Ecology of Danger‐dependent Cytokine‐boosted Spontaneous Abortion in the CBA × DBA/2 Mouse Model. I. Synergistic Effect of LPS and (TNF‐α + IFN‐γ) on Pregnancy Loss
Bibliographic record
Abstract
PROBLEM: Previous data have shown "danger" signals, such as bacterial lipopolysaccharide (LPS) acting via toll-like (tlr) receptors are required for early pregnancy failure in several murine abortion models. Indeed, the abortion rate increased in the CBA x DBA/2 model after a gestation day (gd) 7.5 injection of tumour necrosis factor (TNF)-alpha + interferon (IFN)-gamma only if the LPS-tlr signalling pathway was intact. High rates of cytokine-boosted abortion >80% loss can be achieved in certain animal colonies, that have a high endogenous (spontaneous) rate of resorption (30-50%). A specific role for LPS has been postulated to determine both the endogenous and cytokine-boosted losses. METHODS: To test the role of LPS in spontaneous and cytokine-boosted abortions, recombinant TNF-alpha + IFN-gamma, and LPS were injected in different doses and sequences intraperitoneally (i.p.) into CBA x DBA/2 mated mice in the Toronto General Research Institute animal facility where the endogenous abortion rate is <30%. The effects of poly IC, a tlr3 agonist that induces IFN-gamma that can reverse LPS-induced tolerance, and effects of anti-MD-1 on TNF-alpha induction by LPS, poly IC, CPG, or HSP in vitro were also examined. RESULTS: A high endogenous rate of loss similar to that seen in Clamart could be achieved by increasing exposure to LPS on the morning after mating (gd 0.5). The magnitude by which the abortion rate could be increased by an i.p. injection of 2000 u TNF-alpha + 1000 u IFN-gamma on gd 7.5 was independent of the endogenous rate of loss, and could not be increased by doubling the dose. One microgram of LPS given on day 7.5 achieved a similar rate of loss, and if given with the cytokines, synergistically boosted the rate of loss to near Clamart rates. LPS given 1 day prior to the cytokines abrogated the cytokine effect, whereas LPS given day 0.5 had no significant effect on the response to day 7.5 cytokine injection. Blocking MD-1 inhibited TNF-alpha stimulation by poly IC, LPS, CPG, or HSP in vitro, and reduced abortion rates. Poly IC did not avert LPS-type tolerance effects in vivo. CONCLUSIONS: High endogenous rates of abortion in the CBA x DBA/2 model may be explained by exposure to LPS at the time of mating. Increased rates of loss triggered by cytokines later in pregnancy may depend on increased absorption of LPS from intestinal flora.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".