PubMed · 13096816
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G DE TAKATS, C L PIRANI. [General considerations].. https://pubmed.ncbi.nlm.nih.gov/13096816/
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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.
BACKGROUND: The purpose of this study was to compare the long-term outcomes of children randomized to surgery or balloon angioplasty (BA) for native coarctation (CoA). A prior randomized, short-term comparison of BA and surgery for native CoA in 36 children demonstrated equivalent relief of obstruction. The risk of aneurysm formation and possibly restenosis was higher among patients treated with BA. METHODS AND RESULTS: Blood pressure, residual aortic obstruction, and exercise performance were evaluated. Need for repeat intervention was reviewed. Aortic arch anatomy was assessed with magnetic resonance angiography. For subjects who were not available to return for evaluation, the most recent clinical record was utilized. Among the 36 subjects initially randomized, 21 returned for evaluation (11 BA, 10 surgery). The average time since initial intervention to evaluation for all subjects was 10.6+/-4.7 years for BA subjects and 11.3+/-3.7 years for surgical subjects. Resting blood pressure, CoA gradient, exercise performance, MRI analysis of the aortic arch, and need for repeat interventions were not different for the 2 treatment strategies. There was a higher incidence of aneurysm formation (35% versus 0%) and a greater difference in blood pressure between the right and left legs with exercise among BA subjects. Some aneurysms developed late, first being detected more than 5 years after the initial intervention. Only 50% of BA subjects remained free of both aneurysm formation and repeat intervention compared with 87.5% of surgical subjects (P=0.03). CONCLUSIONS: BA for the treatment of childhood CoA is associated with a higher incidence of aneurysm formation and iliofemoral artery injury than surgery. These differences should be considered when undertaking treatment for native CoA during childhood.
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