Exploring the utility of metabolic profiling in stratifying patient groups in Inflammatory Bowel Disease

The pathogenesis of IBD, involving dynamic interactions between the microbiome, innate and adaptive immune systems, genetics and environmental factors, is a major focus of academic interest, in order to reveal more about the heterogeneous clinical course of the disease and in pursuit of improved therapeutic targets. Metabonomics has been previously used with a variety of biofluids to successfully distinguish IBD from controls, but the complex metabolic data also have potential to unlock insights into pathogenesis and better understand how to better stratify patients for personalised clinical care. In the largest urinary metabonomics IBD study to date, changes in the white European cohort confirmed previous published findings, highlighting discriminatory metabolites of gut microbial and inflammatory pathway sources. Significant metabolic differences were seen when comparing IBD patients and controls from South Asia to white North Europeans, demonstrating the influence of ethnicity on the metabolic profile and showing metabolite changes related to host-nutrition-microbiome interactions. Results from longitudinal measurements of the IBD metabolome in the same individuals over several years indicate relative stability despite the relapsing-remitting course of the disease and different treatments. This early finding suggests clinical outcomes may only have subtly discernible changes on metabolic profiles, potentially limiting its application as a disease-monitoring tool. 16S rRNA profiling, employed to characterise the microbiome, showed reduced microbial diversity in IBD and 4 key bacterial genera - Veillonella, Acidaminococcus, Lactobacillus and Streptococcus - associated with disease. Significant urinary and faecal metabolites in the same patients were correlated with these bacteria to demonstrate the feasibility of multi-omic integration in IBD. Furthermore, the breath VOC profiles of IBD patients obtained by SIFT-MS were distinct from those of heathy controls, with the significant compounds originating from microbial sources, and inflammatory pathways, demonstrating the potential of this technology and another facet to metabolic profiling in IBD.Open Acces

Promoting school connectedness : planning and evaluating practice in educational settings

D. App. Ed. Psy. ThesisThis thesis explores school connectedness and ways in which this might be promoted. It contains four chapters: a systematic literature review, a critical consideration of research methodology and ethics, an empirical research project and a reflexive chapter, which considers the personal and professional implications of the thesis. Chapter 1: The systematic literature review explores the features of wider-school initiatives which have been suggested to promote school connectedness. Thematic synthesis was used to analyse five key papers, following a detailed process of searching and selecting. The features were grouped into three analytical themes: Practical Features, Features of the Relational Climate and Process Features. A theoretical framework about how school connectedness could be promoted was developed from the findings. This could be argued to begin to address comments within the literature about a research-practice gap in this area. Chapter 2: This chapter includes the rationale for the empirical research question following the systematic literature review. It also details how and why particular decisions were made about the research focus and design. Ethical considerations and the importance of reflexivity within this context are also explored. Chapter 3: The empirical report explores the relationship between school connectedness and staff and students eating lunch together. The project was undertaken in an Alternative Provision setting, where this practice was already in place. A qualitative approach to the research project was adopted. A focus group with staff members and two dyadic interviews with students were transcribed and analysed using a hybrid approach of deductive and inductive Thematic Analysis. The data was analysed using the findings of the Systematic Literature Review, which were constructed to form a theoretical framework about how school connectedness might be promoted. Findings are discussed with regards to the relationship between school connectedness and staff and students eating together. The use of the theoretical framework to evaluate practice and explore how school connectedness might be promoted is also discussed. Chapter 4: This chapter provides a reflective account about the research process and outcomes. It allows a space for consideration about what has changed for me as a result of engaging in this project and how this might shape my future practice and research. It also summarises the implications for further research and wider practice

Design Principles for Data Analysis

The data science revolution has led to an increased interest in the practice of data analysis. While much has been written about statistical thinking, a complementary form of thinking that appears in the practice of data analysis is design thinking -- the problem-solving process to understand the people for whom a product is being designed. For a given problem, there can be significant or subtle differences in how a data analyst (or producer of a data analysis) constructs, creates, or designs a data analysis, including differences in the choice of methods, tooling, and workflow. These choices can affect the data analysis products themselves and the experience of the consumer of the data analysis. Therefore, the role of a producer can be thought of as designing the data analysis with a set of design principles. Here, we introduce design principles for data analysis and describe how they can be mapped to data analyses in a quantitative, objective and informative manner. We also provide empirical evidence of variation of principles within and between both producers and consumers of data analyses. Our work leads to two insights: it suggests a formal mechanism to describe data analyses based on the design principles for data analysis, and it provides a framework to teach students how to build data analyses using formal design principles.Comment: arXiv admin note: text overlap with arXiv:1903.0763

Linguistic Structures and Economic Outcomes

Linguistic structures have recently started to attract attention from economists as determinants of economic phenomena. This paper provides the first comprehensive review of this nascent literature and its achievements so far. First, we explore the complex connections between language, culture, thought and behaviour. Then, we summarize the empirical evidence on the relationship between linguistic structures and economic and social outcomes. We follow up with a discussion of data, empirical design and identification. The paper concludes by discussing implications for future research and policy

Talking in the present, caring for the future: Language and environment

This paper identifies a new source that explains environmental behaviour: the presence of future tense marking in language. We predict that languages that grammatically mark the future affect speakers' intertemporal preferences and thereby reduce their willingness to address environmental problems. We first show that speakers of languages with future tense marking are less likely to adopt environmentally responsible behaviours and to support policies to prevent environmental damage. We then document that this effect holds across countries: future tense marking is an important determinant of climate change policies and global environmental cooperation. The results suggest that there may be deep and surprising obstacles for attempts to address climate change

Activator protein transcription factors coordinate human IL-33 expression from noncanonical promoters in chronic airway disease

IL-33 is a cytokine central to type 2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how expression is regulated is undefined. Here we show that increased IL33 expression occurs from multiple noncanonical promoters in human chronic obstructive pulmonary disease (COPD), and it facilitates production of alternatively spliced isoforms in airway cells. We found that phorbol 12-myristate 13-acetate (PMA) can activate IL33 promoters through protein kinase C in primary airway cells and lines. Transcription factor (TF) binding arrays combined with RNA interference identified activator protein (AP) TFs as regulators of baseline and induced IL33 promoter activity. ATAC-Seq and ChIP-PCR identified chromatin accessibility and differential TF binding as additional control points for transcription from noncanonical promoters. In support of a role for these TFs in COPD pathogenesis, we found that AP-2 (TFAP2A, TFAP2C) and AP-1 (FOS and JUN) family members are upregulated in human COPD specimens. This study implicates integrative and pioneer TFs in regulating IL33 promoters and alternative splicing in human airway basal cells. Our work reveals a potentially novel approach for targeting IL-33 in development of therapeutics for COPD

Fibrin exposure triggers αIIbβ3-independent platelet aggregate formation, ADAM10 activity and glycoprotein VI shedding in a charge-dependent manner

Background Collagen and fibrin engagement and activation of glycoprotein (GP) VI induces proteolytic cleavage of the GPVI ectodomain generating shed soluble GPVI (sGPVI). Collagen‐mediated GPVI shedding requires intracellular signalling to release the sGPVI, mediated by A Disintegrin And Metalloproteinase 10 (ADAM10); however, the precise mechanism by which fibrin induces GPVI shedding remains elusive. Plasma sGPVI levels are elevated in patients with coagulopathies, sepsis, or inflammation and can predict onset of sepsis and sepsis‐related mortality; therefore, it is clinically important to understand the mechanisms of GPVI shedding under conditions of minimal collagen exposure. Objectives Our aim was to characterize mechanisms by which fibrin‐GPVI interactions trigger GPVI shedding. Methods Platelet aggregometry, sGPVI ELISA, and an ADAM10 fluorescence resonance energy transfer assay were used to measure fibrin‐mediated platelet responses. Results Fibrin induced αIIbβ3‐independent washed platelet aggregate formation, GPVI shedding, and increased ADAM10 activity, all of which were insensitive to pre‐treatment with inhibitors of Src family kinases but were divalent cation‐ and metalloproteinase‐dependent. In contrast, treatment of washed platelets with other GPVI ligands, collagen, and collagen‐related peptide caused αIIbβ3‐dependent platelet aggregation and GPVI release but did not increase constitutive ADAM10 activity. Conclusions Fibrin engages GPVI in a manner that differs from other GPVI ligands. Inclusion of polyanionic molecules disrupted fibrin‐induced platelet aggregate formation and sGPVI release, suggesting that electrostatic charge may play a role in fibrin/GPVI engagement. It may be feasible to exploit this property and specifically disrupt GPVI/fibrin interactions whilst sparing GPVI/collagen engagement.Fibrin engages GPVI in a manner that differs from other GPVI ligands. Inclusion of polyanionic molecules disrupted fibrin‐induced platelet aggregate formation and sGPVI release, suggesting that electrostatic charge may play a role in fibrin/GPVI engagement. It may be feasible to exploit this property and specifically disrupt GPVI/fibrin interactions whilst sparing GPVI/collagen engagement.National Health and Medical Research Council of Australia; Australian Research Council; THANZ Science and Education Research Gran

DIY John Curtin: Uncertain futures for heritage and citizenship in the era of digital friends and foes

This article introduces some of the problems confronting the popularization of national, civic and cultural heritage in the era of complex digital systems and social networks. Taking contemporary knowledge of John Curtin (Australia’s wartime PM) as its point of departure, the discussion explores some of the broader transformations of the conditions of citizenship, communication, heritage and knowledge production, and considers their implications for civic education and the uses of archives. In a novel thought experiment, the article explores some ways in which the figure of ‘John Curtin’ may be repurposed and reinvented for a new kind of DIY civic education based on user-led innovation