1,183 research outputs found

    Towards personalized medicine for metastatic urothelial cancer

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    Towards personalized medicine for metastatic urothelial cancer

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    Image simulations of highly magnified clumpy galaxies

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    Strong gravitational lensing is a fundamental tool for studying the high-redshift Universe since the magnification it produces enables it to reach spatial resolutions that would otherwise be unattainable. Background sources placed in proximity to the caustics of a galaxy cluster lead to such a high degree of magnification, that they allow for the observation of regions as small as stellar clusters. This is a crucial process to comprehend the mechanisms responsible for galaxy formation and evolution in the early Universe. In this Thesis, we develop a python-based pipeline aimed at simulating observations of high-redshift clumpy galaxies with three different instruments: HST/ACS, JWST/NIRCAM and Euclid/VIS. These sources are modeled by combining the host galaxy and stellar clumps as multiple luminous components. Each of them is defined using elliptical Sérsic surface brightness profiles. We place these sources near the caustics of five different galaxy clusters in order to generate highly magnified gravitational arcs. This tool is highly flexible, allowing us to change the parameters in order to simulate very diverse sources under different observing conditions. Our simulator, hence, enables us to directly compare the performance of past, present, and future instruments when dealing with sub-kpc substructures. The second part of this work shows two applications of our simulator. Firstly, we focus on the issue of identifying stellar clumps in strongly lensed galaxies. In order to complete this task we rely on the recently developed modeling code GravityFM. We define a procedure to increase the contrast of the visible stellar clumps in images simulated with the abovementioned instruments and we attempt a statistical comparison of the detections. Secondly, we show how the images generated with our pipeline can be combined with other simulators, such as SimCADO image simulator for E-ELT/MICADO, which also includes the support from the Adaptive Optics system MORFEO

    Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

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    Cancer genomes harbor a broad spectrum of structural variants (SVs) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assembled complex rearrangements, including a 1.55-Mbp chromothripsis event, and we uncover a complex SV pattern termed templated insertion (TI) thread, characterized by short (mostly <1 kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50 kbp in size. TI threads occur in 3% of cancers, with a prevalence up to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read-based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements

    THREE CHAPTERS ON FAIRNESS PREFERENCES

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    Investigating yttrium ruthenate pyrochlore as an anodic electrocatalyst in proton exchange membrane water electrolysis

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    As the energy transition progresses, the demand for energy storage solutions to support intermittent renewable production is ever-increasing. Hydrogen storage is receiving increased interest and support due to its promising sustainability and flexibility. Proton- exchange, or polymer electrolyte, membrane (PEM) electrolyzers are a key technology supporting hydrogen storage systems. Reducing anodic catalysts costs by proposing alternatives to the standard and expensive rare-earth metal oxide catalysts are key to accelerating commercialization of PEM water electrolyzers. Yttrium ruthenate pyrochlore Y2Ru2O7 (YRO) has stood out as promising alternative due to enhanced oxygen evolution reaction (OER) activity, high stability, and low onset overpotential in acidic PEM conditions. Obstacles remain, including low electrical conductivity. This work investigates YRO as a suitable OER catalyst for PEM water electrolysis. In assessing the catalyst suitability, the impacts of pre-calcination in sol-gel synthesis of YRO, mechanical post-processing of powders, and ink preparation on result quality and catalyst performance are unveiled via rotating disc electrode (RDE) characterization. Pre-calcination, grinding and milling, and lengthy and cooled sonication of inks contribute to improved results quality. A half-cell apparatus is developed and verified as a proof of concept for increased electrochemical characterization flexibility and improved representation of electrolyzer operational conditions. Test station membrane electrode assembly (MEA) characterization reveals undoped YRO undergoes severe and irreversible degradation as a single component catalyst in PEM electrolysis. Hydrogen crossover and low electrical conductivity are chief drivers for the high losses and degrading performance

    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 political economy of peri-urban transformations in Zimbabwe under globalisation - a case study of Harare

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    The bulk of urban studies in sub-Saharan Africa has, hitherto, focused on the impacts of structural adjustment programmes on urban productivity and citizen welfare. However, little is known about the dynamics (Mbiba & Huchzermeyer, 2002: 114) of the structural gaps between the stated policy prescriptions and implementation practices, on one hand, and on the other, between the policy practices and lived experiences of ordinary residents in the marginalised urban spaces in developing countries that neoliberal economic structural reforms have engendered. Meanwhile the dominant perspectives on the nature and meaning of “‘peri-urban’” have intensified instead of stemming the crises of managing increasingly contested urban frontiers in the poorer countries (Mbiba & Huchermeyer, 2002: 114; Simon, et al., 2004; Lombard, 2016). Using Harvey’s (2003) revised and extended Marxist perspective of “primitive accumulation by dispossession” on jambanja, the study critically engages with the “multiple realities” (Giddens, 1984) of radically transformed peri-urban landscapes in a case study of Harare. The study deploys a mixed method strategy to capture multiple data sets through semi-structured interviews, focus group discussions and biographical accounts (Creswell & Brown, 1992; Mouton, 2003: 196) across different contexts of the ‘peri-urban’ in Harare. These contexts range from Zimbabwe’s abandoned neoliberal structural reform programme (Bond & Manyanya, 2003; Mbiba, 2017a: 8-9) to the country’s elitist policy projects of jambanja and Operation Murambatsvina (Moyo, 2013a; 2013b) post-2000. Drawing on the lived experiences of purposively selected town planners and ordinary peri-urban residents, the study builds conceptual blocks to bridge the gaps between the official policy prescriptions and the everyday life experiences of intended beneficiary ordinary residents. The study concludes that the emerging palimpsest peri-urban interface in sub Saharan Africa can be productive sites for understanding the dynamics of informalised The bulk of urban studies in sub-Saharan Africa has, hitherto, focused on the impacts of structural adjustment programmes on urban productivity and citizen welfare. However, little is known about the dynamics (Mbiba & Huchzermeyer, 2002: 114) of the structural gaps between the stated policy prescriptions and implementation practices, on one hand, and on the other, between the policy practices and lived experiences of ordinary residents in the marginalised urban spaces in developing countries that neoliberal economic structural reforms have engendered. Meanwhile the dominant perspectives on the nature and meaning of “‘peri-urban’” have intensified instead of stemming the crises of managing increasingly contested urban frontiers in the poorer countries (Mbiba & Huchermeyer, 2002: 114; Simon, et al., 2004; Lombard, 2016). Using Harvey’s (2003) revised and extended Marxist perspective of “primitive accumulation by dispossession” on jambanja, the study critically engages with the “multiple realities” (Giddens, 1984) of radically transformed peri-urban landscapes in a case study of Harare. The study deploys a mixed method strategy to capture multiple data sets through semi-structured interviews, focus group discussions and biographical accounts (Creswell & Brown, 1992; Mouton, 2003: 196) across different contexts of the ‘peri-urban’ in Harare. These contexts range from Zimbabwe’s abandoned neoliberal structural reform programme (Bond & Manyanya, 2003; Mbiba, 2017a: 8-9) to the country’s elitist policy projects of jambanja and Operation Murambatsvina (Moyo, 2013a; 2013b) post-2000. Drawing on the lived experiences of purposively selected town planners and ordinary peri-urban residents, the study builds conceptual blocks to bridge the gaps between the official policy prescriptions and the everyday life experiences of intended beneficiary ordinary residents. The study concludes that the emerging palimpsest peri-urban interface in sub Saharan Africa can be productive sites for understanding the dynamics of informalised The bulk of urban studies in sub-Saharan Africa has, hitherto, focused on the impacts of structural adjustment programmes on urban productivity and citizen welfare. However, little is known about the dynamics (Mbiba & Huchzermeyer, 2002: 114) of the structural gaps between the stated policy prescriptions and implementation practices, on one hand, and on the other, between the policy practices and lived experiences of ordinary residents in the marginalised urban spaces in developing countries that neoliberal economic structural reforms have engendered. Meanwhile the dominant perspectives on the nature and meaning of “‘peri-urban’” have intensified instead of stemming the crises of managing increasingly contested urban frontiers in the poorer countries (Mbiba & Huchermeyer, 2002: 114; Simon, et al., 2004; Lombard, 2016). Using Harvey’s (2003) revised and extended Marxist perspective of “primitive accumulation by dispossession” on jambanja, the study critically engages with the “multiple realities” (Giddens, 1984) of radically transformed peri-urban landscapes in a case study of Harare. The study deploys a mixed method strategy to capture multiple data sets through semi-structured interviews, focus group discussions and biographical accounts (Creswell & Brown, 1992; Mouton, 2003: 196) across different contexts of the ‘peri-urban’ in Harare. These contexts range from Zimbabwe’s abandoned neoliberal structural reform programme (Bond & Manyanya, 2003; Mbiba, 2017a: 8-9) to the country’s elitist policy projects of jambanja and Operation Murambatsvina (Moyo, 2013a; 2013b) post-2000. Drawing on the lived experiences of purposively selected town planners and ordinary peri-urban residents, the study builds conceptual blocks to bridge the gaps between the official policy prescriptions and the everyday life experiences of intended beneficiary ordinary residents. The study concludes that the emerging palimpsest peri-urban interface in sub Saharan Africa can be productive sites for understanding the dynamics of informalised party-state institutions, political patronage and violence in reproducing urban space. Thus, a reimagining of the peri-urban interface in contemporary sub-Saharan Africa should harness the multiple voices, struggles and experiences in everyday life of residents towards broadening urban theory.College of Agriculture and Environmental SciencesPh. D. (Geography

    From Functioning to Flourishing: How Does Drama-Led Peace Education Help People Know, Experience And Transform Conflict? A Participatory Action-Research Project in a single school

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    Building on my peace-education experience, this inquiry explored a more creative way to co-construct knowledge around conflict and transformation. As well as documenting the development of my educational praxis, this research details how social justice, liberatory education, creativity and action aligned for me and twelve child co-researchers through a participatory action research (PAR) experience. The study comprised four action-research cycles: two group cycles (the Peace PAR project) bookended by two solo-practitioner cycles. The Peace PAR project took place in an English primary school in the Midlands over two school terms, involving 12 inner-city youths aged 10–11 and four adult participants. Together, we undertook a collaborative and democratic inquiry into transformative solutions to complex relational problems. The Peace PAR Project’s process revealed the co-research group’s underlying relational conflict, including the unjust ways we treated each other and were treated by others (including adults). Our developing consciousness initiated our transformation towards radically new senses of self-perception and agency, stimulating more action as we upheld our right to be considered differently by each other and school staff. Using cycles of action and reflection to develop understanding and practice, we co-created an alternative research focus through a radical, inclusive epistemology. Four key themes emerged from the study. First, the project demonstrated how values-led, arts-engaging practices enabled the co-researchers and I to step beyond dominant discourses and rationality to deconstruct our personal and social worlds and offer alternatives. Second, blending PAR and Theatre-of-the-Oppressed methods provided a unique epistemological framework, pedagogical approach and creative methodology based on sensory knowledge substantiation: we understood by seeing, hearing and feeling. Third, the inquiry offers an original contribution to knowledge by shedding light on how young people understand peace, peaceful methods, and peaceful mechanisms of dialogue about conflict. Finally, the study demonstrates the benefits of a short-lived democratic peace education in a school environment dominated by more regulated arrangements of space, time, and bodies. As well as investigating values, oppression, conflict and peace in exploring how arts-engaged research and drama-led peace education might help people experience, know and transform conflict, this study revealed how I taught others and how others taught me within the contextual influences of our shared learning conditions. Our restorative-based, values-led inquiry valued human complexity over procedural simplicity. We concluded that radical change doesn’t need to be violent. Within the Peace PAR project, we made Our Peace
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