Protective role of phosphatidic acid in the cellular response to lysophosphatidylcholine analogues
Bibliographic record
Abstract
The synthetic lysophosphatidylcholine (LPC) analogue edelfosine and the naturally occurring platelet activating factor (PAF) are structurally related lipids. Edelfosine is a potent antitumor drug, while PAF is a neurotoxic lipid that has been implicated in Alzheimer's disease. These LPC analogues are also toxic to budding yeast, which can be used as an excellent model system to investigate their mode of action. LPC analogues induce alterations in membrane organization, lipid metabolism and signaling in yeast. Phosphatidic acid (PA) produced by the activity of PLD alleviates sensitivity of yeast cells to PAF and edelfosine. PA is a key lipid signalling and precursor of all glycerolipids. Recent lipid analysis indicates that diacylglycerol (DAG) accumulates in cells treated with LPC analogues and this could contribute to their toxicity. In fact, sensitivity assays in yeast genetically manipulated to alter PA and DAG levels clearly support a protective role of PA in the response to these lipid drugs. Altogether, the evidence suggests that cells are able to sense altered PA: DAG ratios induced by these metabolically stable lipids. While DAG binding proteins have not been clearly identified in yeast, several yeast proteins recognize PA with high specificity. One such protein is the transcriptional repressor Opi1, which regulates expression of phospholipid biosynthetic genes through its interaction with PA. We provide evidence supporting a role of Opi1 in sensing the membrane changes induced by edelfosine, including i) altered sensitivity of cells lacking Opi1, ii) prevalent nuclear localization and iii) Opi1‐dependent UAS INO gene repression induced by edelfosine.
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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) | 0.000 | 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) | 0.001 | 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".