Expansion of a polyglutamine (polyQ) domain within the first exon of the huntingtin (htt) protein is the underlying cause of Huntington’s disease, a genetic neurodegenerative disorder. PolyQ expansion triggers htt aggregation into oligomers, fibrils, and inclusions. The 17 N-terminal amino acids (Nt17) of htt-exon1, which directly precede the polyQ domain enhances polyQ fibrillization and functions as a lipid-binding domain. A variety of post-translational modifications occur within Nt17, including oxidation of two methionine residues. Here, the impact of oxidation within Nt17 on htt aggregation both in the presence and absence of lipid membranes was investigated. Treatment with hydrogen peroxide (H2O2) reduced fibril formation in a dose-dependent manner, resulting in shorter fibrils and an increased oligomer population. With excessive H2O2 treatments, fibrils developed a unique morphological feature around their periphery. In the presence of total brain lipid vesicles, H2O2 impacted fibrillization in a similar manner. That is, oligomerization was promoted at the expense of fibril elongation. The interaction of unoxidized and oxidized htt with supported lipid bilayers was directly observed using in situ atomic force microscopy. Without oxidation, granular htt aggregates developed on the bilayer surface. However, in the presence of H2O2, distinct plateau-like regions initially developed on the bilayer surface that gave way to rougher patches containing granular aggregates. Collectively, these observations suggest that oxidation of methionine residues within Nt17 plays a crucial role in both the aggregation of htt and its ability to interact with lipid surfaces.
Introduction:Achieving anatomic reduction and re-establishing premorbid occlusion in patients with complex maxillomandibular fractures is challenging even for seasoned surgeons. Historically, surgeons have utilized occlusal splints to help establish occlusal relationships before fracture reduction and fixation. These acrylic splints are fabricated from dental impressions and require manual repositioning of tooth bearing segments along the fracture line to reapproximate premorbid occlusion. The process is laborious, requires a dental lab, and is less efficacious in edentulous patients or those with significantly comminuted fractures; as such it has largely fallen out of practice. Recently, with advances in virtual 3D modeling and printing, we demonstrate that occlusal splints can be designed from computed tomography scans, manipulated virtually, and printed without obtaining impressions from the patient.Methods/Results:In our series of 3 patients with complex maxillomandibular fractures, occlusal splints were created by 1) obtaining maxillofacial computed tomography scans, 2) reducing the fractures virtually, and 3) using orthognathic virtual surgery software to create the splint. The time between planning and delivery of the splint was 4 to 7 days. These splints were successfully utilized to help establish premorbid occlusion in conjunction with maxillomandibular fixation and aided in expeditious intraoperative fracture reduction and fixation.Conclusions:In the treatment of complex facial fractures, occlusal splints can be a useful adjunct in the operative reduction and fixation of fractures. With the advent of virtual preoperative surgical planning via 3D modeling and 3D printing, these occlusal splints can be created of a sufficient fidelity to avoid the strict need for dental impressions.
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