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 microglia; strongest in neutrophils | 0.75 |
| chemistry Open Targets | compounds already reach it: dasatinib anhydrous, bosutinib, ilorasertib +3 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 1,010 | 0.91 |
| pathways Reactome | 9 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress HCK in microglia; measure phospho-ERK and phospho-AKT response to GDNF and uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release).
- Cell type
- microglia
- 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
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- 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 HCK in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: phospho-ERK and phospho-AKT response to GDNF; uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release). Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- HCK in microglia, braak+0.12 (p 0.756) → -0.40 (p 0.285)receipt 13927
- HCK in dopamine neurons, braak-0.42 (p 0.265) → +0.25 (p 0.517)receipt 13928
Swarm cases
receipt 13928: HCK in dopamine neurons, braak
- power
- full sample -0.11 (p 0.677, n 18), 95% CI -0.55 to +0.38. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.11 (p 0.677, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.09 (p 0.728, n 18). could be the mix.
- skeptic
- leave-one-out range -0.27 to +0.02, sign flips 1; without severely affected donors -0.11 (p 0.677, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HCK in dopamine neurons.
case closed: nothing better to follow up.
receipt 13927: HCK in microglia, braak
- power
- full sample -0.16 (p 0.526, n 18), 95% CI -0.58 to +0.33. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.05 (p 0.834, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.04 (p 0.881, n 18). could be the mix.
- skeptic
- leave-one-out range -0.30 to -0.06, sign flips 0; without severely affected donors -0.16 (p 0.526, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HCK in microglia.
case closed: nothing better to follow up.
Receipts
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