Analysing the role of Pten in the murine small intestine

Colorectal cancer is a significant cause of mortality in the UK, being the third most common cancer type. Activating mutations within the Phosphoinositide 3-Kinase/Akt pathway have previously been reported in a significant proportion of sporadic colorectal cancers. Phosphatase and tensin homolog mutated on chromosome 10 (PTEN) is an antagonist of the PI3K/Akt pathway, and as such is a well characterised tumour suppressor. In this thesis I aimed to characterise the role of Pten within the murine intestine, with respect to homeostasis of otherwise normal epithelium, and also in the context of activated Wnt signalling and activation of the oncogene k-Ras. This has been achieved using a Cre-LoxP-based approach to conditionally delete Pten specifically from the adult murine intestinal epithelium. Deletion of Pten alone is reported here to have little immediate effect on normal homeostasis of the intestinal epithelium or the intestinal stem cell. At extended timepoints after Pten loss, delayed formation of hamartomas and adenomas within the intestine is reported. In the context of activated Wnt signalling, additional loss of Pten is found to accelerate tumourigenesis, resulting in adenocarcinoma formation. These lesions are characterised by strong activation and membrane localisation of Akt. Co-ordinate deletion of Pten and activation of k-Ras is reported here to show strong synergy in promoting the formation of both papillomatous lesions of biliary epithelia and widespread hyperplasia of the forestomach squamous epithelium. Lesions within the biliary epithelium are characterised by strong activation of Akt, with gall bladder lesions again showing membrane localisation of Akt. In the intestine, preliminary data reported here also indicates synergy between Pten loss and k-Ras activation in promoting hyperproliferation of the epithelium. Together, these data therefore indicate that, in normal intestinal epithelium, PTEN is a weak tumour suppressor, but is critical for suppressing neoplasia in the context of other mutations.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models

Over the past 20 years, huge advances have been made in modelling human diseases such as cancer using genetically modified mice. Accurate in vivo models are essential to examine the complex interaction between cancer cells, surrounding stromal cells, tumour-associated inflammatory cells, fibroblast and blood vessels, and to recapitulate all the steps involved in metastasis. Elucidating these interactions in vitro has inherent limitations, and thus animal models are a powerful tool to enable researchers to gain insight into the complex interactions between signalling pathways and different cells types. This review will focus on how advances in in vivo models have shed light on many aspects of cancer biology including the identification of oncogenes, tumour suppressors and stem cells, epigenetics, cell death and context dependent cell signalling

A creative health placement: challenging student nurses to learn creatively

This document is the Accepted Manuscript version of a published work that appeared in final form in [Nursing Times]. To access the final edited and published work see https://www.nursingtimes.net/roles/nurse-educators/creative-health-challenging-student-nurses-to-learn-from-the-arts-11-03-2024/There is a drive to promote population health as a preventative measure. The use of creative health has been advocated to relieve pressures on healthcare services, but this can only be achieved by greater awareness of and immersion in such practices. The creative health placement at the University of Chester responded to this need, offering 60 nursing students the experience of an arts-based practice learning placement and the chance to explore their personal wellbeing. Such learning presented a challenge for students, requiring them to reflect on their expectations of nursing placements and respond creatively to the healthcare issues facing our profession

Analysing the role of Pten in the murine small intestine

Colorectal cancer is a significant cause of mortality in the UK, being the third most common cancer type. Activating mutations within the Phosphoinositide 3-Kinase/Akt pathway have previously been reported in a significant proportion of sporadic colorectal cancers. Phosphatase and tensin homolog mutated on chromosome 10 (PTEN) is an antagonist of the PI3K/Akt pathway, and as such is a well characterised tumour suppressor. In this thesis I aimed to characterise the role of Pten within the murine intestine, with respect to homeostasis of otherwise normal epithelium, and also in the context of activated Wnt signalling and activation of the oncogene k-Ras. This has been achieved using a Cre-LoxP-based approach to conditionally delete Pten specifically from the adult murine intestinal epithelium. Deletion of Pten alone is reported here to have little immediate effect on normal homeostasis of the intestinal epithelium or the intestinal stem cell. At extended timepoints after Pten loss, delayed formation of hamartomas and adenomas within the intestine is reported. In the context of activated Wnt signalling, additional loss of Pten is found to accelerate tumourigenesis, resulting in adenocarcinoma formation. These lesions are characterised by strong activation and membrane localisation of Akt. Co-ordinate deletion of Pten and activation of k-Ras is reported here to show strong synergy in promoting the formation of both papillomatous lesions of biliary epithelia and widespread hyperplasia of the forestomach squamous epithelium. Lesions within the biliary epithelium are characterised by strong activation of Akt, with gall bladder lesions again showing membrane localisation of Akt. In the intestine, preliminary data reported here also indicates synergy between Pten loss and k-Ras activation in promoting hyperproliferation of the epithelium. Together, these data therefore indicate that, in normal intestinal epithelium, PTEN is a weak tumour suppressor, but is critical for suppressing neoplasia in the context of other mutations

Panopticism and Complicity: The State of Surveillance and Everyday Oppression in Libraries, Archives, and Museums

Historically, libraries, archives, and museums—or LAM institutions—have been complicit in enacting state power by surveilling and policing communities. This article broadens previous scholars’ critiques about individual institutions to LAM institutions writ large, drawing connections between these sites and ongoing racist, classist, and oppressive designs. We do so by dialing in on the ethical premise that justifies panoptic systems, utilitarianism, and how the glorification of pragmatism reifies systems of control and oppression. First, we revisit LIS applications of Benthamian and Foucauldian ideas of panoptic power to examine the role of LAM institutions as sites of social enmity. We then describe examples of surveillance and state power as they manifest in contemporary data infrastructure and information practices, showing how LAM institutional fixations with utilitarianism reify the U.S. carceral state through norms such as the aggregation and weaponization of user data and the overreliance on metrics. We argue that such practices are akin to widespread systems of surveillance and criminalization. Finally, we reflect on how LAM workers can combat structures that rely on oppressive assumptions and claims to information authority. Pre-print first published online February 10, 202

Openness in Teachers’ Digital Competence Frameworks: Looking for the Open Educator

There has been a wide variety of definitions of digital competence, from early narrow and technology-focused explanations to more recent attempts , such as the one by Ferrari (2013), who describes it as a complex concept encompassing a wide set of skills, attitudes and knowledge when performing tasks with Information and Communication Technologies (ICT). Furthermore, there have been various different attempts to describe teachers’ digital competence, as the literature review by McGarr and McDonagh (2019) demonstrates. These authors evidence that models either depict teachers’ digital competence in diverse taxonomies of areas and dimensions, or as a hierarchical and progressive evolution from low to high levels of awareness and ability. They observe that openness does not have a presence in most of the taxonomic models and thus they propose openness as a dimension of their four-part model, under the label of attitudes. In this current work, we analyse international and national teachers’ digital competence frameworks and review whether openness has been included in them, and, if so, how it is described. In the case of frameworks that offer a model of increasing performance, we observe the levels at which open-related concepts appear. An initial review of the frameworks by the European Commission, UNESCO, ISTE (US) and INTEF (Spain) indicates that ‘openness’ typically does not constitute a dimension in itself and tends to appear at intermediate and high levels of teachers’ digital competence, except from the UNESCO framework, where access to OER (Open Educational Resources) is present already at the lowest level. In this paper we reflect on the need for international and national frameworks of teacher professional development to boost openness: in particular, for open educational practices to be included at lower levels of teachers’ pre-service and in-service professional education. We argue that becoming an open educator requires both the development of the dispositions associated with reflective practice and the confidence to challenge neo-liberal educational assumptions in order to embrace participatory, equitable and open educational practices from the early stages of the development of teachers’ digital competence. References Ferrari, A. (2013) ‘DIGCOMP: A Framework for Developing and Understanding Digital Competence in Europe‘, Luxembourg: Publications Office of the European Union. Available at: https://publications.jrc.ec.europa.eu/repository/bitstream/JRC83167/lb-na-26035-enn.pdf McGarr, O. & McDonagh, A. (2019) ‘Digital Competence in Teacher Education‘, Output 1 of the Erasmus+ funded Developing Student Teachers’ Digital Competence (DICTE) project. Available at: https://dicte.oslomet.no/ Tur, Gemma; Marín, Victoria I.; Havemann, Leo; Keefer, Jeffrey; Marsh, J. Dawn; Nascimbeni, Fabio; Crump, Helen; Baker, Nick and García Vallejo, Mari Cruz (2018). Open Education as a threshold concept in Teacher Education: a theoretical framework for further research. In: OER18: Open to All, 18-19 Apr 2018, Bristol. http://oro.open.ac.uk/58239/ Tur, G., Havemann, L., Marsh, D., Keefer, J. M., & Nascimbeni, F. (2020). Becoming an open educator: towards an open threshold framework. Research in Learning Technology, 28. https://doi.org/10.25304/rlt.v28.233

DNA evidence for global dispersal and probable endemicity of protozoa

<p>Abstract</p> <p>Background</p> <p>It is much debated whether microbes are easily dispersed globally or whether they, like many macro-organisms, have historical biogeographies. The ubiquitous dispersal hypothesis states that microbes are so numerous and so easily dispersed worldwide that all should be globally distributed and found wherever growing conditions suit them. This has been broadly upheld for protists (microbial eukaryotes) by most morphological and some molecular analyses. However, morphology and most previously used evolutionary markers evolve too slowly to test this important hypothesis adequately.</p> <p>Results</p> <p>Here we use a fast-evolving marker (ITS1 rDNA) to map global diversity and distribution of three different clades of cercomonad Protozoa (<it>Eocercomonas </it>and <it>Paracercomonas</it>: phylum Cercozoa) by sequencing multiple environmental gene libraries constructed from 47–80 globally-dispersed samples per group. Even with this enhanced resolution, identical ITS sequences (ITS-types) were retrieved from widely separated sites and on all continents for several genotypes, implying relatively rapid global dispersal. Some identical ITS-types were even recovered from both marine and non-marine samples, habitats that generally harbour significantly different protist communities. Conversely, other ITS-types had either patchy or restricted distributions.</p> <p>Conclusion</p> <p>Our results strongly suggest that geographic dispersal in macro-organisms and microbes is not fundamentally different: some taxa show restricted and/or patchy distributions while others are clearly cosmopolitan. These results are concordant with the 'moderate endemicity model' of microbial biogeography. Rare or continentally endemic microbes may be ecologically significant and potentially of conservational concern. We also demonstrate that strains with identical 18S but different ITS1 rDNA sequences can differ significantly in terms of morphological and important physiological characteristics, providing strong additional support for global protist biodiversity being significantly higher than previously thought.</p

Motivation in physical education across the primary-secondary school transition

The purpose of this study was to examine the temporal patterns of approach-avoidance achievement goals, implicit theories of ability and perceived competence in physical education across the transition from primary to secondary school. We also evaluated the predictive utility of implicit theories and perceived competence with regard to achievement goal adoption, and determined the moderating influence of gender on temporal patterns and antecedent–goal relationships. One hundred and forty pupils (mean age at start of study = 11.37 years, SD =.28) completed measures of entity and incremental beliefs, perceived competence and goals on four occasions during a 12-month period. Mastery-approach, performance-approach and perform-ance-avoidance goals, as well as entity and incremental beliefs, exhibited a linear decline over time. Mastery-avoidance goals showed no significant change. Girls exhibited a linear decline in perceived competence, whereas for boys the trajectory was curvilinear. Competence perceptions predicted initial scores, but not rate of change, on mastery-approach and both types of performance goals. Incrementa

Structural, functional, and metabolic alterations in human cerebrovascular endothelial cells during toxoplasma gondii infection and amelioration by verapamil in vitro

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Toxoplasma gondii (T. gondii), the causative agent of toxoplasmosis, is a frequent cause of brain infection. Despite its known ability to invade the brain, there is still a dire need to better understand the mechanisms by which this parasite interacts with and crosses the blood–brain barrier (BBB). The present study revealed structural and functional changes associated with infection and replication of T. gondii within human brain microvascular endothelial cells (BMECs) in vitro. T. gondii proliferated within the BMECs and disrupted the integrity of the cerebrovascular barrier through diminishing the cellular viability, disruption of the intercellular junctions and increasing permeability of the BMEC monolayer, as well as altering lipid homeostasis. Proton nuclear magnetic resonance (1H NMR)-based metabolomics combined with multivariate data analysis revealed profiles that can be attributed to infection and variations in the amounts of certain metabolites (e.g., amino acids, fatty acids) in the extracts of infected compared to control cells. Notably, treatment with the Ca2+ channel blocker verapamil rescued BMEC barrier integrity and restricted intracellular replication of the tachyzoites regardless of the time of treatment application (i.e., prior to infection, early-and late-infection). This study provides new insights into the structural and functional changes that accompany T. gondii infection of the BMECs, and sheds light upon the ability of verapamil to inhibit the parasite proliferation and to ameliorate the adverse effects caused by T. gondii infection