Language：English   Publishing type：Research paper (scientific journal)  

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

Authorship：Last author,　Corresponding author   Publisher：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

Authorship：Last author,　Corresponding author   Publisher：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

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：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

Authorship：Last author,　Corresponding author   Publisher：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

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.yexcr.2024.114057

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/acel.14043

Open Access

Authorship：Lead author,　Corresponding author   Publisher：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

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1113/JP285349

Open Access

Language：English   Publishing type：Research paper (scientific journal)  

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

Authorship：Lead author,　Corresponding author   Publisher：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

Authorship：Last author,　Corresponding author   Publisher：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

Authorship：Corresponding author   Publisher：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

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi.org/10.1371/journal.pcbi.1009989

Open Access

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：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

Authorship：Lead author  

Authorship：Lead author   Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English  

DOI： https://doi.org/10.1038/s41417-021-00401-w

Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： https://doi.org/10.1038/s41388-021-02021-y

Open Access

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

Preventing clinical drug-induced liver injury (DILI) remains a major challenge, because DILI develops via multifactorial mechanisms. Immune and inflammatory reactions are considered important mechanisms of DILI; however, biomarkers from in vitro systems using immune cells have not been comprehensively studied. The aims of this study were (1) to identify promising biomarker genes for predicting DILI in an in vitro coculture model of peripheral blood mononuclear cells (PBMCs) with a human liver cell line, and (2) to evaluate these genes as predictors of DILI using a panel of drugs with different clinical DILI risk. Transcriptome-wide analysis of PBMCs cocultured with HepG2 or differentiated HepaRG cells that were treated with several drugs revealed an appropriate separation of DILI-positive and DILI-negative drugs, from which 12 putative biomarker genes were selected. To evaluate the predictive performance of these genes, PBMCs cocultured with HepG2 cells were exposed to 77 different drugs, and gene expression levels in PBMCs were determined. The MET proto-oncogene receptor tyrosine kinase (MET) showed the highest area under the receiver-operating characteristic curve (AUC) value of 0.81 among the 12 genes with a high sensitivity/specificity (85/66%). However, a stepwise logistic regression model using the 12 identified genes showed the highest AUC value of 0.94 with a high sensitivity/specificity (93/86%). Taken together, we established a coculture system using PBMCs and HepG2 cells and selected biomarkers that can predict DILI risk. The established model would be useful in detecting the DILI potential of compounds, in particular those that involve an immune mechanism.

DOI： 10.1007/s00204-020-02882-4

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Cancer cells adapt to various stress conditions by optimizing gene expression profiles via transcriptional and translational regulation. However, whether and how EXOSC9, a component of the RNA exosome complex, regulates adaptation to stress conditions and tumorigenicity in cancer cells remain unclear. Here, we examined the effects of EXOSC9 depletion on cancer cell growth under various stress conditions. EXOSC9 depletion attenuated growth and survival under various stress conditions in cancer cells. Interestingly, this also decreased the number of P-bodies, which are messenger ribonucleoprotein particles (mRNPs) required for stress adaptation. Meanwhile, EXOSC2/EXOSC4 depletion also attenuated P-body formation and stress resistance with decreased EXOSC9 protein. EXOSC9-mediated stress resistance and P-body formation were found to depend on the intact RNA-binding motif of this protein. Further, RNA-seq analyses identified 343 EXOSC9-target genes, among which, APOBEC3G contributed to defects in stress resistance and P-body formation in MDA-MB-231 cells. Finally, EXOSC9 also promoted xenografted tumor growth of MDA-MB-231 cells in an intact RNA-binding motif-dependent manner. Database analyses further showed that higher EXOSC9 activity, estimated based on the expression of 343 target genes, was correlated with poorer prognosis in some cancer patients. Thus, drugs targeting activity of the RNA exosome complex or EXOSC9 might be useful for cancer treatment.

DOI： 10.1038/s41598-020-66455-2

Open Access

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Histone H3 lysine-9 di-methylation (H3K9me2) and lysine-27 tri-methylation (H3K27me3) are linked to repression of gene expression, but the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. Here, we report that lysine demethylases 7A (KDM7A) and 6A (UTX) play crucial roles in tumor necrosis factor (TNF)-α signaling in endothelial cells (ECs), where they are regulated by a novel TNF-α-responsive microRNA, miR-3679-5p. TNF-α rapidly induces co-occupancy of KDM7A and UTX at nuclear factor kappa-B (NF-κB)-associated elements in human ECs. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and are both required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods furthermore uncover increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A and UTX recruitments. Simultaneous pharmacological inhibition of KDM7A and UTX significantly reduces leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM7A and UTX is essential for NF-κB-dependent regulation of genes that control inflammatory responses of ECs.

DOI： 10.15252/embj.2019103949

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/bioinformatics/btz032

Open Access

Web of Science

PubMed

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Springer  

DOI： 10.1007/978-3-030-14160-8_13

Other Link： https://dblp.uni-trier.de/db/conf/cibb/cibb2017.html#ShimamuraMKITM17

Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1007/978-3-030-14160-8_12

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research Inc.  

DOI： 10.1158/0008-5472.CAN-17-1904

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

DOI： 10.1016/j.celrep.2017.12.057

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pcbi.1005509

Open Access

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/bioinformatics/btw138

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

Language：Japanese   Publisher：Japanese Classification Society  

<p> A novel functional clustering method for domain-dependent functional data is proposed. The functional data are defined on sequential domains and they might have particular clusters on each domain. Our approach, <i><font face="roman">Moving Functional k-means Clustering</font></i>, is to classify the peculiar domains based on each sequential set of clusters. A typical functional clustering with fixed number of clusters is applied to the domains, then we relabel the set of clusters to keep the previous labels as many as possible. We demonstrate our method with large scale sensing data of environmental radio activity level in Fukushima Prefecture. </p>

DOI： 10.32146/bdajcs.4.43

CiNii Research

Language：Japanese   Publisher：Japanese Society of Computational Statistics  

In this paper, we propose a method for extracting useful information of the customer's purchase tendency from data recorded in a group-buying coupon site. To begin with, we classify the customers using cluster analysis according to categories of purchased coupon. We also show the relationship between the customer's attributes and the categories of coupons using correspondence analysis. Through comparison of the results for all customers and for the customers in each cluster, we discuss the in-depth interpretation.

DOI： 10.20551/jscswabun.28.2_139

CiNii Research

Language：English  

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Kluwer Academic Publishers  

DOI： 10.1007/978-3-319-01264-3_3

Scopus

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.5351/CSAM.2014.21.3.225

Web of Science

Language：English   Publishing type：Research paper (international conference proceedings)  

Language：Japanese   Publisher：Japanese Society of Computational Statistics  

In this paper, we propose a method for identifying an irregular domain of multi dimensional data that are observed continuously and its application to sensing data. We partition the data into three subdomains on each dimension - "irregularly high valued domains", "irregularly low valued domains" and "other domains". Then we detect the subdomains in which the irregularities are observed simultaneously. We demonstrate our method with an actual example using sensing data of environmental radio activity level in Fukushima Prefecture.

DOI： 10.20551/jscswabun.27.2_65

CiNii Research

Language：Japanese  

In this paper, we propose a method for extracting useful information of the customer's purchase tendency from data recorded in a group-buying coupon site. To begin with, we classify the customers using cluster analysis according to categories of purchased coupon. We also show the relationship between the customer's attributes and the categories of coupons using correspondence analysis. Through comparison of the results for all customers and for the customers in each cluster, we discuss the in-depth interpretation.

CiNii Research

Language：Japanese  

In this paper, we propose a method for identifying an irregular domain of multi dimensional data that are observed continuously and its application to sensing data. We partition the data into three subdomains on each dimension - "irregularly high valued domains", "irregularly low valued domains" and "other domains". Then we detect the subdomains in which the irregularities are observed simultaneously. We demonstrate our method with an actual example using sensing data of environmental radio activity level in Fukushima Prefecture.

CiNii Research

Language：Japanese   Publisher：日本計算機統計学会  

DOI： 10.20551/jscssymo.27.0_97

CiNii Research

Language：Japanese   Publisher：日本計算機統計学会  

DOI： 10.20551/jscssymo.27.0_93

CiNii Research

Language：Japanese   Publisher：日本計算機統計学会  

DOI： 10.20551/jscstaikai.26.0_19

CiNii Research

Event date： 2022.10

Language：Japanese   Presentation type：Poster presentation  

Event date： 2022.10

Language：Japanese   Presentation type：Poster presentation  

Event date： 2021.12

Presentation type：Oral presentation (general)  

Event date： 2021.12

Event date： 2021.12

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2021.10

Event date： 2021.10

Language：Japanese  

Event date： 2021.10

Event date： 2021.10

Event date： 2021.7

Language：Chinese  

Event date： 2019.9

Language：Japanese  

Event date： 2019.8

Language：English   Presentation type：Oral presentation (invited, special)  

Event date： 2018.2

Language：English   Presentation type：Oral presentation (general)  

Venue： 滋賀大学   Country：Japan  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2017.9

Language：English   Presentation type：Oral presentation (general)  

Country：Spain  

Event date： 2017.9

Language：English   Presentation type：Oral presentation (general)  

Country：Italy  

Event date： 2017.9

Language：English   Presentation type：Oral presentation (general)  

Country：Italy  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2017.8

Language：English   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2017.5

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Country：Italy  

Event date： 2016.9

Event date： 2016.9

Language：English   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2015.11

Event date： 2015.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2015.11

Language：English   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2015.7

Language：English   Presentation type：Oral presentation (general)  

Country：Italy  

Event date： 2014.8

Language：English   Presentation type：Oral presentation (general)  

Country：Switzerland  

Event date： 2014.8

Language：English   Presentation type：Oral presentation (general)  

Country：Switzerland  

Event date： 2014.7

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Country：Japan  

Event date： 2013.11

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Country：Japan  

Event date： 2013.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2013.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2013.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2013.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2013.8

Language：English   Presentation type：Oral presentation (invited, special)  

Country：Korea, Republic of  

Event date： 2013.7

Language：English   Presentation type：Oral presentation (invited, special)  

Country：Netherlands  

Event date： 2013.6

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Country：Korea, Republic of  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2012.6

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Country：Japan  

Event date： 2012.5

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2012.2

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Country：Japan  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (invited, special)  

Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Language：English   Presentation type：Oral presentation (invited, special)  

Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (general)