Astrocyte reactivity subtypes in neurodegeneration¶
Analysis ID: SDA-2026-04-01-gap-007
Date: 2026-04-02
Domain: neurodegeneration
Hypotheses Generated: 7
Knowledge Graph Edges: 20
Key Hypotheses¶
- Purinergic Signaling Polarization Control (score: 0.544)
- Epigenetic Memory Erasure via TET2 Activation (score: 0.508)
- Mechanosensitive Ion Channel Reprogramming (score: 0.492)
- Circadian Rhythm Entrainment of Reactive Astrocytes (score: 0.456)
- Lipid Droplet Dynamics as Phenotype Switches (score: 0.450)
- Metabolic Switch Targeting for A1→A2 Repolarization (score: 0.437)
- Mitochondrial Transfer Pathway Enhancement (score: 0.430)
This notebook presents a computational analysis including differential gene expression, pathway enrichment, and multi-dimensional hypothesis scoring. Data is simulated based on known biology from the Allen Brain Cell Atlas (SEA-AD) and published literature.
1. Setup and Data Generation¶
Generated expression data for 20 genes x 5 cell types Samples per condition: 50 Primary cell type: Astrocytes
2. Differential Expression Heatmap¶
Log2 fold change of gene expression between disease and control samples across cell types. Significance: * p<0.05, ** p<0.01, *** p<0.001 (Mann-Whitney U test).
Significant changes (p < 0.05): 15 / 100
3. Volcano Plot: Astrocytes Expression¶
Differential expression in astrocytes — the primary cell type of interest for this analysis. Red = upregulated in disease, blue = downregulated. Dashed line = p=0.05 threshold.
Significantly upregulated: 6 Significantly downregulated: 3
4. Statistical Analysis¶
Comprehensive statistical testing including non-parametric Mann-Whitney U tests, effect sizes (Cohen's d), and one-way ANOVA for cell-type variation.
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STATISTICAL ANALYSIS SUMMARY
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Significant results (p < 0.05): 15 gene-cell type pairs
Gene Cell_Type Log2FC P_value Cohens_d Effect
GFAP Astrocytes 1.116078 4.124343e-10 1.222615 Large
TNF Astrocytes 1.031309 1.584327e-09 1.401397 Large
VIM Astrocytes 1.060215 1.960212e-09 1.255548 Large
C3 Microglia 1.176194 1.370289e-08 1.004777 Large
SERPINA3 Astrocytes 1.088615 4.157355e-08 1.096681 Large
IL1B Microglia 1.030613 5.893940e-08 1.081526 Large
TNF Microglia 1.072407 6.366071e-08 0.975124 Large
C3 Astrocytes 1.025201 1.086143e-07 0.943032 Large
LCN2 Astrocytes 1.171552 2.859964e-07 1.114945 Large
SLC1A2 Exc Neurons -0.525285 1.435665e-04 -0.691124 Medium
GJA1 Astrocytes -0.584446 1.695207e-04 -0.600624 Medium
NDRG2 Astrocytes -0.517253 1.791111e-04 -0.797081 Medium
SLC1A3 Astrocytes -0.569227 2.416420e-04 -0.741019 Medium
SLC1A2 Astrocytes -0.482449 1.728873e-03 -0.754410 Medium
CLU Inh Neurons 0.354014 2.963010e-02 0.539867 Medium
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ONE-WAY ANOVA: Expression Variation Across Cell Types (Disease)
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GFAP F= 12.60 p=2.45e-09 ***
S100B F= 0.66 p=6.20e-01 ns
AQP4 F= 0.67 p=6.10e-01 ns
ALDH1L1 F= 0.47 p=7.59e-01 ns
VIM F= 14.57 p=1.09e-10 ***
SERPINA3 F= 17.34 p=1.53e-12 ***
LCN2 F= 10.03 p=1.57e-07 ***
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MULTIPLE TESTING CORRECTION (Bonferroni)
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Tests performed: 15
Significant before correction: 15
Significant after Bonferroni: 14
5. Pathway Enrichment Analysis¶
Hypergeometric test for enrichment of analysis target genes in curated biological pathways (Reactome/KEGG-style). Identifies which molecular processes are overrepresented.
Pathway Enrichment Results:
Pathway Overlap Overlap_Genes Fold_Enrichment P_value Significant
Reactive Astrogliosis 5 SERPINA3, LCN2, GFAP, VIM, S100B 2381.0 4.726969e-18 True
Glutamate Transport 1 AQP4 571.4 1.748950e-03 True
Potassium Homeostasis 1 AQP4 571.4 1.748950e-03 True
Complement Cascade 0 - 0.0 1.000000e+00 False
Neuroinflammation 0 - 0.0 1.000000e+00 False
Lipid Metabolism 0 - 0.0 1.000000e+00 False
Gap Junction Signaling 0 - 0.0 1.000000e+00 False
Neuroprotection 0 - 0.0 1.000000e+00 False
6. Hypothesis Multi-Dimensional Scoring¶
Top hypotheses scored across 6 key dimensions: mechanistic plausibility, evidence strength, novelty, feasibility, therapeutic impact, and druggability.
7. Knowledge Graph Edges¶
Causal relationships extracted from the multi-agent debate:
| Source | Relation | Target | Confidence |
|---|---|---|---|
| P2RY1 | associated_with | neurodegeneration | 0.655 |
| P2RY1 | interacts_with | P2RX7 | 0.655 |
| P2RX7 | associated_with | neurodegeneration | 0.655 |
| P2RX7 | interacts_with | P2RY1 | 0.655 |
| TET2 | associated_with | neurodegeneration | 0.581 |
| PIEZO1 | associated_with | neurodegeneration | 0.599 |
| PIEZO1 | interacts_with | KCNK2 | 0.599 |
| KCNK2 | associated_with | neurodegeneration | 0.599 |
| KCNK2 | interacts_with | PIEZO1 | 0.599 |
| HK2 | associated_with | neurodegeneration | 0.506 |
| BMAL1 | associated_with | neurodegeneration | 0.519 |
| DGAT1 | associated_with | neurodegeneration | 0.529 |
| DGAT1 | interacts_with | SOAT1 | 0.529 |
| SOAT1 | associated_with | neurodegeneration | 0.529 |
| SOAT1 | interacts_with | DGAT1 | 0.529 |
| MIRO1 | associated_with | neurodegeneration | 0.513 |
| BMAL1 | co_discussed | HK2 | 0.4 |
| BMAL1 | co_discussed | MIRO1 | 0.4 |
| BMAL1 | co_discussed | P2RY1 | 0.4 |
| BMAL1 | co_discussed | SOAT1 | 0.4 |
Total edges: 20
Methodology¶
This analysis was generated by SciDEX's multi-agent scientific debate system:
- Theorist generates novel hypotheses based on known biology
- Skeptic challenges assumptions and identifies weaknesses
- Domain Expert assesses druggability, feasibility, and clinical relevance
- Synthesizer ranks hypotheses and extracts knowledge graph edges
Gene expression data is simulated based on published SEA-AD atlas findings (Allen Institute for Brain Science).
Generated: 2026-04-02 22:02 UTC Platform: SciDEX Source: GitHub