Harnessing Cytosine for Tunable Nanoparticle Self-Assembly Behavior Using Orthogonal Stimuli

Nucleobases control the assembly of DNA, RNA, etc. due to hydrogen bond complementarity. By combining these unique molecules with state-of-the-art synthetic polymers, it is possible to form nanoparticles whose self-assembly behavior could be altered under orthogonal stimuli (pH and temperature). Herein, we report the synthesis of cytosine-containing nanoparticles via aqueous reversible addition-fragmentation chain transfer polymerization-induced self-assembly. A poly(N-acryloylmorpholine) macromolecular chain transfer agent (mCTA) was chain-extended with cytosine acrylamide, and a morphological phase diagram was constructed. By exploiting the ability of cytosine to form dimers via hydrogen bonding, the self-assembly behavior of cytosine-containing polymers was altered when performed under acidic conditions. Under these conditions, stable nanoparticles could be formed at longer polymer chain lengths. Furthermore, the resulting nanoparticles displayed different morphologies compared to those at pH 7. Additionally, particle stability post-assembly could be controlled by varying pH and temperature. Finally, small-angle X-ray scattering was performed to probe their dynamic behavior under thermal cycling

Abstract 13159: Subclinical Cardiac Magnetic Resonance Imaging Reveals Subtle Myocardial Tissue Abnormalities in Individuals With Arrhythmogenic Cardiomyopathy-Associated Genetic Variants

Introduction: With expanding genomic sequencing, incidental identification of patients with disease-causing variants who do not have overt disease is increasingly common. For example, secondary findings of desmosome gene variants associated with arrhythmogenic cardiomyopathy (ACM) are recommended for clinical return but exhibit low penetrance. Additional biomarkers, such as myocardial tissue characteristics, are needed to uncover early disease in patients with genetic risk. Hypothesis: Patients with desmosome variants (G + ) but no clinical phenotype have abnormal ventricular volumes, left ventricular (LV) mass, native T1, T2, post-contrast T1, synthetic extracellular volume (sECV), and late gadolinium enhancement (LGE) via cardiac MRI. Methods: G + individuals were ascertained after clinical confirmation of likely pathogenic/pathogenic desmosome variants from 64548 sequenced Geisinger MyCode patients. MRI studies with myocardial mapping from a single scanner were included. Controls were identified from clinical MRI studies read as having normal biventricular structure and function. Patients who met diagnostic criteria for any cardiomyopathy were excluded from both groups. Ventricular volumes, mass, and tissue properties were defined by manual segmentation. Results: Qualifying studies were identified for 18 G + and 19 genotype unknown (G + ) controls, with similar age and sex. Biventricular volumes and function, as well as LV mass, were similar (Figure). Native T1 was elevated (mean±SEM 1027±9 ms G + vs. 979±15 ms G + ; p = 0.04). No significant differences were found in post-contrast T1, sECV, or native T2. Atypical LGE patterns were noted in 5/18 G + vs. 0/19 G + (p = 0.02). Conclusion: Elevated native T1 and atypical LGE, perhaps due to subclinical fibrosis, were detected in G + patients with normal mass and volume and no overt clinical cardiomyopathy. Longitudinal follow up with larger cohorts will help assess the prognostic significance of these findings. </jats:p

In vivo assessment of blood flow patterns in abdominal aorta of mice with MRI: implications for AAA localization

Abdominal aortic aneurysms (AAA) localize in the infrarenal aorta in humans, while they are found in the suprarenal aorta in mouse models. It has been shown previously that humans experience a reversal of flow during early diastole in the infrarenal aorta during each cardiac cycle. This flow reversal causes oscillatory wall shear stress (OWSS) to be present in the infrarenal aorta of humans. OWSS has been linked to a variety of proatherogenic and proinflammatory factors. The presence of reverse flow in the mouse aorta is unknown. In this study we investigated blood flow in mice, using phase-contrast magnetic resonance (PCMR) imaging. We measured blood flow in the suprarenal and infrarenal abdominal aorta of 18 wild-type C57BL/6J mice and 15 apolipoprotein E (apoE)−/− mice. Although OWSS was not directly evaluated, results indicate that, unlike humans, there is no reversal of flow in the infrarenal aorta of wild-type or apoE−/− mice. Distensibility of the mouse aortic wall in both the suprarenal and infrarenal segments is higher than reported values for the human aorta. We conclude that normal mice do not experience the reverse flow in the infrarenal aorta that is observed in humans