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  • Public defence: 2018-12-18 13:00 A103, Umeå
    Dorafshan Esfahani, Eshagh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University.
    Methyltransferase Ash1, histone methylation and their impact on Polycomb repression2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antagonistic interactions between Polycomb Group (PcG) and Trithorax Group (TrxG) proteins orchestrate the expression of key developmental genes. Distinct maternally loaded repressors establish the silenced state of these genes in cells where they should not be expressed and later PcG proteins sense whether a target gene is inactive and maintain the repression throughout multiple cell divisions. PcG proteins are targeted to genes by DNA elements called Polycomb Response Elements (PREs). The proteins form two major classes of complexes, namely Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). Mechanistic details of Polycomb repression are not fully understood, however, tri-methylation of Lysine 27 of histone H3 (H3K27me3) is essential for this process. Using Drosophila cell lines deficient for either PRC1 or PRC2, I investigated the role of H3K27 methylation and the interdependence of PRC1 complexes for their recruitment to PREs. My results indicate that recruitment of PcG complexes to PREs proceed via multiple pathways and that H3K27 methylation is not needed for their targeting. However, the methylation is required to stabilize interactions of PRE-anchored PcG complexes with surrounding chromatin.

    TrxG proteins prevent erroneous repression of Polycomb target genes where these genes need to be expressed. Ash1 is a TrxG protein which binds Polycomb target genes when they are transcriptionally active. It contains a SET domain which methylates Lysine 36 of histone H3 (H3K36). In vitro, histone H3 methylated at K36 is a poor substrate for H3K27 methylation by PRC2. This prompted a model where Ash1 counteracts Polycomb repression through H3K36 methylation. However, this model was never tested in vivo and does not consider several experimental observations. First, in the ash1 mutant flies the bulk H3K36me2/H3K36me3 levels remain unchanged. Second, in Drosophila, there are two other H3K36-specific histone methyltransferases, NSD and Set2, which should be capable to inhibit PRC2. Third, Ash1 contains multiple evolutionary conserved domains whose roles have not been investigated. Therefore, I asked whether H3K36 methylation is critical for Ash1 to counteract Polycomb repression in vivo and whether NSD and Set2 proteins contribute to this process. I used flies lacking endogenous histone genes and complemented them with transgenic histone genes where Lysine 36 is replaced by Arginine. In these animals, I assayed erroneous repression of HOX genes as a readout for erroneous Polycomb repression. I used the same readout in the NSD or Set2 mutant flies. I also asked if other conserved domains of Ash1 are essential for its function. In addition to SET and domain, Ash1 contains three AT hook motifs as well as BAH and PHD domains. I genetically complemented ash1 loss of function animals with transgenic Ash1 variants, in each, one domain of Ash1 is deleted. I found that Ash1 is the only H3K36-specific histone methyltransferase which counteracts Polycomb repression in Drosophila. My findings suggest that the model, where Ash1 counteracts PcG repression by inhibiting PRC2 via methylation of H3K36, has to be revised. I also showed that, in vivo, Ash1 acts as a multimer and requires SET, BAH and PHD domains to counteract Polycomb repression.

    This work led to two main conclusions. First, trimethylation of H3K27 is not essential for targeting PcG proteins to PREs but acts afterwards to stabilize their interaction with the chromatin of the neighboring genes. Second, while SET domain is essential for Ash1 to oppose Polycomb repression, methylation of H3K36 does not play a central role in the process.

    The full text will be freely available from 2019-12-18 00:01
  • Public defence: 2018-12-19 09:00 Aulan, Vårdvetarhuset, Umeå
    Hitimana, Regis
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Health economic evaluation for evidence-informed decisions in low-resource settings: the case of Antenatal care policy in Rwanda2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: The general aim of this thesis is to contribute to the use of health economic evidence for informed health care decisions in low-resource settings, using antenatal care (ANC) policy in Rwanda as a case study. Despite impressive and sustained progress over the last 15 years, Rwanda’s maternal mortality ratio is still among the highest in the world. Persistent gaps in health care during pregnancy make ANC a good candidate among interventions that can, if improved, contribute to better health and well-being of mothers and newborns in Rwanda.

    Methods: Data used in this thesis were gathered from primary and secondary data collections. The primary data sources included a cross-sectional household survey (N=922) and a health facility survey (N=6) conducted in Kigali city and the Northern Province, as well as expert elicitation with Rwandan specialists (N=8). Health-related quality of life (HRQoL) for women during the first-year post-partum was measured using the EQ-5D-3L instrument. The association between HRQoL and adequacy of ANC utilization and socioeconomic and demographic predictors was tested through bivariate and linear regression analyses (Paper I). The costs of current ANC practices in Rwanda for both the health sector and households were estimated through analysis of primary data (Paper II). Incremental cost associated with the implementation of the 2016 World Health Organization (WHO) ANC recommendations compared to current practice in Rwanda was estimated through simulation of attendance and adaptation of the unit cost estimates (Paper III). Incremental health outcomes of the 2016 WHO ANC recommendations were estimated as life-years saved from perinatal and maternal mortality reduction obtained from the expert elicitation (Paper III). Lastly, a systematic review of the evidence base for the cost and cost-effectiveness of routine ultrasound during pregnancy was conducted (Paper IV). The review included 606 studies published between January 1999 and April 2018 and retrieved from PubMed, Scopus, and the Cochrane database.

    Results: Sixty one percent of women had not adequately attended ANC according to the Rwandan guidelines during their last pregnancy; either attending late or fewer than four times. Adequate utilization of ANC was significantly associated with better HRQoL after delivery measured using EQ-VAS, as were good social support and household wealth. The most prevalent health problems were anxiety or depression and pain or discomfort. The first ANC visit accounted for about half the societal cost of ANC, which was $44 per woman (2015 USD) in public/faith-based facilities and $160 in the surveyed private facility. Implementing the 2016 WHO recommendations in Rwanda would have an incremental national annual cost between $5.8 million and $11 million across different attendance scenarios. The estimated reduction in perinatal mortality would be between 22.5% and 55%, while maternal mortality reduction would range from 7% to 52.5%. Out of six combinations of attendance and health outcome scenarios, four were below the GDP-based cost-effectiveness threshold. Out of the 606 studies on cost and cost-effectiveness of ultrasound during pregnancy retrieved from the databases, only nine reached the data extraction stage. Routine ultrasound screening was reported to be a cost-effective intervention for screening pregnant women for cervical length, for vasa previa, and congenital heart disease, and cost-saving when used for screening for fetal malformations.

    Conclusions: The use of health economic evidence in decision making for low-income countries should be promoted. It is currently among the least used types of evidence, yet there is a huge potential of gaining many QALYs given persistent and avoidable morbidity and mortality. In this thesis, ANC policy in Rwanda was used as a case to contribute to evidence informed decision-making using health economic evaluation methods. Low-income countries, particularly those that that still have a high burden of maternal and perinatal mortality should consider implementing the 2016 WHO ANC recommendations.

  • Public defence: 2019-01-18 13:00 Hörsal E, Humanisthuset, Umeå
    Kuuse, Anna-Karin
    Umeå University, Faculty of Arts, Department of Creative Studies (Teacher Education).
    ”Liksom ett annat uppdrag”: iscensättning av social rättvisa i musikundervisningens retorik och praktik2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis is to identify, describe, and problematize constructions of social justice in Swedish music education. The thesis has an ethnographic design, and presents four empirical studies. The studies, in the shape of four scientific articles, emblematise musical practices in community schools of music and art, as well as in elementary schools. The conceptual framework of the concept of social justice precipitates a focus on the prime object of study, El Sistema. Music education as organised by El Sistema explicitly communicates social aims, and the programme operates in both Swedish community schools of music and art, and in elementary schools. All together, the empirical data consist of marketing material (films and written documents), observational field-notes and sound recordings from one semester’s fieldwork in a children’s music educational group (ages 7-9), as well as sound-recorded focus group interviews with music teachers from both community schools of music and art and elementary schools. Article I shows how different conceptions of music, children, emotions, and social transformation are constructed to legitimate El Sistema in the Swedish community schools of music and art. Here, the objects of study are films and written texts published on El Sistema’s Swedish website. Article II elaborates how musical agency is performed by participating children in relation to conceptions of music education and social justice constructed in the educational practice. Articles III and IV elaborate teachers’ negotiations and constructions of teacher roles and the educational task in relation to conceptions of social justice. Within a comprehensive social constructionist perspective, participants’ opportunities for action and negotiation, in practice, are perceived as determined by societal, institutional and local preconditions, and by overarching and established conceptions that are typical for certain eras. With this theoretical point of departure, both local and societal conceptions of the musical subject, its objectives, means, and aims, as well as conceptions about accessibility, equality, democracy and social justice, are constantly negotiated. Thus, apparently natural and established ideas can be problematized. Based on all studies’ results, relations between established conceptions, structural preconditions, and social relations are scrutinised from the way they influence performances of the music educational practice. The final discussion encompasses consequences for teachers’ ability to reflect, as well as children’s and young peoples’ meaning making through musical actions. The thesis’ critical perspective aims at evoking new questions, and generating new knowledge concerning the preconditions and the content of institutionally financed music education.

  • Public defence: 2019-01-25 10:00 S104, Umeå
    Sciuto, Claudia
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies, Environmental Archaeology Lab.
    Carved Mountains and Moving Stones: applications of Near Infrared Spectroscopy for Mineral Characterisation in Provenance Studies2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The study of stone artefacts is a combination of anthropological archaeology and geology, rooted in analytical techniques for determining the materials’ composition, typological stylistic classification and interpretation of cultural patterns. In this thesis, the archaeology of materials is considered in the context of sites- and landscape transformation, economic history and development of techniques. Focus has been on applications of near infrared spectroscopy (NIR) for characterising minerals in different case studies. Interdisciplinary protocols are implemented in order to account for the various aspects of stone artefacts, merging geochemical investigation and digital documentation.

    This thesis consists of two parts: an introductory text and five research publications. In the first paper, a NIR portable probe is tested to measure iron oxide-based pigments in rock paintings in Flatruet (Sweden). The study demonstrates that the probe is useful for characterising different sections of paint in-situ and pinpointing similarities and dissimilarities in the pigments used for the figures. The second and third papers are aimed at studying the use of raw materials for tool production in a Mesolithic settlement in Northern Sweden. In the second paper is shown that hyperspectral imaging helps characterise the mineral composition of a selected group of tools and the spectral signature of quartz, quartzite, and flint are examined. In the third paper, hyperspectral imaging-based classification is applied to the entire dataset of lithic tools and flakes collected during excavation of the site. The objects are divided into categories of raw materials according to their spectral features and the distribution is visualised on a 3D GIS platform. The fourth paper deals with the application of hyperspectral imaging, a field probe (MicroNIR) and portable Energy-Dispersive X-Ray Fluorescence (ED-XRF), for in-situ characterisation of building materials on the inner wall of the fortified citadel of Carcassonne (France). The research shows how the combination of these analytical methods in conjunction with a stratigraphic study of the architecture helps to understand the use and re-use of materials in different construction phases. The last paper shows how an in-field NIR-probe may be used in landscape surveys for instant characterisations of different stone types. This study was carried out in the district of Montescaglioso, Southern Italy, to highlight patterns of use and distribution of artefacts made of local calcarenite (limestone) in the period between the 6th and 3rd century BC.