HighlightsThe functional architecture among regulatory structures, and the whole brain, is less modular in confirmed cases of SUDEP and those at high-risk.Altered functional organisation may mean potential impairment of communication among key regulatory circuits.SUDEP is associated with regional connectivity disruptions among cortical and sub-cortical regulatory sites.Medial thalamic connectivity was significantly altered in SUDEP compared with all control groups, including those at high-risk.Increases in the number, and a shift in organisation, of hubs appears to relate to lower mortality risk.

Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane bound protease, Matriptase, or mutation of its inhibitor, Hai1. Unrestricted Matriptase activity also predisposes to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, NfkB signalling, and IP3R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in hai1a mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.