Hyperexcitable neurons in brain organoids: Individuals with Angelman syndrome experience intellectual disability and seizures throughout their lives. In this condition, ubiquitin-mediated degradation of a key potassium channel is disrupted, allowing for the neuronal excitability and network synchronization that leads to seizure. Sun et al. used brain organoid technology to study what happens in human neurons with a mutation in a ubiquitin ligase that is implicated in Angelman syndrome. In these in vitro models and in a mouse model of Angelman syndrome, antagonists for the potassium channel normalized neuronal excitability. Science , this issue p. 1486

Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates. Interaction mapping by SPLASH identifies many pair-wise interactions, 40% of which form alternative structures, suggesting extensive structural heterogeneity. Analysis of shared interactions between serotypes reveals a conserved macro-organization whereby interactions can be preserved at physical locations beyond sequence identities. We further observe that longer-range interactions are preferentially disrupted inside cells, and show the importance of new interactions in virus fitness. These findings deepen our understanding of Flavivirus genome organization and serve as a resource for designing therapeutics in targeting RNA viruses.