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 astrocytes; strongest in myonuclei | 0.75 |
| 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 | 1 Parkinson's papers of 112 | 0.91 |
| pathways Reactome | 14 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress ADCY2 in astrocytes; measure IL-1β and TNF release and surface HLA-DR 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
- IL-1β and TNF release and surface HLA-DR
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves IL-1β 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 ADCY2 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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
- ADCY2 in dopamine neurons, braak-0.66 (p 0.053) → +0.32 (p 0.399)receipt 9066
- ADCY2 in astrocytes, braak+0.52 (p 0.151) → -0.22 (p 0.565)receipt 9065
Swarm cases
receipt 9066: ADCY2 in dopamine neurons, braak
- power
- full sample -0.18 (p 0.476, n 18), 95% CI -0.60 to +0.31. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.16 (p 0.515, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.18 (p 0.487, n 18). could be the mix.
- skeptic
- leave-one-out range -0.29 to -0.06, sign flips 0; without severely affected donors -0.18 (p 0.476, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ADCY2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 9065: ADCY2 in astrocytes, braak
- power
- full sample +0.08 (p 0.767, n 18), 95% CI -0.41 to +0.52. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.00 (p 0.990, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.02 (p 0.942, n 18). could be the mix.
- skeptic
- leave-one-out range -0.00 to +0.23, sign flips 1; without severely affected donors +0.08 (p 0.767, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ADCY2 in astrocytes.
case closed: nothing better to follow up.
Receipts
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