3 hypotheses
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8 open gaps
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0 live debates
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0 tokens funded
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3/7 hub

What we know

  • 3 active hypothesises in scope
  • 8 open frontiers with evidence gaps
  • 10 indexed papers in corpus
3 hypotheses in scope top ranked
23 open frontiers
0 in-flight debates
0 tokens funded

Top hypotheses

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  1. #1 Context-Dependent Cx43 Modulation Based on Disease Stage 72% promoted combination GJA1 (Cx43) - context-dependent Connexin-43 gap junction / hemichannel intercellular communication PMID:40007760PMID:29587860 +8 refs
  2. #2 TNF-α/IL-1β-Cx43 Hemichannel Axis as Upstream Link Between SASP and Synaptic Pruning 66% proposed combination TNF, IL1B → GJA1 → C1Q/C3 TLR4/MyD88/NF-κB innate immune signaling PMID:25643695PMID:40007760 +2 refs
  3. #3 Closed-loop neuromodulation-inspired cytokine axis suppression to restore Cx43 hemichannel-mediated synaptic homeostasis via inflammatory interneuron crosstalk in cellular senescence 53% active cross_disease_analogy GJA1 (Cx43) TNF-α/IL-1β-Cx43 hemichannel axis / SASP-synapse coupling PMID:37683629 (2023)PMID:27647860 (2016) +1 refs

Open frontiers

All gaps →
Can cellular stress response pathways distinguish between protective and pathological protein transfer?

The debate raised the possibility that stress responses facilitate both beneficial and harmful protein transmission, but the molecular basis for this selectivity is unresolved. Understanding these discrimination mechanisms could enable selective therapeutic blocking. Source: Debate session sess_SDA-2026-04-08-gap-pubmed-20260406-062207-5a703c17 (Analysis: SDA-2026-04-08-gap-pubmed-20260406-062207-5a703c17)

priority 73%
What are the downstream signaling pathways linking ARF6/exocyst to VE-cadherin trafficking?

While ARF6 and exocyst complex are identified as VE-cadherin interactors involved in trafficking and recycling, the specific signaling cascades and regulatory mechanisms remain undefined. This limits understanding of how junctional remodeling is precisely controlled. Gap type: unexplained_observation Source paper: Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion. (2024, Nat Commun, PMID:39232006)

priority 56%
Can TFEB chronic activation cause lysosomal storage dysfunction that counteracts therapeutic benefits?

While TFEB activation was proposed to enhance lysosomal clearance, the skeptic raised concerns about chronic overactivation leading to cellular stress. The long-term consequences of sustained TFEB enhancement remain unexplored. Source: Debate session sess_sda-2026-04-01-002 (Analysis: sda-2026-04-01-002)

priority 80%
Do mitochondrial-lysosome contact site defects precede or follow autophagy dysfunction in different NDDs?

The debate mentioned contact site engineering but did not establish the temporal relationship between contact site dysfunction and broader autophagy failure. This sequence determines whether contact sites represent primary therapeutic targets or downstream consequences. Source: Debate session sess_sda-2026-04-01-gap-011 (Analysis: sda-2026-04-01-gap-011)

priority 70%
Can lysosomal membrane stabilizers selectively prevent tau seeding without disrupting normal autophagy?

While tau-induced lysosomal damage promotes seeding, the therapeutic hypothesis assumes membrane stabilization won't impair essential lysosomal dynamics. This selectivity has not been demonstrated experimentally. Source: Debate session sess_SDA-2026-04-03-gap-tau-prop-20260402003221 (Analysis: SDA-2026-04-03-gap-tau-prop-20260402003221)

priority 70%
Which extracellular vesicle subtypes are the primary carriers of pathological tau between neurons?

While extracellular vesicles were identified as tau carriers, the specific vesicle populations (exosomes vs microvesicles vs other) and their relative contributions remain undefined. This knowledge gap limits targeted therapeutic intervention strategies. Source: Debate session sess_SDA-2026-04-02-gap-tau-propagation-20260402 (Analysis: SDA-2026-04-02-gap-tau-propagation-20260402)

priority 82%
How does cholesterol gradient disruption differentially affect amyloidogenic vs synaptic raft domains in human neurons?

The concept of selective cholesterol modulation was discussed but mechanistic details of domain-specific targeting remain unclear. Understanding how to therapeutically manipulate cholesterol gradients without compromising synaptic integrity is essential for developing effective interventions. Source: Debate session sess_SDA-2026-04-01-gap-lipid-rafts-2026-04-01 (Analysis: SDA-2026-04-01-gap-lipid-rafts-2026-04-01)

priority 75%
Do bioenergetic checkpoints (ATP/ADP ratios) causally control astrocyte subtype differentiation or merely correlate with it?

The synthesizer proposed that metabolic sensors guide astrocyte fate decisions, but the debate lacks direct evidence for causality versus correlation. Establishing causality is essential for developing metabolic interventions that reliably control astrocyte phenotypes. Source: Debate session sess_SDA-2026-04-10-sda-2026-04-01-gap-007 (Analysis: sda-2026-04-01-gap-007)

priority 78%

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