Search

Abstract To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10−7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10−5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

Boron nitride (BN) is a layered two-dimensional insulator with excellent chemical, thermal, mechanical, and optical properties. We present a comprehensive characterization of hBN as a dielectric thin film using a high impedance measurement system (100 T Ω) to reveal the AC conductivity and dielectric properties of reactively RF sputtered 200 nm thick films to 480 °C. The experimental results are analyzed with reference to various theoretical models proposed for electrical conduction in disordered or amorphous semiconductors. Electrical measurements indicate that the mechanism behind hBN AC conductivity is via correlated barrier hopping (CBH) and is assigned to localized states at the Fermi level, where N(EF) ∼ 1018 eV−1 cm−3. Our measurements also reveal a σ dc component, with resistance reducing from ∼1010 Ω (50 °C) to 3 × 108 Ω (480 °C). Single RC parallel circuit fits to Cole–Cole plots are achieved signifying a sole conduction path with capacitance values of ∼8 × 10−11 F. These findings may be of interest to material and device scientists and could open new pathways for hBN both as a dielectric material encapsulant and for semiconductor device applications including high-temperature operation. [ABSTRACT FROM AUTHOR]