Comparison of the Proinflammatory and Procoagulant Properties of Nuclear, Mitochondrial, and Bacterial DNA
Why this work is in the frame
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Bibliographic record
Abstract
PURPOSE: Cell-free DNA (CFDNA) is elevated in sepsis and correlates with mortality. This DNA may come from nuclear, mitochondrial, or bacterial sources. Cell-free DNA from all three sources may play a pathogenic role in sepsis via activation of coagulation through the contact pathway, whereas CpG motifs on bacterial and mitochondrial DNA may additionally stimulate inflammatory responses via Toll-like receptor 9. This study elucidates the relative effects of nuclear, mitochondrial, and bacterial DNA on inflammatory and procoagulant pathways with relevance to sepsis. METHODS: DNA was extracted from plasma of septic patients and control subjects, and nuclear and mitochondrial CFDNA concentrations were measured by quantitative polymerase chain reaction. Viability of primary cultured human neutrophils was measured by flow cytometry for phosphatidyl serine exposure and cell permeability to propidium iodide. Continuous thrombin generation was measured with a fluorogenic substrate (Technothrombin, Vienna, Austria). Interleukin 6 secretion was measured by enzyme-linked immunosorbent assay. Platelet activation was measured by flow cytometry for P-selectin and activated αIIbβ3. RESULTS: Mitochondrial DNA and nuclear DNA were elevated in plasma from septic patients compared with control subjects. Both mitochondrial and bacterial DNA prolonged neutrophil viability. Bacterial DNA increased neutrophil interleukin 6 secretion, but mitochondrial and nuclear DNA did not. Nuclear, mitochondrial, and bacterial DNA increased thrombin generation in platelet-poor plasma to a similar degree in a FXI- and FXII-dependent manner, indicating dependence on the intrinsic pathway of coagulation. Independently of coagulation, DNA from all three sources was capable of causing activation of platelet integrin αIIbβ3. CONCLUSIONS: Cell-free DNA from nuclear, mitochondrial, and bacterial sources have varying proinflammatory effects, although all three have similar procoagulant and platelet-stimulating potential. The pathophysiological effects of CFDNA in sepsis may vary with the source of DNA.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it