The relationship between tooth size discrepancy and archform classification in orthodontic patients

Background: To determine the relationship between clinically significant tooth size discrepancies (TSD) and archform classification in orthodontic patients. Material and Methods: Two hundred and forty consecutive sets of pre-treatment orthodontic study models were scanned and landmarked. All models had permanent teeth erupted from first molar to first molar in both arches. Sixty sets of images were classified into two groups of 30 according to the presence (group 1) or absence (group 2) of a clinically significant overall or anterior TSD (>2 SD from Bolton’s original means). Mean upper and lower archforms were created for each group using a fourth degree polynomial curve. Upper and lower archforms in each group were classified as square, tapering or ovoid; their distribution was analysed using the Fisher test with a 5% level of significance. To evaluate the intra-operator error when determining archform type, the 60 archforms were re-classified by the same operator two weeks later. The unweighted Kappa statistic at 95% confidence intervals was used to determine the similarity of the classification on the two occasions. Results: Reproducibility of the classification of archform was very good (unweighted Kappa statistic of 0.83 with a 95% confidence interval of 0.73, 0.93). There was no statistically significant difference in the distribution of archform type between group 1 and group 2 for the upper ( p =0.3305) or lower ( p =0.6310) arches. Conclusions: The presence of a clinically significant TSD and archform classification do not appear to be related

The Relationship Between Tooth Size Discrepancy and Archform Classification in Orthodontic Patients

Background To determine the relationship between clinically significant tooth size discrepancies (TSD) and archform classification in orthodontic patients. Material and Methods Eighty teeth with artificial white spot lesions were randomly divided into four groups: (A) distilled and deionized water, (B) Nd:YAG laser, (C) CPP-ACP crème, & (D) CPP-ACP plus laser. SMH was measured using Vickers diamond indenter in Vickers Hardness Number (VHN). Two samples of each group were analyzed using scanning electron microscope (SEM). The results were analyzed with the SPSS 17/win. Results Reproducibility of the classification of archform was very good (unweighted Kappa statistic of 0.83 with a 95% confidence interval of 0.73, 0.93). There was no statistically significant difference in the distribution of archform type between group 1 and group 2 for the upper (p=0.3305) or lower (p=0.6310) arches. Conclusions The presence of a clinically significant TSD and archform classification do not appear to be related

Recognition and Stigma of Prescription Drug Abuse Disorder: Personal and Community Determinants

Background Prescription drug abuse (PDA) disorders continue to contribute to the current American opioid crisis. Within this context, our study seeks to improve understanding about stigma associated with, and symptom recognition of, prescription drug abuse. Aims Model the stigma and symptom recognition of PDA in the general population. Methods A randomized, nation-wide, online, vignette-focused survey of the general public (N = 631) was implemented with an oversample for rural counties. Logit estimation was used for analysis, with regional and county-level sociodemographic variables as controls. Results Individual respondents that self-identify as having or having had “a prescription drug abuse issue” were less likely to correctly identify the condition and were 4 times more likely to exhibit stigma. Male respondents were approximately half as likely to correctly identify PDA as female respondents while older respondents (55+) were more likely to correctly identify PDA, relative to those aged 35–54. Being both male and younger was associated with slightly more stigma, in that they were less likely to disagree with the stigma statement. Conclusions In light of the continued risks that individuals with PDA behaviors face in potentially transitioning to illicit opioid use, the findings of this survey suggested a continued need for public education and outreach. Of particular note is the perspective of those who have self-identified with the condition, as this population faces the largest risks of adverse health outcomes from illicit drug use within the survey respondents

Ozone depletion events observed in the high latitude surface layer during the TOPSE aircraft program

During the Tropospheric Ozone Production about the Spring Equinox (TOPSE) aircraft program, ozone depletion events (ODEs) in the high latitude surface layer were investigated using lidar and in situ instruments. Flight legs of 100 km or longer distance were flown 32 times at 30 m altitude over a variety of regions north of 58° between early February and late May 2000. ODEs were found on each flight over the Arctic Ocean but their occurrence was rare at more southern latitudes. However, large area events with depletion to over 2 km altitude in one case were found as far south as Baffin Bay and Hudson Bay and as late as 22 May. There is good evidence that these more southern events did not form in situ but were the result of export of ozone-depleted air from the surface layer of the Arctic Ocean. Surprisingly, relatively intact transport of ODEs occurred over distances of 900–2000 km and in some cases over rough terrain. Accumulation of constituents in the frozen surface over the dark winter period cannot be a strong prerequisite of ozone depletion since latitudes south of the Arctic Ocean would also experience a long dark period. Some process unique to the Arctic Ocean surface or its coastal regions remains unidentified for the release of ozone-depleting halogens. There was no correspondence between coarse surface features such as solid ice/snow, open leads, or polynyas with the occurrence of or intensity of ozone depletion over the Arctic or subarctic regions. Depletion events also occurred in the absence of long-range transport of relatively fresh “pollution” within the high latitude surface layer, at least in spring 2000. Direct measurements of halogen radicals were not made. However, the flights do provide detailed information on the vertical structure of the surface layer and, during the constant 30 m altitude legs, measurements of a variety of constituents including hydroxyl and peroxy radicals. A summary of the behavior of these constituents is made. The measurements were consistent with a source of formaldehyde from the snow/ice surface. Median NOx in the surface layer was 15 pptv or less, suggesting that surface emissions were substantially converted to reservoir constituents by 30 m altitude and that ozone production rates were small (0.15–1.5 ppbv/d) at this altitude. Peroxyacetylnitrate (PAN) was by far the major constituent of NOy in the surface layer independent of the ozone mixing ratio

Large-Scale Conformational Changes of Trypanosoma cruzi Proline Racemase Predicted by Accelerated Molecular Dynamics Simulation

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a life-threatening illness affecting 11–18 million people. Currently available treatments are limited, with unacceptable efficacy and safety profiles. Recent studies have revealed an essential T. cruzi proline racemase enzyme (TcPR) as an attractive candidate for improved chemotherapeutic intervention. Conformational changes associated with substrate binding to TcPR are believed to expose critical residues that elicit a host mitogenic B-cell response, a process contributing to parasite persistence and immune system evasion. Characterization of the conformational states of TcPR requires access to long-time-scale motions that are currently inaccessible by standard molecular dynamics simulations. Here we describe advanced accelerated molecular dynamics that extend the effective simulation time and capture large-scale motions of functional relevance. Conservation and fragment mapping analyses identified potential conformational epitopes located in the vicinity of newly identified transient binding pockets. The newly identified open TcPR conformations revealed by this study along with knowledge of the closed to open interconversion mechanism advances our understanding of TcPR function. The results and the strategy adopted in this work constitute an important step toward the rationalization of the molecular basis behind the mitogenic B-cell response of TcPR and provide new insights for future structure-based drug discovery

The Distinct Conformational Dynamics of K-Ras and H-Ras A59G

Ras proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma-phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to-GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non-transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species

The Democratic Biopolitics of PrEP

PrEP (Pre-Exposure Prophylaxis) is a relatively new drug-based HIV prevention technique and an important means to lower the HIV risk of gay men who are especially vulnerable to HIV. From the perspective of biopolitics, PrEP inscribes itself in a larger trend of medicalization and the rise of pharmapower. This article reconstructs and evaluates contemporary literature on biopolitical theory as it applies to PrEP, by bringing it in a dialogue with a mapping of the political debate on PrEP. As PrEP changes sexual norms and subjectification, for example condom use and its meaning for gay subjectivity, it is highly contested. The article shows that the debate on PrEP can be best described with the concepts ‘sexual-somatic ethics’ and ‘democratic biopolitics’, which I develop based on the biopolitical approach of Nikolas Rose and Paul Rabinow. In contrast, interpretations of PrEP which are following governmentality studies or Italian Theory amount to either farfetched or trivial positions on PrEP, when seen in light of the political debate. Furthermore, the article is a contribution to the scholarship on gay subjectivity, highlighting how homophobia and homonormativity haunts gay sex even in liberal environments, and how PrEP can serve as an entry point for the destigmatization of gay sexuality and transformation of gay subjectivity. ‘Biopolitical democratization’ entails making explicit how medical technology and health care relates to sexual subjectification and ethics, to strengthen the voice of (potential) PrEP users in health politics, and to renegotiate the profit and power of Big Pharma

The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the divide between clinical domain knowledge and formal gene curation criteria

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes

Novel Allosteric Sites on Ras for Lead Generation

Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs