Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in syncytiotrophoblasts | 0.75 |
| chemistry Open Targets | compounds already reach it: atezolizumab, envafolimab, bintrafusp alfa +10 | 0.90 |
| trials ClinicalTrials.gov | 200 Parkinson's trials, 5 stopped | 0.92 |
| literature PubMed | 1 Parkinson's papers of 1,660 | 0.91 |
| pathways Reactome | 8 pathways; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress CD274 in microglia; measure glucocerebrosidase (GCase) activity and LC3-II and p62 flux 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
- glucocerebrosidase (GCase) activity and LC3-II and p62 flux
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves glucocerebrosidase (GCase) 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 CD274 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: glucocerebrosidase (GCase) activity and LC3-II and p62 flux; 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
- CD274 in dopamine neurons, braak-0.47 (p 0.197) → +0.21 (p 0.586)receipt 8143
- CD274 in microglia, braak-0.61 (p 0.078) → -0.03 (p 0.946)receipt 8142
Swarm cases
receipt 8143: CD274 in dopamine neurons, braak
- power
- full sample -0.16 (p 0.521, n 18), 95% CI -0.58 to +0.33. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.10 (p 0.702, 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 -0.31 to -0.05, sign flips 0; without severely affected donors -0.16 (p 0.521, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CD274 in dopamine neurons.
case closed: nothing better to follow up.
receipt 8142: CD274 in microglia, braak
- power
- full sample -0.28 (p 0.254, n 18), 95% CI -0.66 to +0.21. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.28 (p 0.265, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.31 (p 0.214, n 18). could be the mix.
- skeptic
- leave-one-out range -0.40 to -0.16, sign flips 0; without severely affected donors -0.28 (p 0.254, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CD274 in microglia.
case closed: nothing better to follow up.
Receipts
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