Molecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cells

Cytokine-driven signalling shapes immune homeostasis and guides inflammatory responses mainly through induction of specific gene expression programmes both within and outside the immune cell compartment. These transcriptional outputs are often amplified via cytokine synergy, which sets a stimulatory threshold that safeguards from exacerbated inflammation and immunopathology. In this study, we investigated the molecular mechanisms underpinning synergy between two pivotal Th1 cytokines, IFN-γ and TNF-α, in human intestinal epithelial cells. These two proinflammatory mediators induce a unique state of signalling and transcriptional synergy implicated in processes such as antiviral and antitumour immunity, intestinal barrier and pancreatic β-cell dysfunction. Since its discovery more than 30 years ago, this biological phenomenon remains, however, only partially defined. Here, using a functional genomics approach including RNAi perturbation screens and small-molecule inhibitors, we identified two new regulators of IFN-γ/TNF-α-induced chemokine and antiviral gene and protein expression, a Bcl-2 protein BCL-G and a histone demethylase UTX. We also discovered that IFN-γ/TNF-α synergise to trigger a coordinated shutdown of major receptor tyrosine kinases expression in colon cancer cells. Together, these findings extend our current understanding of how IFN-γ/TNF-α synergy elicits qualitatively and quantitatively distinct outputs in the intestinal epithelium. Given the well-documented role of this synergistic state in immunopathology of various disorders, our results may help to inform the identification of high quality and biologically relevant druggable targets for diseases characterised by an IFN-γ/TNF-α high immune signature

"I have nothing to say, only to show": appropriation in the poetries of Trevor Joyce, Alan Halsey, and Susan Howe

This thesis studies contemporary poetry’s innovations in textual borrowing and the range and scope of its appropriative practices. The restrictions of the inherited definitions of appropriation include a limited capacity for expression and meaningfulness, a partial concept of appropriation’s critical capacity, and an inadequate sense of the poet’s individual and unique practice of appropriation. This thesis resolves the problematic constraints limiting contemporary definitions of appropriation by tracing the history of the practice to reveal an enduring relation between appropriation and poetic expression. Close readings of Trevor Joyce’s, Alan Halsey’s, and Susan Howe’s poetry serve as evidence of contemporary poetry’s development of appropriation beyond the current ascriptions and offer some direction on how the critical understanding of appropriation might be extended and redefined. Here, appropriation is recognized as another source of lyric expression, critical innovation, and conceptual development in contemporary poetry. This thesis encourages a new perspective on the purpose and processes of poetic appropriation and the consequences of its declarative potential for both poet and poem.