The consequences of cavity creation on the folding landscape of a repeat protein depend upon context.

The effect of introducing internal cavities on protein native structure and global stability has been well documented, but the consequences of these packing defects on folding free-energy landscapes have received less attention. We investigated the effects of cavity creation on the folding landscape of the leucine-rich repeat protein pp32 by high-pressure (HP) and urea-dependent NMR and high-pressure small-angle X-ray scattering (HPSAXS). Despite a modest global energetic perturbation, cavity creation in the N-terminal capping motif (N-cap) resulted in very strong deviation from two-state unfolding behavior. In contrast, introduction of a cavity in the most stable, C-terminal half of pp32 led to highly concerted unfolding, presumably because the decrease in stability by the mutations attenuated the N- to C-terminal stability gradient present in WT pp32. Interestingly, enlarging the central cavity of the protein led to the population under pressure of a distinct intermediate in which the N-cap and repeats 1-4 were nearly completely unfolded, while the fifth repeat and the C-terminal capping motif remained fully folded. Thus, despite modest effects on global stability, introducing internal cavities can have starkly distinct repercussions on the conformational landscape of a protein, depending on their structural and energetic context.

Pediatric Supracondylar Humerus Fractures Can Be Safely Treated by Orthopaedic Surgeons With and Without Pediatric Fellowship Training.

BACKGROUND: The purpose of this study was to compare the outcomes of pediatric patients who were surgically treated for a supracondylar humerus fracture by pediatric fellowship-trained orthopaedic surgeons (PFT) to the outcomes of those surgically treated by orthopaedic surgeons without pediatric fellowship training (NPFT). We hypothesized that there would be no differences in patient outcomes. METHODS: A retrospective review of pediatric patients who underwent surgical treatment for a supracondylar humerus fracture with closed reduction and percutaneous pinning (CRPP) or open reduction and percutaneous pinning (ORPP) at a regional level 1 trauma center over a 5-year period was performed. Exclusion criteria were inadequate follow up or absence of postoperative radiographs. RESULTS: A total of 201 patients met the inclusion criteria. Pediatric-fellowship trained orthopaedic surgeons treated 15.9% of patients. There was no statistically significant difference in carrying angle, Baumann's angle, or lateral rotation percentage at final follow up between PFT and NPFT groups. There was no permanent neurovascular compromise in either group. Patients treated by NPFT were more likely to return to the operating room for pin removal. CONCLUSION: In this study, there was no difference in radiographic outcomes for patients with supracondylar humerus fractures surgically treated by either group. This suggests that pediatric supracondylar humerus fractures may be appropriately treated in communities without a pediatric-fellowship trained orthopaedic surgeon without compromised outcomes.Level of Evidence: III.