Interaction of Survival and Death Signaling in Basal Forebrain Neurons: Roles of Neurotrophins and Proneurotrophins
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Full frame distilled prediction
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.
- Candidate categories
- none
- Consensus categories
- none
- Domain
- Candidate signal: noneConsensus signal: none
- Study design
- Candidate signal: Bench or experimentalConsensus signal: Bench or experimental
- Genre
- Candidate signal: EmpiricalConsensus signal: Empirical
- Teacher disagreement score
- 0.089
- Threshold uncertainty score
- 0.445
- Validation status
machine_predicted_unvalidated·codex-gemma-dda1882f352a
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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 | 0.001 |
| 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)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
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.
- Teacher spread
- 0.248 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
Proneurotrophins bind with high affinity to p75 neurotrophin receptor (p75NTR) and lack the capacity to bind Trk receptors, suggesting that proneurotrophins can elicit apoptosis via p75NTR even in cells expressing survival-promoting Trk receptors. In the CNS, basal forebrain (BF) neurons are particularly vulnerable to degeneration in Alzheimer's disease, and are among the few populations of brain neurons that express p75NTR throughout life. These neurons also express Trk receptors and may be concomitantly exposed to both proneurotrophins and mature neurotrophins during development, disease, or after injury. We investigated the interaction of mature and proneurotrophin signaling in these CNS neurons. Kainic acid-induced seizures elicited production of pro-NGF by BF astrocytes before caspase activation in p75NTR-positive BF neurons, demonstrating local production of proneurotrophins under pathological conditions and suggesting apoptotic signaling in vivo. Mechanisms of proneurotrophin-induced death were analyzed in cultured BF neurons, and required both p75NTR and its coreceptor sortilin. Surprisingly, exposure to both mature neurotrophins and proneurotrophins demonstrated that Trk phosphorylation did not prevent pro-NGF-induced apoptosis via p75NTR. However, activation of PI3K (phosphatidylinositol 3-kinase)/Akt and MEK (mitogen-activated protein kinase kinase)/Erk pathways prevented pro-NGF-induced apoptosis, revealing a novel critical checkpoint in survival versus apoptotic signaling downstream of Trk activation, and suggesting that pro-NGF blocks survival signaling by preventing Akt and Erk activation. This study shows that proneurotrophins are produced in the brain under pathological conditions, and can elicit apoptosis of BF neurons even when Trk receptors are activated.
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.
The record
- Venue
- Journal of Neuroscience
- Topic
- Nerve injury and regeneration
- Field
- Neuroscience
- Canadian institutions
- Hospital for Sick ChildrenUniversity of Toronto
- Funders
- National Institutes of HealthNational Institute of Neurological Disorders and StrokeAmerican Health Assistance Foundation
- Keywords
- Trk receptorNeurotrophinLow-affinity nerve growth factor receptorBiologyCell biologyProtein kinase BTropomyosin receptor kinase AMAPK/ERK pathwayBasal forebrainReceptorNerve growth factorSignal transductionNeuroscienceCentral nervous systemBiochemistry
- Has abstract in OpenAlex
- yes