の相補性に関して解析を行ったところ、構造的分類と相互作用の特徴との間に、「並行型ダイマーは、疎水性相互作用が強く、一方、垂直型ダイマーは静電的相互作用が優先的である」及び「巻き付き型では疎水性相互作用と形状の相補性が強い」という傾向を見出すことができた。現在細かい点の詰めと論文としてまとめる準備をしている。また、ここで得られた相補性の解析手法を利用して、生物学的に意味のある面と結晶学的な面を区別する手法を開発し、ウェブサーバとして公開を開始した。
モノヌクレオチド結合タンパク質の機能データベースの構築と構造機能相関の解析

木下賢吾

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 若手研究(B)

Institution: 横浜市立大学

2001 - 2002

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本研究では、構造ゲノムプロジェクトの進展を念頭において、タンパク質の立体構造情報からその機能を予測する「第一原理的機能予測法」の開発を目指している。そこでは、従来行われていたような進化的類縁関係(配列の類似性)からの機能の類推ではなく、タンパク質の立体構造・機能相関というタンパク質の機能を直接決めているメカニズムを解明し利用することを目指す。このために(1)構造および機能がわかっているタンパク質のなかで数多くの立体構造が明らかにされているものヌクレオチド結合タンパク質に置いて、立体構造と機能情報で整理されたデータベースを構築し、(2)このデータベースから構造機能相関の経験的ルールを導き出し、構造からの機能予測法の開発を行う。 14年度には前年度に同定した103のスーパーファミリー毎に機能情報を付加し、機能の類似性と構造の類似性の相関関係をしらべ、モノヌクレオチドの認識はモノヌクレオチド全体ではなくモノヌクレオチドの各部分(塩基、糖、燐酸)ごとに認識の共通パターンが存在し、その部分ごとに類似性検索を行うことによりモノヌクレオチド結合部分の予測の可能性が見えてきた。 15年度には、全年度に見出したモノヌクレオチト結合のルールを基にした類似性検索法を開発し、実際に機能未知のたんばく質において、結合部位の予測を行い、良好な結果を得ることが出来た。現在これらの予測結果の実験的なサポートを得るために共同研究者を展開する準備を進めている。
蛋白質化学機能の立体構造からの第一原理的予測法の開発

池口満徳, 木下賢吾

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 特定領域研究(C)

Institution: 横浜市立大学

2001 - 2001

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本研究では、構造ゲノムプロジェクトの進展を念頭において、タンパク質の立体構造情報からその機能を予測する「第一原理的機能予測法」の開発を目指した。そこでは、従来行われていたような進化的類縁関係(配列の類似性)からの機能の類推ではなく、タンパク質の立体構造-機能相関というタンパク質の機能を直接決めているメカニズムを解明し利用することを目指す。このために(1)構造および機能がわかっているタンパク質のデータベースを構築し、(2)このデータベースから構造機能相関の経験的ルールを導き出し、(3)分子シミュレーションを使って経験的ルールの物理化学的な基礎付けと一般化を狙った。本研究では、立体構造の蓄積のあるモノヌクレオチド結合タンパク質を取り上げた。本年度は、モノヌクレオチド結合蛋白質データベースの整備を行い、結合部位の立体構造の分類、代表決定を行った。その結果、103スーパーファミリー内に1137種の認識構造を同定した。本研究は、タンパク質のモノヌクレオチド結合について体系的に整理、解析した初めてのものである。また、分子認識に対する動的揺らぎの影響を調べるため、高精度で高効率な分子動力学シミュレーションソフトウエアの開発を行った。このソフトウエアの並列化効率、精度は、世界的に高いレベルにある。さらに、このソフトウエアを適用して、モノヌクレオチド結合タンパク質である酵素HPPKに対する分子動力学計算を行い、モノヌクレオチド結合部位周辺の動きの解析を行った。その結果、非結合状態での蛋白質の熱揺らぎの中に、分子認識によって誘起される構造変化が内在していることが分かった。
Energy Transfer in a Protein Molecule: From Chemical Reaction to Structural Change

KIDERA Akinori, KINOSHITA Kengo, KITAO Akio

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

1999 - 2001

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Anharmonic dynamics of a protein molecule was studied by molecular dynamics simulations of the vibrational energy transferred of myoglobin. It was found that there are two distinct schemes of the energy transfer, depending on temperature. At near zero temperature, the vibrational energy is transferred as a process of the Fermi resonance, from one mode exclusively to a limited number of modes having resonance frequencies. On the other hand, as temperature increases, the resonance type transfer is dominated by the off-resonance energy transfer through the various mode-coupling terms. Near room temperature, the energy transfers involves the higher order coupling terms together with the indirect transfers through intermediate modes. At about 170 K, we have observed a glass transition-line phenomenon in the vibrational energy transfer.
蛋白質化学機能の立体構造からの第一原理的予測法の開発

池口満徳, 木下賢吾

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 特定領域研究(C)

Institution: 東京大学

2000 - 2000

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ゲノム配列決定の次の課題は、遺伝子機能の特定である。特に創薬への応用を考える際、遺伝子産物である蛋白質の化学的な機能、つまり蛋白質と他分子との間の相互作用を理解することが重要である。そこで本研究では、データベース解析と分子シミュレーションの互いの利点を生かした解析法を開発することにより、立体構造に基づいた化学機能の予測法の開発を目指した。当面の対象として、すでに多くの立体構造が明らかにされているモノヌクレオチド結合蛋白質を扱った。まず、2000年4月のPDBから,モノヌクレオチド結合蛋白質667個,1190結合部位を同定した。これらの結合部位はそのままでは統計処理に適さない冗長性を含んでいるので、原子の空間配置の類似度に基づき代表構造425個を選別した。これら代表構造に対して、分子シミュレーションと連携しやすい物性として、分子表面、静電ポテンシャル分布を計算しデータベース化を行った。PDBの記述は必ずしも完全ではなく、系統的な構造-機能相関の解析の妨げとなってきた。これに対して、モノヌクレオチド結合蛋白質立体構造データベースを構築し、インターネット上に公開できたことは今年度の重要な成果である。また、近年の超並列計算機を念頭においた並列計算技術を開発し、分子動力学計算システムに応用した。このシステムを、代表構造の一つであるRas蛋白質に適用し、結合部位の表面形状,電場揺らぎ及び結合自由エネルギーの解析を行った.この結果、静的な立体構造を対象とするだけでは不十分であり、立体構造の柔らかさ、特に結晶が得られにくい基質非結合状態が重要であることがわかってきた。機能予測における非結合状態の構造の重要性は、動的構造まで含めた解析手法の構築により初めて得られる知見である。

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