Human long intrinsically disordered protein regions are frequent targets of positive selection

Intrinsically disordered regions occur frequently in proteins and are characterized by a lack of a well-defined three-dimensional structure. Although these regions do not show a higher-order of structural organization, they are known to be functionally important. Disordered regions are rapidly evolving, largely attributed to relaxed purifying selection and an increased role of genetic drift. It has also been suggested that positive selection might contribute to their rapid diversification. However, for our own species it is currently unknown whether positive selection has played a role during the evolution of these protein regions. Here we address this question by investigating the evolutionary pattern of more than 6,600 human proteins with intrinsically disordered regions and their ordered counterparts. Our comparative approach with data from more than 90 mammalian genomes uses a-priori knowledge of disordered protein regions and we show that this increases the power to detect positive selection by an order of magnitude. We can confirm that human intrinsically disordered regions evolve more rapidly, not only within humans but also across the entire mammalian phylogeny. They have, however, experienced substantial evolutionary constraint, hinting at their fundamental functional importance. We find compelling evidence that disordered protein regions are frequent targets of positive selection and estimate that the relative rate of adaptive substitutions differs 4-fold between disordered and ordered protein regions in humans. Our results suggest that disordered protein regions are important targets of genetic innovation and that the contribution of positive selection in these regions is more pronounced than in other protein parts

A Century of Change towards Prevention and Minimal Intervention in Cariology

Publisher Copyright: © International & American Associations for Dental Research 2019. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.Better understanding of dental caries and other oral conditions has guided new strategies to prevent disease and manage its consequences at individual and public health levels. This article discusses advances in prevention and minimal intervention dentistry over the last century by focusing on some milestones within scientific, clinical, and public health arenas, mainly in cariology but also beyond, highlighting current understanding and evidence with future prospects. Dentistry was initially established as a surgical specialty. Dental caries (similar to periodontitis) was considered to be an infectious disease 100 years ago. Its ubiquitous presence and rampant nature—coupled with limited diagnostic tools and therapeutic treatment options—meant that these dental diseases were managed mainly by excising affected tissue. The understanding of the diseases and a change in their prevalence, extent, and severity, with evolutions in operative techniques, technologies, and materials, have enabled a shift from surgical to preventive and minimal intervention dentistry approaches. Future challenges to embrace include continuing the dental profession’s move toward a more patient-centered, evidence-based, less invasive management of these diseases, focused on promoting and maintaining oral health in partnership with patients. In parallel, public health needs to continue to, for example, tackle social inequalities in dental health, develop better preventive and management options for existing disease risk groups (e.g., the growing aging population), and the development of reimbursement and health outcome models that facilitate implementation of these evolving strategies. A century ago, almost every treatment involved injections, a drill or scalpel, or a pair of forceps. Today, dentists have more options than ever before available to them. These are supported by evidence, have a minimal intervention focus, and result in better outcomes for patients. The profession’s greatest challenge is moving this evidence into practice.preprintPeer reviewe

Slowing Down and Scattering of Ions in Solids

The interaction of particle beams with solids yields three parts, i.e. reflected particles, penetrating particles and trapped particles. At very low energies particle reflection is dominant, at very high energies penetration is the most important effect. Trapped particles are the result of energy loss processes, which on the other hand cause radiation damage in the solid. In the energy range discussed here, i.e. above energies where quantum effects, diffraction etc. are important and below energies where nuclear reactions, relativistic effects etc. may occur, the particle trajectories are classical. The energy loss process can be treated separately as nuclear and electronic stopping power. The collisions of the projectiles with target atoms are hence binary collisions involving a properly chosen screened Coulomb-potential. In single crystals the structural properties enable channeling, which is a very useful tool in sol id state analysis. The electronic stopping includes contributions from single collision processes and collective excitations. Both effects can be described by a dielectric response function. The range of applications covers analytical methods, means to modify solid state properties and also the production of thin films

SPUTTER DEPTH PROFILING OF OPTICAL WAVEGUIDES USING SECONDARY ION MASS SPECTROMETRY

The technique of sputter depth profiling by means of secondary ion mass spectrometry of samples with high resistivity is reviewed. As examples we discuss optical waveguides made in lithium niobate by titanium indiffusion and implantation and also yttrium iron garnet waveguides grown by liquid phase epitaxy on gadolinium gallium garnet. Depth profiling of these waveguide structures has been performed and the necessary precautions to prevent charging by the primary ion beam are discussed. In some cases, coating with a metallic layer is adequate, but a more universal method is charge neutralization by an additional electron beam

Data-driven output-only methods for damage detection with a focus on deep learning algorithms

Downloa

H3K9me-Independent Gene Silencing in Fission Yeast Heterochromatin by Clr5 and Histone Deacetylases

Nucleosomes in heterochromatic regions bear histone modifications that distinguish them from euchromatic nucleosomes. Among those, histone H3 lysine 9 methylation (H3K9me) and hypoacetylation have been evolutionarily conserved and are found in both multicellular eukaryotes and single-cell model organisms such as fission yeast. In spite of numerous studies, the relative contributions of the various heterochromatic histone marks to the properties of heterochromatin remain largely undefined. Here, we report that silencing of the fission yeast mating-type cassettes, which are located in a well-characterized heterochromatic region, is hardly affected in cells lacking the H3K9 methyltransferase Clr4. We document the existence of a pathway parallel to H3K9me ensuring gene repression in the absence of Clr4 and identify a silencing factor central to this pathway, Clr5. We find that Clr5 controls gene expression at multiple chromosomal locations in addition to affecting the mating-type region. The histone deacetylase Clr6 acts in the same pathway as Clr5, at least for its effects in the mating-type region, and on a subset of other targets, notably a region recently found to be prone to neo-centromere formation. The genomic targets of Clr5 also include Ste11, a master regulator of sexual differentiation. Hence Clr5, like the multi-functional Atf1 transcription factor which also modulates chromatin structure in the mating-type region, controls sexual differentiation and genome integrity at several levels. Globally, our results point to histone deacetylases as prominent repressors of gene expression in fission yeast heterochromatin. These deacetylases can act in concert with, or independently of, the widely studied H3K9me mark to influence gene silencing at heterochromatic loci

Misty, Spellbound and the lost Gothic of British girls’ comics.

This article is a case study of the 1970s British girls’ comics Spellbound (DC Thomson, 1976–1977) and Misty (IPC, 1978–1980). These mystery anthology comics followed the more famous American horror comics from publishers like EC Comics - but were aimed at pre-teen girls. The article situates these comics with respect to Gothic critical theory and within the wider landscape of British girls’ comics. Firstly, it closely considers and compares the structure and content of their stories with respect to theories of the terror and horror Gothic. It discovers that both comics offer similar fare, with a subversive streak that undercuts established horror archetypes. The article then looks closely at both titles’ aesthetics and their use of the page to draw comparisons. It uses comics theory and Gothic cinematic theory to demonstrate that the appearance of Misty is more strongly Gothic than the aesthetic of Spellbound. Finally, it considers a selection of stories from both comics and analyses their common themes using Gothic critical theory. It argues that both comics rework Gothic themes into new forms that are relevant to their pre-teen and teenage readers. It concludes by summarising the study’s findings and suggesting that these comics offer a “Gothic for Girls” that is part cautionary tale and part bildungsroman. This article is published as part of a collection on Gothic and horror

Influence of surgical approach on component positioning in primary total hip arthroplasty

Background: Minimal invasive surgery (MIS) has gained growing popularity in total hip arthroplasty (THA) but concerns exist regarding component malpositioning. The aim of the present study was to evaluate femoral and acetabular component positioning in primary cementless THA comparing a lateral to a MIS anterolateral approach. Methods: We evaluated 6 week postoperative radiographs of 52 hips with a minimal invasive anterolateral approach compared to 54 hips with a standard lateral approach. All hips had received the same type of implant for primary cementless unilateral THA and had a healthy hip contralaterally. Results: Hip offset was equally restored comparing both approaches. No influence of the approach was observed with regard to reconstruction of acetabular offset, femoral offset, vertical placement of the center of rotation, stem alignment and leg length discrepancy. However, with the MIS approach, a significantly higher percentage of cups (38.5 %) was malpositioned compared to the standard approach (16.7 %) (p = 0.022). Conclusions: The MIS anterolateral approach allows for comparable reconstruction of stem position, offset and center of rotation compared to the lateral approach. However, surgeons must be aware of a higher risk of cup malpositioning for inclination and anteversion using the MIS anterolateral approach

Advancements in diagnosing oral potentially malignant disorders: leveraging Vision transformers for multi-class detection

Objectives: Diagnosing oral potentially malignant disorders (OPMD) is critical to prevent oral cancer. This study aims to automatically detect and classify the most common pre-malignant oral lesions, such as leukoplakia and oral lichen planus (OLP), and distinguish them from oral squamous cell carcinomas (OSCC) and healthy oral mucosa on clinical photographs using vision transformers. Methods: 4,161 photographs of healthy mucosa, leukoplakia, OLP, and OSCC were included. Findings were annotated pixel-wise and reviewed by three clinicians. The photographs were divided into 3,337 for training and validation and 824 for testing. The training and validation images were further divided into five folds with stratification. A Mask R-CNN with a Swin Transformer was trained five times with cross-validation, and the held-out test split was used to evaluate the model performance. The precision, F1-score, sensitivity, specificity, and accuracy were calculated. The area under the receiver operating characteristics curve (AUC) and the confusion matrix of the most effective model were presented. Results: The detection of OSCC with the employed model yielded an F1 of 0.852 and AUC of 0.974. The detection of OLP had an F1 of 0.825 and AUC of 0.948. For leukoplakia the F1 was 0.796 and the AUC was 0.938. Conclusions: OSCC were effectively detected with the employed model, whereas the detection of OLP and leukoplakia was moderately effective. Clinical relevance: Oral cancer is often detected in advanced stages. The demonstrated technology may support the detection and observation of OPMD to lower the disease burden and identify malignant oral cavity lesions earlier

Glioma imaging in Europe: A survey of 220 centres and recommendations for best clinical practice

Objectives: At a European Society of Neuroradiology (ESNR) Annual Meeting 2015 workshop, commonalities in practice, current controversies and technical hurdles in glioma MRI were discussed. We aimed to formulate guidance on MRI of glioma and determine its feasibility, by seeking information on glioma imaging practices from the European Neuroradiology community. Methods: Invitations to a structured survey were emailed to ESNR members (n=1,662) and associates (n=6,400), European national radiologists’ societies and distributed via social media. Results: Responses were received from 220 institutions (59% academic). Conventional imaging protocols generally include T2w, T2-FLAIR, DWI, and pre- and post-contrast T1w. Perfusion MRI is used widely (85.5%), while spectroscopy seems reserved for specific indications. Reasons for omitting advanced imaging modalities include lack of facility/software, time constraints and no requests. Early postoperative MRI is routinely carried out by 74% within 24–72 h, but only 17% report a percent measure of resection. For follow-up, most sites (60%) issue qualitative reports, while 27% report an assessment according to the RANO criteria. A minority of sites use a reporting template (23%). Conclusion: Clinical best practice recommendations for glioma imaging assessment are proposed and the current role of advanced MRI modalities in routine use is addressed. Key Points: • We recommend the EORTC-NBTS protocol as the clinical standard glioma protocol.• Perfusion MRI is recommended for diagnosis and follow-up of glioma.• Use of advanced imaging could be promoted with increased education activities.• Most response assessment is currently performed qualitatively.• Reporting templates are not widely used, and could facilitate standardisation