Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.04 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in astrocytes (513 nCPM) | 1.00 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| 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 | 4 pathways; mostly protein handling | 0.90 |
Knock down and overexpress HIF3A in astrocytes; measure proteasome activity and the load of ubiquitinated protein 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.
- Molecular readout
- proteasome activity and the load of ubiquitinated protein
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves proteasome activity 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 HIF3A in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: proteasome activity and the load of ubiquitinated protein; 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
- HIF3A in dopamine neurons, braak-0.21 (p 0.586) → -0.18 (p 0.646)receipt 6106
- HIF3A in astrocytes, braak+0.15 (p 0.697) → -0.09 (p 0.825)receipt 6105
Swarm cases
receipt 6106: HIF3A in dopamine neurons, braak
- power
- full sample -0.16 (p 0.538, n 18), 95% CI -0.58 to +0.34. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.08 (p 0.741, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.12 (p 0.633, n 18). could be the mix.
- skeptic
- leave-one-out range -0.32 to -0.08, sign flips 0; without severely affected donors -0.16 (p 0.538, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HIF3A in dopamine neurons.
case closed: nothing better to follow up.
receipt 6105: HIF3A in astrocytes, braak
- power
- full sample +0.01 (p 0.976, n 18), 95% CI -0.46 to +0.47. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.02 (p 0.935, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.10 (p 0.696, n 18). could be the mix.
- skeptic
- leave-one-out range -0.11 to +0.13, sign flips 7; without severely affected donors +0.01 (p 0.976, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HIF3A in astrocytes.
case closed: nothing better to follow up.
Receipts
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