Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Imagining neighbourhood-based community : an autoethnography

This research is an autoethnographic investigation of consumption experiences, public and quasi-public spaces, and their relationship to community within an inner city neighbourhood. The research specifically focuses on the gentrifying inner city, where class-based processes of change can have implications for people’s abilities to remain within, or feel connected to place. However, the thesis draws on broader theories of the throwntogetherness of the contemporary city (e.g., Amin and Thrift, 2002; Massey 2005) to argue that the city is a space where place-based meanings cannot be seen to be fixed, and are instead better understood as events of place – based on ever shifting interrelations between the trajectories of people and things. This perspective argues the experience of belonging to community is not just born of a social encounter, but also draws on the physical and symbolic elements of the context in which it is situated. The thesis particularly explores the ways people construct identifications within this shifting urban environment. As such, consumption practices and spaces offer one important lens through which to explore the interplay of the physical, social and symbolic. Consumer research tells us that consumption practices can facilitate experiences in which identity-defining meaning can be generated and shared. Consumption spaces can also support different kinds of collective identification – as anchoring realms for specific cultural groups or exposure realms that enable individuals to share in the identification practices of others with limited risk (Aubert-Gamet & Cova, 1999). Furthermore, the consumption-based lifestyles that gentrifying inner city neighbourhoods both support and encourage can also mean that consumption practices may be a key reason that people are moving through public space. That is, consumption practices and spaces may provide a purpose for which – and spatial frame against which – our everyday interactions and connections with people and objects are undertaken within such neighbourhoods. The purpose of this investigation then was to delve into the subjectivities at the heart of identifying with places, using the lens of our consumption-based experiences within them. The enquiry describes individual and collective identifications and emotional connections, and explores how these arise within and through our experiences within public and quasi-public spaces. It then theorises these ‘imaginings’ as representative of an experience of community. To do so, it draws on theories of imagination and its relation to community. Theories of imagined community remind us that both the values and identities of community are held together by projections that create relational links out of objects and shared practices (e.g., Benedict Anderson, 2006; Urry, 2000). Drawing on broader theories of the processes of the imagination, this thesis suggests that an interplay between reflexivity and fantasy – which are products of the critical and the fascinated consciousness – plays a role in this imagining of community (e.g., Brann, 1991; Ricoeur, 1994). This thesis therefore seeks to explore how these processes of imagining are implicated within the construction of an experience of belonging to neighbourhood-based community through consumption practices and the public and quasi-public spaces that frame them. The key question of this thesis is how do an individual’s consumption practices work to construct an imagined presence of neighbourhood-based community? Given the focus on public and quasi-public spaces and our experiences within them, the research also asked how do experiences in the public and quasi-public spaces that frame these practices contribute to the construction of this imagined presence? This investigation of imagining community through consumption practices is based on my own experiences of moving to, and attempting to construct community connections within, an inner city neighbourhood in Melbourne, Australia. To do so, I adopted autoethnographic methodology. This is because autoethnography provides the methodological tools through which one can explore and make visible the subjectivities inherent within the lived experiences of interest to the thesis (Ellis, 2004). I describe imagining community through consumption as an extension of a placebased self. This self is manifest through personal identification in consumption spaces that operate as anchoring realms for specific cultural groups, as well as through a broader imagining of spaces, people, and practices as connected through experiences within realms of exposure. However, this is a process that oscillates through cycles of identification; these anchor one within place personally, but also disrupt those attachments. This instability can force one to question the orientation and motives of these imaginings, and reframe them according to different spaces and reference groups in ways that can also work to construct a more anonymous and, conversely, more achievable collective identification. All the while, the ‘I’ at the heart of this identification is in an ongoing process of negotiation, and similarly, the imagined community is never complete. That is, imagining community is a negotiation, with people and spaces – but mostly with the different identifications of the self. This thesis has been undertaken by publication, and thus the process of imagining community is explored and described through four papers. Of these, the first two focus on specific types of consumption spaces – a bar and a shopping centre – and consider the ways that anchoring and exposure within these spaces support the process of imagining community. The third paper examines the ways that the public and quasi-public spaces that make up the broader neighbourhood context are themselves throwntogether as a realm of exposure, and considers the ways this shapes my imaginings of this neighbourhood as community. The final paper develops a theory of imagined community, as a process of comparison and contrast with imagined others, to provide a summative conceptualisation of the first three papers. The first paper, chapter five, explores this process of comparison and contrast in relation to authenticity, which in itself is a subjective assessment of identity. This chapter was written as a direct response to the recent work of Zukin (2010), and draws on theories of authenticity as applied to personal and collective identification practices by consumer researchers Arnould and Price (2000). In this chapter, I describe how my assessments of the authenticity of my anchoring experiences within one specific consumption space, a neighbourhood bar, are evaluated in comparison to my observations of and affective reactions to the social practices of another group of residents in a different consumption space, the local shopping centre. Chapter five also provides an overview of the key sites and experiences that are considered in more detail in the following two chapters. In chapter six, I again draw on my experiences within the bar introduced in chapter five, this time to explore the process of developing a regular identity within a specific consumption space. Addressing the popular theory of the cafe or bar as third place (Oldenburg, 1999), this paper considers the purpose of developing anchored relationships with people within specific consumption spaces, and explores the different ways this may be achieved in an urban context where the mobilities and lifestyle practices of residents complicate the idea of a consumption space as an anchoring or third place. In doing so, this chapter also considers the manner in which this type of regular identification may be seen to be the beginning of the process of imagining community. In chapter seven, I consider the ways the broader public spaces of the neighbourhood work cumulatively to expose different aspects of its identity by following my everyday movements through the neighbourhood’s shopping centre and main street. Drawing on the theories of Urry (2000), Massey (2005), and Amin (2007, 2008), this chapter describes how these spaces operate as exposure realms, enabling the expression of different senses of the neighbourhood’s spaces, times, cultures, and identities through their physical, social, and symbolic elements. Yet they also enable them to be united: through habitual pathways, group practices of appropriation of space, and memory traces that construct connections between objects and experiences. This chapter describes this as a process of exposure to these different elements. Our imagination begins to expand the scope of the frames onto which it projects an imagined presence; it searches for patterns within the physical, social, and symbolic environment and draws connections between people and practices across spaces. As the final paper, chapter eight, deduces, it is in making these connections that one constructs the objects and shared practices of imagined community. This chapter describes this as an imagining of neighbourhood as a place-based extension of the self, and then explores the ways in which I drew on physical, social, and symbolic elements in an attempt to construct a fit between the neighbourhood’s offerings and my desires for place-based identity definition. This was as a cumulative but fragmented process, in which positive and negative experiences of interaction and identification with people and things were searched for their potential to operate as the objects and shared practices of imagined community. This chapter describes these connections as constructed through interplay between reflexivity and fantasy, as the imagination seeks balance between desires for experiences of belonging, and the complexities of constructing them within the throwntogether context of the contemporary city. The conclusion of the thesis describes the process of imagining community as a reflexive fantasy, that is, as a product of both the critical and fascinated consciousness (Ricoeur, 1994). It suggests that the fascinated consciousness imbues experiences with hope and desire, which the reflexive imagining can turn to disappointment and shame as it critically reflects on the reality of those fascinated projections. At the same time, the reflexive imagination also searches the practices of others for affirmation of those projections, effectively seeking to prove the reality of the fantasy of the imagined community.

Open up the building : architectural relevance of building-users and their participations

As buildings have become more advanced and complex, our ability to understand how they are operated and managed has diminished. Modern technologies have given us systems to look after us but it appears to have taken away our say in how we like our environment to be managed. The aim of this paper is to discuss our research concerning spaces that are sensitive to changing needs and allow building-users to have a certain level of freedom to understand and control their environment. We discuss why, what we call the Active Layer, is needed in modern buildings; how building inhabitants are to interact with it; and the development of interface prototypes to test consequences of having the Active Layer in our environment.

Socio-Spatial Approaches To Literacy Studies: Rethinking the Social Constitution and Politics of Space

Literacy studies have begun to examine the spatial dimension of literacy practices in a way that foregrounds space, and that considers space as constitutive to human relations and practices. This chapter provides an introduction to spatial literacy research, providing a guide to key theorists, themes, and studies that have shaped historical and new developments in spatial approaches to literacy practice and pedagogy. It begins by reconceptualising socio-spatial approaches to literacy research and defines terms. Intersections with related social theories are examined, with an emphasis on critical approaches and the politics of space. It clarifies the relationship between socio-spatial and socio-cultural paradigms, revisiting the spatial in seminal socio-cultural research. It covers new ground,including networks, flows, and deterritorialisation of literacy practice. The chapter concludes with challenges and recommendations for future language research and educational practice.

Career-path analysis using optimal matching and self-organizing maps

This paper is devoted to the analysis of career paths and employability. The state-of-the-art on this topic is rather poor in methodologies. Some authors propose distances well adapted to the data, but are limiting their analysis to hierarchical clustering. Other authors apply sophisticated methods, but only after paying the price of transforming the categorical data into continuous, via a factorial analysis. The latter approach has an important drawback since it makes a linear assumption on the data. We propose a new methodology, inspired from biology and adapted to career paths, combining optimal matching and self-organizing maps. A complete study on real-life data will illustrate our proposal.

The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response

Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants. In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge. The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.

Late Quaternary vegetation history of North Stradbroke Island, Queensland, eastern Australia

Currently there is a paucity of records of late Quaternary palaeoenvironmental variability available from the subtropics of Australia. The three continuous palaeoecological records presented here, from North Stradbroke Island, subtropical Queensland, assist in bridging this large spatial gap in the current state of knowledge. The dominance of arboreal taxa in the pollen records throughout the past >40,000 years is in contrast with the majority of records from temperate Australia, and indicates a positive moisture balance for North Stradbroke Island. The charcoal records show considerable inter-site variability indicating the importance of local-scale events on individual records, and highlighting the caution that needs to be applied when interpreting a single site as a regional record. The variability in the burning regimes is interpreted as being influenced by both climatic and human factors. Despite this inter-site variability, broad environmental trends are identifiable, with changes in the three records comparable with the OZ-INTIMATE climate synthesis for the last 35,000 years.

Characterisation of combustion related acoustic emission sources for diesel engine condition monitoring

This thesis represents a major step forward in understanding the link between the development of combustion related faults in diesel engines and the generation of acoustic emissions. The findings presented throughout the thesis provide a foundation so that future diesel engine monitoring systems are able to more effectively detect and monitor developing faults. In undertaking this research knowledge concerning engine function and relevant failure mechanisms was combined with different modelling methods to generate a framework that was used to effectively identify fault related activity within acoustic emissions recorded from different engines.

Investigation of Association between PFO complicated by cryptogenic stroke and a common variant of the cardiac transcription factor GATA4

Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke.

A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each ). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls () and were highly significant in the combined dataset (). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set , replication set , combined ). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

Multiple sclerosis susceptibility-associated SNPs do not influence disease severity measures in a cohort of Australian MS patients

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine

We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

Recognising team activities from noisy data

Recently, vision-based systems have been deployed in professional sports to track the ball and players to enhance analysis of matches. Due to their unobtrusive nature, vision-based approaches are preferred to wearable sensors (e.g. GPS or RFID sensors) as it does not require players or balls to be instrumented prior to matches. Unfortunately, in continuous team sports where players need to be tracked continuously over long-periods of time (e.g. 35 minutes in field-hockey or 45 minutes in soccer), current vision-based tracking approaches are not reliable enough to provide fully automatic solutions. As such, human intervention is required to fix-up missed or false detections. However, in instances where a human can not intervene due to the sheer amount of data being generated - this data can not be used due to the missing/noisy data. In this paper, we investigate two representations based on raw player detections (and not tracking) which are immune to missed and false detections. Specifically, we show that both team occupancy maps and centroids can be used to detect team activities, while the occupancy maps can be used to retrieve specific team activities. An evaluation on over 8 hours of field hockey data captured at a recent international tournament demonstrates the validity of the proposed approach.

Representing and discovering adversarial team behaviors using player roles

In this paper, we describe a method to represent and discover adversarial group behavior in a continuous domain. In comparison to other types of behavior, adversarial behavior is heavily structured as the location of a player (or agent) is dependent both on their teammates and adversaries, in addition to the tactics or strategies of the team. We present a method which can exploit this relationship through the use of a spatiotemporal basis model. As players constantly change roles during a match, we show that employing a "role-based" representation instead of one based on player "identity" can best exploit the playing structure. As vision-based systems currently do not provide perfect detection/tracking (e.g. missed or false detections), we show that our compact representation can effectively "denoise" erroneous detections as well as enabe temporal analysis, which was previously prohibitive due to the dimensionality of the signal. To evaluate our approach, we used a fully instrumented field-hockey pitch with 8 fixed high-definition (HD) cameras and evaluated our approach on approximately 200,000 frames of data from a state-of-the-art real-time player detector and compare it to manually labelled data.