NRG1‐ERBB4‐PSEN1 Dysfunction in Human Myocarditis and Dilated Cardiomyopathy
Bibliographic record
Abstract
Myocarditis, inflammation of the muscular portion of the heart, can be caused by infection (most often viral), autoimmunity, or chemical exposure. Clinical symptoms are also variable, with some patients, regardless of etiology, experiencing life threatening acute illness, others suffering from chronic disease, and still others who never come to clinical attention at all. The risk factors for developing different patterns of disease are poorly elucidated, but preclinical and limited clinical studies have implicated a role for the signaling cascade involving neuregulin 1 (NRG1), epidermal growth factor related receptor ERBB4, and presenilin 1 (PSEN1). In this study we sought to characterize the same signaling pathway in archival human tissue specimens from patients with a diagnosis of myocarditis. It is hypothesized that variable expression and function of the NRG1‐ERBB4‐PSEN1 signaling axis is associated with different clinical manifestations of myocarditis. Twenty (20) cases of myocarditis and five (5) normal controls were identified from the Cardiovascular Tissue Registry in the Centre for Heart Lung Innovation. Using archival tissue from the left ventricle of each case, protein expression levels, cellular localization, and post‐translational modifications of NRG1, ERBB4, and PSEN1 were evaluated using immunohistochemistry, immunofluorescence, and western blotting. Data analysis was performed using ImagePro Plus for color segmentation and quantification and ImageJ software for densitometry. NRG1, ERBB4 and PSEN1 are expressed at higher levels, up to 4.18‐, 19.96‐ and 38.41‐fold, respectively, in the majority of myocarditis cases, increasing with severity and chronicity, as compared to control cases. All three proteins are seen in extracellular protein aggregates (plaques) in myocarditis cases. ERBB4 and PSEN1 accumulate in the nucleus of myocarditis hearts, and ERBB4 also accumulates at Z lines. NRG1 isoforms range from 50–75 kDa, ERBB4 shows 80 and 120 kDa cleavage products, and PSEN1 aggregates range from 50–250 kDa. Preliminary studies show a distinct difference in expression patterns of NRG1, ERBB4, and PSEN1 in cases of myocarditis as compared to normal controls. Further experiments are likely to establish patterns of expression that correlate with disease severity and temporality. These data are expected to eventually provide diagnostic and therapeutic guidance with respect to the different clinical manifestations of myocarditis. Support or Funding Information This research is funded by the Providence Health Care Research Institute and through donations made to the St. Paul's Hospital Foundation.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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".