Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.46 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (420 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: galunisertib, vactosertib | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 5 Parkinson's papers of 1,334 | 0.76 |
| pathways Reactome | 10 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress TGFBR1 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; existing compounds already reach the inhibition arm.
- 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 TGFBR1 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
- TGFBR1 in microglia, braak+0.08 (p 0.832) → +0.26 (p 0.498)receipt 0404
- TGFBR1 in dopamine neurons, braak+0.29 (p 0.457) → -0.10 (p 0.807)receipt 0405
Swarm cases
receipt 0405: TGFBR1 in dopamine neurons, braak
- power
- full sample +0.03 (p 0.901, n 18), 95% CI -0.44 to +0.49. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.07 (p 0.774, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.05 (p 0.854, n 18). could be the mix.
- skeptic
- leave-one-out range -0.09 to +0.13, sign flips 4; without severely affected donors +0.03 (p 0.901, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TGFBR1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0404: TGFBR1 in microglia, braak
- power
- full sample +0.21 (p 0.413, n 18), 95% CI -0.29 to +0.61. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.22 (p 0.374, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.24 (p 0.341, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.32, sign flips 0; without severely affected donors +0.21 (p 0.413, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TGFBR1 in microglia.
case closed: nothing better to follow up.
Receipts
loading the receipts