Rebuttal from Sergei N. Orlov, Michael M. Model and Ryszard Grygorczyk
Bibliographic record
Abstract
We agree with the title of the counter-argument article by Florian Lang and Else Hoffmann, Cell volume changes are essential step in the cell death machinery (Lang & Hoffmann, 2013), albeit with one important proviso: this statement is true for selected rather than for all cell types and cell death stimuli. Indeed, as shown in the major section of our paper as well as in our recent review (Orlov et al. 2013), cell volume perturbations do not contribute to the triggering or progression of the cell death machinery in several types of cells, including serum-deprived vascular smooth muscle cells (VSMC) or ouabain-treated renal epithelial cells, possessing biochemical markers of apoptosis and necrosis, respectively (Orlov et al. 1999a; Platonova et al. 2011). The proapoptotic action of ouabain documented in Fas-ligand treated Jurkat cells (Panayiotidis et al. 2010) contradicts its antiapoptotic action in rat VSMC (Orlov et al. 1999b). We also would like to point out methodological limitations of several studies cited in the counter argument article. Thus, in demonstrating that pro-caspase-3 activity (Bortner et al. 1997) and DNA degradation (Ajiro et al. 2008) is inhibited by high-K+ medium, the authors did not employ high-Na+ medium as a negative control. This comment seems to be important because in vascular smooth muscle cells, the pro-caspase-3 activity is equally inhibited by elevation of [KCl] and [NaCl], thus showing that augmented ionic strength rather than elevated [Na+]i/[K+]i ratio occurring in dying cells is responsible for the effect. The death of U937 and HeLa cells documented in Cl−-depleted medium (Maeno et al. 2006) might be caused by modulation of the activity of diverse [Cl−]i-sensitive enzymes (Orlov & Hamet, 2006) rather than by inhibition of inwardly directed Na+–K+–2Cl− cotransporter NKCC1 and cell shrinkage. Indeed, to the best of our knowledge, there are no reports of cell death triggered by sustained exposure to bumetanide or other potent NKCC1 inhibitors. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief comment. Comments may be posted up to 6 weeks after publication of the article, at which point the discussion will close and authors will be invited to submit a ‘final word'. To submit a comment, go to http://jp.physoc.org/letters/submit/jphysiol;591/24/6129 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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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 | 0.005 | 0.033 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.004 |
| Scholarly communication | 0.005 | 0.005 |
| Open science | 0.003 | 0.003 |
| Research integrity | 0.011 | 0.026 |
| Insufficient payload (model declined to judge) | 0.017 | 0.024 |
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".