Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in choroid plexus epithelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: avoralstat, berotralstat, human c1-esterase inhibitor +4 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 153 | 0.91 |
| pathways Reactome | 6 pathways; mostly other | 0.30 |
Knock down and overexpress KLKB1 in astrocytes; measure a transcriptome-wide state shift (bulk RNA-seq) and α-synuclein uptake and degradation, and dopamine neuron survival in co-culture.
- Cell type
- astrocytes
- 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
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- 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 KLKB1 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); α-synuclein uptake and degradation, and dopamine neuron survival in co-culture. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- KLKB1 in astrocytes, braak+0.15 (p 0.705) → -0.10 (p 0.802)receipt 13581
- KLKB1 in dopamine neurons, braak+0.33 (p 0.387) → -0.45 (p 0.230)receipt 13582
Swarm cases
receipt 13582: KLKB1 in dopamine neurons, braak
- power
- full sample -0.03 (p 0.894, n 18), 95% CI -0.49 to +0.44. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.03 (p 0.908, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.08 (p 0.754, n 18). could be the mix.
- skeptic
- leave-one-out range -0.19 to +0.08, sign flips 5; without severely affected donors -0.03 (p 0.894, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KLKB1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 13581: KLKB1 in astrocytes, braak
- power
- full sample +0.01 (p 0.956, n 18), 95% CI -0.46 to +0.48. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.05 (p 0.854, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.04 (p 0.874, n 18). could be the mix.
- skeptic
- leave-one-out range -0.12 to +0.13, sign flips 5; without severely affected donors +0.01 (p 0.956, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KLKB1 in astrocytes.
case closed: nothing better to follow up.
Receipts
loading the receipts