INVESTIGATION OF THE PATHOLOGICAL EFFECTS OF HISTONES, DNA, AND NUCLEOSOMES IN A MURINE MODEL OF SEPSIS
Bibliographic record
Abstract
ABSTRACT: Background: In sepsis, neutrophil extracellular traps (NETs) are an important interface between innate immunity and coagulation. The major structural component of neutrophil extracellular traps is nucleosomes (DNA-histone complexes). In vitro, DNA and histones exert procoagulant/cytotoxic effects whereas nucleosomes are not harmful. However, whether DNA, histones, and/or nucleosomes exert harmful effects in vivo remain unclear. Objectives: (1) The aims of the study are to investigate the cytotoxic effects of nucleosomes ± DNase I and heparin in vitro and (2) to investigate whether DNA, histones, and/or nucleosomes are harmful when injected into healthy and septic mice. Methods : The cytotoxic effects of DNA, histones, and nucleosomes (± DNaseI or ±heparin) were assessed in HEK293 cells. Mice underwent cecal ligation and puncture or sham surgery and then received injections of DNA (8 mg/kg), histones (8.5 mg/kg), or nucleosomes at 4 and 6 h. Organs and blood were harvested at 8 h. Cell-free DNA, IL-6, thrombin-anti-thrombin, and protein C were quantified from plasma. Results:In vitro , incubation of HEK293 cells with DNaseI-treated nucleosomes reduced cell survival compared with nucleosome-treated cells, suggesting that DNaseI releases cytotoxic histones from nucleosomes. Addition of heparin to DNaseI-treated nucleosomes rescued cell death. In vivo, administration of histones to septic mice increased markers of inflammation (IL-6) and coagulation (thrombin-anti-thrombin), which was not observed in sham or septic mice administered DNA or nucleosomes. Conclusions: Our studies suggest that DNA masks the harmful effects of histones in vitro and in vivo . Although administration of histones contributed to the pathogenesis of sepsis, administration of nucleosomes or DNA was not harmful in healthy or septic mice.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".