JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln-/- mutants. Eln-/- mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln-/- mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS

Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

Exploring Second Language Learning: Communicative Competence, Pragmatics, and Second Language Literacy

This portfolio is a compilation of the author’s teaching philosophy and three artifacts that explore elements of second language teaching. The teaching philosophy contains the author’s strategies of second language teaching including instructional practice, communicative language teaching theory, and application. This portfolio also contains artifacts of second language teaching that explore communicative competence, formal address pragmatics, and second language literacy. An annotated bibliography of books and articles that have impacted the author’s teaching beliefs and practices is also included

Working at the Intersections: Critical Race Scholarship and Pedagogy Today

Recent conversations in Utah and nationwide highlight the debate and division surrounding Critical Race Theory (CRT) in education. The purpose of this event is to celebrate the ways CRT informs and deepens our teaching, research, and community engagement in higher education. Panelists will explore how they use CRT in the classroom and in their research, and discuss how doing so advances USU’s mission of “cultivating diversity of thought and culture and “serving the public through learning, discovery, and engagement.” Join us for an engaging—and celebratory—discussion that will reenergize our shared purpose in this work and build connections across our university.https://digitalcommons.usu.edu/inter_inclusion/1006/thumbnail.jp

Sterilization of lung matrices by supercritical carbon dioxide

Lung engineering is a potential alternative to transplantation for patients with end-stage pulmonary failure. Two challenges critical to the successful development of an engineered lung developed from a decellularized scaffold include (i) the suppression of resident infectious bioburden in the lung matrix, and (ii) the ability to sterilize decellularized tissues while preserving the essential biological and mechanical features intact. To date, the majority of lungs are sterilized using high concentrations of peracetic acid (PAA) resulting in extracellular matrix (ECM) depletion. These mechanically altered tissues have little to no storage potential. In this study, we report a sterilizing technique using supercritical carbon dioxide (ScCO(2)) that can achieve a sterility assurance level 10(−6) in decellularized lung matrix. The effects of ScCO(2) treatment on the histological, mechanical, and biochemical properties of the sterile decellularized lung were evaluated and compared with those of freshly decellularized lung matrix and with PAA-treated acellular lung. Exposure of the decellularized tissue to ScCO(2) did not significantly alter tissue architecture, ECM content or organization (glycosaminoglycans, elastin, collagen, and laminin), observations of cell engraftment, or mechanical integrity of the tissue. Furthermore, these attributes of lung matrix did not change after 6 months in sterile buffer following sterilization with ScCO(2), indicating that ScCO(2) produces a matrix that is stable during storage. The current study's results indicate that ScCO(2) can be used to sterilize acellular lung tissue while simultaneously preserving key biological components required for the function of the scaffold for regenerative medicine purposes

Loss of angiotensin II type 2 receptor improves blood pressure in elastin insufficiency

There is ample evidence supporting a role for angiotensin II type 2 receptor (A

Tool Measures Depths of Defects on a Case Tang Joint

A special-purpose tool has been developed for measuring the depths of defects on an O-ring seal surface. The surface lies in a specially shaped ringlike fitting, called a capture feature tang, located on an end of a cylindrical segment of a case that contains a solid-fuel booster rocket motor for launching a space shuttle. The capture feature tang is a part of a tang-and-clevis, O-ring joint between the case segment and a similar, adjacent cylindrical case segment. When the segments are joined, the tang makes an interference fit with the clevis and squeezes the O-ring at the side of the gap

Layerless fabrication with continuous liquid interface production

Despite the increasing popularity of 3D printing, also known as additive manufacturing (AM), the technique has not developed beyond the realm of rapid prototyping. This confinement of the field can be attributed to the inherent flaws of layer-by-layer printing and, in particular, anisotropic mechanical properties that depend on print direction, visible by the staircasing surface finish effect. Continuous liquid interface production (CLIP) is an alternative approach to AM that capitalizes on the fundamental principle of oxygen-inhibited photopolymerization to generate a continual liquid interface of uncured resin between the growing part and the exposure window. This interface eliminates the necessity of an iterative layer-by-layer process, allowing for continuous production. Herein we report the advantages of continuous production, specifically the fabrication of layerless parts. These advantages enable the fabrication of large overhangs without the use of supports, reduction of the staircasing effect without compromising fabrication time, and isotropic mechanical properties. Combined, these advantages result in multiple indicators of layerless and monolithic fabrication using CLIP technology

Genetic background influences murine prostate gene expression: implications for cancer phenotypes

Microarray analyses to quantitate transcript levels in the prostates of five inbred mouse strains identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors