PubMed · 14801764
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J FREUNDLICH, H H PITTS. 1951. Abdominal aneurysm.. https://pubmed.ncbi.nlm.nih.gov/14801764/
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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.
AIMS: We investigated the effect of plasma levels of human tissue inhibitor of metalloproteinase (hTIMP)-1 on arterial lesion development and aneurysm formation in apolipoprotein-E-deficient mice (ApoE(-/-)). METHODS: Control and transgenic mice were fed either a chow diet or a high-fat diet for 90 and 180 days. RESULTS: hTIMP-1 has a tendency to decrease atherosclerotic lesions, but did not attain significance (approximately 6% reduction in hTIMP-1(+/+), p = 0.075, and approximately 4% in hTIMP-1(+/0), p = 0.088 vs. control). Immunohistological and histological analyses revealed a reduction in macrophage accumulation (23% of control in hTIMP(+/0), p = 0.065, and 49% of control in hTIMP(+/+), p < 0.05) but not in collagen degradation within the lesion in transgenic mice. Moreover, elastin degradation in sites of pseudo-microaneurysms was reduced in transgenic mice (37% of control in hTIMP-1(+/0), p < 0.05, and 50% of control in hTIMP-1(+/+), p < 0.05). DNA array analysis of matrix metalloproteinase (MMP) expression followed by real-time PCR quantification revealed a significant up-regulation of MMP-3, MMP-12 and MMP-13 in arterial lesions of ApoE(-/-) mice fed a high-fat diet in comparison with the same mice fed a chow diet. CONCLUSION: These data show that hTIMP-1 reduces aneurysm formation in ApoE(-/-) mice but does not protect them against the development of arterial lesions.
PURPOSE: To develop a new technique for intravascular guidance and the release of magnetized ferromagnetic nanoparticles using a polymerized filament by means of an external magnetic field. MATERIALS AND METHODS: Ferromagnetic nanoscaled beads were embedded in temperature-sensitive gels to form filaments after polymerization. Deflection of the filaments was assessed in a Stereotaxis Niobe magnetic navigation system (MNS) in comparison with dedicated guide wires. The curvature was measured as a surrogate parameter for deflection. In combination with commercially available catheters, the filaments were navigated in a perfused aneurysmatic vessel model and a perfused branched vessel model under the influence of two permanent magnets of the Niobe MNS. The magnetic field vector was varied in all three dimensions. After positioning, the magnetic colloid-containing filaments were exposed to an electromagnetic field of 45 kA/m, 200 kHz for a period of 5 minutes for non-invasive heating. RESULTS: The filaments showed superior deflectability compared to the dedicated guide wires (p = 0.0091). The curvature was 0.54 +/- 0.12 mm(-1) for the filaments and 0.33 +/- 0.21 mm(-1) for the guide wires. In combination with angiography catheters, magnetic guidance and accumulation of specially designed filaments were possible in the perfused vessel model. Inductive heating allowed non-invasive disintegration and releasing of the nanoparticles in all filaments. CONCLUSION: This feasibility study shows that magnetic guidance and targeting of a specially designed magnetic colloid-containing filament and subsequent disintegration are feasible. This technique offers the potential for controlled local drug release.