Role of caspases in murine limb bud cell death induced by 4‐hydroperoxycyclophosphamide, an activated analog of cyclophosphamide
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Bibliographic record
Abstract
BACKGROUND: Caspases play a pivotal role in the regulation and execution of apoptosis, an essential process during limb development. Caspase 8 activation is usually downstream of the Fas/FasL death receptors, whereas caspase 9 mediates the mitochondrial signaling pathway of apoptosis. Caspase 3 is an effector caspase. Previous studies have shown that the exposure of embryonic murine limbs in vitro to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated analog of the anticancer alkylating agent, cyclophosphamide, induced limb malformations and apoptosis. The goal of this study was to determine the role of caspases in mediating apoptosis in this model system. METHODS: Limb buds from gestational day 12 CD-1 mice were excised and cultured in roller bottles in a chemically defined medium for up to 6 days in the absence or presence of 4-OOHCPA. Apoptosis was indicated by internucleosomal DNA fragmentation, as detected by TUNEL staining. The profile of caspase activation was characterized by Western blot analysis and immunohistochemistry of control and treated limbs. To determine the consequences to limb morphology of inhibiting caspase activation, DEVD-CHO, a caspase-3 inhibitor, was added to the cultures. RESULTS: Limbs cultured in the presence of 4-OOHCPA were growth retarded and malformed; apoptosis was increased in the apical ectodermal ridge and interdigital areas. Western blot analysis showed that 4-OOHCPA exposure did not activate procaspases 8 or 9 in limbs. In contrast, procaspase-3 cleavage was increased in a concentration and time-dependent manner after exposure of limbs to 4-OOHCPA. Immunoreactive activated caspase-3 was localized in the interdigital areas and the apical ectodermal ridge region in control limbs; staining in these areas and in the interdigital areas was increased dramatically in limbs exposed to 4-OOHCPA. Inhibition of caspase 3 activation with DEVD-CHO partially protected limbs from insult with 4-OOHCPA. CONCLUSION: Caspase-dependent and caspase-independent pathways of cell death are both important is mediating the abnormal limb development triggered by insult with 4-OOHCPA.
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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