This thesis proposes and discusses a statistical model for interpreting forensic DNA mixtures. We develop methods for estimation of model parameters and assessing the uncertainty of the estimated quantities. Further, we discuss how to interpret the mixture in terms of predicting the set of contributors. We emphasise the importance of challenging any interpretation of a particular mixture, and for this purpose we develop a set of diagnostic tools that can be used in assessing the adequacy of the model to the data at hand as well as in a systematic validation of the model on experimental data. An important feature of this work is that all methodology is developed entirely within the framework of the adopted model, ensuring a transparent and consistent analysis. To overcome the challenge that lies in handling the large state space for DNA profiles, we propose a representation of a genotype that exhibits a Markov structure. Further, we develop methods for efficient and exact computation in a Bayesian network. An implementation of the model and methodology is available through the R package DNAmixtures.

According to the United Nations High Commissioner for Refugees (UNHCR), by 2012 there were 15.4 million refugees and 28.8 million internally displaced persons (IDPs) forced to flee their homes due to war or violent conflict across the globe. Upon arrival in their host settings, forced migrants struggle with acute health and material needs, as well as issues related to identity, politics, power and place. The Karen ethnic minority of Burma (also known as Myanmar) has been involved in a prolonged civil conflict with the Burmese military government for nearly six decades. This fighting has resulted in massive internal displacement and refugee flight, and although a ceasefire was signed in 2012, continued violence has been reported. This study among the displaced Karen population along the Thai-Burma border examines the relationships between traditional – or indigenous – medicine, the population's health needs, and the broader social and political context. Research was conducted using an ethnographic case-study approach among 170 participants along the Thai-Burma border between 2003 and 2011. Research findings document the rapid evolution and formalisation of the Karen traditional medical system. Findings show how the evolutionary process was influenced by social needs, an existing base medical knowledge among traditional health practitioners, and a dynamic social and political environment. Evidence suggests that that Karen traditional medicine practitioners, under the leadership of the Karen National Union (KNU) Department of Health and Welfare, are serving neglected and culturally-specific health needs among border populations. Moreover, this research also provides evidence that Karen authorities are revitalising their traditional medicine, as part of a larger effort to strengthen their social infrastructure including the Karen self-determination movement. In particular, these Karen authorities are focused on building a sustainable health infrastructure that can serve Karen State in the long term. From the perspectives of both refugee health and development studies, the revival of Karen traditional medicine within a refugee and IDP setting represents an adaptive response by otherwise medically under-served populations. This case offers a model of healthcare self-sufficiency that breaks with the dependency relationships characteristic of most conventional refugee and IDP health services. And, through the mobilisation of tradition for contemporary needs, it offers a dimension of cultural continuity in a context where discontinuity and loss of culture are hallmarks of the forced migration experience.

Avanços na área da tecnologia de informação proporcionaram mudanças em diversas áreas da atividade humana. A comunicaço cientifica e uma destas áreas. Periódicos científicos, que tradicionalmente utilizam como meio de divulgação a mídia impressa, possuem agora como alternativa a midia eletrônica. Alguns periódicos científicos lançados no final do século XX estão disponíveis exclusivamente no formato eletrônico. Esta tese de Doutorado analisa de forma específica as dinâmicas de acesso e uso dos periódicos científicos eletônicos brasileiros na área da Ciência da Informação. Discutem-se diversos tópicos fundamentais para a compreensão deste assunto. O estudo do acesso dos usuários aos periódicos foi realizado através da análise dos arquivos de log de acesso gerados pelos servidores web onde estão hospedados os periódicos selecionados para a pesquisa. O estudo relacionado ao uso que os usuários fazem dos periódicos foi realizado através da análise de um questionário enviado para os docentes dos programas de pós-graduação em Ciência da Informação, credenciados pela Coordenação de Aperfeicoamento de Pessoal de Nível Superior CAPES, até a data de 30 de junho de 2001. A pesquisa identifica vários comportamentos dos usários quando do acesso aos periódicos científicos eletrônicos brasileiros, bem como algumas barreiras para uma utilização mais efetiva deste recurso. As conclusões da pesquisa sao relevantes para a elaboraço de novos periódicos cientificos eletrônicos. O prototipo de um sistema de informação eletrônico, voltado para o gerenciamento do processo de elaboração de um periódico científico eletrônico, e apresentado em sugestões para futuras pesquisas. Este protótipo materializa algumas das idéias discutidas ao longo do texto. / Electronic journals, Scientific Communication, Information Science, Information Technology

This essay demonstrates how three popular writers of the twentieth century have created novels that contain echoes of Eliot's poem. They are F. Scott Fitzgerald's The Great Gatsby (1925), Ernest Hemingway's The Sun Also Rises (1926), and John Steinbeck's To a God Unknown (1933). I chose these particular novels because they exemplify widely different and distinctive echoes of the poem. Fitzgerald's use of waste land imagery is readily perceptible the most effective in defining and summing up the temper of the Jazz Age in America. Hemingway's borrowing lies principally in parallel characterization (Jake Barnes as he Fisher King is the outstanding example) and in depicting a morally and spiritually bankrupt world by showing that a satisfactory sexual relationship between man and woman is impossible. Steinbeck's borrowing is unique. HIs novel not only contains the Fisher King figure, desert land imagery, water motif, and the quest theme, but his protagonist, Joseph Wayne, like Eliot's Fisher King-Tiresias protagonist, is able to metamorphose from one "personage" into another. Steinbeck's borrowings are not used by him for the purpose of depicting the world of the Twenties, or any era. He may have done no more than build upon a piece of literature from the immediate past as Eliot had done from the more remote past when he created The Waste Land. There is also a possibility that Steinbeck disagrees with some of Eliot's philosophical ideas and playfully chides the poet for harboring them. In showing the nfluence of the poem on three important American novelists, perhaps this essay will disprove Karl Shapiro's statement that "at no point in the career of Eliot has there been the slightest indication of literary following,"5 and will furnish proof that Robert E. Knoll's statement regarding the influence of The Waste Land is a valid one: What The Rape of the Lock was to the Augustans and Tintern Abbey to the Romantics, The Waste Land has become to the Moderns, It is inescapable.6

No description available.

<strong>Chapter 1</strong> Provides an overview of drug discovery with particular emphasis on library selection and hit identification methods using virtual based approaches. <strong>Chapter 2</strong> Gives an outline of the bone morphogenetic protein (BMP) signalling pathway and literature BMP pathway modulators. The association between the regulation of BMP pathway and cardiomyogenesis is also described. <strong>Chapter 3</strong> Describes the use of ligand based virtual screening to discover small molecule activators of the BMP signalling pathway. A robust cell based BMP responsive gene activity reporter assay was developed to test the libraries of small molecules selected. Hit molecules from the screen were synthesised to validate activity. It was found that a group of known histone deacetylase (HDAC) inhibitors displayed most promising activity. These were evaluated in a secondary assay measuring the expression of two BMP pathway regulated genes, hepcidin and Id1, using reverse transcription polymerase chain reaction (RT-PCR). 188 was discovered to increase expression of both BMP-responsive genes. <strong>Chapter 4</strong> Provides an overview of existing cannabinoid receptor (CBR) modulating molecules and their connection to progression of atherosclerosis. <strong>Chapter 5</strong> Outlines the identification and optimisation of selective small molecule agonists acting at the cannabinoid 2 receptor (CB₂R). Ligand based virtual screen was undertaken and promising hits were synthesised to allow structure activity relationship (SAR) to be developed around the hit molecule providing further information of the functional groups tolerated at the active site. Subsequent studies led to the investigation and optimisation of physicochemical properties around 236 leading to the development of a suitable compound for in vivo testing. Finally, a CB₂R selective compound with favourable physicochemical properties was evaluated in vivo in a murine inflammation model and displayed reduced recruitment of monocytes to the site of inflammation.

Improving the repopulation potential of human umbilical cord blood (UCB) haemopoietic stem cells (HSCs) remains a paramount goal in HSC transplantation (HSCT) therapy. This implies enhancing the homing and engraftment potential of UCB-CD34+CD133+ cells to the bone marrow (BM). Although an array of molecules continues to be identified as ‘key’ homing molecules, the molecular mechanisms controlling HSC homing are still not fully understood. The regulatory implications of hypoxia in the BM, with the concomitant stabilisation of hypoxia inducible transcription factor-1α (HIF-1α), are becoming more apparent, yet at the commencement of this thesis no study had explored whether hypoxia induced signalling can be adopted to regulate the homing and engraftment of transplanted HSCs. The aim of this DPhil project was thus to investigate whether hypoxic conditions as detected in the BM influence the adhesion of UBC-CD133+ cells to osteoblasts, BM stromal cells and BM endothelial cells-60 (BMEC-60), as well as their transmigration towards chemokine SDF-1α across BMEC-60. Increasing the exposure of UCB-CD133+ cells to 1.5% O2 doubled the percentage of transmigrating cells (p<0.05), and while hypoxia stimulated UCB-CD133+ cells preferentially adhered to IL-1β stimulated BMEC-60, their adhesion to non-stimulated (BMEC-60) was significantly improved (p<0.001). To help unravel the underlying molecular mechanisms, we attempted to examine the potential involvement of hypoxia regulated scaffolding protein HEF-1/NEDD9/Cas-L (HEF-1) in the increased percentage of migrating UCB-CD133+ cells after hypoxia pre-conditioning. The role of HEF-1 in HSCs is unexplored, and its multifunctional contribution in a variety of processes including cell migration, attachment and invasion make HEF-1 a prime candidate as a contributing homing molecule. After identifying a suitable short-hairpin RNA (shRNA) sequence to knockdown HEF-1, generating lentiviral (LV)-particles in house and optimising transduction protocols, HEF-1 knockdown was achieved in haemopoietic model cell lines KG-1 and KG-1A (KG-1/KG-1A–HEF1). Significantly decreased KG-1A–HEF1 cell adhesion to non-stimulated BMEC-60 was detected. Together, these studies provide a promising platform to further explore the role of HEF-1 in hypoxia induced UCB-CD133+ cell transmigration towards the key homing molecule SDF-1α.

The intimate relationship between the higher-order chromatin organisation and the regulation of gene expression is increasingly attracting attention in the scientific community. Thanks to high-resolution microscopy, genome-wide molecular biology tools (3C, ChIP-on-chip), and bioinformatics, detailed structures of chromatin loops, territories, and nuclear domains are gradually emerging. However, to fully reveal a comprehensive map of nuclear organisation, some fundamental questions remain to be answered in order to fit all the pieces of the jigsaw together. The underlying mechanisms, precisely organising the interaction of the different parts of chromatin need to be understood. Previous work in our lab hypothesised and verified the “transcription factory” model for the organisation of mammalian genomes. It is widely assumed that active polymerases track along their templates as they make RNA. However, after allowing engaged polymerases to extend their transcripts in tagged precursors (e.g., Br-U or Br-UTP), and immunolabelling the now-tagged nascent RNA, active transcription units are found to be clustered in nuclei, in small and numerous sites we call “transcription factories”. Previous work suggested the transcription machinery acts both as an enzyme as well as a molecular tie that maintains chromatin loops, and the different classes of polymerases are concentrated in their own dedicated factories. This thesis aims to further characterise transcription factories. Different genes are transcribed by different classes of RNA polymerase (i.e., I, II, or III), and the resulting transcripts are processed differently (e.g., some are capped, others spliced). Do factories specialise in transcribing particular subsets of genes? This thesis developed a method using replicating minichromosomes as probes to examine whether transcription occurs in factories, and whether factories specialise in transcribing particular sets of genes. Plasmids encoding the SV40 origin of replication are transfected into COS-7 cells, where they are assembled into minichromosomes. Using RNA fluorescence in situ hybridisation (FISH), sites where minichromosomes are transcribed are visualised as discrete foci, which specialise in transcribing different groups of genes. Polymerases I, II, and III units have their own dedicated factories, and different polymerase II promoters and the presence of an intron determine the nuclear location of transcription. Using chromosome conformation capture (3C), minichromosomes with similar promoters are found in close proximity. They are also found close to similar endogenous promoters and so are likely to share factories with them. In the second part of this thesis, I used RNA FISH to confirm results obtained by tiling microarrays. Addition of tumour necrosis factor alpha (TNF alpha) to human umbilical vein endothelial cells induces an inflammatory response and the transcription of a selected sub-set of genes. My collaborators used tiling arrays to demonstrate a wave of transcription that swept along selected long genes on stimulation. RNA FISH confirmed these results, and that long introns are co-transcriptionally spliced. Results are consistent with one polymerase being engaged on an allele at any time, and with a major checkpoint that regulates polymerase escape from the first few thousand nucleotides into the long gene.

Background: Have you ever wondered what top athletes occupy themselves with after their career? Most scientists agree that it is important to take advantage of the qualities and traits that elite athletes received through sport. Therefore, are athletes able to use and exploit their sports background in business? Purpose: The purpose of this study is to investigate which traits former elite athletes consider important in an effective business leader. Furthermore, the purpose is to examine the traits that former elite athletes feel that they have developed during their sporting careers, which they now have the use of in their leading position in the business world. Question: What is, according to former elite athletes, essential for an effective leader in business? What traits have these former elite athletes, in their view, developed during their active career? Methodology: The study uses a qualitative method which is based on six semi-structured interviews with former Olympians. All interviews were conducted by phone or videoconference call. Conclusion: The authors answer the questions and try to clearify the respondents’ interpretations of the key traits of effective leaders. The authors believe that it is also possible to identify some traits that the respondents brought from the sport and that they now use in their civilian career. Finally, suggestions for further research / Bakgrund: Har du någon gång funderat på vad elitidrottare sysselsätter sig med efter sin avslutade karriär? Flertalet forskare är överens om är att det är viktigt att ta tillvara på de egenskaper och kunskaper som elitidrottaren fått genom idrotten. Därför har ett intresse skapats för huruvida elitidrottare är kapabla att använda och utnyttja sina kunskaper inom näringslivet. Syfte: Syftet med denna studie är att undersöka vilka egenskaper som före detta elitidrottare anser är viktiga hos effektiva ledare inom näringslivet? Vidare är syftet att undersöka vilka egenskaper som före detta elitidrottare uppfattar att de har utvecklat under sin idrottsliga karriär, som de nu har användning av i sin ledande position inom näringslivet. Frågeställningar: Vilka egenskaper är, enligt före detta elitidrottares uppfattning, viktiga för en effektiv ledare inom näringslivet? Vilka egenskaper hos före detta elitidrottare har, enligt deras uppfattning, utvecklats under den aktiva karriären? Metod: Studien använder en kvalitativ metod som är baserad på sex semistrukturerade intervjuer med före detta olympier. Samtliga intervjuer har genomförts via telefon eller videointervju. Slutsats: I slutsatsen besvarar författarna på studiens frågeställningar och försöker klargöra för respondenternas tolkningar av viktiga egenskaper hos effektiva ledare. Författarna anser att det även går att urskilja några egenskaper som respondenterna fått med sig från idrotten och som de nu har användning för inom sin civila karriär. Slutligen ges förslag på vidare forskning.

Animal testing is still the common method to test the efficacy of new drugs, but tissue engineered in vitro models are becoming more acceptable for replacing and reducing animal testing in anti-cancer drug screening by developing in vitro three-dimensional (3D) tumour models for anti-cancer drug testing. In this study, three-dimensional (3D) culture methods were developed to mimic the tumour microenvironment. 3D culturing is to seed, maintain and expand cultured cells in three-dimensional space, in contrast to the traditional two-dimensional (2D) method in which the cells attach to the bottom of culture containers as monolayers. To mimic the intercellular interplay for tumour study, cell co-culture was applied. In this thesis, perfusion culture showed a better homeostasis for 3D tumour model growth over 17 days, with a more controllable working platform and a more reliable response-dose correlation for data interpretation. In the Matrigel sandwich system, the co-culture of breast cancer cells and endothelial cells demonstrated the morphology featuring a vascular network and tumour structures, with the thickness of the three-dimensional structure around 100µm and tubule length 200-400 µm, and maintained for 10 days. The comparisons studies between Matrigel sandwich and other methods suggest that though not fully characterised, Matrigel is still a valuable scaffold choice for developing co-culture 3D tumour model. Finally, the combination of perfusion and co-culture showed the potential of applying this model in angiogenesis assay, with a drug response profile combining cell viability and morphology to mimic in vivo tumour physiology.