The Funneled Energy Landscape Theory is currently the most widely accepted theory of protein folding. In this dissertation, the basic concepts of the Energy Landscape Theory are introduced, highlighting some of its major successes in the studies of protein folding and binding kinetics. In particular, the focus is on an idealized native-topology based (Go-type) model that corresponds to a perfectly funneled energy landscape. This simple model has proven to accurately predict the folding mechanism of many proteins, even when simplifying approximations are made. While there exists much evidence that models based on perfectly funneled energy landscapes are sufficient in many cases, there are indications that in other cases the idealized view needs some added complexity to faithfully represent folding and binding mechanisms. By exploring experimentally studied systems where the simplest Go-type models are insufficient, new paradigms and concepts add to our current understanding of protein folding, binding, and aggregation

STUDY DESIGN: Reliability study. OBJECTIVES: The radiographic diagnosis of non-union is not standardized. Prior authors have suggested using a cutoff of <1 mm interspinous process motion (ISPM) on flexion-extension radiographs, but the ability of practicing surgeons to make these measurements reliably is not clear. METHODS: 29 practicing spine surgeons measured ISPM on 19 levels of ACDF from 9 patients. Surgeons relied on these measurements to report on fusion status. Inter-observer correlation co-efficients (ICC), standard error (SEM) and the minimum detectable difference (MD) of these measurements were calculated. We screened for clerical errors by checking measurements more than one standard deviation from the group mean. RESULTS: The ICC for ISPM was .76 (.64; .88) with a SEM of 1 mm and a MD of 2.76 mm. Agreement on fusion status was moderate, with an ICC of .6 (.44; .76). After screening for and removing clerical errors, the ICC improved to .82 (.71; .91), SEM improved to .83 mm, and MD improved to 2.29 mm. Six reviewers had an ICC >.9. The ICC from these high performing reviewers was .94 (.9; .97), SEM was .45 mm, and MD was 1.26 mm. CONCLUSIONS: The MD of 2.29 mm in our study group was not precise enough to support a cutoff of <1 mm ISPM as the sole measurement technique in screening for non-union after ACDF, and there was only moderate agreement amongst surgeons on fusion status based on dynamic radiographs. More stringent techniques are necessary to avoid mis-diagnosing non-union in clinical studies. Future studies should consider auditing measurements to identify clerical errors.