Akt-dependent Pp2a activity is required for epidermal barrier formation during late embryonic development

Acquisition of epidermal barrier function occurs late in mouse gestation. Several days before birth a wave of barrier acquisition sweeps across murine fetal skin, converging on dorsal and ventral midlines. We investigated the molecular pathways active during epidermal barrier formation. Akt signaling increased as the barrier wave crossed epidermis and Jun was transiently dephosphorylated. Inhibitor experiments on embryonic explants showed that the dephosphorylation of Jun was dependent on both Akt and protein phosphatase 2A (Pp2a). Inhibition of Pp2a and Akt signaling also caused defects in epidermal barrier formation. These data are compatible with a model for developmental barrier acquisition mediated by Pp2a regulation of Jun dephosphorylation, downstream of Akt signaling. Support for this model was provided by siRNA-mediated knockdown of Ppp2r2a (Pr55α or B55α), a regulatory subunit of Pp2a expressed in an Akt-dependent manner in epidermis during barrier formation. Ppp2r2a reduction caused significant increase in Jun phosphorylation and interfered with the acquisition of barrier function, with barrier acquisition being restored by inhibition of Jun phosphorylation. Our data provide strong evidence that Ppp2r2a is a regulatory subunit of Pp2a that targets this phosphatase to Jun, and that Pp2a action is necessary for barrier formation. We therefore describe a novel Akt-dependent Pp2a activity that acts at least partly through Jun to affect initial barrier formation during late embryonic epidermal development

The Use of Condition Score to Determine Glycerol Concentration in the Treatment of Waterlogged Leather: an Empirical Solution

In recent years the treatment of waterlogged archaeological leather, unlike wood, has received little attention in the conservation literature. The selection of treatments for wet leather is generally thought to be less critical than that for wet wood. However variations in the treatment of leather do affect the success of the treatment process. By examining these effects we may identify which are the critical elements of the treatment. At the Museum of London (MoL) the treatment of waterlogged leather with glycerol impregnation and freeze drying, follows a method developed in the early 1980’s for the efficient treatment of large quantities of material (1). This study aims to build upon that work, by establishing the most effective concentration of glycerol to use with each individual artefact. To do this it has been necessary to implement a procedure to evaluate the relative success of treatments. This has been carried out using an experimental design similar to those commonly used in industrial and medical research (2). This study forms part of a larger research project reviewing our approach to the conservation of archaeological leather. It is hoped that other aspects of the leather treatment process will be investigated by the authors over the next few years

The upside of cultural differences: towards a more balanced treatment of culture in cross-cultural management research

Purpose –This introductory paper to the Special Issue encourages scholars to look at commonly considered phenomena in international business and cross-cultural research in new ways and to theorize and explore how cultural diversity, distance, and foreignness create value for global organizations. These considerations should result in a more balanced treatment of culture in cross-cultural management research. Design/methodology/approach – The idea that there are negative consequences associated with cultural differences is pervasive in hypotheses formulation and empirical testing in international business and cross-cultural management literature, as reflected in widely used constructs such as “cultural distance”, “cultural misfit”, “foreignness”, and related concepts. Consistent with a Positive Organizational Scholarship (POS) perspective on culture and cultural differences, the authors emphasize the positive role of distance and diversity across national, cultural, institutional, and organizational dimensions. In addition, they provide an overview of the contributions to the Special Issue. Findings – Examining the positive side of culture is not only beneficial theoretically in terms of filling the existing gaps in the literature, but is also crucial for the practice of international and global business. Accordingly, the contributions to the Special Issue highlight how explicitly considering positive phenomena can help better understand when and how cultural diversity, distance, and foreignness can enhance organizational effectiveness and performance at multiple levels. They include five research papers, a Distinguished Scholar Essay by Kim Cameron, the founder of the POS movement, and an interview piece with Richard Nisbett, a pioneer researcher in culture and cognition

Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo

The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-β- lactamase (NDM-1). Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene.Methods: We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo.Results:In vitro, the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. In a murine model of lethal E. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem.Conclusions: These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem- resistant infections in multiple genera of Gram-negative pathogens

Big Data and Changes in Audit Technology: Contemplating a Research Agenda

This study explores the most recent episode in the evolution of audit technology, namely the incorporation of Big Data and Data Analytics (BDA) into audit firm approaches. Drawing on 22 interviews with individuals with significant experience in developing, implementing or assessing the impact of BDA in auditing, together with publicly available documents on BDA published within the audit field, the paper provides a holistic overview of BDA-related changes in audit practice. In particular, the paper focuses on three key aspects, namely the impact of BDA on the nature of the relationship between auditors and their clients; the consequences of the technology for the conduct of audit engagements and the common challenges associated with embedding BDA in the audit context. The study’s empirical findings are then used to establish an agenda of areas suitable for further research on the topic. The study is one of the first empirical accounts providing a perspective on the rise of BDA in auditing

Isolation of Oropouche Virus from Febrile Patient, Ecuador.

We report identification of an Oropouche virus strain in a febrile patient from Ecuador by using metagenomic sequencing and real-time reverse transcription PCR. Virus was isolated from patient serum by using Vero cells. Phylogenetic analysis of the whole-genome sequence showed the virus to be similar to a strain from Peru

Systematic techniques for assisting recruitment to trials (START): study protocol for embedded, randomized controlled trials

BACKGROUND: Randomized controlled trials play a central role in evidence-based practice, but recruitment of participants, and retention of them once in the trial, is challenging. Moreover, there is a dearth of evidence that research teams can use to inform the development of their recruitment and retention strategies. As with other healthcare initiatives, the fairest test of the effectiveness of a recruitment strategy is a trial comparing alternatives, which for recruitment would mean embedding a recruitment trial within an ongoing host trial. Systematic reviews indicate that such studies are rare. Embedded trials are largely delivered in an ad hoc way, with interventions almost always developed in isolation and tested in the context of a single host trial, limiting their ability to contribute to a body of evidence with regard to a single recruitment intervention and to researchers working in different contexts. METHODS/DESIGN: The Systematic Techniques for Assisting Recruitment to Trials (START) program is funded by the United Kingdom Medical Research Council (MRC) Methodology Research Programme to support the routine adoption of embedded trials to test standardized recruitment interventions across ongoing host trials. To achieve this aim, the program involves three interrelated work packages: (1) methodology - to develop guidelines for the design, analysis and reporting of embedded recruitment studies; (2) interventions - to develop effective and useful recruitment interventions; and (3) implementation - to recruit host trials and test interventions through embedded studies. DISCUSSION: Successful completion of the START program will provide a model for a platform for the wider trials community to use to evaluate recruitment interventions or, potentially, other types of intervention linked to trial conduct. It will also increase the evidence base for two types of recruitment intervention. TRIAL REGISTRATION: The START protocol covers the methodology for embedded trials. Each embedded trial is registered separately or as a substudy of the host trial

Improving recruitment to a study of telehealth management for long-term conditions in primary care: two embedded, randomised controlled trials of optimised patient information materials

Background: Patient understanding of study information is fundamental to gaining informed consent to take part in a randomised controlled trial. In order to meet the requirements of research ethics committees, patient information materials can be long and need to communicate complex messages. There is concern that standard approaches to providing patient information may deter potential participants from taking part in trials. The Systematic Techniques for Assisting Recruitment to Trials (MRC-START) research programme aims to test interventions to improve trial recruitment. The aim of this study was to investigate the effect on recruitment of optimised patient information materials (with improved readability and ease of comprehension) compared with standard materials. The study was embedded within two primary care trials involving patients with long-term conditions. Methods: The Healthlines Study involves two linked trials evaluating a telehealth intervention in patients with depression (Healthlines Depression) or raised cardiovascular disease risk (Healthlines CVD). We conducted two trials of a recruitment intervention, embedded within the Healthlines host trials. Patients identified as potentially eligible in each of the Healthlines trials were randomised to receive either the original patient information materials or optimised versions of these materials. Primary outcomes were the proportion of participants randomised (Healthlines Depression) and the proportion expressing interest in taking part (Healthlines CVD). Results: In Healthlines Depression (n = 1364), 6.3 % of patients receiving the optimised patient information materials were randomised into the study compared to 4.0 % in those receiving standard materials (OR = 1.63, 95 % CI = 1.00 to 2.67). In Healthlines CVD (n = 671) 24.0 % of those receiving optimised patient information materials responded positively to the invitation to participate, compared to 21.9 % in those receiving standard materials (OR = 1.12, 95 % CI = 0.78 to 1.61). Conclusions: Evidence from these two embedded trials suggests limited benefits of optimised patient information materials on recruitment rates, which may only be apparent in some patient populations, with no effects on other outcomes. Further embedded trials are needed to provide a more precise estimate of effect, and to explore further how effects vary by trial context, intervention, and patient population