研究者詳細 - 松井　佑介

論文 - 松井　佑介

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Improved Prediction Accuracy for Late-Onset Preeclampsia Using cfRNA Profiles: A Comparative Study of Marker Selection Strategies. 招待有り査読有り国際誌 Open Access

Akiha Nakano, Kohei Uno, Yusuke Matsui

Healthcare (Basel, Switzerland) 13 巻 ( 10 ) 2025年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Late-onset pre-eclampsia (LO-PE) remains difficult to predict because placental angiogenic markers perform poorly once maternal cardiometabolic factors dominate. Methods: We reanalyzed a publicly available cell-free RNA (cfRNA) cohort (12 EO-PE, 12 LO-PE, and 24 matched controls). After RNA-seq normalization, we derived LO-PE candidate genes using (i) differential expression and (ii) elastic-net feature selection. Predictive accuracy was assessed with nested Monte-Carlo cross-validation (10 × 70/30 outer splits; 5-fold inner grid-search for λ). Results: The best LO-PE elastic-net model achieved a mean ± SD AUROC of 0.88 ± 0.08 and F1 of 0.73 ± 0.17-substantially higher than an EO-derived baseline applied to the same samples (AUROC ≈ 0.69). Enrichment analysis highlighted immune-tolerance and metabolic pathways; three genes (HLA-G, IL17RB, and KLRC4) recurred across >50% of cross-validation repeats. Conclusions: Plasma cfRNA signatures can outperform existing EO-based screens for LO-PE and nominate biologically plausible markers of immune and metabolic dysregulation. Because the present dataset is small (n = 48) and underpowered for single-gene claims, external validation in larger, multicenter cohorts is essential before clinical translation.

DOI： 10.3390/healthcare13101162

Open Access

PubMed

HuTAge: a comprehensive human tissue- and cell-specific ageing signature atlas

Koichi Himori, Zhang Bingyuan, Kazuki Hatta, Yusuke Matsui

Bioinformatics Advances 5 巻 ( 1 ) 2025年4月

担当区分：最終著者掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

Abstract

Summary

Ageing is a complex process that involves interorgan and intercellular interactions. To obtain a clear understanding of ageing, cross-tissue single-cell data resources are required. However, a complete resource for humans is not available. To bridge this gap, we developed HuTAge, a comprehensive resource that integrates cross-tissue age-related information from The Genotype-Tissue Expression project with cross-tissue single-cell information from Tabula Sapiens to provide human tissue- and cell-specific ageing molecular information.

Availability and implementation

HuTAge is implemented within an R Shiny application and can be freely accessed at https://igcore.cloud/GerOmics/HuTAge/home. The source code is available at https://github.com/matsui-lab/HuTAge.

DOI： 10.1093/bioadv/vbaf072

その他リンク： https://academic.oup.com/bioinformaticsadvances/article-pdf/5/1/vbaf072/62856785/vbaf072.pdf

Integrative network analysis reveals novel moderators of Aβ-Tau interaction in Alzheimer's disease. 査読有り国際誌 Open Access

Akihiro Kitani, Yusuke Matsui

Alzheimer's research & therapy 17 巻 ( 1 ) 頁： 70 - 70 2025年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Although interactions between amyloid-beta and tau proteins have been implicated in Alzheimer's disease (AD), the precise mechanisms by which these interactions contribute to disease progression are not yet fully understood. Moreover, despite the growing application of deep learning in various biomedical fields, its application in integrating networks to analyze disease mechanisms in AD research remains limited. In this study, we employed BIONIC, a deep learning-based network integration method, to integrate proteomics and protein-protein interaction data, with an aim to uncover factors that moderate the effects of the Aβ-tau interaction on mild cognitive impairment (MCI) and early-stage AD. METHODS: Proteomic data from the ROSMAP cohort were integrated with protein-protein interaction (PPI) data using a Deep Learning-based model. Linear regression analysis was applied to histopathological and gene expression data, and mutual information was used to detect moderating factors. Statistical significance was determined using the Benjamini-Hochberg correction (p < 0.05). RESULTS: Our results suggested that astrocytes and GPNMB + microglia moderate the Aβ-tau interaction. Based on linear regression with histopathological and gene expression data, GFAP and IBA1 levels and GPNMB gene expression positively contributed to the interaction of tau with Aβ in non-dementia cases, replicating the results of the network analysis. CONCLUSIONS: These findings suggest that GPNMB + microglia moderate the Aβ-tau interaction in early AD and therefore are a novel therapeutic target. To facilitate further research, we have made the integrated network available as a visualization tool for the scientific community (URL: https://igcore.cloud/GerOmics/AlzPPMap ).

DOI： 10.1186/s13195-025-01705-x

Open Access

PubMed

Predicting Alzheimer's Cognitive Resilience Score: A Comparative Study of Machine Learning Models Using RNA-seq Data

Akihiro Kitani, Yusuke Matsui

2024年8月

担当区分：責任著者出版者・発行元：Cold Spring Harbor Laboratory

Alzheimer's disease (AD) is an important research topic. While amyloid plaques and neurofibrillary tangles are hallmark pathological features of AD, cognitive resilience (CR) is a phenomenon where cognitive function remains preserved despite the presence of these pathological features. This study aimed to construct and compare predictive machine learning models for CR scores using RNA-seq data from the Religious Orders Study and Memory and Aging Project (ROSMAP) and Mount Sinai Brain Bank (MSBB) cohorts. We evaluated support vector regression (SVR), random forest, XGBoost, linear, and transformer-based models. The SVR model exhibited the best performance, with contributing genes identified using Shapley additive explanations (SHAP) scores, providing insights into biological pathways associated with CR. Finally, we developed a tool called the resilience gene analyzer (REGA), which visualizes SHAP scores to interpret the contributions of individual genes to CR. REGA is available at https://igcore.cloud/GerOmics/REsilienceGeneAnalyzer/.

DOI： 10.1101/2024.08.25.609610

Toward a systems glycogenomics approach to understanding diseases 招待有り

松井佑介

Glycoforum 27 巻 ( 4 ) 頁： A12 2024年8月

The Human Glycome Atlas Project for cataloging all glycan-related omics data in human. 査読有り国際誌 Open Access

Kiyoko F Aoki-Kinoshita, Hiromune Ando, Kiyohiko Angata, Morihisa Fujita, Jun-Ichi Furukawa, Hiroyuki Kaji, Koichi Kato, Ken Kitajima, Yasuhiko Kizuka, Yusuke Matsui, Kazuki Nakajima, Shoko Nishihara, Tetsuya Okajima, Kazuma Sakamoto, Chihiro Sato, Morten Thaysen-Andersen, Akira Togayachi, Hirokazu Yagi, Kenji Kadomatsu

Glycobiology 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The Human Glycome Atlas (HGA) Project was launched in April 2023, spearheaded by three Japanese institutes: the Tokai National Higher Education and Research System, the National Institutes of Natural Sciences, and Soka University. This was the first time that a field in the life sciences was adopted by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) for a Large-scale Academic Frontiers Promotion Project. This project aims to construct a knowledgebase of human glycans and glycoproteins as a standard for the human glycome. A high-throughput pipeline for comprehensively analyzing 20,000 blood samples in its first five years is planned, at which time an access-controlled version of a human glycomics knowledgebase, called TOHSA, will be released. By the end of the final tenth year, TOHSA will provide a central resource linking human glycan data with other omics data including disease-related information.

DOI： 10.1093/glycob/cwae052

Open Access

PubMed

A Computational Approach to Interpreting the Embedding Space of Dimension Reduction

Bingyuan Zhang, Kohei Uno, Hayata Kodama, Koichi Himori, Yusuke Matsui

2024年6月

担当区分：最終著者,　責任著者出版者・発行元：Cold Spring Harbor Laboratory

Summary

Nonlinear dimension reduction methods are widely applied in studies analyzing gene and protein expression, by revealing patterns of discrete groups and continuous orders in high-dimensional data. However, the tools are limited to understanding the obtained embedding structures of biological mechanisms, hindering the full exploitation of data. Here, we propose a novel framework to interpret embedding systematically by identifying and mapping associated biological functions. The method performs statistical tests and visualizes significantly enriched functions essential for the organization of the embedding structure, by applying it to the embedding results of two datasets: the Genotype Tissue Expression dataset and aCaenorhabditis elegansembryogenesis dataset, one capturing distinct cluster structures and the other capturing continuous developmental trajectories. We identified the associated functions for interpreting the two embeddings and confirmed it as a useful explainable AI tool in exploratory data analysis by providing annotations to the embedding space.

DOI： 10.1101/2024.06.23.600292

GPNMB+ microglia moderate the amyloid beta-tau interaction in early Alzheimer’s disease

Akihiro Kitani, Yusuke Matsui

2024年6月

担当区分：最終著者,　責任著者出版者・発行元：Cold Spring Harbor Laboratory

Summary

Although interactions between amyloid-beta (Aβ) and tau proteins have been implicated in Alzheimer’s disease (AD), the detailed mechanisms by which these interactions contribute to disease progression remain unclear. In this study, we evaluated proteomics and protein–protein interaction data using BIONC, a deep learning-based network integration method to investigate factors moderating the effects of the Aβ-tau interaction in mild cognitive impairment and early-stage AD. Our results suggested that astrocytes and GPNMB+ microglia moderate the Aβ-tau interaction. Based on linear regression with histopathological and gene expression data, GFAP and IBA1 levels andGPNMBgene expression positively contributed to the interaction of tau with Aβ in non-dementia cases, replicating the results of the network analysis. These findings indicate that GPNMB+ microglia moderate the Aβ-tau interaction in early AD and therefore are a novel therapeutic target.

Graphical Abstract

DOI： 10.1101/2024.06.14.599092

Evaluating Desk-Assisted Standing Techniques for Simulated Pregnant Conditions: An Experimental Study Using a Maternity-Simulation Jacket

Kohei Uno, Kako Tsukioka, Hibiki Sakata, Tomoe Inoue-Hirakawa, Yusuke Matsui

Healthcare 12 巻 ( 9 ) 頁： 931 - 931 2024年5月

担当区分：最終著者掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Lower back pain, a common issue among pregnant women, often complicates daily activities like standing up from a chair. Therefore, research into the standing motion of pregnant women is important, and many research studies have already been conducted. However, many of these studies were conducted in highly controlled environments, overlooking everyday scenarios such as using a desk for support when standing up, and their effects have not been adequately tested. To address this gap, we measured multimodal signals for a sit-to-stand (STS) movement with hand assistance and verified the changes using a t-test. To avoid imposing strain on pregnant women, we used 10 non-diseased young adults who wore jackets designed to simulate pregnancy conditions, thus allowing for more comprehensive and rigorous experimentation. We attached surface electromyography (sEMG) sensors to the erector spinae muscles of participants and measured changes in muscle activity, skeletal positioning, and center of pressure both before and after wearing a Maternity-Simulation Jacket. Our analysis showed that the jacket successfully mimicked key aspects of the movement patterns typical in pregnant women. These results highlight the possibility of developing practical strategies that more accurately mirror the real-life scenarios met by pregnant women, enriching the current research on their STS movement.

DOI： 10.3390/healthcare12090931

Systematic identification of exercise-induced anti-aging processes involving intron retention

Hayata Kodama, Hirotaka Ijima, Yusuke Matsui

2024年4月

担当区分：最終著者,　責任著者出版者・発行元：Cold Spring Harbor Laboratory

Abstract

Exercise is one of the most promising anti-aging interventions for maintaining skeletal muscle health in older adults. Nine “Aging Hallmarks”, proposed by López-Otín, offer insights into the aging process; however, the link between these hallmarks and exercise is not fully elucidated. In this study, we conducted a systematic multi-omics analysis of skeletal muscles, focusing on aging and exercise, based on gene signatures for aging hallmarks. It is posited that mRNA splicing activity, linked to genomic instability, constitutes a fundamental hallmark of aging, and it exhibits divergent expression patterns in response to aging and exercise. Additionally, we analysed splicing events and discovered that intron retention (IR) is significantly impacted by aging, exhibiting contrasting changes to those induced by resistance training in the older cohort. The isoforms characterised by IR are notably enriched in mitochondrial functions. Conclusively, our results underscore the significance of splicing mechanisms as a novel aspect of aging hallmarks in skeletal muscles and propose a new mechanism by which exercise exerts its anti-aging effects on skeletal muscles through intron retention.

Key points summary

Skeletal muscle aging involves significant structural and functional changes, including loss of muscle mass, decline in strength, and mitochondrial dysfunction, all influenced by genomic instability.

Exercise has been identified as a key intervention that counters genomic instability and modulates mRNA splicing patterns, particularly through the regulation of Intron Retention, to mitigate aging effects in skeletal muscle.

We reveal the novel role of IR, especially in principal isoforms, where it is linked to critical cellular processes like mitochondrial function, suggesting a targeted pathway through which exercise exerts its anti-aging effects.

The findings provide new insights into the molecular mechanisms underlying the beneficial effects of exercise on aging skeletal muscle.

This study lays the groundwork for future research on exercise-induced modulation of mRNA splicing as a therapeutic strategy for aging and potentially age-related diseases, pointing towards a significant shift in how we approach aging intervention strategies.

DOI： 10.1101/2024.04.25.591048

BRAFV600E Promotes Anchorage-Independent Growth but Inhibits Anchorage-Dependent Growth in hTERT / Cdk4-Immortalized Normal Human Bronchial Epithelial Cells

Nao Muraki, Nozomi Kawabe, Ayano Ohashi, Kanna Umeda, Masahito Katsuda, Aya Tomatsu, Mikina Yoshida, Kazuki Komeda, John D. Minna, Ichidai Tanaka, Masahiro Morise, Miyoko Matsushima, Yusuke Matsui, Tsutomu Kawabe, Mitsuo Sato

Experimental Cell Research 頁： 114057 - 114057 2024年4月

Network-based cytokine inference implicates Oncostatin M as a driver of an inflammation phenotype in knee osteoarthritis 招待有り査読有り国際共著 Open Access

Iijima H, Zhang F, Ambrosio F, Matsui Y.

Aging Cell 頁： e14043 2024年2月

Single-cell Glycogenomics Deciphers Links Between Altered Transcriptional Regulation and Aberrant Glycosylation in Alzheimer’s Disease

Yusuke Matsui, Akira Togayachi, Kazuma Sakamoto, Kiyohiko Angata, Kenji Kadomatsu, Shoko Nishihara

2023年12月

担当区分：筆頭著者,　責任著者出版者・発行元：Cold Spring Harbor Laboratory

Summary

Glycosylation is increasingly recognized as a potential new therapeutic target in Alzheimer’s disease. In recent years, evidence for Alzheimer’s disease-specific glycoproteins has been established. However, the mechanisms of their dysregulation, including tissue and cell type specificity, are not fully understood. We aimed to explore upstream regulators of aberrant glycosylation by integrating multiple data sources and using a glycogenomics approach. We identified dysregulation by the glycosyltransferase PLOD3 in oligodendrocytes as an upstream regulator in cerebral vessels, and found that it is involved in COL4A5 synthesis, which is strongly correlated with amyloid fiber formation. Furthermore, COL4A5 was suggested to interact with astrocytes via ECM receptors as a ligand. This study suggests directions for new therapeutic strategies for Alzheimer’s disease targeting glycosyltransferases.

Graphical Abstract

DOI： 10.1101/2023.12.25.573290

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals. 査読有り国際共著 Open Access

Iijima H, Ambrosio F, Matsui Y.

J Physiol. 2023年12月

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals. 国際誌 Open Access

Hirotaka Iijima, Fabrisia Ambrosio, Yusuke Matsui

The Journal of physiology 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Accumulated fat in skeletal muscle (i.e. myosteatosis), common in sedentary older individuals, compromises skeletal muscle health and function. A mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy ageing. Using a network medicine paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study explored the shared molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for fat accumulation. Specifically, gene set enrichment analyses with network propagation revealed Pgc-1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity in aged muscle, but not in young counterparts. Integrated in silico and in situ approaches to induce Pgc-1α overexpression in aged muscle promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. These findings suggest that the Pgc-1α-mitochondrial fatty acid oxidation axis is a shared mechanism by which physical activity regulates age-related myosteatosis. The network medicine paradigm introduced provides mechanistic insight into exercise adaptation in elderly skeletal muscle and offers translational opportunities to advance exercise prescription for older populations. KEY POINTS: Fat accumulation is a quintessential feature of aged skeletal muscle. While increasing physical activity levels has been proposed as an effective strategy to reduce the fat in skeletal muscle (i.e. myosteatosis), the molecular cascade underlying these benefits has been poorly defined. This study implemented a series of network medicine approaches and uncovered Pgc-1α as a mechanistic driver of the regulation of fibro-adipogenic progenitors (FAPs) by physical activity. Integrated in silico and in situ approaches to induce Pgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. Together, the findings of the current study suggest a novel hypothesis that physical activity reduces myosteatosis via upregulation of Pgc-1α-mediated mitochondrial fatty acid oxidation and subsequent inhibition of FAP adipogenesis.

DOI： 10.1113/JP285349

Open Access

PubMed

Unbiased estimation of the population-level motor module

Yusuke Matsui, Kohei Uno, Ippei Nojima

2023年6月

担当区分：筆頭著者,　責任著者出版者・発行元：Cold Spring Harbor Laboratory

Summary

Motor module is a functional neurophysiological command for muscle coordination. In clinical settings, population-level characterization and comparison of motor modules are necessary to evaluate pathophysiological mechanisms and intervention effects. Previous studies have estimated individual motor modules and then compared them, but the validity of capturing the distribution of the latent population has not been fully understood. Our study aimed to address this issue by investigating the accuracy of estimating the population mean of motor modules. Through simulation experiments, we found that previous individual-based approach did not converge regardless of sample size and was vulnerable to noise. We developed an unbiased estimation algorithm using the framework of functional data analysis, which significantly improved estimation accuracy. Our findings highlight statistical challenges for motor module analysis and suggest the need for further research on new computational algorithms using large-scale clinical data.

Graphical Abstract

DOI： 10.1101/2023.06.25.23291878

Pgc-1α is an exercise-responsive regulator of myosteatosis in older individuals

Hirotaka Iijima, Fabrisia Ambrosio, Yusuke Matsui

2023年2月

担当区分：最終著者,　責任著者出版者・発行元：Cold Spring Harbor Laboratory

SUMMARY

Accumulated fat in skeletal muscle, common in sedentary older individuals, compromises skeletal muscle health and function. Mechanistic understanding ofhowphysical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy aging. Using a network paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study uncovered a novel molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for the fat accumulation. Specifically, gene set enrichment analyses (GSEA) with network propagation revealedPgc1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity. Integratedin silicoandin situapproaches to inducePgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAPs adipogenesis. These findings suggest thatPgc1α is a master regulator by which physical activity regulates fat accumulation in aged skeletal muscle.

GRAPHICAL ABSTRUCT

DOI： 10.1101/2023.02.07.527478

Network-based cytokine inference implicates Oncostatin M as a driver for inflammation phenotype of knee osteoarthritis

Hirotaka Iijima, Fan Zhang, Fabrisia Ambrosio, Yusuke Matsui

2023年1月

担当区分：責任著者出版者・発行元：Cold Spring Harbor Laboratory

SUMMARY

Inflammatory cytokines released by the synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage-specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network-based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M, as a driver for the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of Oncostatin M recapitulated “inflammation” phenotype of knee osteoarthritis and highlighted high-value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation-driven osteoarthritis phenotype.

GRAPHICAL ABSTRACT

DOI： 10.1101/2023.01.24.525463

Types of anomalies in two-dimensional video-based gait analysis in uncontrolled environments 招待有り査読有り Open Access

Yuki Sugiyama ,Kohei Uno ,Yusuke Matsui

PLoS Computational Biology 2023年1月

Types of anomalies in two-dimensional video-based gait analysis in uncontrolled environments Open Access

Yuki Sugiyama, Kohei Uno, Yusuke Matsui

PLOS Computational Biology 19 巻 ( 1 ) 頁： e1009989 - e1009989 2023年1月

担当区分：最終著者,　責任著者掲載種別：研究論文（学術雑誌）出版者・発行元：Public Library of Science (PLoS)

Two-dimensional video-based pose estimation is a technique that can be used to estimate human skeletal coordinates from video data alone. It is also being applied to gait analysis and in particularly, due to its simplicity of measurement, it has the potential to be applied to gait analysis of large populations. However, it is considered difficult to completely homogenize the environment and settings during the measurement of large populations. Therefore, it is necessary to appropriately deal with technical errors that are not related to the biological factors of interest. In this study, by analyzing a large cohort database, we have identified four major types of anomalies that occur during gait analysis using OpenPose in uncontrolled environments: anatomical, biomechanical, and physical anomalies and errors due to estimation. We have also developed a workflow for identifying and correcting these anomalies and confirmed that this workflow is reproducible through simulation experiments. Our results will help obtain a comprehensive understanding of the anomalies to be addressed during pre-processing for 2D video-based gait analysis of large populations.

DOI： 10.1371/journal.pcbi.1009989

Open Access

理学療法におけるデータサイエンスとAIの利活用と課題理学療法の教育分野におけるデータサイエンスとAIの利活用と課題招待有り査読有り

松井佑介

理学療法 2022年4月

理学療法におけるデータサイエンスとAIの利活用と課題理学療法の教育分野におけるデータサイエンスとAIの利活用と課題招待有り

松井佑介

理学療法 39 巻 ( 4 ) 頁： 336 - 342 2022年4月

Meta-analysis integrated with multi-omics data analysis to elucidate pathogenic mechanisms of age-related knee osteoarthritis in mice. 査読有り国際共著国際誌 Open Access

Hirotaka Iijima, Gabrielle Gilmer, Kai Wang, Sruthi Sivakumar, Christopher Evans, Yusuke Matsui, Fabrisia Ambrosio

The journals of gerontology. Series A, Biological sciences and medical sciences 77 巻 ( 7 ) 頁： 1321 - 1334 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the majority of clinically-presenting KOA, the bulk of our mechanistic understanding of KOA has been derived using surgically induced post-traumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics data analysis to elucidate pathogenic mechanisms of age-related KOA in mice. Protein-level data were integrated with transcriptomic profiling to reveal inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of cartilage aging were unique from those observed following PTOA, with less than 3% overlap between the two models. At the nexus of the three aging hallmarks, Advanced Glycation End-Product (AGE)/Receptor for AGE emerged as the most statistically robust pathway associated with age-related KOA. This pathway was further supported by analysis of mass spectrometry data. Notably, the change in AGE-RAGE signaling over time was exclusively observed in male mice, suggesting sexual dimorphism in the pathogenesis of age-induced KOA in murine models. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a sex-dependent driver of age-related KOA.

DOI： 10.1093/gerona/glab386

PubMed

Pan-cancer methylome analysis for cancer diagnosis and classification of cancer cell of origin. 招待有り査読有り

Dai Shimizu, Kenzui Taniue, Yusuke Matsui, Hiroshi Haeno, Hiromitsu Araki, Fumihito Miura, Mitsuko Fukunaga, Kenji Shiraishi, Yuji Miyamoto, Seiichi Tsukamoto, Aya Komine, Yuta Kobayashi, Akihiro Kitagawa, Yukihiro Yoshikawa, Kuniaki Sato, Tomoko Saito, Shuhei Ito, Takaaki Masuda, Atsushi Niida, Makoto Suzuki, Hideo Baba, Takashi Ito, Nobuyoshi Akimitsu, Yasuhiro Kodera, Koshi Mimori

Cancer gene therapy 2021年11月

Pan-cancer methylome analysis for cancer diagnosis and classification of cancer cell of origin. 査読有り国際誌

Cancer gene therapy 29 巻 ( 5 ) 頁： 428 - 436 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The accurate and early diagnosis and classification of cancer origin from either tissue or liquid biopsy is crucial for selecting the appropriate treatment and reducing cancer-related mortality. Here, we established the CAncer Cell-of-Origin (CACO) methylation panel using the methylation data of the 28 types of cancer in The Cancer Genome Atlas (7950 patients and 707 normal controls) as well as healthy whole blood samples (95 subjects). We showed that the CACO methylation panel had high diagnostic potential with high sensitivity and specificity in the discovery (maximum AUC = 0.998) and validation (maximum AUC = 1.000) cohorts. Moreover, we confirmed that the CACO methylation panel could identify the cancer cell type of origin using the methylation profile from liquid as well as tissue biopsy, including primary, metastatic, and multiregional cancer samples and cancer of unknown primary, independent of the methylation analysis platform and specimen preparation method. Together, the CACO methylation panel can be a powerful tool for the classification and diagnosis of cancer.

DOI： 10.1038/s41417-021-00401-w

PubMed

Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents. 招待有り査読有り Open Access

Kazumasa Komura, Teruo Inamoto, Takuya Tsujino, Yusuke Matsui, Tsuyoshi Konuma, Kazuki Nishimura, Taizo Uchimoto, Takeshi Tsutsumi, Tomohisa Matsunaga, Ryoichi Maenosono, Yuki Yoshikawa, Kohei Taniguchi, Tomohito Tanaka, Hirofumi Uehara, Koichi Hirata, Hajime Hirano, Hayahito Nomi, Yoshinobu Hirose, Fumihito Ono, Haruhito Azuma

Oncogene 2021年9月

Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents. 査読有り国際誌 Open Access

Oncogene 40 巻 ( 43 ) 頁： 6210 - 6222 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clones derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clones in bladder cancer (BC) by comprehensive proteomic analysis. CRT-recurrent BC cells exhibited a cell-cycle-independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double-strand breaks (DSBs). With DNA repair analyses employing the CRISPR/cas9 system, we revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic nonhomologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment, and the resistance to DSBs by increased BUB1B/BUBR1 depends on the functional ATM. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. A dataset analysis identified FOXM1 as a putative BUB1B/BUBR1-targeting transcription factor causing its increased expression. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner, aside from the canonical activity of BUB1B/BUBR1 on the G2/M checkpoint, and offer novel clues to overcome CRT resistance.

DOI： 10.1038/s41388-021-02021-y

Open Access

PubMed

RoDiCE: robust differential protein co-expression analysis for cancer complexome. 招待有り査読有り国際誌 Open Access

Yusuke Matsui, Yuichi Abe, Kohei Uno, Satoru Miyano

Bioinformatics (Oxford, England) 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

MOTIVATION: The full spectrum of abnormalities in cancer-associated protein complexes remains largely unknown. Comparing the co-expression structure of each protein complex between tumor and healthy cells may provide insights regarding cancer-specific protein dysfunction. However, the technical limitations of mass spectrometry-based proteomics, including contamination with biological protein variants, causes noise that leads to non-negligible over- (or under-) estimating co-expression. RESULTS: We propose a robust algorithm for identifying protein complex aberrations in cancer based on differential protein co-expression testing. Our method based on a copula is sufficient for improving identification accuracy with noisy data compared to conventional linear correlation-based approaches. As an application, we use large-scale proteomic data from renal cancer to show that important protein complexes, regulatory signaling pathways and drug targets can be identified. The proposed approach surpasses traditional linear correlations to provide insights into higher-order differential co-expression structures. AVAILABILITY AND IMPLEMENTATION: https://github.com/ymatts/RoDiCE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI： 10.1093/bioinformatics/btab612

PubMed

Pre-stimulus alpha oscillation and post-stimulus cortical activity differ in localization between consciously perceived and missed near-threshold somatosensory stimuli. 招待有り査読有り国際誌 Open Access

Jun-Ichi Uemura, Aiko Hoshino, Go Igarashi, Yusuke Matsui, Makoto Chishima, Minoru Hoshiyama

The European journal of neuroscience 54 巻 ( 4 ) 頁： 5518 - 5530 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Conscious perception of a near-threshold (NT) stimulus is characterized by the pre- and post-stimulus brain state. However, the power of pre-stimulus neural oscillations and strength of post-stimulus cortical activity that lead to conscious perception have rarely been examined in individual cortical areas. This is because most previous electro- and magnetoencephalography (EEG and MEG, respectively) studies involved scalp- and sensor-level analyses. Therefore, we recorded MEG during a continuous NT somatosensory stimulus detection task and applied the reconstructed source data in order to identify cortical areas where the post-stimulus cortical activity and pre-stimulus alpha oscillation predict the conscious perception of NT somatosensory stimuli. We found that the somatosensory hierarchical processing areas, prefrontal areas and cortical areas belonging to the default mode network showed stronger cortical activity for consciously perceived trials in the post-stimulus period, but the cortical activity in primary somatosensory area (SI) is independent of conscious perception during the early stage of NT stimulus processing. In addition, we revealed that the pre-stimulus alpha oscillation only in SI is predictive of conscious perception. These findings suggest that the bottom-up stream of somatosensory information flow following SI and pre-stimulus alpha activity fluctuation in SI as a top-down modulation are crucial constituents of conscious perception.

DOI： 10.1111/ejn.15388

PubMed

An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury 査読有り国際誌

Oda Shingo, Uchida Yuka, Aleo Michael D., Koza-Taylor Petra H., Matsui Yusuke, Hizue Masanori, Marroquin Lisa D., Whritenour Jessica, Uchida Eri, Yokoi Tsuyoshi

ARCHIVES OF TOXICOLOGY 95 巻 ( 1 ) 頁： 149 - 168 2020年8月

EXOSC9 depletion attenuates P-body formation, stress resistance, and tumorigenicity of cancer cells 査読有り国際誌 Open Access

Yoshino Seiko, Matsui Yusuke, Fukui Yuya, Seki Masahide, Yamaguchi Kiyoshi, Kanamori Akane, Saitoh Yurika, Shimamura Teppei, Suzuki Yutaka, Furukawa Yoichi, Kaneko Shuichi, Seiki Motoharu, Murakami Yoshinori, Inoue Jun-ichiro, Sakamoto Takeharu

SCIENTIFIC REPORTS 10 巻 ( 1 ) 頁： 9275 - 9275 2020年6月

Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells 査読有り国際誌 Open Access

Higashijima Yoshiki, Matsui Yusuke, Shimamura Teppei, Nakaki Ryo, Nagai Nao, Tsutsumi Shuichi, Abe Yohei, Link Verena M., Osaka Mizuko, Yoshida Masayuki, Watanabe Ryo, Tanaka Toshihiro, Taguchi Akashi, Miura Mai, Ruan Xiaoan, Li Guoliang, Inoue Tsuyoshi, Nangaku Masaomi, Kimura Hiroshi, Furukawa Tetsushi, Aburatani Hiroyuki, Wada Youichiro, Ruan Yijun, Glass Christopher K., Kanki Yasuharu

EMBO JOURNAL 39 巻 ( 7 ) 頁： e103949 2020年4月

Pathogenic Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type Diffuse Astrocytic Gliomas. 査読有り国際誌 Open Access

Fumiharu Ohka, Keiko Shinjo, Shoichi Deguchi, Yusuke Matsui, Yusuke Okuno, Keisuke Katsushima, Miho Suzuki, Akira Kato, Noboru Ogiso, Akane Yamamichi, Kosuke Aoki, Hiromichi Suzuki, Shinya Sato, Nirmala Arul Rayan, Shyam Prabhakar, Jonathan Göke, Teppei Shimamura, Reo Maruyama, Satoru Takahashi, Akio Suzumura, Hiroshi Kimura, Toshihiko Wakabayashi, Hui Zong, Atsushi Natsume, Yutaka Kondo

Cancer research 79 巻 ( 19 ) 頁： 4814 - 4827 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (IDH) status. Although IDH-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than IDH-mutant type, lack of knowledge regarding relevant molecular drivers for this type of tumor has hindered the development of therapeutic agents. Here, we examined human IDH-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks p53 and NF1 and spontaneously develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma (DAG-nonMF). During tumor formation, enhancer of zeste homolog (EZH2) and the other polycomb repressive complex 2 (PRC2) components were upregulated even at an early stage of tumorigenesis, together with an increased number of genes with H3K27me3 or H3K27me3 and H3K4me3 bivalent modifications. Among the epigenetically dysregulated genes, frizzled-8 (Fzd8), which is known to be a cancer- and stem cell reprogramming-related gene, was gradually silenced during tumorigenesis. Genetic and pharmacologic inhibition of EZH2 in MADM mice showed reactivation of aberrant H3K27me3 target genes, including Fzd8, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG-nonMF that depends on EZH2 activity and provides a strong rationale for targeting EZH2 as a promising therapeutic approach for this type of glioma. SIGNIFICANCE: EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4814/F1.large.jpg.

DOI： 10.1158/0008-5472.CAN-19-1272

PubMed

A network of networks approach for modeling interconnected brain tissue-specific networks. 査読有り Open Access

Kawakubo H, Matsui Y, Kushima I, Ozaki N, Shimamura T

Bioinformatics (Oxford, England) 35 巻 ( 17 ) 頁： 3092 - 3101 2019年9月

GIMLET: Identifying Biological Modulators in Context-Specific Gene Regulation Using Local Energy Statistics 査読有り

T SHIMAMURA, Y MATSUI, S MIYANO

Lecture Notes in Bioinformatics 10834 巻頁： 124 - 137 2019年

Tumor subclonal progression model for cancer hallmark acquisition 査読有り

Y MATSUI, S MIYANO, T SHIMAMURA

Lecture Notes in Bioinformatics 10834 巻頁： 115 - 123 2019年

A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer. 査読有り国際誌 Open Access

Tomoko Saito, Atsushi Niida, Ryutaro Uchi, Hidenari Hirata, Hisateru Komatsu, Shotaro Sakimura, Shuto Hayashi, Sho Nambara, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Takaaki Masuda, Keishi Sugimachi, Taro Tobo, Haruto Nishida, Tsutomu Daa, Kenichi Chiba, Yuichi Shiraishi, Tetsuichi Yoshizato, Masaaki Kodama, Tadayoshi Okimoto, Kazuhiro Mizukami, Ryo Ogawa, Kazuhisa Okamoto, Mitsutaka Shuto, Kensuke Fukuda, Yusuke Matsui, Teppei Shimamura, Takanori Hasegawa, Yuichiro Doki, Satoshi Nagayama, Kazutaka Yamada, Mamoru Kato, Tatsuhiro Shibata, Masaki Mori, Hiroyuki Aburatani, Kazunari Murakami, Yutaka Suzuki, Seishi Ogawa, Satoru Miyano, Koshi Mimori

Nature communications 9 巻 ( 1 ) 頁： 2884 - 2884 2018年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.

DOI： 10.1038/s41467-018-05226-0

Open Access

Web of Science

PubMed

ER stress signaling promotes the survival of cancer "Persister Cells" tolerant to EGFR tyrosine Kinase inhibitors 査読有り Open Access

Hideki Terai, Shunsuke Kitajima, Danielle S. Potter, Yusuke Matsui, Laura Gutierrez Quiceno, Ting Chen, Tae-Jung Kim, Maria Rusan, Tran C. Thai, Federica Piccioni, Katherine A. Donovan, Nicholas Kwiatkowski, Kunihiko Hinohara, Guo Wei, Nathanael S. Gray, Eric S. Fischer, Kwok-Kin Wong, Teppei Shimamura, Anthony Letai, Peter S. Hammerman, David A. Barbie

Cancer Research 78 巻 ( 4 ) 頁： 1044 - 1057 2018年2月

Identification of Cardiomyocyte-Fated Progenitors from Human-Induced Pluripotent Stem Cells Marked with CD82 査読有り Open Access

Masafumi Takeda, Yasuharu Kanki, Hidetoshi Masumoto, Shunsuke Funakoshi, Takeshi Hatani, Hiroyuki Fukushima, Akashi Izumi-Taguchi, Yusuke Matsui, Teppei Shimamura, Yoshinori Yoshida, Jun K. Yamashita

Cell Reports 22 巻 ( 2 ) 頁： 546 - 556 2018年

ハイブリッドサイエンスの新時代〜生命科学とデータ科学を繋ぐ〜ゲノムワイドCRISPRスクリーニングによるEGFR-TKI+転写阻害剤相乗作用の分子機構の理解

寺井秀樹, Potter Danielle, 北嶋俊輔, 松井佑介, Kim Tae-Jung, Rusan Maria, Thai Tran, Piccioni Federica, Donovan Katherine, Kwiatkowski Nicholas, 日野原邦彦, Wei Guo, Gray Nathanael, Fischer Eric, 島村徹平, Letai Anthony, Hammerman Peter, Barbie David

生命科学系学会合同年次大会 2017年度巻頁： [1PW08 - 6] 2017年12月

phyC: Clustering cancer evolutionary trees 査読有り Open Access

Yusuke Matsui, Atsushi Niida, Ryutaro Uchi, Koshi Mimori, Satoru Miyano, Teppei Shimamura

PLOS COMPUTATIONAL BIOLOGY 13 巻 ( 5 ) 頁： e1005509 2017年5月

(DM)-M-3: detection of differential distributions of methylation levels 査読有り Open Access

Yusuke Matsui, Masahiro Mizuta, Satoshi Ito, Satoru Miyano, Teppei Shimamura

BIOINFORMATICS 32 巻 ( 15 ) 頁： 2248 - 2255 2016年8月

NECAB3 Promotes Activation of Hypoxia-inducible factor-1 during Normoxia and Enhances Tumourigenicity of Cancer Cells 査読有り Open Access

Hiroki J. Nakaoka, Toshiro Hara, Seiko Yoshino, Akane Kanamori, Yusuke Matsui, Teppei Shimamura, Hiroshi Sato, Yoshinori Murakami, Motoharu Seiki, Takeharu Sakamoto

SCIENTIFIC REPORTS 6 巻頁： 22784 2016年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Unlike most cells, cancer cells activate hypoxia inducible factor-1 (HIF-1) to use glycolysis even at normal oxygen levels, or normoxia. Therefore, HIF-1 is an attractive target in cancer therapy. However, the regulation of HIF-1 during normoxia is not well characterised, although Mint3 was recently found to activate HIF-1 in cancer cells and macrophages by suppressing the HIF-1 inhibitor, factor inhibiting HIF-1 (FIH-1). In this study, we analysed Mint3-binding proteins to investigate the mechanism by which Mint3 regulates HIF-1. Yeast two-hybrid screening using Mint3 as bait identified N-terminal EF-hand calcium binding protein 3 (NECAB3) as a novel factor regulating HIF-1 activity via Mint3. NECAB3 bound to the phosphotyrosine-binding domain of Mint3, formed a ternary complex with Mint3 and FIH-1, and co-localised with Mint3 at the Golgi apparatus. Depletion of NECAB3 decreased the expression of HIF-1 target genes and reduced glycolysis in normoxic cancer cells. NECAB3 mutants that binds Mint3 but lacks an intact monooxygenase domain also inhibited HIF-1 activation. Inhibition of NECAB3 in cancer cells by either expressing shRNAs or generating a dominant negative mutant reduced tumourigenicity. Taken together, the data indicate that NECAB3 is a promising new target for cancer therapy.

DOI： 10.1038/srep22784

Open Access

Web of Science

PubMed

Classification of customers and analysis of purchase tendency in a group-buying coupon site. 招待有り査読有り

Igarashi S, Matsui Y, Minami M, Mizuta M

J Soc Comp Stat 28 巻 ( 2 ) 頁： 1 - 8 2015年

移動関数k-means法の提案とその応用査読有り

松井佑介, 小宮由里子, 南弘征, 水田正弘

データ分析の理論と応用 4 巻 ( 1 ) 頁： 43 - 55 2015年

記述言語：日本語出版者・発行元：日本分類学会

本論文では，関数データにおける部分的な特徴を考慮した「移動関数k-means法」を提案し，実際の適用例を通してその有効性を示す．具体的には，従来の関数データクラスタリングのように定義域を固定せずに，部分的な区間を逐次的に移動させながら関数クラスタリングを行う．また本手法を，福島県における空間線量率を測定した大規模センシングデータに適用し，従来手法では検出しにくいようなクラスターの同定に対して有効であることを示す．

DOI： 10.32146/bdajcs.4.43

CiNii Research

共同購入型クーポンサイトにおける顧客の分類及び群ごとの購買傾向の解析査読有り

五十嵐千人, 松井佑介, 南弘征, 水田正弘

計算機統計学 28 巻 ( 2 ) 頁： 139 - 146 2015年

記述言語：日本語出版者・発行元：日本計算機統計学会

本論文では, 共同購入型クーポンサイトに蓄積された購買データを用いて, 顧客の購買傾向に関する有用な知見を得るための方法論を示す. 具体的には, 購入したクーポンのジャンルに基づき顧客をクラスタリングし, また対応分析を用いて, 顧客の属性とクーポンのジャンルの関係性を図示する. さらに, 全顧客を対象とした場合と, 顧客クラスター別の場合の両方を試み, 対比を通じて, 関係性の詳細を明らかにした.

DOI： 10.20551/jscswabun.28.2_139

CiNii Research

SDA for mixed-type data and its application to analysis of environmental radio activity level data. 査読有り

Matsui Y,Mizuta M.

COMPSTAT2014 頁： 673-680 2014年8月

Comparison of two distribution valued dissimilarities and its application for symbolic clustering 査読有り

Yusuke Matsui, Yuriko Komiya, Hiroyuki Minami, Masahiro Mizuta

Studies in Classification, Data Analysis, and Knowledge Organization 46 巻頁： 37 - 46 2014年

Symbolic Cluster Analysis for Distribution Valued Dissimilarity 査読有り

Matsui Y, Minami H, Mizuta, M

Communications for Statistical Applications and Methods. 21 巻 ( 3 ) 頁： 225 - 234 2014年

SDA for mixed-type data and its application to analysis of environmental radio activity level data. 査読有り

Matsui Y, Mizuta M

COMPSTAT2014 頁： 673 - 680 2014年

多次元値関数データにおける異常領域の検出法とセンシングデータへの応用査読有り

松井佑介, 小宮由里子, 南弘征, 水田正弘

計算機統計学 27 巻 ( 2 ) 頁： 65 - 77 2014年

記述言語：日本語出版者・発行元：日本計算機統計学会

本論文では,時間に依存して連続的に得られる多次元のデータにおける異常領域の検出法を提案する.はじめに,各次元ごとに異常領域を特定する方法を考え,「値が異常に高い領域」,「値が異常に低い領域」,「その他の領域」の3つに区分する.その上で,複数の次元において同時に異常となる領域を同定する方法を述べる.福島県における空間線量率を測定したセンシングデータを用いて,本手法が有効であることを示す.

DOI： 10.20551/jscswabun.27.2_65

CiNii Research

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