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  • Public defence: 2019-12-12 10:00 Vivi Täckholmsalen (Q-salen) NPQ-huset, Stockholm
    Ólafsson, Einar B.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Signaling determinants in Trojan horse-mediated dissemination of Toxoplasma gondii2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Toxoplasma gondii is an obligate intracellular parasite that infects all warm-blooded vertebrates including one third of the global human population. While infection is typically asymptomatic in healthy human hosts, reactivated and acute infection in immunosuppressed or immunecompromised individuals can lead to lethal toxoplasmic encephalitis After ingestion, the parasite crosses the intestinal epithelium and rapidly achieves systemic dissemination, ultimately establishing chronic infection in the brain. Shortly after crossing the intestinal epithelium T. gondii encounters dendritic cells (DCs). Paradoxically, T. gondii tachyzoites exploit the inherent migratory ability of DCs for dissemination via a “Trojan horse” mechanism. Within minutes of active invasion by T. gondii tachyzoites, DCs adopt a hypermigratory phenotype that mediates rapid systemic dissemination of T. gondii in mice. Previous studies have demonstrated that the hypermigratory phenotype involves cytoskeletal rearrangement, redistribution of integrins and high-velocity in vitro cell migration (termed hypermotility), which is initiated by GABAergic signaling. However, the downstream effectors of GABAergic signaling in parasitized DCs remain enigmatic. Leukocyte migration often relies on adhesion and proteolysis of extracellular matrix (ECM). However, the role of ECM proteolysis in hypermigration has not been addressed. In this thesis, the migratory activation of T. gondii-infected DCs is characterized in terms of cell signaling and ECM proteolysis.

    In paper I we demonstrate that MMP-mediated proteolytic activity of DCs is abolished upon T. gondii infection. To investigate DC pericellular proteolysis at the single cell level, we developed a high-content imaging and automated image analysis method. With pharmacological inhibitors and gene silencing, we show that T. gondii-infected DCs lose the ability to degrade ECM through the upregulation of TIMP1 and the loss of podosome structures.

    In paper II we show that the hypermigratory phenotype induced by GABAergic signaling in T. gondii-infected DCs is dependent on L-type voltage dependent Ca2+ channel (L-VDCC) activation, predominantly CaV1.3. Pharmacological antagonism of CaV1.3 and gene silencing of cav1.3 blocked hypermotility. Further, inhibition of L-VDCCs with benidipine significantly reduced T. gondii dissemination in a mouse model.

    In paper III we address the impact of TIMP1 on the migratory activation of T. gondii-infected DCs. Using pharmacological antagonism and shRNA-mediated gene silencing, we demonstrate that secreted TIMP1 induces motility and migration in T. gondii-infected DCs by activating ITGB1-FAK signaling through interactions with CD63.

    In paper IV we report that the GTPase Ras functions as a molecular switch in the migratory activation of T. gondii-infected DCs. We identify that VDCC-CaM-CaMkII and Met signaling converge on Ras-mediated Erk phosphorylation leading to migratory activation of T. gondii-infected DCs.

    In summary, my thesis details novel host signaling pathways hijacked by the protozoan parasite T. gondii in Trojan horse DCs for dissemination. Through the investigation of host-parasite interactions, we shed new light on mechanisms that govern leukocyte migration and strategies employed by T. gondii to achieve pervasive dissemination. Gaining further insights into the biology that underlies T. gondii pathogenesis and persistence will help ameliorate toxoplasmosis in at-risk groups.

  • Public defence: 2019-12-13 10:00 Vivi Täckholmsalen (Q-salen), NPQ-huset, Stockholm
    Keehnen, Naomi L.P.
    Stockholm University, Faculty of Science, Department of Zoology.
    Immunity & the butterfly: A functional genomic study of natural variation in immunity2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Butterflies are ubiquitous and abundant, occurring in a wide variety of environments that contain diverse microbial communities with varied pathogenic pressures. These pathogens and parasites present a constant threat to organisms, and have led to the evolution of complex and intricate immune responses. Despite strong selection against immunological threats, organisms display great variation in their immune capabilities, both on the genetic and physiological level. Investigating this variation remains challenging, since differences in immune responses might arise from changes in the amount, size or performance of cells or organs. Disentangling these relative contributions is important, as the targets of selection are expected to differ, ranging from immune genes directly related to the phenotype to genes indirectly involved via cell proliferation. This thesis focuses on characterizing the immune system of the butterfly Pieris napi and investigating its remarkable variation across populations by using both phenotypic and genotypic measurements. By integrating RNA-seq with life history measurements, I found that the cost of infection and wounding in the final larval stage carries over the metamorphic boundary in P. napi (Paper II). Using population comparisons, I identified both the action and potential targets of natural selection in wild populations within their respective immune responses (Paper I, III & IV). The immune genes in P. napi show increased genetic variation compared to the rest of the genome, and microevolutionary selection dynamics act on these genes between and among populations (Paper I). I measured the cellular immune responses related to phagocytosis and melanization in common garden reared larvae originating from two allopatric populations (Spain, Sweden) (Paper III & IV). The two populations were found to differ in their blood cell composition, and overall phagocytic capability, driven by the increased phagocytic propensity of each cell type (Paper III). However, genome wide analysis of divergence between these populations found no excess genetic differentiation in genes annotated to phagocytic capacity, suggesting that our observed population differences might arise from genes affecting the activation or transdifferentiation of cells, which currently lack functional annotation. Interestingly, genes involved in glutamine metabolism, which have been linked to immune cell differentiation in mammals, did show divergence between the populations. In addition, the populations also differed in prophenoloxidase activity, a common method for quantifying immune related melanization in insects, along with the abundance of the cell-type (oenocytoids) related to this important immune function (Paper IV). Integrative analysis using both transcriptomic and genomic data revealed that the genes involved in this phenotype showed no significant differentiation between the populations. However, a gene involved with proper trafficking of melanogenic enzymes in vertebrates was found to be highly expressed and highly diverged between the two populations, providing an interesting candidate for future studies. This thesis demonstrates the advantages of integrating several genomic tools with lab experiments to quantify natural variation in the immune system of butterflies.

     

  • Public defence: 2019-12-13 10:00 Nordenskiöldsalen, Geovetenskapens hus, Stockholm
    Dankić, Andrea
    Stockholm University, Faculty of Humanities, Department of Ethnology, History of Religions and Gender Studies.
    Att göra hiphop: En studie av musikpraktiker och sociala positioner2019Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This dissertation explores music-making processes within the genre of Swedish hip-hop during the first half of the 2010s. Hip-hop is often associated with strong notions about authenticity based both on musical tradition regarding style and aesthetics, as well as social categories such as race, gender, class and place. While hip-hop scholarship has often focused on analyzing social categories as part of identity politics, the practical music-making aspect has often been neglected. The aim of this dissertation is to analyze how hip-hop musicking has been constituted by the combination of musical practices, skills, social positions, and knowledge. The prerequisites of Swedish hip-hop music are analyzed, with a particular focus on the intersection between practical music-making and gender, race, ethnicity, generation and place.

    The primary empirical material consists of qualitative interviews with and observations among club DJs, battle rappers, and hosts at battle rap events, as well as both the participants and the instructors at musical camps. Material from social media is also a part of the empirical material.

    The musicological concept of musicking with its understanding of music as a collection of social processes is an important theoretical foundation for this study. Thinking in terms of musicking instead of music enabled me to broaden the scope of possible social settings where the fieldwork was conducted, as well as the choice of study participants. In order to define the practices, knowledges, skills, and positions specific to the hip-hop context, I introduced the concept of hip-hop musicking. The term “hip-hop musicking” signifies the conceptual marriage of practical music-making and the identity formations within processes of hip-hop music-making. I argue that the concept of musicking benefits from an intersectional perspective, as social positions enable and shape musical practice.

    In the dissertation, the concept of an ideal–typical hip-hop position, inspired by Weber’s ideal type, is used to explore the processes behind music-making that are involved in hip-hop musicking. The ideal–typical individual is understood to be a young man racialized as non-white, is (often) angry, has a criminal record, and is from a vulnerable urban area in Stockholm. Throughout the empirical material, this hip-hop position appears in what is understood as the reproduction of stereotypical ideas of hip-hop music as a masculine and racialized coded sphere. However, it also appears in musicking where feminism is in focus.

    The results of the dissertation show that ideas about this ideal–typical social position strongly affect who is given recognition for their dedication to hip-hop musicking. This is relevant, as ideas about authenticity are important both for the empirical field and for hip-hop scholarship. At times, the study’s participants criticized this position, but at other times, they reproduced it. I argue that the ideal–typical hip-hop position can be understood as something constant that is also involved in change processes. Therefore, development is ongoing in terms of what is considered hip-hop musicking, while aspects of the ideal–typical position are allowed to remain the same. A part of the goal of musicking includes fighting with the ideal–typical and the normative. This, in turn, reproduces power relations while simultaneously involving possibilities for change.

  • Public defence: 2019-12-16 10:00 sal 14, hus 5, Kräftriket, Stockholm
    Krüger, Oliver
    Stockholm University, Faculty of Science, Department of Mathematics.
    On linear graph invariants related to Ramsey and edge numbers: or how I learned to stop worrying and love the alien invasion2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis we study the Ramsey numbers, R(l,k), the edge numbers, e(l,k;n) and graphs that are related to these. The edge number e(l,k;n) may be defined as the least natural number m for which all graphs on n vertices and less than m edges either contains a complete subgraph of size l or an independent set of size k. The Ramsey number R(l,k) may then be defined as the least natural number n for which e(l,k;n) = ∞ .

    In Paper I, IV and V we study strict lower bounds for e(l,k;n). In Paper I we do this in the case where l = 3 by, in particular, showing e(G) ≥ (1/3)(17n(G) - 35α(G) - N(C4;G)) for all triangle-free graphs G, where N(C4;G) denotes the number of cycles of length 4 in G. In Paper IV we describe a general method for generating similar inequalities to the one above but for graphs that may contain triangles, but no complete subgraphs of size 4. We then show a selection of the inequalities we get from the computerised generation. In Paper V we study the inequality 

    e(G) ≥ (1/2)(ceil((7l - 2)/2)n(G) - l floor((5l + 1)/2)α(G))

    for l ≥ 2, and examine the properties of graphs G without cliques of size l+1 such that G is minimal with respect to the above inequality not holding, and show for small l that no such graphs G can exist.

    In Paper II we study constructions of graphs G such that e(G) - e(3,k;n) is small when n ≤ 3.5(k-1). We employ a description of some of these graphs in terms of 'patterns' and a recursive procedure to construct them from the patterns. We also present the result of computer calculations where we actually have performed such constructions of Ramsey graphs and compare these lists to previously computed lists of Ramsey graphs.

    In Paper III we develop a method for computing, recursively, upper bounds for Ramsey numbers R(l,k). In particular the method uses bounds for the edge numbers e(l,k;n). In Paper III we have implemented this method as a computer program which we have used to improve several of the best known upper bounds for small Ramsey numbers R(l,k).

  • Public defence: 2019-12-19 10:00 Nordenskiöldsalen, Geovetenskapens hus, Stockholm
    Mu, Xin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Protein stability and mobility in live cells: Revelation of the intracellular diffusive interaction organization mechanisms2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biochemical processes inside living cells take place in a confined and highly crowded environment. As such, macromolecular crowding, one of the most important physicochemical properties of cytoplasm, is an essential element of cell physiology. It not only gives rise to steric repulsion, but also promotes non-specific, transient, interactions (referred to as diffusive interactions) between molecules. Since diffusive interactions are a key way to achieving a highly organized intracellular environment, without such interactions, the cell is just “a bag of molecules”. Therefore, understanding how diffusive interactions modulate protein behavior in live cells is of fundamental importance for revealing the mechanisms of molecular recognition, as well as for understanding the cause of protein misfolding diseases.

    This thesis focuses on how macromolecular crowding influences the stability and diffusive motions of proteins within living cells by modulating their diffusive interactions. First, we investigated the thermal stability of superoxide dismutase 1 (SOD1), a protein involved in the development of familial amyotrophic lateral sclerosis (ALS), in mammalian and E. coli cells. Intriguingly, the major thermodynamic consequence of macromolecular crowding is due not only to conventional steric repulsions, but primarily to the detailed chemical nature of the diffusive protein interactions in live cells. Secondly, we presented a mutational study of how these diffusive interactions influence the rotation of proteins in the mammalian and bacterial cytosol. The result is a quantitative description of the physicochemical code for the intracellular protein motion, showing that it depends critically on the surface details of protein and the type of the host cell as well. Thirdly, we characterized the impact of  intracellular protein concentration by altering the volume of E. coli cells by osmotic shock. The results obtained show that the intracellular diffusion of proteins is not determined by the chemical properties of the protein surface alone, but also by the frequency of concentration-dependent encounters. Moreover, it appears that eukaryotes and bacteria have achieved fidelity of biological processes through different evolutionary strategies. Overall, these observations have numerous implications for both functional protein design and deciphering the evolution of the surface characteristics of proteins.

    Subsequently, we attempted to shed new light on the Hofmeister series, using protein-folding kinetics as observable. The results indicate that the Hofmeister series cannot be explained entirely by the traditional Kosmotropes/Chaotropes classification. Strong hetero-ion pairing cannot be ignored when trying to understand the effects of salts on protein salting-in and salting-out behaviors.

  • Public defence: 2019-12-20 10:00 Magnélisalen, Kemiska övningslaboratoriet, Stockholm
    Iadaresta, Francesco
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Textile Related Chemicals: Analytical Approaches Towards the Assessment of Human and Environmental Exposures2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The textile manufacturing chain involves an extensive use of chemicals as early as fabric-production. To confer special features to textile materials, more chemicals are required in subsequent steps. Furthermore, potentially harmful substances can end up in clothes as transformation products. Compounds that are not covalently bonded to the fabrics have high probability to be released on the skin or into the environment when the clothes are worn or laundered.

    In order to remove interfering compounds from solvent extracts of investigated textiles, a cleanup step based on solid phase extraction using graphitic carbon black was developed resulting in effective dye removal. In a pilot screening, nitroanilines were detected up to 0.57 mg/g, which was 2-3 order of magnitude higher than measured quinolines.

    Human exposure to chemicals can occur through skin contact. Benzothiazole was chosen as model compound for in-vitro experiments. Its permeation was experimentally determined in order to estimate dermal exposure. Carcinogenic and non-carcinogenic risks, associated to wearing t-shirt containing BT, according to international standards, were found to be below the acceptable exposure levels.

    It has been shown that chemical concentrations decreased during domestic washing. A procedure was developed for enrichment and clean-up of textile related compounds from water samples. The method was applied to three wastewater treatment plant effluents located in Stockholm. Tolyltriazole, 1-benzotriazole, and UV-P were detected within the range of 53-1148 ng/L.

    Suspect and non-target screening methodology was developed do detect and identify substances in textile materials. The occurrence of thirteen suspect compounds, belonging to quinolines, nitroanilines, benzotriazoles, benzothiazoles and phthalates, was confirmed through suspect analysis approach. Furthermore, using a non-target screening approach, compounds not included in the suspect list such as nitrophenols, organophosphate and acridine were identified.

    In order to remove interfering compounds from the textile extracts, a cleanup step based on solid phase extraction using graphitic carbon black was developed resulting in effective dye removal. In a pilot screening, nitroanilines were detected up to 0.57 mg/g, which was 2-3 times higher than measured quinolines.

    Human exposure to chemicals can occur through skin contact. Benzothiazole was chosen as model compound for in-vitro experiments. Its permeation was experimentally determined in order to estimate dermal exposure. Carcinogenic and non-carcinogenic risks, associated to wearing t-shirt containing BT, according to international standards, were found to be below the acceptable exposure levels.

    It has been shown that chemical concentrations decreased during domestic washing. A procedure was developed for enrichment and clean-up of textile related compounds from water samples. The method was applied to three wastewater treatment plant effluents located in Stockholm. Tolyltriazole, 1-benzotriazole, and UV-P were detected within the range of 53-1148 ng/L.  

    Suspect and non-target screening methodology was developed do detect and identify substances in textile materials. The occurrence of thirteen suspect compounds, belonging to quinolines, nitroanilines, benzotriazoles, benzothiazoles and phthalates, was confirmed through suspect approach. Furthermore, using a non-target screening approach, compounds not included in suspect list such as nitrophenols, organophosphate and acridine were identified.

  • Public defence: 2019-12-20 10:00 Vivi Täckholmsalen (Q-salen) NPQ-huset, Stockholm
    Rowiński, Piotr K.
    Stockholm University, Faculty of Science, Department of Zoology.
    Evolutionary consequences of maternal effects and stress2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Maternal effects occur when maternal environment or phenotype influence offspring phenotype, in addition to genetic contribution of the mother. As maternal effects often influence phenotypes that are under natural selection, they hence have evolutionary consequences. Further, the expression of both maternal effects and evolutionary potential has been argued to depend on environmental conditions, but the evidence of this dependency for the process of adaptation has been inconclusive. The main objective of this thesis was to investigate evolutionary consequences of maternal effects and stressful or variable environmental conditions.

    I started by performing a meta-analysis of quantitative genetic studies that investigated expression of additive genetic, maternal, and residual variance under both stressful and benign environmental conditions (Paper I). Data spanning over many animal taxa and stress types revealed that high levels of environmental stress correlated with increased expression of genetic and residual variances. However, against our predictions, maternal effects were relatively unaffected by stress.

    In Paper II and III, I explored the evolutionary divergences of traits previously shown to be under maternal control. Specifically, in Paper II, I performed a second meta-analysis, that investigated if parents of common frogs (Rana temporaria) influenced offspring development time to mediate the effects of time constraints, across a latitudinal cline. I found that reproductive delay in the parental generation correlated with decreased development time in tadpoles of northern R. temporaria populations, suggesting that parental effects may further decrease development time in populations from time-constrained environments.

    In Paper III, I used an annual killifish system, to explore if environmental unpredictability, measured by variation in precipitation during rainy season, correlated with maternally mediated variation in embryo development time (bet-hedging). Although I found significant among-species differences in variation in development time, there was no clear linear relationship between variation in development time and precipitation. The results suggest that either bet-hedging is not important for persistence in the unpredictable annual killifish habitats, or that other ecological factors, rather than precipitation unpredictability, influenced evolution of variation in development times.

    Lastly, I investigated if occurrence of placenta correlated with increased offspring brain size among poeciliid fish (Paper IV). In contrast to our prediction, I did not find any consistent differences in relative brain size between the fry of placental and non-placental species. It is possible that either the poeciliid placental structures do not have a sufficient capacity to transfer resources necessary for increased brain development, or that other factors, such as sexual selection, or differences in food abundance and competition, shaped brain evolution among poeciliids.

    In conclusion, the results of this thesis suggest that environmental stress may influence evolutionary potential by increasing genetic variation available for selection, that time-constrained habitats may be conducive to evolution of parental effects on offspring development times, and that maternal influence on offspring traits may be difficult to detect, as many ecological factors may potentially influence evolution of life-history and morphology traits.

  • Public defence: 2019-12-20 13:00 Nordenskiöldsalen, Geovetenskapens hus, Stockholm
    Edenroth Cato, Fanny
    Stockholm University, Faculty of Social Sciences, Department of Child and Youth Studies.
    Det högkänsliga subjektets tillblivelse: Diskursiva praktiker om identitet, förmåga och funktionsvariation2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This dissertation examines discursive practices about the highly sensitive person (HSP) from the perspective of knowledge production, categorization and community formation. In contemporary Sweden it has become increasingly common to talk about oneself in terms of being constituted in a particular way, e.g., as having a brain that functions differently than the average. The HSP often represents a person with exceptional capabilities and vulnerabilities, such as a sensitive nervous system and an empathetic disposition. The HSP discourse shares commonalities with the discourse of disability activism related to neuropsychiatric diagnoses. Namely, that by using specific discursive strategies, communities are being formed. The HSP community works to counteract the negative preconceived notions about high sensitivity, and bring to light the ignorance surrounding the needs of HSPs in society.

    This compilation thesis consists of a summarizing introduction and three articles. The empirical material covers posts from an online discussion forum for parents, and one aimed at young people, blogs composed by teenage girls, and children’s books written by different types of experts. These discursive arenas are analyzed with concepts from discursive psychology and poststructuralist theory. The results show how psychological and biomedical discourses are producing citizen subjects in relation to governing in specific social contexts. Within a Foucauldian tradition such forms of governance are termed biopolitics and biosociality.

    The first article examines how the HSP category is transforming notions of good motherhood. It suggests that mothers’ interaction in an online discussion forum reflects the intensive mothering norms of child-centered parenting. Mothers share their therapeutic narratives while highlighting the problems surrounding an incomprehensible social environment and the ordeals of having a guilty conscience. Through the prism of the highly sensitive child, however, motherhood acquires new anticipatory, considerate and susceptible norms, and strategies that constitute a highly sensitive parenting style.

    The second article studies how young people take different stances in discursive struggles concerning the HSP category online. The article illustrates how youths disclose the weaknesses and strengths of being highly sensitive, as well as objecting to norms of biosociality that are connected to the HSP. According to these findings young people are pioneering a new informed ethics of the self as they perform HSP subjectivity.

    The third article investigates children’s books that may be used as therapeutic tools aimed at informing and educating both adults and children about girls’ experiences of being HSPs, or of having a neuropsychiatric diagnosis. In these books dis/abilities are often transformed into exceptional capabilities. Through a process of identification, the girl protagonists may come to manage their behavior and emotions according to the premise of the diagnosis, thus, redefining their personhood as ideal citizen subjects.

    In conclusion, norms of biosociality and biopolitical governance regulate citizens to confess and assert their capabilities and dis/abilities, yet the discursive practices also reflect the construction of social problems and their potential solutions. Citizens appear to struggle to (re)define such problems in an identity political manner in order to (re)produce knowledge on their own terms.