Human Genotyping and An Experimental Model Reveal NPR-C as A Possible Contributor to Morbidity In Coarctation Of The Aorta

Coarctation of the aorta (CoA) is a common congenital cardiovascular (CV) defect characterized by a stenosis of the descending thoracic aorta. Treatment exists, but many patients develop hypertension (HTN). Identifying the cause of HTN is challenging because of patient variability (e.g., age, follow-up duration, severity) and concurrent CV abnormalities. Our objective was to conduct RNA sequencing of aortic tissue from humans with CoA to identify a candidate gene for mechanistic studies of arterial dysfunction in a rabbit model of CoA devoid of the variability seen with humans. We present the first known evidence of natriuretic peptide receptor C (NPR-C; aka NPR3) downregulation in human aortic sections subjected to high blood pressure (BP) from CoA versus normal BP regions (validated to PCR). These changes in NPR-C, a gene associated with BP and proliferation, were replicated in the rabbit model of CoA. Artery segments from this model were used with human aortic endothelial cells to reveal the functional relevance of altered NPR-C activity. Results showed decreased intracellular calcium ([Ca2+]i) activity to C-type natriuretic peptide (CNP). Normal relaxation induced by CNP and atrial natriuretic peptide was impaired for aortic segments exposed to elevated BP from CoA. Inhibition of NPR-C (M372049) also impaired aortic relaxation and [Ca2+]i activity. Genotyping of NPR-Cvariants predicted to be damaging revealed that rs146301345 was enriched in our CoA patients, but sample size limited association with HTN. These results may ultimately be used to tailor treatment for CoA based on mechanical stimuli, genotyping, and/or changes in arterial function

Superposition of Liquid–Liquid and Solid–Liquid Equilibria of Linear and Branched Molecules: Ternary Systems

Oiling-out is an unwanted phenomenon during crystallization processes since it influences the product properties negatively and should, therefore, be avoided. To reduce the time of process development, thermodynamic modeling is usually applied. In the course of fitting model parameters, thermodynamic data of the present molecules are required. In case of branched molecules these thermodynamic data are often not available. To overcome this limitation, a methodology, which allows for the prediction of liquid–liquid equilibria (LLE) of binary systems containing branched molecules was developed recently. The developed methodology was applied in this contribution in order to predict the superposition of ternary LLE and solid–liquid equilibria (SLE) of the system <i>n</i>-hexadecane + 2,2,4,4,6,8,8-heptamethyl­nonane + ethanol. To consider the influence of the molecular architecture on phase equilibria, the lattice cluster theory in combination with the chemical association lattice model was applied. The prediction of the ternary phase equilibria was based on the binary subsystems. It could be shown that the ternary LLE and the ternary SLE can be predicted in very good agreement with experimental data using the same set of model parameters. All model parameters were fitted using only binary LLE data of linear alkanes dissolved in ethanol. Neither binary experimental data of the branched alkane nor ternary ones were used for parameter fitting

Superposition of Liquid–Liquid and Solid–Liquid Equilibria of Linear and Branched Molecules: Binary Systems

Crystallization from solution is a promising unit operation to separate linear and branched isomers. To reduce the number of experiments, a thermodynamic modeling approach is proposed to calculate the required phase equilibria. Hereby, the thermodynamic data of pure substances are required to fit model parameters, but the branched isomers are often not available. Therefore, a methodology which allows for the prediction of phase equilibria of systems containing branched molecules was developed in this contribution. The basic idea is to fit the model parameters to experimental data of linear molecules and combine these parameters with information about the molecular architecture of the branched isomers to predict the phase equilibria of these isomers. For this purpose the lattice cluster theory which considers directly the molecular architecture was applied in combination with the chemical association lattice model. As model systems linear and branched alkanes dissolved in an alcohol were investigated. The developed methodology is able to predict the binary liquid–liquid equilibria of the branched alkanes dissolved in an alcohol in good agreement to experimental data. Furthermore, the thermodynamic model is able to simultaneously calculate the liquid–liquid equilibrium and the solid–liquid equilibrium with the same model parameters in good agreement with experimental data