P8 Propionate anions accumulated in propionic acidaemia influences the cardiac gene expression landscape
Bibliographic record
Abstract
Propionic acidaemia (PA) is an autosomal recessive disorder characterised by malfunctional mitochondrial propionyl-CoA carboxylase. Consequences of this inborn error of metabolism (IEM) is defective catabolism of propiogenic substrates (branched-chain amino acids, odd-number fatty acids, etc.) leading to mitochondrial accumulation of propionyl CoA and its derivatives. Accumulation of propionate derivatives in the cytoplasm and plasma leads to intra- and extracellular metabolic acidosis. The clinical manifestation is severe; arrhythmia and cardiomyopathy (hypertrophic and dilated) are cited as major causes of death. Little is known of the underlying mechanisms. Since butyrate is in the same homologous series as propionate, and is itself a well-established inhibitor of histone deacetylases (HDACs), it is plausible pro-hypertrophic signalling in PA is epigenetically regulated. Therefore, we investigated the effects of propionate on cardiomyocytes. In preliminary work, culturing neonatal rat ventricular myocytes (NRVMs) in a chemical milieu mimicking PA (6 mM propionate; 200 M ammonium; 18 mM bicarbonate; pH 7.15) increased significantly cardiomyocyte area. Treating adult rat VMs with PA-medium increased significantly histone-3 lysine-9 acetylation, phenocopying the effects of butyrate. To determine the gene expression profile associated with PA, RNA-sequencing was performed on polyadenylated RNA extracted from NRVMs, treated with control-, butyrate-, or PA-medium. In PA-medium, Differentially Expressed Gene analysis demonstrated 3.0% of genes were upregulated and 3.0% downregulated (FDR<0.0001). Gene Ontology Enrichment Analysis using DAVID revealed ‘cardiac muscle contraction’ and ‘metabolic pathways’ as being significantly enriched. 1.9% of genes were upregulated in both PA and butyrate, representing candidates that could be regulated by HDACs. We are currently validating these hits.
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How this classification was reachedexpand
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".