Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.24 (overall 0.50) | 0.24 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in lymphatic endothelial cells | 0.75 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 1,666 | 0.91 |
| pathways Reactome | 10 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress TGFBR2 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.
- 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 TGFBR2 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
- TGFBR2 in dopamine neurons, braak+0.22 (p 0.574) → -0.15 (p 0.697)receipt 0243
- TGFBR2 in microglia, braak+0.12 (p 0.749) → -0.01 (p 0.982)receipt 0242
Swarm cases
receipt 0243: TGFBR2 in dopamine neurons, braak
- power
- full sample +0.06 (p 0.817, n 18), 95% CI -0.42 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.11 (p 0.667, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.15 (p 0.555, n 18). could be the mix.
- skeptic
- leave-one-out range -0.02 to +0.20, sign flips 4; without severely affected donors +0.06 (p 0.817, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TGFBR2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0242: TGFBR2 in microglia, braak
- power
- full sample +0.05 (p 0.840, n 18), 95% CI -0.43 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.04 (p 0.881, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.09 (p 0.735, n 18). could be the mix.
- skeptic
- leave-one-out range -0.08 to +0.17, sign flips 3; without severely affected donors +0.05 (p 0.840, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TGFBR2 in microglia.
case closed: nothing better to follow up.
Receipts
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