The Brain, Not the Kidney, is the Source of Erythropoietin in Response to Hypoxic Hypoxia
Bibliographic record
Abstract
Erythropoietin (EPO), the principle regulator of erythropoiesis, is central to our understanding of tissue hypoxia. For over a century, the kidney has been regarded as the primary site of EPO production. While multiple extra‐renal sources have been identified, their physiological significance remains largely uninvestigated. Further, studies investigating the source of EPO production use severe (non‐survivable) levels of hypoxia, despite that levels encountered in most pathophysiological states are mild to moderate. The assumption being that the response to less severe hypoxic stimuli is linearly scaled. Our objective was to investigate whole‐body EPO production in response to clinically‐relevant levels of hypoxia. We performed a multi‐organ, temporal analysis of EPO expression in response to moderate (F I O 2 = 0.15) and severe (F I O 2 = 0.09) hypoxic hypoxia. Using the Cre‐lox system, we proved that the brain, and not the kidney, was the sole responder to moderate hypoxia and the primary responder to severe. Thus, the erythropoietic response to hypoxia involves multiple tissues in a degree‐ and duration‐dependent manner with the brain as the first and primary site of EPO production. These data identify a critical shift in our understanding of oxygen carrying capacity in hypoxic hypoxia from peripheral to central regulation. Support or Funding Information This work was funded in part by grants from the Canadian Institutes of Health Research (JAS; Grant # MOP111159) and the Natural Sciences and Engineering Research Council of Canada (JAS). JAS is also a new investigator with the Heart and Stroke Foundation of Ontario.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".