Health and disease are directly related to the RTK-RAS-MAPK signalling cascade. After more than three decades of intensive research, understanding its spatiotemporal features is afflicted with major conceptual shortcomings. Here we consider how the compilation of a vast array of accessory proteins may resolve some parts of the puzzles in this field, as they safeguard the strength, efficiency and specificity of signal transduction. Targeting such modulators, rather than the constituent components of the RTK-RAS-MAPK signalling cascade may attenuate rather than inhibit disease-relevant signalling pathways.

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Risk factors of nonhealing wounds include persistent bacterial infections and rapid onset of dehydration; therefore, wound dressings should be used to accelerate the healing process by helping to disinfect the wound bed and provide moisture. Herein, we introduce a transparent tributylammonium alginate surface-modified cationic polyurethane (CPU) wound dressing, which is appropriate for full-thickness wounds. We studied the physicochemical properties of the dressing using Fourier transform infrared, 1H NMR, and 13C NMR spectroscopies and scanning electron microscopy, energy-dispersive X-ray, and thermomechanical analyses. The surface-modified polyurethane demonstrated improved hydrophilicity and tensile Young’s modulus that approximated natural skin, which was in the range of 1.5–3 MPa. Cell viability and in vitro wound closure, assessed by MTS and the scratch assay, confirmed that the dressing was cytocompatible and possessed fibroblast migratory-promoting activity. The surface-modified CPU had up to 100% antibacterial activity against Staphylococcus aureus and Escherichia coli as Gram-positive and Gram-negative bacteria, respectively. In vivo assessments of both noninfected and infected wounds revealed that the surface-modified CPU dressing resulted in a faster healing rate because it reduced the persistent inflammatory phase, enhanced collagen deposition, and improved the formation of mature blood vessels when compared with CPU and commercial Tegaderm wound dressing.

Vesicle biogenesis, trafficking and signaling via Endoplasmic reticulum-Golgi network support essential developmental processes and their disruption lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation. Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding. Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking. Disease modeling in zebrafish validates further the dominant behavior of the mutants and their differential impact on brain and body plan formation, recapitulating the variable disease expression. In-depth in vivo analyses traces back impaired neural precursors’ proliferation and planar cell polarity-dependent cell movements as the earliest detectable effects. Our findings document a key role of ARF3 in Golgi function and demonstrate its pleiotropic impact on development.