The Evolution of the Flute

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Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin

Background: Despite the well-documented association between loss of E-cadherin and carcinogenesis, as well as the link between restoration of its expression and suppression of proliferation in carcinoma cells, the ability of E-cadherin to modulate growth-promoting cell signalling in normal epithelial cells is less well understood and frequently contradictory. The potential for E-cadherin to co-ordinate different proliferation-associated signalling pathways has yet to be fully explored. Methodology/Principal Findings: Using a normal human urothelial (NHU) cell culture system and following a calcium-switch approach, we demonstrate that the stability of NHU cell-cell contacts differentially regulates the Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-Regulated Kinase (ERK) and Phosphatidylinositol 3-Kinase (PI3-K)/AKT pathways. We show that stable cell contacts down-modulate the EGFR/ERK pathway, whilst inducing PI3-K/AKT activity, which transiently enhances cell growth at low density. Functional inactivation of E-cadherin interferes with the capacity of NHU cells to form stable calcium-mediated contacts, attenuates E-cadherin-mediated PI3-K/AKT induction and enhances NHU cell proliferation by allowing de-repression of the EGFR/ERK pathway and constitutive activation of beta-catenin-TCF signalling. Conclusions/Significance: Our findings provide evidence that E-cadherin can differentially and concurrently regulate specific growth-related signalling pathways in a context-specific fashion, with direct, functional consequences for cell proliferation and population growth. Our observations not only reveal a novel, complex role for E-cadherin in normal epithelial cell homeostasis and tissue regeneration, but also provide the basis for a more complete understanding of the consequences of E-cadherin loss on malignant transformation

Health-related quality of life and Chlamydia trachomatis infection in sexually experienced female inner-city students: a community-based cross-sectional study.

This cross-sectional study was undertaken to compare health-related quality of life (EQ-5D) in women with and without undiagnosed Chlamydia trachomatis infection. We analysed data from 2401 multi-ethnic sexually active female students aged 16-27 years who were recruited to a randomised controlled trial of chlamydia screening - the prevention of pelvic infection trial in 2004-2006. At recruitment, all participants were asked to provide self-taken vaginal swabs for chlamydia testing and to complete a sexual health questionnaire including quality of life (EQ-5D). Most women (69%) had an EQ-5D of one representing 'perfect health' in the five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. We therefore compared the proportion of women with an EQ-5D score < 1 implying 'less than perfect health' in women with and without chlamydia infection, and women with symptomatic chlamydia versus the remainder. The proportion of women with EQ-5D score < 1 was similar in women with and without undiagnosed chlamydia: 34% (47/138) versus 31% (697/2263; RR 1.11, 95% CI 0.87 to 1.41). However, more women with symptomatic chlamydia had EQ-5D score < 1 than the remainder: 45% (25/55) versus 31% (714/2319; RR 1.47, CI 1.10 to 1.98). In this community-based study, EQ-5D scores were similar in women with and without undiagnosed chlamydia. However, a higher proportion of women with symptomatic chlamydia infection had 'less than perfect health'. Undiagnosed chlamydia infection may not have a major short-term effect on health-related quality of life, but EQ-5D may not be the best tool to measure it in this group

The Effects of Malignant Transformation on Susceptibility of Human Urothelial Cells to CD40-Mediated Apoptosis

Background: The tumor necrosis factor (TNF) superfamily of ligands and receptors mediates immune cell survival. Some members possess a death domain, a protein motif that functions to transmit apoptotic signals, whereas others, such as CD40, do not. CD40 is expressed by both normal and malignant epithelial cells. To investigate the functional significance of this expression, we studied the effects of ligation of CD40, Fas, and TNF receptors (TNFRs) on the proliferation and survival of normal and malignant human urothelial cells and urothelial cells with disabled p53 function. Methods: Normal and malignant human urothelial cells were cultured with soluble TNF family agonists (CD40 ligand [CD40L], TNF-α, anti-Fas antibody, or cocultured with mouse fibroblasts stably transfected with plasmids that caused the cells to constitutively express CD40L or CD32; cell proliferation was estimated by an [3H]thymidine incorporation assay, and apoptosis was determined by Annexin V staining and by a DNA fragmentation assay. Messenger RNA levels for CD40 and potential downstream effector molecules were quantified by polymerase chain reaction-based and ribonuclease protection assays, respectively, and nuclear factor (NF) κB nuclear translocation was detected by immunofluorescence. All statistical tests were two-sided. Results: Soluble trimeric CD40L inhibited the growth of normal and malignant urothelial cells but did not induce apoptosis. Cell surface-presented CD40L induced massive apoptosis in CD40-positive transitional cell carcinoma cells but not in normal urothelial cells. Normal cells underwent CD40L-mediated apoptosis only in the presence of other TNFR agonists. An agonistic anti-CD40 antibody presented on the surface of CD32-transfected fibroblasts also induced apoptosis in transitional cell carcinoma cells and in normal urothelial cells. Apoptotic responses of tumor (but not normal) cells to soluble agonists were enhanced by blocking protein synthesis. Karyotypically normal urothelial cells with disabled p53 function underwent apoptosis during coculture with CD40L-expressing fibroblasts alone but were not additionally sensitive to additional TNFR agonists. Conclusions: Susceptibility to CD40 ligation-induced apoptosis may be a novel mechanism for eliminating neoplastically transformed urothelial cells. Loss of CD40 expression may be an important adaptive mechanism for transitional cell carcinoma development and progressio

Empirical demonstration of environmental sensing in catalytic RNA: evolution of interpretive behavior at the origins of life

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: The origins of life on the Earth required chemical entities to interact with their environments in ways that could respond to natural selection. The concept of interpretation, where biotic entities use signs in their environment as proxy for the existence of other items of selective value in their environment, has been proposed on theoretical grounds to be relevant to the origins and early evolution of life. However this concept has not been demonstrated empirically. RESULTS: Here, we present data that certain catalytic RNA sequences have properties that would enable interpretation of divalent cation levels in their environment. By assaying the responsiveness of two variants of the Tetrahymena ribozyme to the Ca(2+) ion as a sign for the more catalytically useful Mg(2+) ion, we show an empirical proof-of-principle that interpretation can be an evolvable trait in RNA, often suggested as a model system for early life. In particular we demonstrate that in vitro, the wild-type version of the Tetrahymena ribozyme is not interpretive, in that it cannot use Ca(2+) as a sign for Mg(2+). Yet a variant of this sequence containing five mutations that alter its ability to utilize the Ca(2+) ion engenders a strong interpretive characteristic in this RNA. CONCLUSIONS: We have shown that RNA molecules in a test tube can meet the minimum criteria for the evolution of interpretive behaviour in regards to their responses to divalent metal ion concentrations in their environment. Interpretation in RNA molecules provides a property entirely dependent on natural physico-chemical interactions, but capable of shaping the evolutionary trajectory of macromolecules, especially in the earliest stages of life's history.This work was supported by a STARS grant from the Templeton Foundation to C.S., A.R., and N.L., the Oregon Space Grant Consortium, and the Center for Life in Extreme Environments at Portland State University

A Case of Urogenital Human Schistosomiasis from a Non-endemic Area

© 2015 Calvo-Cano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

"It's making contacts" : notions of social capital and implications for widening access to medical education

Acknowledgements Our thanks to the Medical Schools Council (MSC) of the UK for funding Study A; REACH Scotland for funding Study B; and Queen Mary University of London, and to the medical school applicants and students who gave their time to be interviewed. Our thanks also to Dr Sean Zhou and Dr Sally Curtis, and Manjul Medhi, for their help with data collection for studies A and B respectively. Our thanks also to Dr Lara Varpio, Uniformed Services University of the USA, for her advice and guidance on collating data sets and her comments on the draft manuscript.Peer reviewedPublisher PD

Leech breach: a first record of the invasive freshwater leech Helobdella europaea (Hirudinea: Glossiphoniidae) in Fiji

Context. The freshwater flat leech Helobdella europaea Kutschera, 1987 is a small annelid indigenous to South America. This invasive species feeds on the haemolymph of host aquatic invertebrates, with occurrences reported from Europe, USA, Taiwan, North Africa, Hawai‘i, Australia and New Zealand. A large number of individuals were discovered in the Ba River catchment, Fiji, during a 2015–2020 freshwater biodiversity survey, raising concerns of potential impacts on endemic Fijian aquatic invertebrate fauna and ecosystem integrity. Aims. To facilitate assessments of its spread and ethology, this study employed morphological and phylogenetic analyses for verification of taxonomic identity. Methods. Phylogenetic trees were constructed using a 658 bp fragment of the mitochondrial DNA cox1 (COI) gene. The first complete mitochondrial genome sequence of H. europaea was also determined using selective multiple displacement amplification and Oxford Nanopore Technology to provide a reference for future comparative analyses and source tracking of spread to other regions. Key results. Morphological and COI analyses identified all Fijian leech specimens collected (n = 16) as H. europaea, reporting the first occurrence of this species on a south-west Pacific Island. The complete mitochondrial genome was sequenced. Conclusions. Confirmation of its presence in Fiji is a national biosecurity concern and will guide the Biosecurity Authority of Fiji and national agencies in further ecosystem assessment and response strategies. Implications. With the complete mitochondrial genome of H. europaea now available, transmission pathway traceability is possible in other regions where this species may be detected