3,052 research outputs found

    Zinc as a potential therapy for Burkitt’s lymphoma

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    Burkitts lymphoma (BL) is a form of non-Hodgkin lymphoma (NHL) that arises from germinal center B cells. BL is characterized by translocations of the C-MYC oncogene to immunoglobulin light and heavy chain loci resulting in its constitutive deregulated expression. BL shows a rapid and aggressive growth pattern. There are three different forms of BL; sporadic BL (sBL), immunodeficiency-associated BL and endemic BL (eBL) which accounts for ~50% of all paediatric cancers in Sub-Saharan Africa. Due to financial restrictions, treatment and supportive care options are limited resulting in poorer outcomes in low - middle income countries (LMICs). Thus, there is a need to develop new affordable effective low toxicity treatments for eBL. Prior to this study, a panel of BL cell lines were tested against an in-house custom drug repurposing library developed in our lab (FMC Library) that contains ~100 approved and commonly used drug. This screen identified the nutritional supplement zinc acetate as an effective anti-BL candidate. Dose response studies showed that all BL cell lines tested had little/no response to zinc at 50 μM whereas 100 μM zinc killed all BL cell lines. In contrast, 100 μM zinc acetate induced no killing against a panel of non-BL cell lines including acute myeloid leukaemia (AML) which is a non BL cell tumour, diffuse large B cell lymphoma (DLBCL) which represent a B cell lymphoma that arise from germinal centre B cells and BV infected lymphoblastoid cell lines (LCL) as a control cells. The latter were used as karyotypically normal B cell controls. Cell death in BL cells was associated with positive flow cytometry staining for propidium iodide and annexin V and activation of caspase 3 and 9 (western blotting) indicating cell death by apoptosis. The proto-oncogene C-MYC is mutated or deregulated in >50% of cancers. In BL, deregulated expression occurs as a consequence of translocation of C-MYC on chromosome 8q24 to either the immunoglobulin heavy chain enhancer region on 14q32 (85% of cases) or the immunoglobulin kappa light chain or lambda loci on 2p12 or 22q11, respectively (15% of cases). Thus, the effect of zinc on C-MYC protein levels were studied. Western blot analysis showed that 100 μM zinc was able to reduce C-MYC protein levels rapidly and sustainably in BL cell lines whereas no change in C-MYC protein levels was observed in non-BL cell lines. Zinc-induced reduction of C-MYC protein levels was time-dependent, reducing by approximately 20% after 6 hours with little/no protein detectable after 24 hours. C-MYC protein levels were not reduced following treatment with 50 μM zinc. Quantitative real time PCR (qRT-PCR) also showed a rapid reduction in C-MYC mRNA levels in BL cell lines after 6 hours exposure to 100 μM but not upon exposure to 50μM. Again, no reduction in C-MYC mRNA levels was seen in non-BL cell lines. Translocations of other genes to the immunoglobulin loci occur in other forms of NHL. The DLBCL cell line SU-DHL-4 has a t(14;18) translocation resulting in deregulated expression of the protooncogene BCL2. Western blotting showed no decrease in BCL-2 protein levels in SU-DHL-4 in response to either 100 μM or 50 μM zinc acetate after 6 or 24 hours indicating a selectivity of zinc action against C-MYC protein in BL cells. To further investigate the role of altered C-MYC expression in zinc-mediated killing of BL cells, the eBL cell lines Raji and Namalwa were stably transfected with C-MYC using a piggyBac transposon system that allows gene expression under a constitutively active promoter. However, overexpression of C-MYC from an alternative promoter did not rescue BL cells from killing by 100μM zinc. Although western blotting showed that C-MYC protein levels were protected after 6 hours, protein reduction and loss of viability was again observed after 24 hours indicating that loss of C-MYC is important in zinc-mediated killing of BL cells. In a second approach to rescue C-MYC expression, the proteasome inhibitor Bortezomib was used to inhibit C-MYC protein degradation via the ubiquitin-proteasome system (UPS). Whilst increases were observed in overall ubiquitinated proteins indicating bortezomib was working, western blotting and flow cytometry showed no rescue of C-MYC protein levels. Furthermore, bortezomib did not rescue cells from zinc-mediated killing after 24 hours. In conclusion, findings from this study have identified that 100 mM zinc is effective at killing BL cell lines selectively, and that this killing is associated with activation of apoptotic markers. Treatment with zinc resulted in a rapid and sustained reduction in C-MYC mRNA and protein levels that could not be rescued through constitutive overexpression or the use of proteasome inhibitors. Given that zinc deficiency is common in sub-Saharan Africa and that zinc supplementation is safely used to treat diarrhoeal episodes in children, the studies proposed here indicate that zinc may safely be used as an adjunctive therapy to target C-MYC in BL

    Application of disposable chiral plasmonics for biosensing and Raman spectroscopy

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    This thesis explores the capabilities of disposable chiral plasmonic metafilm assays, termed Disposable Plasmonic Assays, as a promising platform for biosensing and surface-enhanced Raman spectroscopy. The sensing and Raman properties of these metafilms arise from the excitation of surface plasmons when exposed to incident light. These plasmonic properties strongly depend on the geometric characteristics of the constituent nanostructures found in the metafilms. Specifically, the primary nanostructure employed throughout this research is the chiral 'shuriken' star, which generates chiral electromagnetic fields exhibiting greater chiral asymmetry than circularly polarized light. Monitoring changes in the resonance positions of the characteristic optical rotatory dispersion spectra produced by the Disposable Plasmonic Assays allows for the observation of surface binding events. By measuring resonance shift data and through the utilisation of various gold film functionalisation techniques, these assays are demonstrated as versatile, label-free biosensing platforms capable of specifically detecting a wide range of target proteins and virus particles from complex solutions. Furthermore, the multiplexing performance of these assays is showcased, enabling the detection of multiple different antigens and virions in a single experiment. These results highlight the potential of plasmonic metafilms as rapid and disposable point-of-care immunoassays for diagnostic applications. In addition to biosensing, the chiral geometry of Disposable Plasmonic Assays is exploited for the chiral discrimination of metal nanoparticles and small molecules using Surface Enhanced Raman Spectroscopy (SERS). By linking helicoid shaped gold nanoparticles to the metafilm surface via a dithiol linker, the chiral properties of both nanoparticles and metafilms combine, resulting in the creation of differential electromagnetic 'hotspot' regions based on their symmetry combinations. The electromagnetic intensity in these regions corresponds to the SERS signal obtained from the achiral dithiol linker molecule, facilitating a deeper understanding of the chirally dependent SERS phenomenon. These findings serve to validate and explain the differential SERS data obtained enantiomers of biomolecules and drug molecules from silver modified Disposable Plasmonic Assays

    Displacement and the Humanities: Manifestos from the Ancient to the Present

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    This is the final version. Available on open access from MDPI via the DOI in this recordThis is a reprint of articles from the Special Issue published online in the open access journal Humanities (ISSN 2076-0787) (available at: https://www.mdpi.com/journal/humanities/special_issues/Manifestos Ancient Present)This volume brings together the work of practitioners, communities, artists and other researchers from multiple disciplines. Seeking to provoke a discourse around displacement within and beyond the field of Humanities, it positions historical cases and debates, some reaching into the ancient past, within diverse geo-chronological contexts and current world urgencies. In adopting an innovative dialogic structure, between practitioners on the ground - from architects and urban planners to artists - and academics working across subject areas, the volume is a proposition to: remap priorities for current research agendas; open up disciplines, critically analysing their approaches; address the socio-political responsibilities that we have as scholars and practitioners; and provide an alternative site of discourse for contemporary concerns about displacement. Ultimately, this volume aims to provoke future work and collaborations - hence, manifestos - not only in the historical and literary fields, but wider research concerned with human mobility and the challenges confronting people who are out of place of rights, protection and belonging

    Choreographing tragedy into the twenty-first century

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    What makes a tragedy? In the fifth century BCE this question found an answer through the conjoined forms of song and dance. Since the mid-twentieth century, and the work of the Tanztheater Wuppertal Pina Bausch, tragedy has been variously articulated as form coming apart at the seams. This thesis approaches tragedy through the work of five major choreographers and a director who each, in some way, turn back to Bausch. After exploring the Tanztheater Wuppertal’s techniques for choreographing tragedy in chapter one, I dedicate a chapter each to Dimitris Papaioannou, Akram Khan, Trajal Harrell, Ivo van Hove with Wim Vandekeybus, and Gisèle Vienne. Bringing together work in Queer and Trans* studies, Performance studies, Classics, Dance, and Classical Reception studies I work towards an understanding of the ways in which these choreographers articulate tragedy through embodiment and relation. I consider how tragedy transforms into the twenty-first century, how it shapes what it might mean to live and die with(out) one another. This includes tragic acts of mythic construction, attempts to describe a sense of the world as it collapses, colonial claims to ownership over the earth, and decolonial moves to enact new ways of being human. By developing an expanded sense of both choreography and the tragic one of my main contributions is a re-theorisation of tragedy that brings together two major pre-existing schools, to understand tragedy not as an event, but as a process. Under these conditions, and the shifting conditions of the world around us, I argue that the choreography of tragedy has and might continue to allow us to think about, name, and embody ourselves outside of the ongoing catastrophes we face

    Exploring therapeutic vulnerabilities in tumours with GLI1 oncogene activation

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    Deregulation of oncogene expression is one of the main drivers in tumorigenesis. Genetic alterations, such as gene amplification and structural variation, or epigenetic mechanisms based on the chemical modification of DNA or histones, facilitate the activation of proto-oncogenes that convey growth and survival advantages to the cells. Previously, our group identified focal amplification of the chromosome arm 12q in 14 of 60 glioblastoma patients (23.3 %) of which 4 patients harboured fusion genes with the oncogene GLI Family Zinc Finger 1 (GLI1). In this study, I investigated the frequency and structure of GLI1 fusion genes, mechanisms of GLI1 transcriptional activation, GLI1-dependent tumour cell phenotype, and the potential value of GLI1 as a therapeutic target in precision-oncology in glioblastoma and liposarcoma. Initially, I identified GLI1 fusion genes linked with focal amplification on chromosome arm 12q in three independent glioblastoma cohorts (HIPO016, HIPO043, and TCGA-GB). GLI1 fusion genes were associated with high expression of GLI1 and its target genes, such as HHIP, PTCH1, and FOXS1. The boundary of the 12q amplification region often coincided with the GLI1 locus, presumably causing the breakage within the gene and the formation of fusion transcripts. The analysis of sarcoma tumours of the NCT MASTER study revealed high GLI1 expression in subtypes of osteosarcoma and soft tissue sarcoma. In addition, GLI1 fusion genes were found in liposarcoma and leiomyosarcoma. Furthermore, the disruption of a CTCF binding site upstream of the GLI1 locus upregulated the RNA expression of GLI1 and its target genes and increased cell proliferation. These data suggest that fusion-related genetic and epigenetic mechanisms regulate GLI1 expression. To explore its oncogenic function, I conducted phenotypic assays with and without GLI1 suppression and observed a reduction in tumour cell proliferation, anchorage-independent growth and increased apoptosis upon shRNA depletion or inhibition with the GLI1 inhibitor GlaB. The downregulation of several DNA repair pathways upon GLI1 depletion suggested that patients with aberrant GLI1 expression might benefit from combined GLI1 and DNA repair inhibitor therapy. To address this question, I performed a pre-clinical drug combination screen of GLI1 and DNA repair/cell cycle checkpoint inhibitors in glioblastoma and liposarcoma cell lines. In the primary screen, I tested inhibitors individually to identify effective and selective drugs of which the most promising candidates were tested in combination in the subsequent secondary screen. Both glioblastoma and liposarcoma showed high sensitivities to the SHH inhibitor JK184 and the GLI1 inhibitor GlaB. Synergistic effects were observed when GLI1 inhibitors were combined with inhibitors of the ATR/CHK1 axis, i.e., the CHK1 inhibitor LY2606368 or the ATR inhibitor Berzosertib. The independent validation of the screening results in cellular assays showed an increased effect of the combination treatment compared to the single agents on short- and long-term tumour cell proliferation. I furthermore confirmed the reduction in tumour growth upon treatment with GlaB and LY2606368 in a glioblastoma cerebral organoid model. In conclusion, these data suggest that concurrent targeting of the SHH/GLI1 and ATR/CHK1 axes provides a possible precision-therapy approach for tumours with high GLI1 expression

    Comparative genomics of recent adaptation in Candida pathogens

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    [eng] Fungal infections pose a serious health threat, affecting >1,000 million people and causing ~1.5 million deaths each year. The problem is growing due to insufficient diagnostic and therapeutic options, increased number of susceptible patients, expansion of pathogens partly linked to climate change and the rise of antifungal drug resistance. Among other fungal pathogens, Candida species are a major cause of severe hospital-acquired infections, with high mortality in immunocompromised patients. Various Candida pathogens constitute a public health issue, which require further efforts to develop new drugs, optimize currently available treatments and improve diagnostics. Given the high dynamism of Candida genomes, a promising strategy to improve current therapies and diagnostics is to understand the evolutionary mechanisms of adaptation to antifungal drugs and to the human host. Previous work using in vitro evolution, population genomics, selection inferences and Genome Wide Association Studies (GWAS) have partially clarified such recent adaptation, but various open questions remain. In the three research articles that conform this PhD thesis we addressed some of these gaps from the perspective of comparative genomics. First, we addressed methodological issues regarding the analysis of Candida genomes. Studying recent adaptation in these pathogens requires adequate bioinformatic tools for variant calling, filtering and functional annotation. Among other reasons, current methods are suboptimal due to limited accuracy to identify structural variants from short read sequencing data. In addition, there is a need for easy-to-use, reproducible variant calling pipelines. To address these gaps we developed the “personalized Structural Variation detection” pipeline (perSVade), a framework to call, filter and annotate several variant types, including structural variants, directly from reads. PerSVade enables accurate identification of structural variants in any species of interest, such as Candida pathogens. In addition, our tool automatically predicts the structural variant calling accuracy on simulated genomes, which informs about the reliability of the calling process. Furthermore, perSVade can be used to analyze single nucleotide polymorphisms and copy number-variants, so that it facilitates multi-variant, reproducible genomic studies. This tool will likely boost variant analyses in Candida pathogens and beyond. Second, we addressed open questions about recent adaptation in Candida, using perSVade for variant identification. On the one hand, we investigated the evolutionary mechanisms of drug resistance in Candida glabrata. For this, we used a large-scale in vitro evolution experiment to study adaptation to two commonly-used antifungals: fluconazole and anidulafungin. Our results show rapid adaptation to one or both drugs, with moderate fitness costs and through few mutations in a narrow set of genes. In addition, we characterize a novel role of ERG3 mutations in cross-resistance towards fluconazole in anidulafungin-adapted strains. These findings illuminate the mutational paths leading to drug resistance and cross-resistance in Candida pathogens. On the other hand, we reanalyzed ~2,000 public genomes and phenotypes to understand the signs of recent selection and drug resistance in six major Candida species: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis. We found hundreds of genes under recent selection, suggesting that clinical adaptation is diverse and complex. These involve species-specific but also convergently affected processes, such as cell adhesion, which could underlie conserved adaptive mechanisms. In addition, using GWAS we predicted known drivers of antifungal resistance alongside potentially novel players. Furthermore, our analyses reveal an important role of generally-overlooked structural variants, and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Taken together, our findings provide novel insights on how Candida pathogens adapt to human-related environments and suggest candidate genes that deserve future attention. In summary, the results of this thesis improve our knowledge about the mechanisms of recent adaptation in Candida pathogens, which may enable improved therapeutic and diagnostic applications.[cat] Les infeccions fúngiques representen una greu amenaça per a la salut, afectant a més de 1.000 milions de persones i causant aproximadament 1,5 milions de morts cada any. El problema està augmentant a causa d’unes opcions terapèutiques i diagnòstiques insuficients, l'increment del nombre de pacients susceptibles, l'expansió dels patògens parcialment vinculada al canvi climàtic i l'augment de la resistència als fàrmacs antifúngics. D’entre diversos fongs patògens, els llevats del gènere Candida són una causa important d'infeccions nosocomials, amb una alta mortalitat en pacients immunodeprimits. Diverses espècies de Candida constitueixen un problema de salut pública, cosa que requereix més esforços per a desenvolupar nous medicaments, optimitzar els tractaments disponibles i millorar els diagnòstics. Tenint en compte el dinamisme genòmic d’aquests patògens, una estratègia prometedora per millorar les teràpies i diagnòstics actuals és comprendre els mecanismes evolutius d'adaptació als fàrmacs antifúngics i a l’hoste humà. Treballs anteriors utilitzant l'evolució in vitro, la genòmica de poblacions, les inferències de selecció i els estudis d'associació de genoma complet (GWAS, per les sigles en anglès) han aclarit parcialment aquesta adaptació recent, però encara hi ha diverses preguntes obertes. En els tres articles que conformen aquesta tesi doctoral, hem abordat algunes d'aquestes preguntes des de la perspectiva de la genòmica comparativa. En primer lloc, hem abordat qüestions metodològiques relatives a l'anàlisi dels genomes de les espècies Candida. L'estudi de l'adaptació recent en aquests patògens requereix eines bioinformàtiques adequades per a la detecció, filtratge i anotació funcional de variants genètiques. Entre altres raons, els mètodes actuals són subòptims a causa de la limitada precisió per identificar variants estructurals a partir de dades de seqüenciació amb lectures curtes. A més, hi ha una necessitat d’eines computacionals per a la detecció de variants que siguin senzilles d'utilitzar i reproduibles. Per abordar aquestes mancances, hem desenvolupat el mètode bioinformàtic "personalized Structural Variation detection" (perSVade), una eina que permet la detecció, filtratge i anotació de diversos tipus de variants, incloent-hi les variants estructurals, directament des de les lectures. PerSVade permet la identificació precisa de les variants estructurals en qualsevol espècie d'interès, com ara els patògens Candida. A més, la nostra eina prediu automàticament la precisió de la detecció d’aquestes variants en genomes simulats, la qual cosa informa sobre la fiabilitat del procés. Finalment, perSVade es pot utilitzar per analitzar altres tipus de variants, com els polimorfismes de nucleòtid únic o els canvis en el nombre de còpies, facilitant així estudis genòmics integrals i reproduibles. Aquesta eina probablement impulsarà les anàlisis genòmiques en els patògens Candida i també en altres espècies. En segon lloc, hem abordat algunes de les preguntes obertes sobre l'adaptació recent en els llevats Candida, utilitzant perSVade per a la identificació de variants. D'una banda, hem investigat els mecanismes evolutius de resistència als fàrmacs antifúngics en Candida glabrata. Per a això, hem utilitzat un experiment d'evolució in vitro a gran escala per estudiar l'adaptació a dos antifúngics comuns: el fluconazol i l’anidulafungina. Els nostres resultats mostren una adaptació ràpida a un o ambdós fàrmacs, amb un cost per al creixement moderat i a través de poques mutacions en un nombre reduït de gens. A més, hem caracteritzat un paper nou de les mutacions en ERG3 en la resistència creuada al fluconazol en soques adaptades a anidulafungina. Aquests descobriments aclareixen els processos mutacionals que condueixen a la resistència als fàrmacs i a la resistència creuada en els patògens Candida. D'altra banda, hem re-analitzat aproximadament 2.000 genomes i fenotips disponibles en repositoris públics per a comprendre els senyals genòmics de selecció recent i de resistència a fàrmacs antifúngics, en sis espècies rellevants de Candida: C. auris, C. glabrata, C. albicans, C. tropicalis, C. parapsilosis i C. orthopsilosis. Hem trobat centenars de gens sota selecció recent, suggerint que l'adaptació clínica és diversa i complexa. Aquests gens estan relacionats amb funcions específiques de cada espècie, però també trobem processos alterats de manera similar en diferents patògens, com per exemple l’adhesió cel·lular, cosa que indica fenòmens d’adaptació conservats. A part, utilitzant GWAS hem predit mecanismes esperats de resistència a antifúngics i també possibles nous factors. A més, les nostres anàlisis revelen un paper important de les variants estructurals, generalment poc estudiades, i suggereixen una implicació inesperada de la recombinació (para)sexual en la propagació de la resistència. En conjunt, els nostres descobriments proporcionen noves perspectives sobre com els patògens Candida s'adapten als entorns humans, i suggereixen gens candidats que mereixen investigacions futures. En resum, els resultats d’aquesta tesi milloren el nostre coneixement sobre els mecanismes d'adaptació recent en els patògens Candida, cosa que pot permetre el disseny de noves teràpies i diagnòstics

    The role of AD protective variant PLCγ2P522R in modulating microglia mediated clearance and synaptic pruning

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    PLCG2-P522R, a rare coding variant in the Phospholipase C gamma-2 (PLCG2) gene, has been found to be protective against late onset Alzheimer's disease (AD). Within the central nervous system, PLCγ2 is most abundantly expressed in microglia, and microglial mediated neuroinflammatory system has emerged as a major contributor to the molecular and phenotypic changes observed in the AD brain. However, the mechanism by which the P522R variant of PLCγ2 reduces AD pathology is still unknown. BV2 (mouse microglia) cells and human induced pluripotent stem-cells (hiPSC) derived microglia were used in this thesis work to evaluate the role of PLCγ2 in modifying various disease-relevant microglia functions. PLCγ2WT and PLCγ2P522R expression constructs were transfected into BV2 cells to examine the effects of PLCγ2 overexpression on various microglia functions including amyloid beta (Aβ) clearance and synaptic targeting, and various transcriptional changes linked to AD. hiPSCs were genome edited using CRISPR/Cas9 to generate both heterozygous and homozygous forms of the PLCG2_P522R variant in healthy controls. These hiPSC derived microglia were used to explore the effects of the PLCγ2P522R basal level on disease-relevant processes, such as microglial capacity to uptake Aβ and synapses. Microglia transcriptional changes were examined using targeted qPCR analysis to investigate changes in expression of key microglial genes. Mitochondrial function and calcium level changes were also investigated in these microglia cells to determine their metabolic fitness. In addition, the microglia were subjected to acute and chronic treatment of oligomeric Aβ to examine the impact of PLCγ2P522R on microglia's ability to respond to acute and chronic stress. As a result, the effects of Aβ oligomers on lysosomal biogenesis and phagocytic capacities of these microglia were examined further. As a result of PLCγ2 overexpression, Aβ uptake and other immune- provoking cargoes like zymosan were significantly increased. In contrast, the uptake of synaptosomes in BV2 cells overexpressing PLCγ2 was considerably reduced. Similarly, microglia generated from hiPSCs also showed enhanced clearance of Aβ and preservation of synapses by PLCγ2P522R variants. In the PLCγ2P522R microglia variants, the expression of multiple genes, including IL-10 and CX3CR1, as well as mitochondrial function, cytoplasmic calcium flux, and cellular motility were all increased. It was found that the protective effect of PLCγ2P522R was vitally dependent on 'allelic-dose', as homozygous cells displayed a lower preservation of synapse and a distinct gene expression profile compared to heterozygous cells. Similarly, microglia with the protective mutation PLCγ2P522R displayed higher inflammatory cytokine IL-1β level, and better response to acute treatment with Aβ oligomers. PLCγ2P522R appeared to resist the quiescence that was seen in WT microglia variants, by increasing cytokine production and lysosomal biogenesis. My findings suggest that the P522R variant in PLCγ2 increases microglia capacity to clear toxic aggregates such as Aβ while preserving synapses. Furthermore, my findings suggests that PLCγ2P522R contributes to greater microglial surveillance, as well as microglia priming towards a pro-inflammatory state, along with an increased capacity to adapt to growing energy demands. This, however, also shows the delicate balance of this system, as increasing the 'dosage' of PLCγ2P522R may result in diminished favourable benefits

    The Impact of Participatory Budgeting on Health and Well-Being: A Qualitative Case Study of a Deprived Community in London

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    Background Participatory budgeting (PB) is a democratic innovation that enables residents to participate directly and collectively decide how to spend public money in their community. Research demonstrates PB improves social well-being through governance, citizens’ participation, empowerment, and improved democracy. Since 2000, PB has increasingly been used in the UK in community development approaches for improving health and well-being outcomes for people living in deprived communities. Yet little is known about how and why PB may impact health and well-being in deprived communities of the UK. This PhD study sought to explore and explain how the application of PB in the Well London programme impacted the health and well-being of people living in a deprived community in London. Methods The study employed a qualitative case study design adopting the constructivist grounded theory (CGT) methodology of Charmaz (2006) to explore critical themes from interviews with stakeholders of the Well London programme in Haringey Borough. Forty-one stakeholders engaged in planning, co-designing, co-commissioning and co-delivering, or benefitted from three interventions commissioned through PB participated in this study between March 2017 and April 2018. Results A cross-case analysis revealed six pathways through which PB improved health, particularly for the underserved. PB maximised participation and meaningful engagement; enhanced direct demand and response to the community’s needs; individual and collective ownership; action on the social determinants of health; and creative partnership working. These pathways were moderated by the democratic and flexible approach of the PB ethos, particularly the inclusion of residents’ voices in the planning and delivery of the interventions. Residents were motivated to act as agents to change their lives by building positive relationships based on social inclusion and integration. As a result, residents’ self-esteem, sense of belonging, self-confidence, self-worth, and individual sense of belonging and community spirit increased. Residents gained a new zeal and agency to tackle the social determinants of health as they understood them in their lives. Conclusion When done correctly, PB can promote health and well-being and build more robust and resilient communities through community-centred democratic decision-making. Interventions should aim to increase critical consciousness, health literacy, and the capacity in deprived communities to tackle life-course issues that prevent residents from enjoying good health and reduce structural barriers to accessing services or interventions to improve health and reduce inequalities. The outcomes of this study have policy and practice implications for strengthening the design, commissioning, and delivery of health interventions in deprived communities of high-income countries

    Designs of Blackness

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    Across more than two centuries Afro-America has created a huge and dazzling variety of literary self-expression. Designs of Blackness provides less a narrative literary history than, precisely, a series of mappings—each literary-critical and comparative while at the same time offering cultural and historical context. This carefully re-edited version of the 1998 publication opens with an estimation of earliest African American voice in the names of Phillis Wheatley and her contemporaries. It then takes up the huge span of autobiography from Frederick Douglass through to Maya Angelou. "Harlem on My Mind," which follows, sets out the literary contours of America’s premier black city. Womanism, Alice Walker’s presiding term, is given full due in an analysis of fiction from Harriet E. Wilson to Toni Morrison. Richard Wright is approached not as some regulation "realist" but as a more inward, at times near-surreal, author. Decadology has its risks but the 1940s has rarely been approached as a unique era of war and peace and especially in African American texts. Beat Generation work usually adheres to Ginsberg and Kerouac, but black Beat writing invites its own chapter in the names of Amiri Baraka, Ted Joans and Bob Kaufman. The 1960s has long become a mythic change-decade, and in few greater respects than as a black theatre both of the stage and politics. In Leon Forrest African America had a figure of the postmodern turn: his work is explored in its own right and for how it takes its place in the context of other reflexive black fiction. "African American Fictions of Passing" unpacks the whole deceptive trope of "race" in writing from Williams Wells Brown through to Charles Johnson. The two newly added chapters pursue African American literary achievement into the Obama-Trump century, fiction from Octavia Butler to Darryl Pinkney, poetry from Rita Dove to Kevin Young

    The Evolution of Political Moments on Network Late Night: From Cautious Big-Tent Entertainment to Biting Narrowcast Infotainment

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    Late night talk shows have been an integral part of U.S. television since the 1950s, and the genre continues to thrive today in an ever changing media landscape. In my dissertation, I argue that the contemporary programs of Late Night with Seth Meyers, The Late Show with Stephen Colbert, and Jimmy Kimmel Live! make up a category of late night talk shows that I term as satirical network late night. From a visual standpoint, these programs look almost identical to past programs like The Tonight Show Starring Johnny Carson or the Late Show with David Letterman with their sets, house bands, monologues, sketches, desk pieces, and guest appearances. However, these satirical network late night programs produce political content that differs vastly from their predecessors. I assert that these programs are steeped in brazen partisanship, amplify the news media, and function as a sensationalized form of infotainment. This is not the big-tent and “least objectionable programming” offered on past network programs like Carson’s Tonight Show. Additionally, this is not what was offered on cable parody news programs such as The Daily Show with Jon Stewart that presented a veiled partisanship, served as a watchdog over the media and political spheres, and lambasted the entertainment-laden modes of modern news reporting and punditry. In less than a decade, satirical network late night has disrupted genre conventions that existed on network television for over sixty years. This research breaks down what makes these new satirical network late night programs’ political content distinct and helps to decipher why these changes took place in mid-2010s
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