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Glycogen Synthase Kinase 3-beta (GSK3β) is a critical regulator of several cellular pathways involved in neuroplasticity and is a potential target for neurotherapeutic development in the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3β have been focused on developing small molecule inhibitors that compete with ATP through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The Disrupted in Schizophrenia (DISC1) protein, has previously been shown to bind and inhibit GSK3β activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3β in a non-competitive mode that is distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3β: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3b binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3b.

The dynamics of cardiac fibrillation can be described by the number, the trajectory, the stability, and the lifespan of phase singularities (PSs). Accurate PS tracking is straightforward in simple uniform tissues but becomes more challenging as fibrosis, structural heterogeneity, and strong anisotropy are combined. In this paper, we derive a mathematical formulation for PS tracking in two-dimensional reaction–diffusion models. The method simultaneously tracks wavefronts and PS based on activation maps at full spatiotemporal resolution. PS tracking is formulated as a linear assignment problem solved by the Hungarian algorithm. The cost matrix incorporates information about distances between PS, chirality, and wavefronts. A graph of PS trajectories is generated to represent the creations and annihilations of PS pairs. Structure-preserving graph transformations are applied to provide a simplified description at longer observation time scales. The approach is validated in 180 simulations of fibrillation in four different types of substrates featuring, respectively, wavebreaks, ionic heterogeneities, fibrosis, and breakthrough patterns. The time step of PS tracking is studied in the range from 0.1 to 10 ms. The results show the benefits of improving time resolution from 1 to 0.1 ms. The tracking error rate decreases by an order of magnitude because the occurrence of simultaneous events becomes less likely. As observed on PS survival curves, the graph-based analysis facilitates the identification of macroscopically stable rotors despite wavefront fragmentation by fibrosis.