PubMed · 5754958
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T I Bertelsen. 1968-06-15. [Red eye].. https://pubmed.ncbi.nlm.nih.gov/5754958/
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Claudin-14 (CLDN14) is a key component of tight junctions (TJs) critical for maintaining paracellular barrier function. Variants of CLDN14 have been linked to Vein of Galen malformations (VOGMs), a rare cerebrovascular disorder; however, the molecular mechanisms underlying their pathogenicity remain unknown. Here, we investigate the mechanistic effects of two VOGM-associated mutations, A113P and V143M, using reinforcement-learning driven enhanced sampling molecular dynamics simulations combined with DiffNets-based deep learning and independent trajectory-wide structural analyses. Our analysis reveals that A113P induces broader structural disruption of CLDN14, perturbing paracellular sealing, pore symmetry, and inter-protomer communication, whereas V143M induces structural rearrangements centred around TM3 and the TM3-ECL2 region. In both cases, mutation-specific alterations are observed in structural stability and interfacial organization across oligomeric assemblies. Notably, these effects are qualitatively consistent across different modelled architectures, despite variability in local responses. In the absence of experimentally resolved structures, the structural perturbations reported here provide a mechanistic understanding of how VOGM-associated variants may influence CLDN14 structure and dynamics.
We describe three different magnetic resonance (MR)-angiography techniques to evaluate aneurysm size, configuration, and neck morphology of experimentally created aneurysms in a rabbit model. In five New Zealand White rabbits an aneurysm was created by endovascular occlusion of the right common carotid artery (CCA) using a pliable balloon and subsequent endoluminal incubation of elastase within the proximal CCA above the balloon and distal ligation of the vessel. In all animals, time-of-flight (TOF), phase contrast and contrast enhanced (CE) MR angiographies (MRA) were performed and compared to conventional digital subtraction angiography results. We found, that aneurysms are best visualized employing CE MRA, however, neck morphology was also found to demonstrate interpretable results when evaluating the axial source data of the TOF MRA. The animal model we used can be employed for testing endovascular devices such as new coil material, or covered stents. The described MRA techniques might then be helpful for pre-interventional planning and maybe even for the follow-up of the thus treated aneurysms.
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