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1. A novel protein Moat prevents ectopic epithelial folding by limiting Bazooka/Par3-dependent adherens junctions

   https://doi.org/10.1091/mbc.E24-04-0177  

   Gu, Lingkun; Sauceda, Rolin; Brar, Jasneet; Fessahaye, Ferdos; Joo, Minsang; Lee, Joan; Nguyen, Jacqueline; Teng, Marissa; Weng, Mo (August 2024, Molecular Biology of the Cell)

   Wallingford, John (Ed.)

   Contractile myosin and cell adhesion work together to induce tissue shape changes, but how they are patterned to achieve diverse morphogenetic outcomes remains unclear. Epithelial folding occurs via apical constriction, mediated by apical contractile myosin engaged with adherens junctions, as in Drosophila ventral furrow formation. While it has been shown that a multicellular gradient of myosin contractility determines folding shape, the impact of multicellular patterning of adherens junction levels on tissue folding is unknown. We identified a novel Drosophila gene  moat essential for differential apical constriction and folding behaviors across the ventral epithelium which contains both folding ventral furrow and nonfolding ectodermal anterior midgut (ectoAMG). We show that Moat functions to downregulate polarity-dependent adherens junctions through inhibiting cortical clustering of Bazooka/Par3 proteins. Such downregulation of polarity-dependent junctions is critical for establishing a myosin-dependent pattern of adherens junctions, which in turn mediates differential apical constriction in the ventral epithelium. In  moat mutants, abnormally high levels of polarity-dependent junctions promote ectopic apical constriction in cells with low-level contractile myosin, resulting in expansion of infolding from ventral furrow to ectoAMG, and flattening of ventral furrow constriction gradient. Our results demonstrate that tissue-scale distribution of adhesion levels patterns apical constriction and establishes morphogenetic boundaries. 

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2. Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability

   https://doi.org/10.1152/ajpcell.00605.2023  

   Brandon, Ken D; Frank, William E; Stroka, Kimberly M (October 2024, American Journal of Physiology-Cell Physiology)

   Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature’s specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics. 

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3. The role of ephaptic coupling and gap junctional coupling in modulating the initiation and dynamics of reentrant arrhythmias

   https://doi.org/10.1371/journal.pone.0330016  

   Wei, Ning; Tolkacheva, Elena G (August 2025, PLOS One)

   Loppini, Alessandro (Ed.)

   Cardiac myocytes synchronize through electrical signaling to contract heart muscles, facilitated by gap junctions (GJs) located in the intercalated disc (ID). GJs provide low-resistance pathways for electrical impulse propagation between myocytes, considered the primary mechanism for electrical communication in the heart. However, research indicates that conduction can persist without GJs. Ephaptic coupling (EpC), which depends on electrical fields in the narrow ID between adjacent myocytes, offers an alternative mechanism for cardiac conduction when GJs are impaired. Research suggests that EpC can enhance conduction velocity (CV) and reduce the likelihood of conduction block (CB), particularly when GJs are impaired, demonstrating the anti-arrhythmic potential of EpC. Reduced GJ communication increases the susceptibility of heart to arrhythmias due to ectopic or triggered activity, highlighting the pro-arrhythmic effect of GJ uncoupling. However, the interplay between GJs and EpC, and their roles in the initiation, dynamics, and termination of arrhythmias, remain unclear. Reentry, characterized by a loop of electrical activity, is a common mechanism underlying arrhythmogenesis in the heart. This study aims to explore the interplay between EpC and GJs on reentry initiation and its underlying dynamics. Specifically, we employed a two-dimensional (2D) discrete bidomain model that integrates EpC to simulate ephaptic conduction during reentry. We quantitatively assessed the outcomes of reentry initiation and the resulting dynamics across different levels of EpC, GJs, and initial perturbations. The results show that sufficiently strong EpC (i.e., sufficiently narrow clefts) tends to suppress reentry initiation, resulting in absent or non-sustained reentrant activity, while also introducing transient instability and heterogeneity into the cardiac dynamics. In contrast, relatively weak EpC (wide clefts) support sustained reentry with a stable rotor. Furthermore, we found that sufficiently strong EpC can lower the maximal dominant frequency observed during reentrant activity. Overall, this suggests that strong EpC exerts an anti-arrhythmic effect. 

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4. Collective Dynamics of Frustrated Biological Neuron Networks

   https://doi.org/10.1103/1258-cl48  

   Li, Guanyu; LeFebre, Ryan; Starman, Alia; Chappell, Patrick; Mugler, Andrew; Sun, Bo (July 2025, PRX Life)

   To maintain normal functionality, it is necessary for a multicellular organism to generate robust responses to external temporal signals. However, the underlying mechanisms to coordinate the collective dynamics of cells remain poorly understood. Here, we study the calcium activity of biological neuron networks excited by periodic ATP stimuli. We use micropatterning to control the cells' physical connectivity. We find that whereas isolated cells become more synchronized in their calcium activity at long driving periods, connected cells become less synchronized, despite expressing more gap junctions which enable calcium exchange. To understand this result, we use a mathematical model in which a bifurcation analysis has previously shown coupling-induced desynchronization in an oscillatory network. Using parameters close to this bifurcation but in the excitable regime, we find that this desynchronization persists and can explain the experimental observations. The model further predicts that co-culturing with gap-junction-deficient cells should restore synchronization, which experiments confirm. Combining quantitative experiments, the physical and biological manipulation of cells, and mathematical modeling, our results suggest that cell-to-cell connectivity significantly affects how populations encode an external temporal signal as it slows down: Sparse networks synchronize due to longer entrainment, whereas highly connected networks can desynchronize due to dynamic frustration. Published by the American Physical Society2025 

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5. Prevention of Protease-Induced Degradation of Desmoplakin via Small Molecule Binding

   https://doi.org/10.3390/jpm14020163  

   Romov, Isabel M; Nowzari, Roujon A; Page, Clay P; Benes, Madeleine R; Borzok, Maegen A; Wright, Nathan T (February 2024, Journal of Personalized Medicine)

   Desmoplakin (DSP) is a large (~260 kDa) protein found in the desmosome, the subcellular structure that links the intermediate filament network of one cell to its neighbor. A mutation “hot-spot” within the NH2-terminal of the DSP protein (residues 299–515) is associated with arrhythmogenic cardiomyopathy. In a subset of DSP variants, disease is linked to calpain hypersensitivity. Previous studies show that calpain hypersensitivity can be corrected in vitro through the addition of a bulky residue neighboring the cleavage site, suggesting that physically blocking calpain accessibility is a viable strategy to restore DSP levels. Here, we aim to find drug-like molecules that also block calpain-dependent degradation of DSP. To do this, we screened ~2500 small molecules to identify compounds that specifically rescue DSP protein levels in the presence of proteases. We find that several molecules, including sodium dodecyl sulfate, palmitoylethanolamide, GW0742, salirasib, eprosarten mesylate, and GSK1838705A prevent wildtype and disease-variant-carrying DSP protein degradation in the presence of both trypsin and calpain without altering protease function. Computational screenings did not predict which molecules would protect DSP, likely due to a lack of specific DSP–drug interactions. Molecular dynamic simulations of DSP–drug complexes suggest that some long hydrophobic molecules can bind in a shallow hydrophobic groove that runs alongside the protease cleavage site. Identification of these compounds lays the groundwork for pharmacological treatment for individuals harboring these hypersensitive DSP variants. 

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