Bibliographic record
Abstract
Two observations led us to test the expression of alternative prion protein (AltPrP) (1). First, many functions were attributed to PrP, a protein encoded in the PRNP gene (2,3). How one gene could encode one protein with such a variety of function is puzzling. Second, we noticed a putative overlapping reading frame in the +3 reading frame of PRNP. This coding sequence overlaps the octapeptide repeat region, a domain well conserved across species. Based on these two considerations only, a strategy was used that undoubtedly established that PRNP encodes two proteins: PrP and AltPrP (1). AltPrP is a tryptophan-rich mitochondrial protein, and its physiological function or its role in prion diseases is still unknown. Previously, a hypothetical-induced frameshifting mechanism was proposed to explain the replication of prions, and the following model was suggested (4). First, a frameshift followed by a compensating frameshift during the translation of PrP results in the production of hybrid PrP molecules with sequence elements of AltPrP. Second, hybrid AltPrP-PrP molecules are capable of stimulating these frameshifting errors. Third, hybrid AltPrP-PrP molecules are the infectious agent and provide nuclei for PrP aggregation. In our experiments, we have had no evidence that AltPrP synthesis involves ribosomal frameshifting. Furthermore, we could not detect hybrid AltPrP-PrP molecules by Western blot, and no experimental data indicated the possibility of frameshifting errors during PrP translation. However, levels of hybrid molecules may be too low to be detected by Western blot. Alternatively, the expression of hybrid molecules may require specific experimental conditions. As noted by Dr Wills, some unresolved gaps persist in the current model of prion replication, despite major breakthroughs in recent years. Nonetheless, the existence and the role for hybrid AltPrP-PrP molecules in prion disease remain speculative. Sensitive proteomic techniques on infectious prion particles may help address this issue. Another strategy to challenge the frameshifting model would be to test if expression of artificial hybrid AltPrP-PrP molecules in cultured cells or in transgenic animals results in spontaneous production of infectious prions.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.727 | 0.545 |
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".