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

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

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

Authorship：Lead author  

Publishing type：Research paper (scientific journal)  

DOI： 10.1093/gerona/glab386

Language：English  

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

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

DOI： 10.1093/bioinformatics/btab612

DOI： 10.1111/ejn.15388

DOI： 10.1007/s00204-020-02882-4

Web of Science

PubMed

DOI： 10.1038/s41598-020-66455-2

Web of Science

PubMed

DOI： 10.15252/embj.2019103949

Web of Science

PubMed

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

DOI： 10.1093/bioinformatics/btz032

Web of Science

PubMed

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

DOI： 10.1158/0008-5472.CAN-19-1272

PubMed

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

DOI： 10.1007/978-3-030-14160-8_13

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/978-3-030-14160-8_12

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

DOI： 10.1038/s41467-018-05226-0

Web of Science

PubMed

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

DOI： 10.1158/0008-5472.CAN-17-1904

Web of Science

PubMed

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

DOI： 10.1016/j.celrep.2017.12.057

Web of Science

PubMed

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

DOI： 10.1371/journal.pcbi.1005509

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

Web of Science

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/978-3-319-01264-3_3

Language：English  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.5351/CSAM.2014.21.3.225

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)