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, including microglia; strongest in endometrial glandular cells | 0.75 |
| chemistry Open Targets | compounds already reach it: satralizumab | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 5 Parkinson's papers of 427 | 0.76 |
| pathways Reactome | 7 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress IL6ST in microglia; measure IL-1β and TNF release and surface HLA-DR 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
- IL-1β and TNF release and surface HLA-DR
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- 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 IL6ST in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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
- IL6ST in dopamine neurons, braak+0.09 (p 0.821) → +0.05 (p 0.891)receipt 5893
- IL6ST in microglia, braak-0.18 (p 0.646) → +0.38 (p 0.311)receipt 5892
Swarm cases
receipt 5893: IL6ST in dopamine neurons, braak
- power
- full sample +0.10 (p 0.702, n 18), 95% CI -0.39 to +0.54. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.11 (p 0.671, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.11 (p 0.677, n 18). could be the mix.
- skeptic
- leave-one-out range -0.02 to +0.18, sign flips 4; without severely affected donors +0.10 (p 0.702, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for IL6ST in dopamine neurons.
case closed: nothing better to follow up.
receipt 5892: IL6ST in microglia, braak
- power
- full sample +0.07 (p 0.794, n 18), 95% CI -0.41 to +0.52. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.07 (p 0.794, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.18 (p 0.471, n 18). could be the mix.
- skeptic
- leave-one-out range -0.02 to +0.22, sign flips 3; without severely affected donors +0.07 (p 0.794, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for IL6ST in microglia.
case closed: nothing better to follow up.
Receipts
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