{
  "abstract": "Background: Traumatic brain injury (TBI) pathology evolves over hours to months, and molecular staging could complement clinical and imaging-based assessment. Single-cell transcriptomics captures cell-type-resolved temporal programs, but whether a transcriptional \"molecular clock\" trained on one injury model can be transferred to others remains unknown. Methods: We compiled four public mouse TBI single-cell/single-nucleus datasets spanning two injury models - controlled cortical impact (GSE277487; CEREBRI) and fluid percussion injury (GSE160763) - plus an independent mild-FPI cohort reserved for validation (GSE247339), totalling 307,991 cells across four pathological stages (control, acute, subacute, chronic). Classifiers were evaluated at cell and sample levels (held-out libraries) against a permutation null, with per-cell-type, strict leave-one-dataset-out (LODO) generalization, glial-only transfer and gene-level SHAP analyses. Results: Within GSE277487, sample-level balanced accuracy reached 0.67 (permutation null 0.32 +/- 0.09; p = 0.001), and the signal was reproduced in the independent mild-FPI cohort (0.40 vs null 0.19 +/- 0.05; p = 0.0010). Cell-level cross-validation overestimated performance by ~0.16, quantifying within-sample leakage. Cross-dataset generalization was poor (strict LODO balanced accuracy 0.20-0.31); the acute immediate-early response was untransferable (recall 0.002) and 80% of chronic (6-month) cells were assigned to the subacute class. Glial-only models raised subacute recall across models (0.91 and 0.75), but precision was indistinguishable from a subacute-only classifier (0.51 vs 0.50; 0.58 vs 0.58) and one-vs-rest AUROC was at or below chance (0.38-0.54) across four classifier families - classifier collapse, not transferable discrimination. The reproducible cross-model component was instead a gene-expression programme: a microglial complement/lysosomal damage programme (Trem2-Apoe axis) was up-regulated across the severe CCI and FPI models (13/13 concordant genes), whereas the immediate-early module was model-specific. Conclusions: A single-cell molecular clock for TBI staging is feasible within datasets once within-sample leakage is controlled, but it does not transfer across datasets as a classifier: apparent cross-model transfer reflected classifier collapse onto the majority class, and the reproducible cross-model component was a microglial complement/lysosomal gene-expression programme. These findings define the boundaries of cross-dataset time inference in TBI and provide evaluation criteria for claims of transferable single-cell classifiers.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurosurgery, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "R. Gao"
    },
    {
      "name": "Q. Yan"
    },
    {
      "name": "L. Zhang"
    },
    {
      "name": "X. Xu"
    },
    {
      "name": "X. Qian"
    },
    {
      "name": "M. Li"
    },
    {
      "name": "Y. Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d7pymcdn1qzt0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.07.749982",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749982v1.full",
  "id": "d7pymcdn1qzt0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749982v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2728|Traumatic Brain Injury and Neurovascular Disturbances"
    ]
  ],
  "openalex": "W7212510711",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749982v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/d7pymcdn1qzt0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:20Z",
      "native_id": "10.64898/2026.09.07.749982",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749982v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Conserved microglial programmes, non-transferable classifiers: boundaries of the single-cell TBI molecular clock",
  "title_text": "Conserved microglial programmes, non-transferable classifiers: boundaries of the single-cell TBI molecular clock",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:20Z",
  "url": "https://research.draconitic.com/paper/d7pymcdn1qzt0",
  "venue": "bioRxiv",
  "versions": []
}