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Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD.

Code ↔ Paper

2 matches between paragraphs of the paper and lines of its authors' code, computed by the harvester (lexical-v1). Click a colored paragraph or line to see its counterpart.

The 2 matches · all tie a paragraph to a whole file, not to given lines: weak matches, whose lines are not tinted
  1. [1] § MATERIALS AND METHODS › Cell-type–specific enrichment ↔ Nori_TETA_7W_Limma/04_Enrichments_TETA.sh, the whole file · a weak match · score 0.78 · scMouse, PSY DEGS, scRNA, mouse brain, Young, enrichment
  2. [2] § MATERIALS AND METHODS › Cell-type–specific enrichment ↔ Nori_TETA_7W_Limma/06_Enrichments_Both.sh, the whole file · a weak match · score 0.78 · scMouse, PSY DEGS, scRNA, mouse brain, Young, enrichment

Paper

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The authors' code

Shell · 41 lines · 2.2 KB · no license · 1 match

  1. # Enrichment.r
  2. # -g = Two columns table of input genes with specific association from your study
  3. # -l = list of two columns tables with gene - disease association. E.g. Gene1 SYN
  4. # -p = make a bubble chart with OR and -log10(FDR)
  5. # -b = background (protein coding = 19776, brain expressed = 15585, WGCNA list = 6029)
  6. # -o = output label for statistics and viz
  7. # -W/-H = width/height of the plot.
  9. mkdir dge/enrichments_ctx/
  10. dge
  11. cp utils/geneset/*.RData dge/enrichments_ctx/
  12. cp utils/Enrichment.r dge/enrichments_ctx/
  13. cp dge/TETA_Dge_HumanID.txt dge/enrichments_ctx/
  14. cp dge/TETA_Dge_MouseID.txt dge/enrichments_ctx/
  16. cd dge/enrichments_ctx/
  18. mkdir STATS/
  20. # scRNA healty
  21. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l Allen_MultiReg_CellMarkers_GeneSet.RData -p -b 19982 -o STATS/Allen_Markers -W 4 -H 4
  22. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l GeneSets_BBLake_2018.RData -p -b 19982 -o STATS/BBLake_Markers -W 4 -H 4
  23. Rscript Enrichment.r -g TETA_Dge_MouseID.txt -l GeneSets_scMouse.RData -p -b 19982 -o STATS/scMouse -W 4 -H 5
  24. Rscript Enrichment.r -g TETA_Dge_MouseID.txt -l GeneSets_Allen_Mouse_PFC.RData -p -b 19982 -o STATS/scMouse_Allen_PFC -W 4 -H 5
  25. Rscript Enrichment.r -g TETA_Dge_MouseID.txt -l GeneSets_Cowan_PFC.RData -p -b 19982 -o STATS/scMouse_Cowan_PFC -W 4 -H 5
  26. Rscript Enrichment.r -g TETA_Dge_MouseID.txt -l GeneSets_AdultMouse.RData -p -b 19982 -o STATS/scMouse_AdultMouse_Brain -W 4 -H 6
  27. Rscript Enrichment.r -g TETA_Dge_MouseID.txt -l GeneSets_YoungMouse.RData -p -b 19982 -o STATS/scMouse_YoungMouse_Brain -W 4 -H 6
  28. Rscript Enrichment.r -g TETA_Dge_MouseID.txt -l GeneSets_OligoMouse.RData -p -b 19982 -o STATS/scMouse_OligoMouse_Brain -W 4 -H 4
  31. # scRNA Disorders
  32. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l ALZ_SingleCell_DEGs.RData -p -b 19982 -o STATS/ALZ_SingleCell -W 4 -H 5
  33. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l ASD_SingleCell_DEGs.RData -p -b 19982 -o STATS/ASD_SingleCell -W 4 -H 5
  35. # Neuropsy
  36. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l PsychENCODE_DEGs.RData -p -b 19982 -o STATS/PSY_DEGS -W 4 -H 3
  37. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l PsychEncode_Modules.RData -p -b 19982 -o STATS/PSY_MODS -W 4 -H 5
  38. Rscript Enrichment.r -g TETA_Dge_HumanID.txt -l ASD_SFARI.RData -p -b 19982 -o STATS/ASD_Sfari -W 4 -H 2
  40. rm *.RData

04_Enrichments_TETA.sh at commit 8dae97d, no license · at the source

Overview

Authors: Noriyoshi Usui1,2,3,4,5,6, Miyuki Doi1,2,6, Stefano Berto7, Kiwamu Matsuoka8, Rio Ishida8,9,10, Hana Miyauchi2, Yuuki Fujiwara4, Koichiro Irie2, Michihiro Toritsuka9,10,11, Takahira Yamauchi8, Takaharu Hirai12,13, Min-Jue Xie4,13,14, Yoshinori Kayashima8, Naoko Umeda14,15, Keiko Iwata4,14,16, Kazuki Okumura8, Taeko Harada17, Taiichi Katayama4, Masatsugu Tsujii18, Hideo Matsuzaki4,13,14, Manabu Makinodan9,10,11, Shoichi Shimada2,4,5,6
ORCID iDs: Noriyoshi Usui, Miyuki Doi, Stefano Berto, Kiwamu Matsuoka, Yuuki Fujiwara, Koichiro Irie, Takahira Yamauchi, Takaharu Hirai, Naoko Umeda, Keiko Iwata, Kazuki Okumura, Taeko Harada, Hideo Matsuzaki, Manabu Makinodan, Shoichi Shimada
18 affiliations
  1. Department of Developmental Neuroscience, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
  2. Department of Neuroscience and Cell Biology, Graduate School of Medicine, The University of Osaka, Suita 565-0871, Japan
  3. Omics Center, Center of Medical Innovation and Translational Research, Graduate School of Medicine, The University of Osaka, Suita 565-0871, Japan
  4. United Graduate School of Child Development, The University of Osaka, Suita 565-0871, Japan
  5. Global Center for Medical Engineering and Informatics, The University of Osaka, Suita 565-0871, Japan
  6. Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka 541-8567, Japan
  7. Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29403, USA
  8. Department of Psychiatry, Nara Medical University, Nara 634-8522, Japan
  9. Division of Transformative Psychiatry and Synergistic Research, International Center for Brain Sciences, Fujita Health University, Aichi 470-1192, Japan
  10. Department of Psychiatry, Fujita Health University, Aichi 470-1192, Japan
  11. Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
  12. Department of Psychiatric and Mental Health Nursing, School of Nursing, University of Fukui, Fukui 910-1193, Japan
  13. Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan
  14. Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui 910-1193, Japan
  15. Department of Maternal and Child Health Nursing, School of Nursing, University of Fukui, Fukui 910-1193, Japan
  16. Laboratory of Pharmacology, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan
  17. Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
  18. School of Contemporary Sociology, Chukyo University, Aichi 470-0393, Japan
Institutions: Niigata University (Japan); The University of Osaka (Japan); Medical University of South Carolina (United States); Nara Medical University (Japan); Fujita Health University (Japan); Kumamoto University (Japan); University of Fukui (Japan); Wakayama Medical University (Japan); Hamamatsu University (Japan); Hamamatsu University School of Medicine (Japan); Chukyo University (Japan)
Journal: Science advances, volume 12, issue 14, article eadz3398
Dates: received 30 May 2025; accepted 27 February 2026; published online 1 April 2026; in print April 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1126/sciadv.adz3398 · PMID 41920999 · PMCID PMC13041773 · OpenAlex W7147461297
Open access: gold, a free copy (OpenAlex)
Status: code verified
Categories: human (organism), mouse (organism), autism (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Connectivity, Preprocessing
MeSH: Autism Spectrum Disorder*, Copper*, Mitophagy*, Oligodendroglia*, Social Behavior*, TOR Serine-Threonine Kinases*, Animals, Disease Models, Animal, Female, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Signal Transduction, White Matter (* major topic)
Journal subjects: Neuroscience
Topic: Trace Elements in Health (Nutrition and Dietetics, Nursing), according to OpenAlex
Funding: Naito Foundation; Takeda Science Foundation (TSF); Uehara Memorial Foundation; Japan Agency for Medical Research and Development (A140, 22gm1510009h0001, 24gm1910004s0402, 21gm6310015h0002, 21wm04250XXs0101, 21uk1024002h0002, 24wm0625510h0001); Japan Society for the Promotion of Science (23K14443, 19H03581, 19K21754, 23H02837, 20K06872, 16H06400, 16H06403, 16H02666, 16H05377, 20H03604, 24K02386, 23H04173); Hirose Foundation; Foundation of Kinoshita Memorial Enterprise; Mochida Memorial Foundation for Medical and Pharmaceutical Research (公益財団法人 持田記念医学薬学振興財団); Inamori Foundation; Moonshot Research and Development Program (JPMJMS239F-1-2); Osaka Medical Research Foundation for Intractable Diseases; CNDD Genomics and Bioinformatics Core (P20GM148302); SENSHIN Medical Research Foundation; University of Osaka MEI Grant
Citations: cited by 1 paper (Europe PMC); 114 references in the paper

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and restricted repetitive behaviors, yet the contribution of trace elements remains poorly defined. We profiled 21 trace elements in individuals with ASD and identified significantly reduced copper levels, which negatively correlated with social symptom severity. Magnetic resonance imaging revealed decreased white matter volume in ASD, which also correlated with social impairment. To explore the mechanisms, we generated a copper-deficient mouse model that displayed ASD-like behaviors and impaired oligodendrocyte (OL) development. Copper deficiency disrupted hypoxia-inducible factor 1α (HIF1α)–dependent angiogenesis and metabolic regulation in the embryonic brain, leading to oxidative stress, mitochondrial dysfunction, and BCL2 interacting protein 3 (BNIP3)-mediated mitophagy in oligodendrocyte progenitor cells. These processes suppressed mechanistic target of rapamycin kinase (mTOR) signaling, reduced OL-lineage cells, and caused hypomyelination. Restoring mTOR activity rescued OL maturation and improved social behavior in copper-deficient mice. These findings identify a copper-HIF1α-BNIP3-mTOR signaling axis that links trace element imbalance to glial dysfunction and ASD-relevant behavioral phenotypes, providing mechanistic insight into neurodevelopment.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Repositories

Its files are read in the Code ↔ Paper reader above, with 2 matches between paragraphs and lines of code.

Zenodo 17730406

License: CC-BY-4.0
State: the link answers, verified on 28 September 2026
Evidence: files inventoried
Size: 1 file
Software Heritage: not checked
Found in: “Data, code, and materials availability:”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Tools: tidyverse (12 files), ggpubr (8 files), ggplot2 (5 files), data.table (4 files), clusterProfiler (3 files), reshape2 (3 files), DESeq2 (2 files), pheatmap (2 files)
Availability: 1 check, the latest on 28 September 2026: the link answers (HTTP 200)
  • 28 September 2026: the link answers (HTTP 200)
16 files
At the source: doi.org/10.5281/zenodo.17730406

BertoLabMUSC/Usui_Metallome_2023

License: none: the authors keep all their rights
State: the link answers, verified on 28 September 2026
Evidence: files inventoried
Commit: 8dae97d3cda84f75fb36081352c4044ea8e3e74d, 26 November 2025
Languages: R (12), Shell (3)
Size: 145 files, 15 scripts
Software Heritage: not archived
Found in: “Data, code, and materials availability:”
Holds: README
Not found: license file, CITATION.cff, environment file, tests, continuous integration, documentation
Tools: tidyverse (12 files), ggpubr (8 files), ggplot2 (5 files), data.table (4 files), clusterProfiler (3 files), reshape2 (3 files), DESeq2 (2 files), pheatmap (2 files)
Availability: 1 check, the latest on 28 September 2026: the link answers
  • 28 September 2026: the link answers
16 files
At the source: github.com/BertoLabMUSC/Usui_Metallome_2023

The paper's code and data availability statement is in the Data section.

Tracing map

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  • 30 scripts, each with its path and the digest of its content;
  • 2 matches between paragraphs of the paper and lines of the code (method lexical-v1);
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Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

No dataset and no data link were found in the paper.

Data, code, and materials availability

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. Bulk RNA-seq data have been deposited in the Gene Expression Omnibus under accession number GSE232864 and are publicly available. Source data and analysis code have been deposited in Zenodo (https://doi.org/10.5281/zenodo.17730406) and GitHub (https://github.com/BertoLabMUSC/Usui_Metallome_2023). No new materials were generated in this study.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 22 authors, 15 MeSH terms, 14 funders, 112 references.

Cite

This paper

Usui, N., Doi, M., Berto, S., Matsuoka, K., Ishida, R., Miyauchi, H., Fujiwara, Y., Irie, K., Toritsuka, M., Yamauchi, T., Hirai, T., Xie, M.-J., Kayashima, Y., Umeda, N., Iwata, K., Okumura, K., Harada, T., Katayama, T., Tsujii, M., . . . Shimada, S. (2026). Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD. Science advances, 12(14), eadz3398. https://doi.org/10.1126/sciadv.adz3398

BibTeX

@article{usui2026copper,
author = {Usui, Noriyoshi and Doi, Miyuki and Berto, Stefano and Matsuoka, Kiwamu and Ishida, Rio and Miyauchi, Hana and Fujiwara, Yuuki and Irie, Koichiro and Toritsuka, Michihiro and Yamauchi, Takahira and Hirai, Takaharu and Xie, Min-Jue and Kayashima, Yoshinori and Umeda, Naoko and Iwata, Keiko and Okumura, Kazuki and Harada, Taeko and Katayama, Taiichi and Tsujii, Masatsugu and Matsuzaki, Hideo and Makinodan, Manabu and Shimada, Shoichi},
title = {{Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD}},
journal = {Science advances},
year = {2026},
month = apr,
volume = {12},
number = {14},
pages = {eadz3398},
publisher = {American Association for the Advancement of Science},
issn = {2375-2548},
doi = {10.1126/sciadv.adz3398},
url = {https://doi.org/10.1126/sciadv.adz3398},
pmid = {41920999},
pmcid = {PMC13041773}
}

RIS

TY - JOUR
AU - Usui, Noriyoshi
AU - Doi, Miyuki
AU - Berto, Stefano
AU - Matsuoka, Kiwamu
AU - Ishida, Rio
AU - Miyauchi, Hana
AU - Fujiwara, Yuuki
AU - Irie, Koichiro
AU - Toritsuka, Michihiro
AU - Yamauchi, Takahira
AU - Hirai, Takaharu
AU - Xie, Min-Jue
AU - Kayashima, Yoshinori
AU - Umeda, Naoko
AU - Iwata, Keiko
AU - Okumura, Kazuki
AU - Harada, Taeko
AU - Katayama, Taiichi
AU - Tsujii, Masatsugu
AU - Matsuzaki, Hideo
AU - Makinodan, Manabu
AU - Shimada, Shoichi
TI - Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD
T2 - Science advances
J2 - Sci Adv
PY - 2026
DA - 2026/04/01
VL - 12
IS - 14
SP - eadz3398
SN - 2375-2548
PB - American Association for the Advancement of Science
DO - 10.1126/sciadv.adz3398
UR - https://doi.org/10.1126/sciadv.adz3398
LA - en
ER -

CSL-JSON

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