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, including microglia; strongest in adipocytes | 0.75 |
| chemistry Open Targets | compounds already reach it: dipyridamole, enoximone, anagrelide hydrochloride +8 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 2 pathways; mostly other | 0.30 |
Knock down and overexpress PDE3B in microglia; measure a transcriptome-wide state shift (bulk RNA-seq) 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
- a transcriptome-wide state shift (bulk RNA-seq)
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves a transcriptome-wide state shift (bulk RNA-seq) 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 PDE3B in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); 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
- PDE3B in microglia, braak+0.04 (p 0.928) → +0.26 (p 0.507)receipt 3549
- PDE3B in dopamine neurons, braak+0.29 (p 0.457) → +0.14 (p 0.722)receipt 3550
Swarm cases
receipt 3550: PDE3B in dopamine neurons, braak
- power
- full sample +0.17 (p 0.493, n 18), 95% CI -0.32 to +0.59. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.18 (p 0.465, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.20 (p 0.434, n 18). could be the mix.
- skeptic
- leave-one-out range +0.06 to +0.30, sign flips 0; without severely affected donors +0.17 (p 0.493, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PDE3B in dopamine neurons.
case closed: nothing better to follow up.
receipt 3549: PDE3B in microglia, braak
- power
- full sample +0.03 (p 0.922, n 18), 95% CI -0.45 to +0.49. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.04 (p 0.888, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.06 (p 0.827, n 18). could be the mix.
- skeptic
- leave-one-out range -0.11 to +0.18, sign flips 7; without severely affected donors +0.03 (p 0.922, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PDE3B in microglia.
case closed: nothing better to follow up.
Receipts
loading the receipts