Distinct calcineurin‐related transgenic approaches rescue or exacerbate the dystrophic phenotype in fibers from crossbred mdx mice despite constant HSP70 expression
Bibliographic record
Abstract
We have shown the dystrophic phenotype to be rescued by driving the slower oxidative myogenic program via calcineurin/NFAT (Cn/NFAT) signaling together with an increase in utrophin A expression (Chakkalakal et al 2004, 2006). However, a recent study suggests an alternate strategy in the rescue of the dystrophic phenotype by overexpressing HSP70 without necessary changes in utrophin A expression (Gehrig et al 2012). We thus set out to examine HSP70 expression in muscles of dystrophic mdx mice crossbred with mice expressing transgenes (Tg) that manipulate the Cn/NFAT pathway. From WBs we found upregulation of utrophin A driven by the Tg overexpression of Cn and its downregulation after the Tg expression of either parvalbumin or calmodulin binding protein. These changes in utrophin A expression occurred without changes in HSP70 levels, indicating that regulation of these two proteins is not correlated. Further, IF experiments showed a robust and rigid co‐localization of HSP70 with MyHC I in Tg‐modified mdx slow fibers displaying impaired Cn/NFAT signaling together with decreased utrophin A expression and a clear exacerbation of the dystrophic phenotype. These results not only underscore the therapeutic potential of targeting Ca +2 /Cn‐based signaling intermediates as effective countermeasures for DMD, but also raise questions to the role of HSP70 in rescuing the dystrophic pathology. Funded by CIHR, NSERC and CRC.
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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 | 0.001 | 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) | 0.002 | 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".