Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched in microglia (221 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: lomvastomig, cobolimab, sabatolimab | 0.81 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 490 | 0.91 |
| pathways Reactome | 1 pathway; mostly immune signalling | 0.90 |
Knock down and overexpress HAVCR2 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 HAVCR2 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
- HAVCR2 in dopamine neurons, braak+0.30 (p 0.441) → +0.19 (p 0.623)receipt 7462
- HAVCR2 in microglia, braak-0.01 (p 0.982) → +0.24 (p 0.530)receipt 7461
Swarm cases
receipt 7462: HAVCR2 in dopamine neurons, braak
- power
- full sample +0.20 (p 0.424, n 18), 95% CI -0.29 to +0.61. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.26 (p 0.298, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.27 (p 0.281, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.36, sign flips 0; without severely affected donors +0.20 (p 0.424, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HAVCR2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 7461: HAVCR2 in microglia, braak
- power
- full sample +0.09 (p 0.709, n 18), 95% CI -0.39 to +0.54. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.08 (p 0.741, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.05 (p 0.854, n 18). could be the mix.
- skeptic
- leave-one-out range -0.04 to +0.20, sign flips 2; without severely affected donors +0.09 (p 0.709, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HAVCR2 in microglia.
case closed: nothing better to follow up.
Receipts
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