Signatures of T cell immunity revealed using sequence similarity with TCRDivER algorithm

Changes in the T cell receptor (TCR) repertoires have become important markers for monitoring disease or therapy progression. With the rise of immunotherapy usage in cancer, infectious and autoimmune disease, accurate assessment and comparison of the "state" of the TCR repertoire has become paramount. One important driver of change within the repertoire is T cell proliferation following immunisation. A way of monitoring this is by investigating large clones of individual T cells believed to bind epitopes connected to the disease. However, as a single target can be bound by many different TCRs, monitoring individual clones cannot fully account for T cell cross-reactivity. Moreover, T cells responding to the same target often exhibit higher sequence similarity, which highlights the importance of accounting for TCR similarity within the repertoire. This complexity of binding relationships between a TCR and its target convolutes comparison of immune responses between individuals or comparisons of TCR repertoires at different timepoints. Here we propose TCRDivER algorithm (T cell Receptor Diversity Estimates for Repertoires), a global method of T cell repertoire comparison using diversity profiles sensitive to both clone size and sequence similarity. This approach allowed for distinction between spleen TCR repertoires of immunised and non-immunised mice, showing the need for including both facets of repertoire changes simultaneously. The analysis revealed biologically interpretable relationships between sequence similarity and clonality. These aid in understanding differences and separation of repertoires stemming from different biological context. With the rise of availability of sequencing data we expect our tool to find broad usage in clinical and research applications

SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell–driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB–inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4+ T cells into TH2 cells rather than TH17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of TH17 cells and inhibit TH17 cell–driven autoimmunity

The social dimension of globalization: A review of the literature

With globalization affecting so many inter-connected areas, it is difficult to grasp its full impact. This literature review of over 120 sources considers the impact of globalization on wages and taxes, poverty, inequality, insecurity, child labour, gender, and migration. Opening with some stylized facts concerning globalization in 1985-2002, the authors then highlight recent findings on these areas, reporting on controversies and on emerging consensus where it exists. There follows a review of national and international policy responses designed to make globalization more sustainable and equitable and to deliver decent jobs, security and a voice in decision-making

Drivers of Change or Cut-Throat Competitors? Challenging Cultures of Innovation of Chinese and Nigerian Migrant Entrepreneurs in West Africa

L'afflux remarquable des entrepreneurs migrants chinois dans différents pays d'Afrique occidentale au cours des dernières années a été heurtée à une résistance de plus en plus farouche par des entrepreneurs locaux établis. Que le premiers ont un avantage concurrentiel sur ce dernier en raison de traits socio-culturels distinctifs, ou si l'efficacité supposée chinoise est juste une caractéristique de toutes les diasporas mercantiles, est ouvert à la question. Cette étude exploratoire des migrants entrepreneuriales chinois et nigérians au Ghana et au Bénin tente de répondre à cette question. Apparemment, les forces culturels des agents du changement migrants ne sont pas limités à des systèmes de valeurs héritées ou religions, comme une éthique protestante ou le confucianisme, mais ils sont adaptés en permanence et ont inventé de nouveau par des réseaux transnationaux de la migration dans un monde globalisé. Il n'y a aucune preuve d'une prétendue supériorité de la culture d’innovation chinois par rapport aux cultures d’innovation africains des migrants entrepreneuriales. Plutôt, il existe une capacité accrue d'innovation d'une diaspora mercantile en général vis à vis des entrepreneurs locaux, indépendamment de l'origine de la culture nationale dans lequel il est intégré. En outre, la rivalité des entrepreneurs migrants chinois et nigérians dans les marchés africains ne conduit pas nécessairement à la concurrence coupe-gorge souvent suspectée sous l'impact de la mondialisation. Souvent, les deux groupes agissent plutôt complémentaires. Cela contribue, sous certaines conditions, même à la réduction de la pauvreté dans le pays d'accueil

Single cell analysis and cell sorting using microfluidic devices with application to circulating tumour cells

This thesis describes the development of integrated microfluidic technology for single cell proteomic analysis, focusing on circulating tumour cells (CTCs). While single cell proteomic analysis has wide applicability across biology and medicine, CTCs form an ideal first application. Circulating tumour cells are intimately involved in metastasis, the step in cancer overwhelmingly responsible for death, yet have proved hard to study. Single cell microfluidic technology is ideal first because the quantity of material available is inherently at the level of a few cells and second because cell to cell variation is of great interest. Chapter 1 is an introduction to the field. In chapter 2 a microfluidic sandwich assay for quantification of protein at the single cell level is described. In chapter 3 the isolation of CTCs in a microfluidic device is described. This relies on taking the output of the CellSearch® system and inputing it to a microfluidic device. While CTCs were identified, the result showed that a more systematic approach is required for counting and integration with the single cell assay previously described. Chapters 4 and 5 describe development of technology suitable for counting and isolation of CTCs integrated into a microfluidic device with single cell proteomic analysis, although the work done here makes use of fluorescently labelled beads and model cell lines rather than CTCs from patient samples. Chapter 4 describes microfluidic cytometry that can be used to count and identify a labelled population of cells, such as stained CTCs. Chapter 5 describes the prelimary development of a sorting system suitable for isolation of CTCs integrated with the cytometer

Single cell analysis and cell sorting using microfluidic devices with application to circulating tumour cells

This thesis describes the development of integrated microfluidic technology for single cell proteomic analysis, focusing on circulating tumour cells (CTCs). While single cell proteomic analysis has wide applicability across biology and medicine, CTCs form an ideal first application. Circulating tumour cells are intimately involved in metastasis, the step in cancer overwhelmingly responsible for death, yet have proved hard to study. Single cell microfluidic technology is ideal first because the quantity of material available is inherently at the level of a few cells and second because cell to cell variation is of great interest. Chapter 1 is an introduction to the field. In chapter 2 a microfluidic sandwich assay for quantification of protein at the single cell level is described. In chapter 3 the isolation of CTCs in a microfluidic device is described. This relies on taking the output of the CellSearch® system and inputing it to a microfluidic device. While CTCs were identified, the result showed that a more systematic approach is required for counting and integration with the single cell assay previously described. Chapters 4 and 5 describe development of technology suitable for counting and isolation of CTCs integrated into a microfluidic device with single cell proteomic analysis, although the work done here makes use of fluorescently labelled beads and model cell lines rather than CTCs from patient samples. Chapter 4 describes microfluidic cytometry that can be used to count and identify a labelled population of cells, such as stained CTCs. Chapter 5 describes the prelimary development of a sorting system suitable for isolation of CTCs integrated with the cytometer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo