Disassociation of ß1-α1-ß2 from the α2-α3 domain of prion protein (PrP) is a prerequisite for the conformational conversion of PrPC into PrPSc: Driven by the free energy landscape.

Misfolding of the cellular prion protein (PrPC) into ß-sheet-rich scrapie form (PrPSc) is associated with transmissible spongiform encephalopathies. A point mutation F198S is responsible for the development of a rare inherited Gerstmann-Straussler-Scheinker disease caused by the aggregation of PrPC. Thus, identification and the structural characterization of aggregation-prone regions are essential to delineate the conversion of PrPC to the disease-associated PrPSc upon F198S mutation. In the present study, molecular dynamics simulations on the wild-type PrP (WT-PrP) and its mutant were performed to explore the structural basis responsible for aggregation driven by the mutation. Secondary structure analysis revealed that the mutant exhibited a partial unfolding on α2 and the complete distortion in the 310-helix of the ß2-α2 loop. Remarkably, the ß2-α2 loop is in proximity to α3 attributed by the long-range hydrophobic interactions and such structural intimacy is not observed in the WT-PrP. Owing to this, the ß1-α1-ß2 regions have separated from α2-α3 domain resulting in the impairment on the hydrogen bond between α1 and α3. Thus, the present study provides a detailed structural description of the F198S mutant in line with previous experimental results and delivers insights into the structural basis responsible for the conversion of PrPC to the disease-associated PrPSc.

N-terminal-pro-brain natriuretic peptide, a surrogate biomarker of combined clinical and hemodynamic outcomes following percutaneous transvenous mitral commissurotomy.

AIM: To examine the relationship between plasma levels of N-terminal-proB type natriuretic peptide (NT-proBNP) and various echocardiographic and hemodynamic parameters in patients with mitral stenosis undergoing percutaneous transvenous mitral commissurotomy (PTMC). MATERIALS AND METHODS: The study population consisted of 100 patients with rheumatic mitral stenosis who underwent PTMC. NT-proBNP levels in these patients were measured before PTMC and 48 hours after PTMC. These levels were then correlated with various echocardiographic and hemodynamic parameters measured before and after PTMC. RESULTS: Eighty-one percent of the study population were women, and the most common presenting symptom was dyspnea which was present in 94% of the patients. Dyspnea New York Heart Association class correlated significantly with baseline NT-proBNP levels (r = 0.63; p < 0.01). The plasma NT-proBNP levels in these patients increased as echocardiogram signs of left atrial enlargement and right ventricular hypertrophy developed (r = 0.59, p < 0.01). Patients in atrial fibrillation had significantly higher NT-proBNP levels than patients in sinus rhythm. Baseline NT-proBNP levels correlated significantly with left atrial volume (r = 0.38; p < 0.01), left atrial volume index (r = 0.45; p < 0.01), systolic pulmonary artery pressures (r = 0.42; p < 0.01), and mean pulmonary artery pressures (r = 0.41; p < 0.01). All patients who underwent successful PTMC showed a significant decrease in NT-proBNP (decreased from a mean 763.8 pg/mL to 348.6 pg/mL) along with a significant improvement in all echocardiographic and hemodynamic parameters (p < 0.01). The percent change in NT-proBNP correlated significantly with the percent improvement noted with left atrial volume (r = 0.39; p < 0.01), left atrial volume index (r = 0.41; p < 0.01), systolic (r = 0.32, p < 0.01), and mean pulmonary artery pressures (r = 0.31, p < 0.01). CONCLUSIONS: The decrease in NT-proBNP levels following PTMC reflects an improvement in clinical and hemodynamic status; hence, it is reasonable to suggest that NT-proBNP is helpful in evaluating the response to PTMC.