Addition of the apical oblique projection increases the detection of acute traumatic shoulder abnormalities in adults

Purpose Plain radiographic evaluation of acute shoulder trauma in adults requires a minimum of two projections, commonly the anteroposterior (AP) and lateral scapular projections, with additional projections taken for diagnosis. The aim of this retrospective study was to determine whether the addition of the apical oblique (AO) projection to the AP and lateral scapular projections increases the number and/or alters the types of abnormalities detected in the examination of acute shoulder trauma. Methods Examinations of 56 adults who had undergone three-projection (AP, lateral scapular, AO) radiographic shoulder examination for acute trauma were allocated into two-projection (AP, lateral scapular) and three-projection cases and assessed by a radiologist. The differences in number and types of abnormalities between the two-projection and three-projection cases were quantified using the one-tailed t test and chi-square goodness-of-fit test, respectively. Results Test-retest reliability was moderate (intra-class correlation coefficient [95%CI], 0.56 [0.15 to 0.80]) for number, and almost perfect (kappa [95%CI], 0.94 [0.85 to 1.00]) for types, of abnormalities detected. There was a significant increase in the number of abnormalities detected across all three-projection versus two-projection cases (difference in means [95%CI], 0.20 [0.01 to 0.39]) and for fractures (difference in means [95%CI], 0.30 [0.11 to 0.49]), but no difference in the types of abnormalities detected (χ 2 = 4.7, p = 0.19). Conclusion This study suggests that adding the AO projection to two-projection examination of acute shoulder trauma increases the number of abnormalities detected; this has potential implications for patient management. Further research investigating differences in types of abnormalities detected between two-projection and three-projection cases is warranted

The Influence of N-Linked Glycans on the MolecularDynamics of the HIV-1 gp120 V3 Loop

N-linked glycans attached to specific amino acids of the gp120 envelope trimer of a HIV virion can modulate the binding affinity of gp120 to CD4, influence coreceptor tropism, and play an important role in neutralising antibody responses. Because of the challenges associated with crystallising fully glycosylated proteins, most structural investigations have focused on describing the features of a non-glycosylated HIV-1 gp120 protein. Here, we use a computational approach to determine the influence of N-linked glycans on the dynamics of the HIV-1 gp120 protein and, in particular, the V3 loop. We compare the conformational dynamics of a non-glycosylated gp120 structure to that of two glycosylated gp120 structures, one with a single, and a second with five, covalently linked high-mannose glycans. Our findings provide a clear illustration of the significant effect that N-linked glycosylation has on the temporal and spatial properties of the underlying protein structure. We find that glycans surrounding the V3 loop modulate its dynamics, conferring to the loop a marked propensity towards a more narrow conformation relative to its non-glycosylated counterpart. The conformational effect on the V3 loop provides further support for the suggestion that N-linked glycosylation plays a role in determining HIV-1 coreceptor tropism.Scopu

A combined computational-experimental approach to define the structural origin of antibody recognition of sialyl-Tn, a tumor-associated carbohydrate antigen.

Anti-carbohydrate monoclonal antibodies (mAbs) hold great promise as cancer therapeutics and diagnostics. However, their specificity can be mixed, and detailed characterization is problematic, because antibody-glycan complexes are challenging to crystallize. Here, we developed a generalizable approach employing high-throughput techniques for characterizing the structure and specificity of such mAbs, and applied it to the mAb TKH2 developed against the tumor-associated carbohydrate antigen sialyl-Tn (STn). The mAb specificity was defined by apparent KD values determined by quantitative glycan microarray screening. Key residues in the antibody combining site were identified by site-directed mutagenesis, and the glycan-antigen contact surface was defined using saturation transfer difference NMR (STD-NMR). These features were then employed as metrics for selecting the optimal 3D-model of the antibody-glycan complex, out of thousands plausible options generated by automated docking and molecular dynamics simulation. STn-specificity was further validated by computationally screening of the selected antibody 3D-model against the human sialyl-Tn-glycome. This computational-experimental approach would allow rational design of potent antibodies targeting carbohydrates

Structural Analysis of the Glycosylated Intact HIV-1 gp120-b12 Antibody Complex Using Hydroxyl Radical Protein Footprinting

Glycoprotein gp120 is a surface antigen and virulence factor of human immunodeficiency virus 1. Broadly neutralizing antibodies (bNAbs) that react to gp120 from a variety of HIV isolates offer hope for the development of broadly effective immunogens for vaccination purposes, if the interactions between gp120 and bNAbs can be understood. From a structural perspective, gp120 is a particularly difficult system because of its size, the presence of multiple flexible regions, and the large amount of glycosylation, all of which are important in gp120-bNAb interactions. Here, the interaction of full-length, glycosylated gp120 with bNAb b12 is probed using high-resolution hydroxyl radical protein footprinting (HR-HRPF) by fast photochemical oxidation of proteins. HR-HRPF allows for the measurement of changes in the average solvent accessible surface area of multiple amino acids without the need for measures that might alter the protein conformation, such as mutagenesis. HR-HRPF of the gp120-b12 complex coupled with computational modeling shows a novel extensive interaction of the V1/V2 domain, probably with the light chain of b12. Our data also reveal HR-HRPF protection in the C3 domain caused by interaction of the N330 glycan with the b12 light chain. In addition to providing information about the interactions of full-length, glycosylated gp120 with b12, this work serves as a template for the structural interrogation of full-length glycosylated gp120 with other bNAbs to better characterize the interactions that drive the broad specificity of the bNAb

Analysis of site-specific N-glycan remodeling in the endoplasmic reticulum and the Golgi

The hallmark of N-linked protein glycosylation is the generation of diverse glycan structures in the secretory pathway. Dynamic, non-template-driven processes of N-glycan remodeling in the endoplasmic reticulum and the Golgi provide the cellular setting for structural diversity. We applied newly developed mass spectrometry-based analytics to quantify site-specific N-glycan remodeling of the model protein Pdi1p expressed in insect cells. Molecular dynamics simulation, mutational analysis, kinetic studies of in vitro processing events and glycan flux analysis supported the defining role of the protein in N-glycan processin

High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

About one-third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below-normal Elmo1 expression in mice ameliorates the albuminuria and glomerular histological changes resulting from long-standing type 1 diabetes, whereas above-normal Elmo1 expression makes both worse. Increasing Elmo1 expression leads to aggravation of oxidative stress markers and enhances the expression of fibrogenic genes. Suppressing Elmo1 action in human patients could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes

Young children’s impressionable use of teleology: the influence of question wording and questioned topic on teleological explanations for natural phenomena

There is a significant body of research on children's preconceptions concerning scientific concepts and the impact this has upon their science education. One active issue concerns the extent to which young children's explanations for the existence of natural kinds rely on a teleological rationale: for example, rain is for watering the grass, or tigers’ stripes are for camouflage. It has been argued that this teleological tendency hampers children's ability to learn about causality in the natural world. This paper investigates two factors (question wording and topic) which it is argued have led to a misestimation of children's teleological tendencies within the area natural phenomena: i.e., those that are time-constrained, natural events or process such as snow, clouds or night. Sixty-six (5- to 8-years-old) children took part in a repeated-measures experiment, answering both open- and leading-questions across 10 topics of natural phenomena. The findings indicate that children's teleological reasoning may have been overestimated as open question forms significantly reduced their tendency to answer teleologically. Moreover, the concept of teleology is more nuanced than often suggested. Consequently, young children may be more able to learn about causal explanations for the existence of natural phenomena than the literature implies

Understanding factors associated with the translation of cardiovascular research: A multinational case study approach

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.This article has been made available through the Brunel Open Access Publishing Fund.Background: Funders of health research increasingly seek to understand how best to allocate resources in order to achieve maximum value from their funding. We built an international consortium and developed a multinational case study approach to assess benefits arising from health research. We used that to facilitate analysis of factors in the production of research that might be associated with translating research findings into wider impacts, and the complexities involved. Methods: We built on the Payback Framework and expanded its application through conducting co-ordinated case studies on the payback from cardiovascular and stroke research in Australia, Canada and the United Kingdom. We selected a stratified random sample of projects from leading medical research funders. We devised a series of innovative steps to: minimize the effect of researcher bias; rate the level of impacts identified in the case studies; and interrogate case study narratives to identify factors that correlated with achieving high or low levels of impact. Results: Twenty-nine detailed case studies produced many and diverse impacts. Over the 15 to 20 years examined, basic biomedical research has a greater impact than clinical research in terms of academic impacts such as knowledge production and research capacity building. Clinical research has greater levels of wider impact on health policies, practice, and generating health gains. There was no correlation between knowledge production and wider impacts. We identified various factors associated with high impact. Interaction between researchers and practitioners and the public is associated with achieving high academic impact and translation into wider impacts, as is basic research conducted with a clinical focus. Strategic thinking by clinical researchers, in terms of thinking through pathways by which research could potentially be translated into practice, is associated with high wider impact. Finally, we identified the complexity of factors behind research translation that can arise in a single case. Conclusions: We can systematically assess research impacts and use the findings to promote translation. Research funders can justify funding research of diverse types, but they should not assume academic impacts are proxies for wider impacts. They should encourage researchers to consider pathways towards impact and engage potential research users in research processes. © 2014 Wooding et al.; licensee BioMed Central Ltd.RAND Europe and HERG, with subsequent funding from the NHFA, the HSFC and the CIHR. This research was also partially supported by the Policy Research Programme in the English Department of Health

An experimental study of executive function and social impairment in Cornelia de Lange syndrome

Background Extreme shyness and social anxiety is reported to be characteristic of adolescents and adults with Cornelia de Lange syndrome (CdLS); however, the nature of these characteristics is not well documented. In this study, we develop and apply an experimental assessment of social anxiety in a group of adolescents and adults with CdLS to determine the nature of the social difficulties and whether they are related to impairments in executive functioning. Methods A familiar and unfamiliar examiner separately engaged in socially demanding tasks comprising three experimental conditions with a group of individuals with CdLS (n = 25; % male = 44; mean age = 22.16; SD = 8.81) and a comparable group of individuals with Down syndrome (DS; n = 20; % male = 35; mean age = 24.35; SD = 5.97). Behaviours indicative of social anxiety were coded. The Behavior Rating Inventory of Executive Function-Preschool version, an informant measure of executive function, was completed by participants’ caregivers. Results Significantly less verbalisation was observed in the CdLS group than the DS group in conditions requiring the initiation of speech. In the CdLS group, impairments in verbalisation were not associated with a greater degree of intellectual disability but were significantly correlated with impairments in both planning and working memory. This association was not evident in the DS group. Conclusions Adolescents and adults with CdLS have a specific difficulty with the initiation of speech when social demands are placed upon them. This impairment in verbalisation may be underpinned by specific cognitive deficits, although further research is needed to investigate this fully