Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in melanocytes | 0.75 |
| chemistry Open Targets | compounds already reach it: bosentan, ambrisentan, aprocitentan +7 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 3 pathways; mostly other | 0.30 |
Knock down and overexpress EDNRB in astrocytes; measure a transcriptome-wide state shift (bulk RNA-seq) and α-synuclein uptake and degradation, and dopamine neuron survival in co-culture.
- Cell type
- astrocytes
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- a transcriptome-wide state shift (bulk RNA-seq)
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves a transcriptome-wide state shift (bulk RNA-seq) 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 EDNRB in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); α-synuclein uptake and degradation, and dopamine neuron survival in co-culture. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- EDNRB in dopamine neurons, braak-0.30 (p 0.436) → +0.78 (p 0.014)receipt 13149
- EDNRB in astrocytes, braak-0.20 (p 0.601) → -0.01 (p 0.982)receipt 13148
Swarm cases
receipt 13149: EDNRB in dopamine neurons, braak
- power
- full sample +0.39 (p 0.111, n 18), 95% CI -0.10 to +0.72. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.38 (p 0.123, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.39 (p 0.105, n 18). could be the mix.
- skeptic
- leave-one-out range +0.33 to +0.55, sign flips 0; without severely affected donors +0.39 (p 0.111, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for EDNRB in dopamine neurons.
case closed: nothing better to follow up.
receipt 13148: EDNRB in astrocytes, braak
- power
- full sample -0.17 (p 0.498, n 18), 95% CI -0.59 to +0.32. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.07 (p 0.781, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.11 (p 0.664, n 18). could be the mix.
- skeptic
- leave-one-out range -0.30 to -0.06, sign flips 0; without severely affected donors -0.17 (p 0.498, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for EDNRB in astrocytes.
case closed: nothing better to follow up.
Receipts
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