Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including brain inhibitory neurons; strongest in müller glia | 0.75 |
| chemistry Open Targets | compounds already reach it: isotretinoin, mofarotene, alitretinoin +7 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 3 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress RARB in dopamine neurons; measure phospho-ERK and phospho-AKT response to GDNF and survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils.
- Cell type
- dopamine neurons
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- phospho-ERK and phospho-AKT response to GDNF
- Functional readout
- survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils
- Rule-out
- If neither arm moves phospho-ERK by 20% or more against non-targeting and empty-vector controls, across three independent differentiations, the hypothesis is wrong.
- Lab request
- CRISPRi knockdown and lentiviral overexpression of RARB in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: phospho-ERK and phospho-AKT response to GDNF; survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- RARB in dopamine neurons, braak+0.42 (p 0.262) → +0.51 (p 0.160)receipt 9711
Swarm cases
receipt 9711: RARB in dopamine neurons, braak
- power
- full sample +0.53 (p 0.025, n 18), 95% CI +0.08 to +0.80. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.58 (p 0.012, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.56 (p 0.015, n 18). not the mix.
- skeptic
- leave-one-out range +0.46 to +0.67, sign flips 0; without severely affected donors +0.53 (p 0.025, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RARB in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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