The investigation of the kinin-kallikrein pathway in prion pathogenicity
Bibliographic record
Abstract
It has been suggested that the conversion of the host-encoded prion protein (PrPc) to the misfolded disease-associated isoform (PrPsc) results in the loss of the putative superoxide dismutase enzyme activity of PrP. Another hallmark of prion diseased brains is atypical inflammation represented by presence of activated microglia capable of generating prodigious amounts of reactive oxygen species (ROS). Increased oxidative stress susceptibility combined with increased exposure to ROS is thought to explain the neurodegeneration observed. Previously, 2D-DIGE analysis of the urine of mice infected with the scrapie strain, ME7, and aged matched controls demonstrated differential abundance of the proteins kininogen, kallikrein and prostaglandin H-isomerase. These proteins are all members of the kinin-kallikrein pathway suggesting its modulation in response to prion disease. Downstream effects of the pathway produce metabolites; prostaglandins, ROS, and nitric oxide which initiate inflammation and contribute to oxidative stress, characteristics that have been demonstrated to be associated with prion diseases. It has not yet been demonstrated whether or not the presence of these proteins in the urine, reflect disease process occurring in the primary site of prion pathology, the brain. Our hypothesis is that the activation of the kinin-kallikrein pathway may be in part responsible for the atypical inflammation and oxidative stress observed in the prion infected brain. Levels of pathway-specific proteins including kininogen as well as the inducible nitric oxide synthase (iNOS) and the B1 receptor in whole brains of ME7 infected C57BL/6 mice were determined. Western blotting has demonstrated that the levels of kininogen statistically fluctuate at the onset of clinical disease. In addition, statistically significant iNOS levels were detected just prior to clinical stages of disease. Real-time PCR and immunohistochemistry staining further support increasing levels of iNOS through disease progression and the activation of the B1 receptor at the terminal stage of disease. To determine whether this is a cause or consequence of the disease the levels of 8-OHdG, a marker of oxidative stress, and glial fibrillary acidic protein (GFAP), a marker of inflammation, were measured at corresponding time points. These studies suggest that the kinin-kallikrein pathway is activated in prion disease and may be involved in the atypical inflammation and oxidative stress observed in the brain.
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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) | 0.000 | 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 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".