Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.08 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (152 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: meperidine hydrochloride, hydrocodone, naloxegol +84 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 7 Parkinson's papers of 1,381 | 0.73 |
| pathways Reactome | 6 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress OPRM1 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 OPRM1 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
- OPRM1 in microglia, braak-0.26 (p 0.493) → +0.16 (p 0.685)receipt 3400
- OPRM1 in dopamine neurons, braak+0.84 (p 0.004) → +0.63 (p 0.067)receipt 3401
Swarm cases
receipt 3401: OPRM1 in dopamine neurons, braak
- power
- full sample +0.75 (p 3.3e-4, n 18), 95% CI +0.44 to +0.90. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.77 (p 2.1e-4, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.85 (p 7.4e-6, n 18). not the mix.
- skeptic
- leave-one-out range +0.71 to +0.79, sign flips 0; without severely affected donors +0.75 (p 3.3e-4, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for OPRM1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 3400: OPRM1 in microglia, braak
- power
- full sample -0.09 (p 0.728, n 18), 95% CI -0.53 to +0.40. 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
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.04 (p 0.874, n 18). could be the mix.
- skeptic
- leave-one-out range -0.25 to +0.04, sign flips 1; without severely affected donors -0.09 (p 0.728, n 18). fragile.
- cell type
- strongest in dopamine neurons: +0.75 (p 3.3e-4, n 18) vs -0.09 in microglia. proposing dopamine neurons.
- axis
- no measure beats "tracks Braak Lewy-body stage" for OPRM1 in microglia.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up OPRM1 · dopamine neurons · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) +0.07 p 0.790 (needs p < 5.4e-4)
Receipts
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