Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.03 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in bergmann glia | 0.75 |
| chemistry Open Targets | compounds already reach it: biib-023, ro-5458640 | 0.81 |
| 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 immune signalling | 0.90 |
Knock down and overexpress TNFSF12 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 TNFSF12 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
- TNFSF12 in microglia, braak-0.45 (p 0.230) → -0.40 (p 0.288)receipt 6706
- TNFSF12 in dopamine neurons, braak-0.19 (p 0.631) → -0.42 (p 0.258)receipt 6707
Swarm cases
receipt 6707: TNFSF12 in dopamine neurons, braak
- power
- full sample -0.32 (p 0.194, n 18), 95% CI -0.69 to +0.17. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.35 (p 0.159, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.44 (p 0.070, n 18). could be the mix.
- skeptic
- leave-one-out range -0.47 to -0.26, sign flips 0; without severely affected donors -0.32 (p 0.194, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TNFSF12 in dopamine neurons.
case closed: nothing better to follow up.
receipt 6706: TNFSF12 in microglia, braak
- power
- full sample -0.41 (p 0.091, n 18), 95% CI -0.74 to +0.07. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.46 (p 0.056, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.46 (p 0.056, n 18). could be the mix.
- skeptic
- leave-one-out range -0.58 to -0.34, sign flips 0; without severely affected donors -0.41 (p 0.091, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TNFSF12 in microglia.
case closed: nothing better to follow up.
Receipts
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