Tensile forces in the neurovascular bundle: A contributor to orthodontic relapse?

OBJECTIVES: The aim of this study is to investigate the neurovascular bundle (NVB) as a potential orthodontic relapse factor. The mechanical properties and the forces generated in the NVB after orthodontic extrusion are explored. MATERIALS AND METHODS: Six NVBs branching from the inferior alveolar nerve to the apices of the mandibular canines and premolars of mature pigs were harvested. Stress relaxation tests were conducted. A standard linear solid model (SLS) was utilized to simulate the orthodontic extrusion of a single rooted tooth with NVB length and cross-sectional diameter of 3.6 and 0.5 mm, respectively, so the NVB was stretched 10% and 20% of its original length. The maximum force within the NVB was then calculated. RESULTS: Based on our data, the average Young's modulus before relaxation ( E 0 ), after relaxation ( E P ) and the difference between Young's moduli before and after relaxation ( E S ) were 324 ± 123, 173 ± 73 and 151 ± 52 kPa, respectively. The theoretical force within the NVB stretched to 10% and 20% strain was 3 and 5 mN, respectively. CONCLUSION: The data from our study indicate that the NVB exhibits stress relaxation, a characteristic trait of viscoelastic materials. SLS model simulation predicted residual forces around 5 mN for elongation up to 20%. We observed strain hardening with additional elongation, which has the potential to cause forces to increase exponentially. Therefore, tensile forces in the NVB should not be ruled out as a contributor to orthodontic relapse, especially in adult patients who may have decreased adaptability of their NVB. Further preclinical and clinical models should be developed to further clarify what is the contribution of the NVB to orthodontic relapse.

α-Sheet secondary structure in amyloid ß-peptide drives aggregation and toxicity in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the deposition of ß-sheet-rich, insoluble amyloid ß-peptide (Aß) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aß oligomers adopt a nonstandard secondary structure, termed "α-sheet." These oligomers form in the lag phase of aggregation, when Aß-associated cytotoxicity peaks, en route to forming nontoxic ß-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aß, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aß-induced paralysis in a transgenic Aß Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

De Novo Designed α-Sheet Peptides Inhibit Functional Amyloid Formation of Streptococcus mutans Biofilms.

Streptococcus mutans is a bacterial species that predominates in the oral microbiome. S. mutans binds to the tooth surface, metabolizes sugars and produces acid, leading to cavity formation. S. mutans can also cause infectious endocarditis. Recent evidence suggests that S. mutans biofilms contain amyloid fibrils. Amyloids are insoluble fibrillar protein aggregates, and bacteria use functional amyloids to improve robustness of their biofilms. While the functional amyloids in bacteria such as Escherichia coli and Staphylococcus aureus have been heavily investigated, little is known about the mechanism of S. mutans amyloid formation. Previous results from our laboratory with the amyloidogenic proteins and peptides from the aforementioned bacteria and other mammalian amyloid systems suggest that amyloid formation progresses via an intermediate that adopts a unique secondary structure-α-sheet. De novo designed peptides with alternating l- and d-amino acid also adopt an α-sheet secondary structure and inhibit amyloid formation by binding to soluble oligomeric species during amyloidogenesis. Inhibition of fibrillization by α-sheet peptides suggests the presence of α-sheet during amyloid formation. To investigate the mechanism of functional amyloid formation in S. mutans, α-sheet peptides were compared to epigallocatechin gallate for their ability to inhibit fibril formation in S. mutans. Inhibition was demonstrated in a biofilm plate assay and on hydroxyapatite surfaces both in S. mutans alone and in bacteria from human saliva. The observed inhibition suggests that an α-sheet mediated mechanism may be operative during functional amyloid formation.