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  • Public defence: 2020-02-28 09:15 Room B21, Uppsala
    Jimenez-Gonzalez, Alejandro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Stolen genes, a shortcut to success: Evolution of metabolic and detoxification capacities in Diplomonads2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parasites do not represent a single evolutionary lineage meaning that they have evolved several times. The changes that parasites have undergone to adapt to such a lifestyle are not entirely understood. This thesis focuses on the study of diplomonads (Fornicata, Metamonada), a group of host-associated or free-living protists, to better understand how they adapted to different environments and hosts.

    Diplomonads, and close relatives, are found in low-oxygen environments. However, some species can withstand fluctuating levels of oxygen. In a first study, we reconstructed the oxygen detoxification pathway of Fornicata and study its evolution. Comparative genomics showed that Fornicata shares a common pathway with lineage-specific modifications. Phylogenetic analyses showed a pathway in a constant change where proteins have been gained and lost.

    In a second study, the Giardia muris genome was sequenced and compared to the genome of G. intestinalis WB. We reconstructed the metabolic capacities of both species. Our analyses showed that the observed differences are the result of gene acquisitions or differential losses that can be explained based on differences in the environment of the hosts.

    Considering what we observed in the two previous studies, we reconstructed the metabolic capacities of four diplomonads. Using cluster analysis, we reconstructed the putative metabolism of the last Diplomonadida common ancestor. Our analyses suggested that this ancestor was, most likely, an obligate host-associated organism. However, we identified that traits associated with parasitic diplomonads evolved in a free-living ancestor.

    In the last study, we analyzed the genome of Hexamita inflata, a free-living, diplomonad. Our analyses showed that Trepomonas sp. PC1 and H. inflata acquired important genes for the adaptation to a secondary free-living in a common ancestor. However, our analyses also showed independent adaptations. The synthesis of glutathione and the acquisition of glutathione peroxidase, most likely, allow H. inflata to detoxify higher levels of oxygen and arsenic than other diplomonads.

    In conclusion, this thesis highlights the value of metabolic analyses to identify how microbial eukaryotes interact with their environment. The phylogenetic approach shows that the acquisition of genes and differential losses have been important processes in the adaptation of different hosts and environments.

    List of papers
    1. Lateral Acquisitions Repeatedly Remodel the Oxygen Detoxification Pathway in Diplomonads and Relatives
    Open this publication in new window or tab >>Lateral Acquisitions Repeatedly Remodel the Oxygen Detoxification Pathway in Diplomonads and Relatives
    2019 (English)In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 11, no 9, p. 2542-2556Article in journal (Refereed) Published
    Abstract [en]

    Oxygen and reactive oxygen species (ROS) are important stress factors for cells because they can oxidize many large molecules. Fornicata, a group of flagellated protists that includes diplomonads, have anaerobic metabolism but are still able to tolerate fluctuating levels of oxygen. We identified 25 protein families putatively involved in detoxification of oxygen and ROS in this group using a bioinformatics approach and propose how these interact in an oxygen detoxification pathway. These protein families were divided into a central oxygen detoxification pathway and accessory pathways for the synthesis of nonprotein thiols. We then used a phylogenetic approach to investigate the evolutionary origin of the components of this putative pathway in Diplomonadida and other Fornicata species. Our analyses suggested that the diplomonad ancestor was adapted to low-oxygen levels, was able to reduce O-2 to H2O in a manner similar to extant diplomonads, and was able to synthesize glutathione and L-cysteine. Several genes involved in the pathway have complex evolutionary histories and have apparently been repeatedly acquired through lateral gene transfer and subsequently lost. At least seven genes were acquired independently in different Fornicata lineages, leading to evolutionary convergences. It is likely that acquiring these oxygen detoxification proteins helped anaerobic organisms (like the parasitic Giardia intestinalis) adapt to low-oxygen environments (such as the digestive tract of aerobic hosts).

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS, 2019
    Keywords
    protists, parasites, reactive oxygen species, horizontal gene transfer, LGT, HGT
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-396618 (URN)10.1093/gbe/evz188 (DOI)000491234700009 ()31504492 (PubMedID)
    Available from: 2019-11-13 Created: 2019-11-13 Last updated: 2020-01-07Bibliographically approved
    2. The compact genome of Giardia muris reveals important steps in the evolution of intestinal protozoan parasites
    Open this publication in new window or tab >>The compact genome of Giardia muris reveals important steps in the evolution of intestinal protozoan parasites
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    2019 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Diplomonad parasites of the genus Giardia have adapted to colonizing different hosts, most notably the intestinal tract of mammals. The human-pathogenic Giardia species, Giardia intestinalis, has been extensively studied at the genome and gene expression level, but no such information is available for other Giardia species. Comparative data would be particularly valuable for Giardia muris, which colonizes mice and is commonly used as a prototypic in vivo model for investigating host responses to intestinal parasitic infection. Here we report the draft-genome of G. muris. We discovered a highly streamlined genome, amongst the most densely encoded ever described for a nuclear eukaryotic genome. G. muris and G. intestinalis share many known or predicted virulence factors, including cysteine proteases and a large repertoire of cysteine-rich surface proteins involved in antigenic variation. Different to G. intestinalis, G. muris maintains tandem arrays of pseudogenized surface antigens at the telomeres, whereas intact surface antigens are present centrally in the chromosomes. The two classes of surface antigens engage in genetic exchange. Reconstruction of metabolic pathways from the G. muris genome suggest significant metabolic differences to G. intestinalis. Additionally, G. muris encodes proteins that might be used to modulate the prokaryotic microbiota. The responsible genes have been introduced in the Giardia genus via lateral gene transfer from prokaryotic sources. Our findings point to important evolutionary steps in the Giardia genus as it adapted to different hosts and it provides a powerful foundation for mechanistic exploration of host-pathogen interaction in the G. muris – mouse pathosystem.Importance The Giardia genus comprises eukaryotic single-celled parasites that infect many animals. The Giardia intestinalis species complex, which can colonize and cause diarrheal disease in humans and different animal hosts has been extensively explored at the genomic and cell biologic levels. Other Giardia species, such as the mouse parasite Giardia muris, have remained uncharacterized at the genomic level, hampering our understanding of in vivo host-pathogen interactions and the impact of host dependence on the evolution of the Giardia genus. We discovered that the G. muris genome encodes many of the same virulence factors as G. intestinalis. The G. muris genome has undergone genome contraction, potentially in response to a more defined infective niche in the murine host. We describe differences in metabolic and microbiome modulatory gene repertoire, mediated mainly by lateral gene transfer, that could be important for understanding infective success across the Giardia genus. Our findings provide new insights for the use of G. muris as a powerful model for exploring host-pathogen interactions in giardiasis.

    Keywords
    parasite, diplomonad, Giardia, streamlined, intestinal colonization, evolutionary biology, horizontal gene transfer, antigenic variation
    National Category
    Evolutionary Biology
    Research subject
    Biochemistry; Evolutionary Genetics; Genetics
    Identifiers
    urn:nbn:se:uu:diva-401095 (URN)10.1101/870949 (DOI)
    Available from: 2020-01-06 Created: 2020-01-06 Last updated: 2020-01-07
    3. Metabolic reconstruction elucidates the lifestyle of the last Diplomonadida common ancestor
    Open this publication in new window or tab >>Metabolic reconstruction elucidates the lifestyle of the last Diplomonadida common ancestor
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The identification of ancestral traits is essential to understand the evolution of any group. In the case of parasitic groups, this helps to understand the adaptation to this lifestyle and a particular host. The last Diplomonadida common ancestor has been considered a parasite because most diplomonads are found associated with various animals. However, most of the Fornicata relatives are free-living and there are free-living diplomonads, making the lifestyle of the Diplomonadida ancestor elusive. Here, we present an exhaustive metabolic analysis of diplomonads and the first description of the putative metabolism of the last Diplomonadida common ancestor. Our study suggests that the synthesis of UDP-N-acetyl-D-galactosamine necessary for the cyst wall and most of the virulence factors identified in diplomonads evolved in a pre-parasitic lifestyle. This last Diplomonadida common ancestor was able to utilize available metabolites, but had a reduced capacity to synthesize nucleotides, lipids and amino acids de novo, suggesting that most likely, it was an obligate host-associated.

    National Category
    Evolutionary Biology
    Research subject
    Biochemistry; Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-401099 (URN)
    Available from: 2020-01-06 Created: 2020-01-06 Last updated: 2020-01-07
    4. The Hexamita inflata genome reveals new trends in diplomonads evolution
    Open this publication in new window or tab >>The Hexamita inflata genome reveals new trends in diplomonads evolution
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Diplomonads are a group of flagellated protists found in oxygen-poor environments. The group is suitable to study transitions between lifestyles, because it contains both parasitic and free-living members. A transcriptome study of the free-living diplomonad Trepomonas sp. PC1 showed that many genes associated with the lifestyle had been acquired via lateral gene transfer, suggesting a reversion from a host-associated to a free-living lifestyle. Here, we present the draft genome of Hexamita inflata, the first of a free-living diplomonad. A comparative analysis of the metabolic capacity shows that H. inflata shares free-living adaptations with Trepomonas sp. PC. Important enzymes for the metabolism of nucleotides were acquired by their common ancestor, suggesting a shared reduced dependence on nucleotide salvage. We also find metabolic differences between the free-living diplomonads, suggesting that they have taken their own evolutionary paths. For example, H. inflata is the first diplomonad able to synthetize both the non-protein thiols L-cysteine and glutathione, and it has the most elaborate pathway for arsenic detoxification. These findings indicate that H. inflata is able to withstand higher levels of arsenic and reactive oxygen species than any other studied diplomonad.

    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-401100 (URN)
    Available from: 2020-01-06 Created: 2020-01-06 Last updated: 2020-01-07
  • Public defence: 2020-02-28 10:15 Polhemsalen, Uppsala
    Johnson, Ben A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Synthetic Molecular Chemistry.
    Interrogating Diffusional Mass and Charge Transport in Catalytic Metal-Organic Frameworks2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Molecular catalysts are efficient and selective for the electrochemical conversion of small molecules for energy conversion. Application of molecular species in a large-scale industrial setting requires stabilization in a heterogeneous support material. Metal-organic frameworks (MOFs), having high surface areas for increased active site density, have shown promise as potential platforms in which to incorporate molecular catalysts. However, moving from a homogenous environment to catalysis in porous media, necessitates efficient mass and charge transport to the imbedded catalysts. Either diffusional charge transport or diffusion of substrate have the potential to limit the overall observed rate of product formation, if they are slower than the intrinsic rate of the catalytic reaction. This thesis seeks to examine the effect of diffusional mass and charge transport on molecular catalysis in MOFs.

    First, chemically driven water oxidation is examined using a molecular ruthenium catalyst covalently grafted in MIL(Cr)-101 (MIL = Materials Institute Lavoisier) (Chapter 3). A formal kinetic analysis using a steady-state reaction-diffusion model revealed the limitations incurred by mass transport of the chemical oxidant through the pores of the framework. Importantly, it was shown that interference from mass transport obscures turn-over frequencies, and intrinsic reaction kinetics are only measured under certain conditions. The following chapter entails a modified electrode with a UiO MOF film (UiO = University of Oslo)  containing a molecular catalyst, which is used for electrochemically mediated water oxidation (Chapter 4). The diffusional electron-hopping process is examined and discussed in the context of optimizing overall catalytic current densities. In Chapter 5, a new UiO-type MOF thin film is developed containing exclusively molecularly discrete naphthalene diimide linkers, which are redox-active. This can potentially provide charge transport pathways to imbedded catalysts in a two-component system. In addition, the electron-hopping diffusion coefficient was characterized in both non-aqueous and aqueous electrolytes. Lastly, the capacity of the charge-hopping process occurring in these redox-active MOF films to drive a model catalytic reaction is quantified (Chapter 6). Analysis by cyclic voltammetry is utilized to gain insight into the contributions to the current from the catalytic reaction, electron-hopping, substrate diffusion in the film, as well as mass transport in solution. 

    List of papers
    1. Formal water oxidation turnover frequencies from MIL-101(Cr) anchored Ru(bda) depend on oxidant concentration
    Open this publication in new window or tab >>Formal water oxidation turnover frequencies from MIL-101(Cr) anchored Ru(bda) depend on oxidant concentration
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    2018 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, p. 7770-7773Article in journal (Refereed) Published
    Abstract [en]

    The molecular water oxidation catalyst [Ru(bda)(L)(2)] has been incorporated into pyridine-decorated MIL-101(Cr) metal-organic frameworks. The resulting MIL-101@Ru materials exhibit turnover frequencies (TOFs) up to ten times higher compared to the homogenous reference. An unusual dependence of the formal TOFs on oxidant concentration is observed that ultimately arises from differing amounts of catalysts in the MOF crystals being active.

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2018
    National Category
    Inorganic Chemistry Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-361265 (URN)10.1039/c8cc02300j (DOI)000438237700009 ()29926035 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Energy AgencyKnut and Alice Wallenberg FoundationEU, European Research Council, ERC-CoG2015-681895_MOFcat
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2018-10-11 Created: 2018-10-11 Last updated: 2020-01-13Bibliographically approved
    2. Electrocatalytic water oxidation by a molecular catalyst incorporated into a metal-organic framework thin film
    Open this publication in new window or tab >>Electrocatalytic water oxidation by a molecular catalyst incorporated into a metal-organic framework thin film
    2017 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 46, no 5, p. 1382-1388Article in journal (Refereed) Published
    Abstract [en]

    A molecular water oxidation catalyst, [Ru(tpy)(dcbpy)(OH2)](ClO4)(2) (tpy = 2,2': 6',2''-terpyridine, dcbpy = 2,2'-bipyridine- 5,5'-dicarboxylic acid) [1], has been incorporated into FTO-grown thin films of UiO-67 (UiO = University of Oslo), by post-synthetic ligand exchange. Cyclic voltammograms (0.1 M borate buffer at pH = 8.4) of the resulting UiO67-[RuOH2]@ FTO show a reversible wave associated with the Ru-III/II couple in the anodic scan, followed by a large current response that arises from electrocatalytic water oxidation beyond 1.1 V vs. Ag/AgCl. Water oxidation can be observed at an applied potential of 1.5 V over the timescale of hours with a current density of 11.5 mu A cm(-2). Oxygen evolution was quantified in situ over the course of the experiment, and the Faradaic efficiency was calculated as 82%. Importantly, the molecular integrity of [1] during electrocatalytic water oxidation is maintained even on the timescale of hours under turnover conditions and applied voltage, as evidenced by the persistence of the wave associated with the Ru-III/II couple in the CV. This experiment highlights the capability of metal organic frameworks like UiO-67 to stabilize the molecular structure of catalysts that are prone to form higher clusters in homogenous phase.

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2017
    National Category
    Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-319681 (URN)10.1039/c6dt03718frsc.li/dalton (DOI)000395442700005 ()27845800 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Energy AgencyKnut and Alice Wallenberg Foundation
    Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2020-01-13Bibliographically approved
    3. Development of a UiO-Type Thin Film Electrocatalysis Platform with Redox-Active Linkers
    Open this publication in new window or tab >>Development of a UiO-Type Thin Film Electrocatalysis Platform with Redox-Active Linkers
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    2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 8, p. 2985-2994Article in journal (Refereed) Published
    Abstract [en]

    Metal–organic frameworks (MOFs) as electrocatalysis scaffolds are appealing due to the large concentration of catalytic units that can be assembled in three dimensions. To harness the full potential of these materials, charge transport to the redox catalysts within the MOF has to be ensured. Herein, we report the first electroactive MOF with the UiO/PIZOF topology (Zr(dcphOH-NDI)), i.e., one of the most widely used MOFs for catalyst incorporation, by using redox-active naphthalene diimide-based linkers (dcphOH-NDI). Hydroxyl groups were included on the dcphOH-NDI linker to facilitate proton transport through the material. Potentiometric titrations of Zr(dcphOH-NDI) show the proton-responsive behavior via the −OH groups on the linkers and the bridging Zr-μ3-OH of the secondary building units with pKa values of 6.10 and 3.45, respectively. When grown directly onto transparent conductive fluorine-doped tin oxide (FTO), 1 μm thin films of Zr(dcphOH-NDI)@FTO could be achieved. Zr(dcphOH-NDI)@FTO displays reversible electrochromic behavior as a result of the sequential one-electron reductions of the redox-active NDI linkers. Importantly, 97% of the NDI sites are electrochemically active at applied potentials. Charge propagation through the thin film proceeds through a linker-to-linker hopping mechanism that is charge-balanced by electrolyte transport, giving rise to cyclic voltammograms of the thin films that show characteristics of a diffusion-controlled process. The equivalent diffusion coefficient, De, that contains contributions from both phenomena was measured directly by UV/vis spectroelectrochemistry. Using KPF6 as electrolyte, De was determined to be De(KPF6) = (5.4 ± 1.1) × 10–11 cm2 s–1, while an increase in countercation size to n-Bu4N+ led to a significant decrease of De by about 1 order of magnitude (De(n-Bu4NPF6) = (4.0 ± 2.5) × 10–12 cm2 s–1).

    National Category
    Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-351270 (URN)10.1021/jacs.7b13077 (DOI)000426617700044 ()29421875 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2020-01-13Bibliographically approved
    4. Analyzing Charge Extraction From an Electroactive MOF Film to a Redox Couple in Solution as a Model for Catalytic Reactions
    Open this publication in new window or tab >>Analyzing Charge Extraction From an Electroactive MOF Film to a Redox Couple in Solution as a Model for Catalytic Reactions
    (English)Manuscript (preprint) (Other academic)
    National Category
    Inorganic Chemistry Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-402205 (URN)
    Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-13
  • Public defence: 2020-02-28 10:15 Brusewitzsalen, Uppsala
    Ericson, Marika
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law. Försvarshögskolan.
    On the Virtual Borderline: Cyber Operations and their Impact on the Paradigms for Peace and War: Aspects of International and Swedish Domestic Law2020Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Contemporary disputes between states contain elements of psychological and information operations, intelligence operations and cyber operations as well as methods for physical use of force. Cyber operations may use, or contribute to, all of these different techniques and methods combined and can be focused on intelligence gathering, preparation of networks for future attacks, sabotage or on preventing access to information. States are also not alone as actors in cyberspace, non-state actors are continuously updating and reinforcing their abilities and capabilities and the dividing line between cyber operations that are a crime conducted by a non-state criminal and operations conducted by states have become increasingly blurred.

    International law, and Swedish domestic law, is built up around two foundational paradigms for peace and war. The paradigms are founded on the concepts of statehood, sovereignty and security. Situations, especially threats to states, are to be sorted into either the paradigm for peace or the paradigm for war and are through the division into paradigms also regulated by separate legal frameworks. There is in law no acknowledged state in between.

    This thesis explores the virtual borderlines of the paradigms for peace and war. It suggests that cyber operations is one development challenging the paradigms for peace and war. It further suggests that states are beginning to form their responses to cyber operations. States are defining cyberspace in terms of territory and sovereignty and they play on thresholds for breaches of sovereignty, interventions and use of force. They in essence structure and argue for a legal space in between the paradigms for peace and war.

    The thesis also takes the findings from research conducted on international law and views the findings from a Swedish domestic law perspective. Sweden adheres to a strict division of threats and situations into paradigms for peace and war. There is no state of emergency in Swedish constitutional law, the paradigm for peace is applied fully until a situation is defined as war or danger of war. The question for law is how to make this bipolar system function where threats cannot be sorted into either peace or war anymore.

  • Public defence: 2020-02-28 10:15 University Hall Room IX, Uppsala
    Mathisen, Tina
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Social and Economic Geography.
    Between being and longing: Young former refugees’ experiences of place attachment and multiple belongings2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on young former refugees’ lived experiences of and reflections on processes of place attachment and negotiation of belonging in Norway. The analysis draws on a postcolonial understanding of migration and belonging, and is inspired by post-structuralism and critical phenomenology. The thesis analyses belonging from two perspectives: as a personal relationship to people and places, and as relationally produced and negotiated through social discourses and boundary-making practices in everyday life. The thesis is based on fieldwork conducted with forty former refugee youths, using multiple methods such as in-depth interviews, participant observation, activity diaries, and auto-photography. In addition, teachers, municipal representatives, peer students, siblings, and parents contributed to the knowledge presented in the thesis. Article I explores how the youths’ translocal networks and practices contributed to the process of attaching to a new place, arguing that it is necessary to understand how ideas of both roots and routes are entangled in the young former refugees’ sense of belonging. Article II discusses the spatial organizing of newly arrived students in school and its social consequences. It is argued that the “foreigner” category is socially constructed through a racialization process in which space, skin colour, and language are key components, and that this process is reinforced in school. Article III explores how generic discourses rendering Muslims “the other” in Norway affect young Muslim girls’ experiences of belonging in different geographical and social spaces. The article highlights how the navigation of belonging that the girls undertook entailed constant work that they could not escape due to their visibility as Muslim girls. Article IV explores place attachment and belonging with a focus on everyday habits and routines, and shows that the youths simultaneously drew on shared knowledge from their social networks and on embodied knowledge gained through the habitual use of place to perform belonging. Overall, the thesis provides a nuanced understanding of young former refugees’ belonging that is both multi-sited and multi-layered.

    List of papers
    1. Unge migranter skaper steder: Translokale og lokale praksiser i rurale områder i Norge og Sverige
    Open this publication in new window or tab >>Unge migranter skaper steder: Translokale og lokale praksiser i rurale områder i Norge og Sverige
    2015 (Norwegian)In: Med sans for sted: Nyere teorier / [ed] Marit Aure, Nina Gunnerud Berg, Jørn Cruickshank, Britt Dale, Bergen: Fagbokforlaget, 2015, 1, p. 213-229Chapter in book (Refereed)
    Place, publisher, year, edition, pages
    Bergen: Fagbokforlaget, 2015 Edition: 1
    National Category
    Human Geography
    Research subject
    Social and Economic Geography
    Identifiers
    urn:nbn:se:uu:diva-270383 (URN)978-82-450-1777-9 (ISBN)
    Funder
    Swedish Research Council Formas
    Available from: 2015-12-28 Created: 2015-12-28 Last updated: 2020-01-30Bibliographically approved
    2. Mangelfullt mangfoldsperspektiv?: (Re)produksjonen av kategoriene “utlending” og“norsk” i skolen
    Open this publication in new window or tab >>Mangelfullt mangfoldsperspektiv?: (Re)produksjonen av kategoriene “utlending” og“norsk” i skolen
    (Norwegian)Manuscript (preprint) (Other academic)
    Abstract [no]

    Artikkelen undersøker hvorfor minoritetsungdom beskriver seg selv som utlendinger i den norske skolen, og spør hvordan skolen som institusjon bidrar til (re)produksjonen av kategoriene «utlending» og «norsk». Undersøkelsen tar utgangspunkt i et feltarbeid der jeg har fulgt og intervjuet ungdom med flyktningbakgrunn og deres lærere i ulike former for språkklasser. Teoretisk bygger artikkelen videre på den akademiske diskusjonen om «norskhet», men hevder at det romlige perspektivet bør tillegges større betydning. Jeg trekker på Sara Ahmeds teoretisering av hvithet  når jeg undersøker hvilken betydning hvithetsnormen har for skolen som institusjon og hvordan ungdommene navigerer innenfor denne. I artikkelen argumenterer jeg for at kategorien «utlending» blir til gjennom en rasialiseringsprosess der rom, hudfarge og språk er sentrale komponenter som forsterkes i skolen.

    Keywords
    nyankomne elever, norskhet, rasialisering, hvithet, mangfold
    National Category
    Social and Economic Geography
    Research subject
    Social and Economic Geography; Health Care Research; Social and Economic Geography
    Identifiers
    urn:nbn:se:uu:diva-401827 (URN)
    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-27Bibliographically approved
    3. Everyday politics of belonging: The ambivalent experience of being young, female and Muslim in rural Norway.
    Open this publication in new window or tab >>Everyday politics of belonging: The ambivalent experience of being young, female and Muslim in rural Norway.
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Here, I explore young female Muslims’ (age 13–17 years) everyday negotiations and practices of belonging in Norwegian towns. The analysis draws on Nira Yuval-Davis’ writing on belonging and the politics of belonging, and illustrates how discourses of belonging/non-belonging to the nation come into play in social encounters. The analysis is presented through three individual stories using an intersectional lens, including a time–space dimension, deconstructing the category ‘Muslim girl’. The stories provide insights into young women’s experiences and challenges regarding the contemporary politics of belonging in Northern Europe, highlighting their strategies for negotiating and creating belonging, including the role space plays in these strategies.

    Keywords
    belonging, gender, place, intersectionality, everyday racism, negative social control
    National Category
    Social Sciences
    Research subject
    Social and Economic Geography
    Identifiers
    urn:nbn:se:uu:diva-401831 (URN)
    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-27Bibliographically approved
    4. “Doing belonging”: Young former refugees and their active engagement with Norwegian local communities
    Open this publication in new window or tab >>“Doing belonging”: Young former refugees and their active engagement with Norwegian local communities
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    This article explores the everyday lives of young former refugees in small Norwegian towns and considers how a focus on “doing belonging” can help us understand the processes of place attachment and social inclusion/exclusion in a time of increasing diversity and social division. By looking at these youths’ everyday activities and social networks using a range of participatory methods, this article describes how former refugee youths actively work to create and maintain a sense of belonging. The study shows that the youths simultaneously draw on shared knowledge from their social networks and on embodied knowledge gained through the habitual use of place to perform belonging. It is argued that embodiment, as in being a particular type of body interacting with people and place, matters; other crucial aspects are freedom to move and experience the materiality of place, and that former refugees’ belonging needs to be understood as relating to other people’s understandings of their right to belong. The study shows that particular structural conditions for doing belonging should be considered by policy makers.

    Keywords
    Belonging, place attachment; embodied politics, activity diaries, auto-photography, refugee youth
    National Category
    Social Sciences
    Research subject
    Social and Economic Geography
    Identifiers
    urn:nbn:se:uu:diva-401835 (URN)
    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-27Bibliographically approved
  • Public defence: 2020-02-28 13:00 A-281 Lennart Kennes Sal, Uppsala
    Ramachandran, Prashanth
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Linnean Centre for Plant Biology.
    Stelar Performance Under Drought: Regulation of Developmental Robustness and Plasticity of the Arabidopsis Root Xylem2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plants have evolved genetic mechanisms to sense, modulate and modify developmental programs in response to the changing environment. This brings forth challenges in stably generating tissue patterns while simultaneously allowing amenability. Gene perturbation studies have identified molecular regulators that control fate specification and differentiation of various tissues. However, we lack a complete understanding of how these processes are influenced by the environment. In this thesis, using Arabidopsis xylem as a model, I show that developmental regulators that function in maintaining a stable growth pattern are also involved in the manifestation of phenotypic plasticity. We found that the generation of a robust xylem developmental program is dependent on a feed forward loop between components of the auxin signalling pathway and the master regulators of xylem development, class III Homeodomain Leucine-Zipper (HD-ZIP III) transcription factors (TFs). By directly activating an auxin signalling activator (MP) and repressor (IAA20), the HD-ZIP III TFs facilitate stable xylem patterning and development. We also show that alterations to the HD-ZIP III mediated xylem developmental program were caused non-cell autonomously by changes in levels and signalling of a key regulator of abiotic stress response, abscisic acid (ABA). The suppression and enhancement of ABA signalling resulted in lower and higher levels respectively of mir165, a known post transcriptional regulator of HD-ZIP III levels. Under conditions of enhanced ABA signalling we found that ABA also acts cell autonomously through master regulators of xylem differentiation, VASCULAR RELATED NAC-DOMAIN (VND) transcription factors. Furthermore, we show that both cell autonomous and non-cell autonomous pathways are employed during water deficit conditions to alter xylem morphology and differentiation rate, likely to enhance water uptake. Taken together, our results show that ABA’s influence on evolutionarily conserved development regulators is important for xylem developmental plasticity. The identification of genetic regulators that control plant phenotypic alterations to limited water availability such as those identified in this thesis will be important to develop tolerant varieties that can survive the extended periods of drought caused by the alarming rise in global temperatures.

    List of papers
    1. PHABULOSA Mediates an Auxin Signaling Loop to Regulate Vascular Patterning in Arabidopsis
    Open this publication in new window or tab >>PHABULOSA Mediates an Auxin Signaling Loop to Regulate Vascular Patterning in Arabidopsis
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    2016 (English)In: Plant Physiology, ISSN 0032-0889, E-ISSN 1532-2548, Vol. 170, no 2, p. 956-970Article in journal (Refereed) Published
    Abstract [en]

    Plant vascular tissues, xylem and phloem, differentiate in distinct patterns from procambial cells as an integral transport system for water, sugars, and signaling molecules. Procambium formation is promoted by high auxin levels activating class III homeodomain leucine zipper (HD-ZIP III) transcription factors (TFs). In the root of Arabidopsis (Arabidopsis thaliana), HD-ZIP III TFs dose-dependently govern the patterning of the xylem axis, with higher levels promoting metaxylem cell identity in the central axis and lower levels promoting protoxylem at its flanks. It is unclear, however, by what mechanisms the HD-ZIP III TFs control xylem axis patterning. Here, we present data suggesting that an important mechanism is their ability to moderate the auxin response. We found that changes in HD-ZIP III TF levels affect the expression of genes encoding core auxin response molecules. We show that one of the HD-ZIP III TFs, PHABULOSA, directly binds the promoter of both MONOPTEROS (MP)/AUXIN RESPONSE FACTOR5, a key factor in vascular formation, and IAA20, encoding an auxin/indole acetic acid protein that is stable in the presence of auxin and able to interact with and repress MP activity. The double mutant of IAA20 and its closest homolog IAA30 forms ectopic protoxylem, while overexpression of IAA30 causes discontinuous protoxylem and occasional ectopic metaxylem, similar to a weak loss-of-function mp mutant. Our results provide evidence that HD-ZIP III TFs directly affect the auxin response and mediate a feed-forward loop formed by MP and IAA20 that may focus and stabilize the auxin response during vascular patterning and the differentiation of xylem cell types.

    National Category
    Botany
    Identifiers
    urn:nbn:se:uu:diva-279586 (URN)10.1104/pp.15.01204 (DOI)000369343300028 ()26637548 (PubMedID)
    Funder
    Swedish Research Council, 2010-5637Swedish Research Council Formas, 2007:1169Carl Tryggers foundation , CTS 07:64Carl Tryggers foundation , CTS 12:82Magnus Bergvall FoundationHelge Ax:son Johnsons stiftelse
    Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2020-01-10Bibliographically approved
    2. Continuous root xylem formation and vascular acclimation to water deficit involves endodermal ABA signalling via miR165
    Open this publication in new window or tab >>Continuous root xylem formation and vascular acclimation to water deficit involves endodermal ABA signalling via miR165
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    2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 3, article id dev159202Article in journal (Refereed) Published
    Abstract [en]

    The plant root xylem comprises a specialized tissue for water distribution to the shoot. Despite its importance, its potential morphological plasticity in response to environmental conditions such as limited water availability has not been thoroughly studied. Here, we identify a role for the phytohormone abscisic acid (ABA) for proper xylem development and describe how ABA signalling-mediated effects on core developmental regulators are employed to alter xylem morphology under limited water availability in Arabidopsis. Plants with impaired ABA biosynthesis and reduced ABA signalling in the cell layer surrounding the vasculature displayed defects in xylem continuity, suggesting that non-cell autonomous ABA signalling is required for proper xylem development. Conversely, upon external ABA application or under limited water availability, extra xylem strands were formed. The observed xylem developmental alterations were dependent on adequate endodermal ABA signalling, which activated MIR165A. This resulted in increased miR165 levels that repress class III HD-ZIP transcription factors in the stele. We conclude that a pathway known to control core developmental features is employed as a means of modifying plant xylem morphology under conditions of environmental stress.

    Place, publisher, year, edition, pages
    COMPANY OF BIOLOGISTS LTD, 2018
    Keywords
    ABA, Arabidopsis thaliana, HD-ZIP III transcription factors, miR165, Xylem
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-347084 (URN)10.1242/dev.159202 (DOI)000424653300014 ()
    Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2020-01-10Bibliographically approved
    3. Xylem developmental plasticity requires ABA mediated VND activation
    Open this publication in new window or tab >>Xylem developmental plasticity requires ABA mediated VND activation
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Agricultural and Veterinary sciences Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-401799 (URN)
    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-10
  • Public defence: 2020-02-28 13:00 Sal IX, Universitetshuset, Uppsala
    Larsson, Ernils
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology.
    Rituals of a Secular Nation: Shinto Normativity and the Separation of Religion and State in Postwar Japan2020Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis explores how the concept of “religion” has been interpreted and negotiated in postwar Japanese courts of law, with a particular focus on its relationship to the adjacent concept “Shinto.” Particular attention is given to the landmark rulings by the Supreme Court on the Tsu Groundbreaking Ceremony case in 1977 and the Ehime Tamagushiryō case in 1997. The central questions discussed in this work relate to how postwar courts have handled the strict separation of religion from the state as established in the 1947 constitution, originally drafted by American servicemen during the occupation of Japan with the aim of preventing a return of “State Shinto.” The study emphasizes the political and ideological questions at the center of lawsuits on state-religion relations in Japan, arguing that these lawsuits must be understood within the greater framework of a hegemonic struggle over postwar national identity. Often filed by plaintiffs representing various “minority” positions, the lawsuits are read as a challenge against what I refer to as a Shinto normative order of discourse, according to which many aspects of Shrine Shinto are considered to be in accordance with common sense and integral to Japanese ethnic and national identity; what it means to be Japanese. Whereas this Shinto normative order of discourse in many ways mirrors prewar ideas about the Japanese national character, it is challenged in courts by liberals, socialists, and religious minorities. Central to this struggle is the question of how religion is to be understood in court. To the opponents of Shinto normativity, religion is understood as a concept which includes Shinto in all its forms, putting Shinto on equal footing with other religions. Proponents of Shinto normativity, on the other hand, argue that while in some ways similar to religion, Shinto is still essentially different from other religions, in particular as it focuses on the public rather than the private. This thesis critically examines both of these positions and how they have been evaluated by postwar courts of law, while also emphasizing the problems in legislating religion caused by the inherent ambiguity of the concept itself.

  • Public defence: 2020-02-28 13:00 Häggsalen, Uppsala
    Ikegami Andersson, Walter
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Exploring the Merits and Challenges of Hyperon Physics: with PANDA at FAIR2020Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Binary hyperon production in antiproton-proton annihilations will be carried out with the PANDA experiment at FAIR, and probes the strong interaction in the non-perturbative regime where the relevant degrees of freedom are unclear. The self-analyzing decays of hyperons provide a straightforward way to study reaction dynamics via the measurement of spin observables. However, since weakly decaying hyperons can travel several centimeters before decaying, they are challenging to reconstruct. Conventional track reconstruction algorithms assume that charge particles originate in the experiment interaction point.

    In this thesis, software tools are developed for the reconstruction and fitting of charged particles in the collaboration-wide software package PandaRoot. Pattern recognition algorithms are developed for the reconstruction of charged particle tracks with displaced vertices. Three algorithms that reconstruct the longitudinal momentum in the Straw Tube Tracker (STT) of PANDA are developed. They are based on a combinatorial approach, a Hough Transform, and a recursive annealing fit. The implementation and performance of these algorithms are presented. The track fitting scheme of PandaRoot is overhauled to treat the five particle species that PANDA is expected to measure, namely electrons, muons, pions, kaons and protons. The new track fitting scheme is outlined and discussed.

    When the PANDA experiment is taken into operation, beam time will be allocated to many different measurements. For this reason, feasibility studies are performed in this thesis. The pp → ΛΛ reaction is simulated at 1.642 GeV/c and the pp → Ξ+Ξ− reaction is simulated at 7.0 and 4.6 GeV/c beam momenta. The simulation and analysis chain of the studies are explained. Expected reconstruction rates are presented. Furthermore, the feasibility of reconstructing spin observables in the reactions is discussed.

  • Public defence: 2020-02-28 13:15 Room C8:305, Uppsala
    Han, Fan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genetic Adaptation and Speciation in Darwin’s Finches and Atlantic Herring2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Natural selection acts on existing genetic variation to drive genetic adaptation of organisms to various ecological niches. Interaction between closely related populations, through processes such as competition and hybridization, may either lead to their divergence or population fusion, which has consequences for adaptation and the formation of species. This thesis aims to use two natural populations, Darwin’s finches and Atlantic herring, as models to explore the genetic mechanisms underlying ecological adaptation and speciation.

    The ecological adaptation of Darwin’s finches across the Galápagos Islands is primarily reflected by variation in beak morphology. Using whole-genome re-sequencing of all Darwin’s finch species, we discover that a locus, HMGA2, is highly associated with variation in beak size. Data collected before and after a severe drought show that this locus plays a critical role for ecological character displacement in large ground finches Geospiza magnirostris and medium ground finches G. fortis.

    Genomic islands of divergence refer to genomic regions of elevated divergence when comparing the genomes of closely related taxa. Establishment of these genomic islands can reflect a role in reproductive isolation or be related to ecological adaptation or background selection. Investigating their properties can shed light on how new species evolve. We study the landscape of genomic islands in Darwin’s finches, and find that the most pronounced genomic islands are likely ancient balanced polymorphisms, which govern adaptive variation in beak morphology.

    Hybridization is increasingly recognized as an important evolutionary process which may lead to speciation. We study two cases of hybridization in Darwin’s finches. In the first case, a new lineage of Darwin’s finches was founded through hybridization between a resident medium ground finch G. fortis and an immigrant Española cactus finch G. conirostris. In the second case, female-biased introgression occurred predominantly from medium ground finches G. fortis to common cactus finches G. scandens. Our genetic analysis on the mosaic genomes of hybrid finches show that non-random mating and natural selection primarily determine the outcome of hybridization.

    We generate a chromosome-level assembly of the Atlantic herring with a total size of 726 Mb, which coincides with a high-resolution linkage map and an LD-based recombination map. This facilitates the identification of an ~8Mb inversion, which is likely to be associated with ecological adaptation in herring to differences in water temperature. The contiguity of the assembly sorts placement of loci under selection that were identified based on a previous, highly fragmented draft assembly of the herring genome.

    List of papers
    1. A beak size locus in Darwin’s finches facilitated character displacement during a drought
    Open this publication in new window or tab >>A beak size locus in Darwin’s finches facilitated character displacement during a drought
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    2016 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 352, no 6284, p. 470-474Article in journal (Refereed) Published
    Abstract [en]

    Ecological character displacement is a process of morphological divergence that reducescompetition for limited resources. We used genomic analysis to investigate the geneticbasis of a documented character displacement event in Darwin’s finches on Daphne Majorin the Galápagos Islands: The medium ground finch diverged from its competitor, the largeground finch, during a severe drought. We discovered a genomic region containing theHMGA2gene that varies systematically among Darwin’s finch species with different beaksizes. Two haplotypes that diverged early in the radiation were involved in the characterdisplacement event: Genotypes associated with large beak size were at a strong selectivedisadvantage in medium ground finches (selection coefficients= 0.59). Thus, a majorlocus has apparently facilitated a rapid ecological diversification in the adaptive radiationof Darwin’s finches.

    National Category
    Genetics and Breeding
    Identifiers
    urn:nbn:se:uu:diva-279968 (URN)10.1126/science.aad8786 (DOI)000374479700050 ()27102486 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council, 80576801Swedish Research Council, 70374401
    Available from: 2016-03-06 Created: 2016-03-06 Last updated: 2019-11-28Bibliographically approved
    2. Gene flow, ancient polymorphism, and ecological adaptation shape the genomic landscape of divergence among Darwin's finches
    Open this publication in new window or tab >>Gene flow, ancient polymorphism, and ecological adaptation shape the genomic landscape of divergence among Darwin's finches
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    2017 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 27, no 6, p. 1004-1015Article in journal (Refereed) Published
    Abstract [en]

    Genomic comparisons of closely related species have identified "islands" of locally elevated sequence divergence. Genomic islands may contain functional variants involved in local adaptation or reproductive isolation and may therefore play an important role in the speciation process. However, genomic islands can also arise through evolutionary processes unrelated to speciation, and examination of their properties can illuminate how new species evolve. Here, we performed scans for regions of high relative divergence (FST) in 12 species pairs of Darwin's finches at different genetic distances. In each pair, we identify genomic islands that are, on average, elevated in both relative divergence (FST) and absolute divergence (dXY). This signal indicates that haplotypes within these genomic regions became isolated from each other earlier than the rest of the genome. Interestingly, similar numbers of genomic islands of elevated dXY are observed in sympatric and allopatric species pairs, suggesting that recent gene flow is not a major factor in their formation. We find that two of the most pronounced genomic islands contain the ALX1 and HMGA2 loci, which are associated with variation in beak shape and size, respectively, suggesting that they are involved in ecological adaptation. A subset of genomic island regions, including these loci, appears to represent anciently diverged haplotypes that evolved early during the radiation of Darwin's finches. Comparative genomics data indicate that these loci, and genomic islands in general, have exceptionally low recombination rates, which may play a role in their establishment.

    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-340985 (URN)10.1101/gr.212522.116 (DOI)000402521400011 ()28442558 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation
    Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2019-11-28Bibliographically approved
    3. Rapid hybrid speciation in Darwin's finches
    Open this publication in new window or tab >>Rapid hybrid speciation in Darwin's finches
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    2018 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 359, no 6372, p. 224-228Article in journal (Refereed) Published
    Abstract [en]

    Homoploid hybrid speciation in animals has been inferred frequently from patterns of variation, but few examples have withstood critical scrutiny. Here we report a directly documented example, from its origin to reproductive isolation. An immigrant Darwin's finch to Daphne Major in the Galápagos archipelago initiated a new genetic lineage by breeding with a resident finch (Geospiza fortis). Genome sequencing of the immigrant identified it as a G. conirostris male that originated on Española >100 kilometers from Daphne Major. From the second generation onward, the lineage bred endogamously and, despite intense inbreeding, was ecologically successful and showed transgressive segregation of bill morphology. This example shows that reproductive isolation, which typically develops over hundreds of generations, can be established in only three.

    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-340986 (URN)10.1126/science.aao4593 (DOI)000419816600048 ()29170277 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2020-02-17Bibliographically approved
    4. Female-biased gene flow between two species of Darwin’s finches
    Open this publication in new window or tab >>Female-biased gene flow between two species of Darwin’s finches
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    2019 (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    The mosaic nature of hybrid genomes is well recognized, but little is known of how they are shaped initially by patterns of breeding, selection, recombination and differential incompatibilities. On the small Galápagos island of Daphne Major two species of Darwin’s finches, Geospiza fortis and G. scandens, hybridize rarely and backcross bidirectionally with little or no loss of fitness under conditions of plentiful food. We used whole genome sequences to compare genomes from periods before and after successful interbreeding followed by backcrossing. We inferred extensive introgression from G. fortis to G. scandens on autosomes and mitochondria but not on the Z chromosome. The unique combination of long-term field observations and genomic data shows that the reduction of gene flow for Z-linked loci reflects female-biased gene flow, arising from hybrid male disadvantage in competition for territories and mates, rather than from genetic incompatibilities at Z-linked loci.

    Keywords
    Darwin's finches, introgression, hybridisation
    National Category
    Ecology Evolutionary Biology Genetics
    Identifiers
    urn:nbn:se:uu:diva-396776 (URN)
    Available from: 2019-11-09 Created: 2019-11-09 Last updated: 2019-11-28
    5. A chromosome-level assembly of the Atlantic herring: detection of a supergene and other signals of selection
    Open this publication in new window or tab >>A chromosome-level assembly of the Atlantic herring: detection of a supergene and other signals of selection
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    2019 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 29, no 11, p. 1919-1928Article in journal (Refereed) Published
    Abstract [en]

    The Atlantic herring is a model species for exploring the genetic basis for ecological adaptation, due to its huge population size and extremely low genetic differentiation at selectively neutral loci. However, such studies have so far been hampered because of a highly fragmented genome assembly. Here, we deliver a chromosome-level genome assembly based on a hybrid approach combining a de novo Pacific Biosciences (PacBio) assembly with Hi-C-supported scaffolding. The assembly comprises 26 autosomes with sizes ranging from 12.4 to 33.1 Mb and a total size, in chromosomes, of 726 Mb, which has been corroborated by a high-resolution linkage map. A comparison between the herring genome assembly with other high-quality assemblies from bony fishes revealed few inter-chromosomal but frequent intra-chromosomal rearrangements. The improved assembly facilitates analysis of previously intractable large-scale structural variation, allowing, for example, the detection of a 7.8-Mb inversion on Chromosome 12 underlying ecological adaptation. This supergene shows strong genetic differentiation between populations. The chromosome-based assembly also markedly improves the interpretation of previously detected signals of selection, allowing us to reveal hundreds of independent loci associated with ecological adaptation.

    Place, publisher, year, edition, pages
    Cold Spring Harbor Laboratory Press (CSHL), 2019
    Keywords
    Atlantic herring, assembly, ecological adaptation, supergene
    National Category
    Genetics Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-396775 (URN)10.1101/gr.253435.119 (DOI)000493952800015 ()31649060 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Research Council of Norway, 254774Wellcome trust, WT108749/Z/15/Z
    Available from: 2019-11-09 Created: 2019-11-09 Last updated: 2019-11-28Bibliographically approved
  • Public defence: 2020-02-28 13:15 The Humanities Theatre, Uppsala
    Boberg, Johan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Philosophy.
    Scientifically Minded: Science, the Subject and Kant’s Critical Philosophy2020Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Modern philosophy is often seen as characterized by a shift of focus from the things themselves to our knowledge of them, i.e., by a turn to the subject and subjectivity. The philosophy of Immanuel Kant is seen as the site of the emergence of the idea of a subject that constitutes the object of knowledge, and thus plays a central role in this narrative. This study examines Kant’s theory of knowledge at the intersection between the history of science and the history of the modern subject, on the one hand, and in the tension between modern experimental and mathematical science and more traditional Aristotelian conceptions of epistemic perfection, on the other.

    The dissertation consists of four chapters. In the first chapter, I examine Kant’s concept of experience, and its relation both to Early Modern experimentalism and to the Wolffian tradition. In the second chapter, I argue that Kant adheres to a broadly Aristotelian conception of epistemic perfection – the ideal of understanding – but transforms this ideal into the self-understanding of reason, where reason can only have insight into the products of its own activity. In the third chapter, I use Kant’s conception of space and time to exemplify such products of reason, and argue that, for Kant, space and time are constructively generated representations that function as principles for ordering empirical knowledge. In the fourth and final chapter, I examine Kant’s conception of the subject, and situate it in relation to both the long history of the modern subject and German Enlightenment philosophy. Whereas the modern philosophical conception of the subject is usually taken to combine an ‘I’ functioning as the subject to which mental acts are attributed and an ‘I’ that has the ability to immediately perceive itself as the subject of these acts, I argue that Kant reconceives this relation between the ‘I’ and its acts as a purely intellectual self-relation. The unity of the ‘I’ is not a perceived unity, but a unity brought about by the intellect.

  • Public defence: 2020-03-03 09:15 Häggsalen, Uppsala
    Tian, Lei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Exploring Dye-Sensitized Mesoporous NiO Photocathodes: from Mechanism to Applications2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Increasing attention has been paid on solar energy conversion since the abundant solar energy possesses the potential to solve the problems on energy crisis and climate change. Dye-sensitized mesoporous NiO film was developed as one of the attractive photocathodes to fabricate p-type dye-sensitized solar cells (p-DSCs) and dye-sensitized photoelectrosynthetic cells (p-DSPECs) for electricity and chemical fuels generation, respectively. In this thesis, we designed a well-structured NiO-dye-TiO2 configuration by an atomic layer deposition (ALD) technique, with an organic dye PB6 as the photosensitizer. From kinetic studies of charge separation, ultrafast hole injection (< 200 fs) was observed from the excited state of PB6 dye into the valence band of NiO; dye regeneration (electron injection) was in t1/2 ≤ 500 fs, which is the fastest reported in any DSCs. On the basis of NiO-dye-TiO2 configuration, we successfully fabricated solid-state p-type DSCs (p-ssDSCs). Insertion of an Al2O3 layer was adopted to reduce charge recombination, i.e. NiO-dye-Al2O3-TiO2. Theoretically, such a configuration is possible to maintain efficient charge separation and depressed charge recombination. Based on NiO-dye-Al2O3-TiO2 configuration, the open-circuit voltage was improved to 0.48 V. Replacing electron conductor TiO2 with ZnO, short-circuit current density was increased to 680 μA·cm-2. The photocatalytic current density for H2 evolution was improve to 100 μA·cm-2 with a near unity of Faraday efficiency in p-DSPECs.

    However, to further improve the performance of p-DSCs is very challenging. In p-ssDSCs, the limitation was confirmed from the poor electronically connection of the electron conductor (TiO2 or ZnO) inside the NiO-dye films. We further investigated the electronic property of surface states on mesoporous NiO film. We found that the surface sates, not the bulk, on NiO determined the conductivity of the mesoporous NiO films. The dye regeneration in liquid p-DSCs with I-/I3- as redox couples was significantly affected by surface states. A more complete mechanism is suggested to understand a particular hole transport behavior reported in p-DSCs, where hole transport time is independent on light intensity. The independence of charge transport is ascribed to the percolation effect in the hole hopping on the surface states.

     

    List of papers
    1. Ultrafast dye regeneration in a core-shell NiO-dye-TiO2 mesoporous film
    Open this publication in new window or tab >>Ultrafast dye regeneration in a core-shell NiO-dye-TiO2 mesoporous film
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    2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 1, p. 36-40Article in journal (Refereed) Published
    Abstract [en]

    In this study, a core-shell NiO-dye-TiO2 mesoporous film was fabricated for the first time, utilizing atomic layer deposition technique and a newly designed triphenylamine dye. The structure of the film was confirmed by SEM, TEM, and EDX. Excitation of the dye led to efficient and fast charge separation, by hole injection into NiO, followed by an unprecedentedly fast dye regeneration (t1/2 [less-than-or-equal] 500 fs) by electron transfer to TiO2. The resulting charge separated state showed a pronounced transient absorption spectrum caused by the Stark effect, and no significant decay was found within 1.9 ns. This indicates that charge recombination between NiO and TiO2 is much slower than that between the NiO and the reduced dye in the absence of the TiO2 layer (t1/2 [approximate] 100 ps).

    Place, publisher, year, edition, pages
    The Royal Society of Chemistry, 2018
    National Category
    Natural Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-335974 (URN)10.1039/C7CP07088H (DOI)000418374800002 ()
    Funder
    Knut and Alice Wallenberg Foundation, 2011.0067Swedish Energy Agency, 43599-1
    Note

    Correction in: PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Volume: 20, Issue: 46, Pages: 29566-29566, DOI: 10.1039/c8cp91912g

    Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2020-01-15Bibliographically approved
    2. Solid state p-type dye sensitized NiO-dye-TiO2 core-shell solar cells
    Open this publication in new window or tab >>Solid state p-type dye sensitized NiO-dye-TiO2 core-shell solar cells
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    2018 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, no 30, p. 3739-3742Article in journal (Refereed) Published
    Abstract [en]

    Solid state p-type dye sensitized NiO-dye-TiO2 core-shell solar cells with an organic dye PB6 were successfully fabricated for the first time. With Al2O3 as an inner barrier layer, the recombination process between injected holes in NiO and injected electrons in TiO2 was significantly suppressed and the charge transport time was also improved.

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2018
    National Category
    Physical Chemistry Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-352467 (URN)10.1039/c8cc00505b (DOI)000429592700013 ()29589009 (PubMedID)
    Funder
    Swedish Energy Agency, 43599-1
    Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2020-01-15Bibliographically approved
    3. Solution-processed nanoporous NiO-dye-ZnO photocathodes: Toward efficient and stable solid-state p-type dye-sensitized solar cells and dye-sensitized photoelectrosynthesis cells
    Open this publication in new window or tab >>Solution-processed nanoporous NiO-dye-ZnO photocathodes: Toward efficient and stable solid-state p-type dye-sensitized solar cells and dye-sensitized photoelectrosynthesis cells
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    2019 (English)In: Nano Energy, ISSN 2211-2855, E-ISSN 2211-3282, Vol. 55, p. 59-64Article in journal (Refereed) Published
    Abstract [en]

    A solution-processed NiO-dye-ZnO photocathode was developed for applications in both solid-state p-type dye-sensitized solar cells (p-ssDSCs) and p-type dye-sensitized photoelectrosynthesis cells (p-DSPECs). In p-ssDSCs, the solar cell using ZnO as electron transport material showed a short circuit current, up to 680 mu A cm(-2), which is 60-fold larger than that previously reported device using TiO2 as electron transport material with similar architecture. In the p-DSPECs, a remarkable photocurrent of 100 mu A cm(-2) was achieved in a pH = 5.0 acetate buffer solution under a bias potential at 0.05 V vs RHE with platinum as the proton reduction catalyst. A Faradaic efficiency approaching 100% for the H-2 evolution reaction was obtained after photoelectrolysis for 9 h. Importantly, the solution-processed NiO-dye-ZnO photocathode exhibited excellent long-term stability in both p-ssDSCs and p-DSPECs. To the best of our knowledge, this is the first study where a solution-processable, nanoporous NiO-dye-ZnO photocathode is used for both p-ssDSCs and p-DSPECs having both excellent device performance and stability.

    Keywords
    Dye-sensitized photocathode, P-type, Solution-processed, Solid-state, Solar cell, Solar fuel
    National Category
    Materials Chemistry Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-374114 (URN)10.1016/j.nanoen.2018.10.054 (DOI)000454636200007 ()
    Funder
    Swedish Energy Agency, 43599-1Swedish Energy Agency, 11674-8
    Note

    Bo Xu and Lei Tian contributed equally to this work.

    Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2020-01-15Bibliographically approved
    4. Mechanistic Insights into Solid-State p-Type Dye-Sensitized Solar Cells
    Open this publication in new window or tab >>Mechanistic Insights into Solid-State p-Type Dye-Sensitized Solar Cells
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    2019 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 123, no 43, p. 26151-26160Article in journal (Refereed) Published
    Abstract [en]

    The study of p-type dye sensitized solar cells (p-DSCs) is appealing but challenging. Although the devices have been studied for 20 years, the light conversion efficiency lags far behind those of n-DSCs. Very recently, on the basis of a core-shell structure, a novel solid-state p-DSC (p-ssDSCs) has been fabricated, which showed great enhancement in open-circuit voltage and dye regeneration rate. To further improve the performance of such devices, charge diffusion, recombination process, and the main limiting factors have to be understood. In the present paper, core-shell p-ssDSCs with ZnO as an electron conductor were fabricated by atomic layer deposition. The charge transport time was determined to be ca. 0.1 ms, which is about 2 orders of magnitude faster than those of typical liquid devices with I-/I-3(-) as a redox mediator. As a consequence, the devices exhibit the highest reported charge diffusion coefficient (D-d)' among p-DSCs. It is ascribed to an electron-limiting diffusion process by the ambipolar diffusion model, suggesting a different charge-transport-determining mechanism in contrast to liquid p-DSCs. The charge recombination rate is 1-2 orders of magnitude slower than its charge transport time, mandating that the estimated charge collection efficiency is near unity. Detailed analysis of the incident photon-to-electron conversion efficiency suggests that the energy conversion efficiency in these p-ssDSCs is currently limited by a large fraction of dyes that is not fully electrically connected in the device.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2019
    National Category
    Physical Chemistry Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-397591 (URN)10.1021/acs.jpcc.9b08251 (DOI)000493865700013 ()
    Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-01-15Bibliographically approved
    5. Rethinking the function of surface states on mesoporous NiO films
    Open this publication in new window or tab >>Rethinking the function of surface states on mesoporous NiO films
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Physical Chemistry
    Research subject
    Chemistry with specialization in Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-402255 (URN)
    Available from: 2020-01-13 Created: 2020-01-13 Last updated: 2020-01-22
  • Public defence: 2020-03-05 09:00 Holmdahlsalen, ingång 100, Uppsala
    Lindgren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Cardiac Arrest – mechanical chest compressions, gender differences and coronary angiography2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cardiac arrest is a major health problem with over 6000 cases of out-of-hospital cardiac arrest (OHCA) and 2500 cases of in-hospital cardiac arrest (IHCA) per year in Sweden. Survival are low. Many factors affect the chances of survival, including effective cardiopulmonary resuscitation and optimal post resuscitation care. These thesis involve these areas. Paper I+II describe a randomized clinical trial (n=2589). We compared a novel CPR algorithm with defibrillations during ongoing chest compressions delivered with a mechanical chest compression device and manual CPR according to guidelines. We found no difference in 4-hour survival, 23.6% with mechanical CPR and 23.7% with manual CPR. The vast majority of survivors in both groups had good neurological outcomes by 6 months. Paper III is a registry study (n=1498). We investigated impact of gender in performance and findings of early coronary angiography (CAG) and percutaneous coronary intervention (PCI), comorbidity and outcome among OHCA victims with an initially shockable rhythm. We found no difference between men and women in rates of ST-elevation/left bundle branch block (LBBB), 40% vs. 38% or rates of CAG, 45% vs. 40%. Among patients without ST-elevation/LBBB more men than women had CAG followed by PCI, 59% vs. 42% (P=0.03) and more advanced coronary artery disease. We found no association between gender and use of early CAG. Paper IV is a retrospective observational single centre study (n=423) of ICU treated victims of cardiac arrest. OHCA and IHCA were compared regarding comorbidity, characteristics of the arrest, treatment including CAG and CAG findings and outcome. OHCA patients had less preexisting comorbidity, lower rates of bystander CPR 71% vs 100% (p<0.001) and longer time to return of spontaneous circulation, 20 vs 10 minutes (p<0.001). OHCA patients more often had a shockable first rhythm, 47% vs 13% (p<0.001) and CA without any obvious non-cardiac origin, 77% vs 50% (p<0.001). OHCA patients more often underwent early CAG, 52% vs 25% (p<0.001) but no difference in rates of subsequent PCI or angiogram with at least one significant stenosis was seen. OHCA and IHCA did not differ in 30-days survival, 42% vs 41% or 1-year survival, 39% vs 33% 

    List of papers
    1. The Study Protocol for the LINC (LUCAS in Cardiac Arrest) Study: a study comparing conventional adult out-of-hospital cardiopulmonary resuscitation with a concept with mechanical chest compressions and simultaneous defibrillation
    Open this publication in new window or tab >>The Study Protocol for the LINC (LUCAS in Cardiac Arrest) Study: a study comparing conventional adult out-of-hospital cardiopulmonary resuscitation with a concept with mechanical chest compressions and simultaneous defibrillation
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    2013 (English)In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 21, p. 5-Article in journal (Refereed) Published
    Abstract [en]

    Background: The LUCAS (TM) device delivers mechanical chest compressions that have been shown in experimental studies to improve perfusion pressures to the brain and heart as well as augmenting cerebral blood flow and end tidal CO2, compared with results from standard manual cardiopulmonary resuscitation (CPR). Two randomised pilot studies in out-of-hospital cardiac arrest patients have not shown improved outcome when compared with manual CPR. There remains evidence from small case series that the device can be potentially beneficial compared with manual chest compressions in specific situations. This multicentre study is designed to evaluate the efficacy and safety of mechanical chest compressions with the LUCAS (TM) device whilst allowing defibrillation during on-going CPR, and comparing the results with those of conventional resuscitation. Methods/design: This article describes the design and protocol of the LINC-study which is a randomised controlled multicentre study of 2500 out-of-hospital cardiac arrest patients. The study has been registered at ClinicalTrials. gov (http://clinicaltrials.gov/ct2/show/NCT00609778?term=LINC&rank=1). Results: Primary endpoint is four-hour survival after successful restoration of spontaneous circulation. The safety aspect is being evaluated by post mortem examinations in 300 patients that may reflect injuries from CPR. Conclusion: This large multicentre study will contribute to the evaluation of mechanical chest compression in CPR and specifically to the efficacy and safety of the LUCAS (TM) device when used in association with defibrillation during on-going CPR.

    Keywords
    Cardiac arrest, Mechanical chest compression, Defibrillation, External chest compressions, Ventricular fibrillation, Asystole, Pulseless electrical activity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-197667 (URN)10.1186/1757-7241-21-5 (DOI)000315588600001 ()
    Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2020-01-16Bibliographically approved
    2. Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest The LINC Randomized Trial
    Open this publication in new window or tab >>Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest The LINC Randomized Trial
    Show others...
    2014 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 1, p. 53-61Article in journal (Refereed) Published
    Abstract [en]

    IMPORTANCE A strategy using mechanical chest compressions might improve the poor outcome in out-of-hospital cardiac arrest, but such a strategy has not been tested in large clinical trials. OBJECTIVE To determine whether administering mechanical chest compressions with defibrillation during ongoing compressions (mechanical CPR), compared with manual cardiopulmonary resuscitation (manual CPR), according to guidelines, would improve 4-hour survival. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial of 2589 patients with out-of-hospital cardiac arrest conducted between January 2008 and February 2013 in 4 Swedish, 1 British, and 1 Dutch ambulance services and their referring hospitals. Duration of follow-up was 6 months. INTERVENTIONS Patients were randomized to receive either mechanical chest compressions (LUCAS Chest Compression System, Physio-Control/Jolife AB) combined with defibrillation during ongoing compressions (n = 1300) or to manual CPR according to guidelines (n = 1289). MAIN OUTCOMES AND MEASURES Four-hour survival, with secondary end points of survival up to 6 months with good neurological outcome using the Cerebral Performance Category (CPC) score. A CPC score of 1 or 2 was classified as a good outcome. RESULTS Four-hour survival was achieved in 307 patients (23.6%) with mechanical CPR and 305 (23.7%) with manual CPR (risk difference, -0.05%; 95% CI, -3.3% to 3.2%; P > .99). Survival with a CPC score of 1 or 2 occurred in 98 (7.5%) vs 82 (6.4%) (risk difference, 1.18%; 95% CI, -0.78% to 3.1%) at intensive care unit discharge, in 108 (8.3%) vs 100 (7.8%) (risk difference, 0.55%; 95% CI, -1.5% to 2.6%) at hospital discharge, in 105 (8.1%) vs 94 (7.3%) (risk difference, 0.78%; 95% CI, -1.3% to 2.8%) at 1 month, and in 110 (8.5%) vs 98 (7.6%) (risk difference, 0.86%; 95% CI, -1.2% to 3.0%) at 6 months with mechanical CPR and manual CPR, respectively. Among patients surviving at 6 months, 99% in the mechanical CPR group and 94% in the manual CPR group had CPC scores of 1 or 2. CONCLUSIONS AND RELEVANCE Among adults with out-of-hospital cardiac arrest, there was no significant difference in 4-hour survival between patients treated with the mechanical CPR algorithm or those treated with guideline-adherent manual CPR. The vast majority of survivors in both groups had good neurological outcomes by 6 months. In clinical practice, mechanical CPR using the presented algorithm did not result in improved effectiveness compared with manual CPR.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-216731 (URN)10.1001/jama.2013.282538 (DOI)000329161400018 ()
    Available from: 2014-01-27 Created: 2014-01-24 Last updated: 2020-01-16Bibliographically approved
    3. Gender differences in utilization of coronary angiography and angiographic findings after out-of-hospital cardiac arrest: A registry study
    Open this publication in new window or tab >>Gender differences in utilization of coronary angiography and angiographic findings after out-of-hospital cardiac arrest: A registry study
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    2019 (English)In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 143, p. 189-195Article in journal (Refereed) Published
    Abstract [en]

    Introduction: We investigated the impact of gender in performance and findings of early coronary angiography (CAG) and percutaneous coronary intervention (PCI), comorbidity and outcome in a large population of out-of-hospital cardiac arrest (OHCA) patients with an initially shockable rhythm.

    Methods: Retrospective cohort study. Data retrieved 2008-2013 from the Swedish Register for Cardio-Pulmonary Resuscitation, Swedeheart Registry and National Patient Register.

    Results: We identified 1498 patients of whom 78% were men. Men and women had the same pathology on the first registered electrocardiogram (ECG): 30% vs. 29% had ST-elevation and 10% vs. 9% had left bundle branch block (LBBB) (P=0.97). Proportions of performed CAG did not differ between genders. Among patients without ST-elevation/LBBB men more often had at least one significant stenosis, 78% vs. 54% (P= 0.001), more multi-vessel disease (P= 0.01), had normal coronary angiography less often, 22% vs. 46% and PCI more often, 59% vs. 42% (P= 0.03). Among patients without STelevation/LBBB on the initial ECG, more men had previously known ischaemic heart disease, 27% vs. 19% (P=0.02) and a presumed cardiac origin of the cardiac arrest, 86% vs. 72% (P< 0.001). Multivariable analysis showed no association between gender and evaluation by early CAG. In men and women, 1-year survival was 56% vs. 50% (P= 0.22) in patients with ST-elevation/LBBB and 48% vs. 51% (P= 0.50) in patients without.

    Conclusion: Despite no gender differences in ECG findings indicating an early CAG, men had more severe coronary artery disease while women more frequently had normal coronary angiography. However, this did not influence 1-year survival.

    Keywords
    Cardiac arrest, Gender differences, Out-of-hospital cardiac arrest, Coronary angiography, Percutaneous coronary intervention, Ventricular fibrillation, CPR, Registry study
    National Category
    Cardiac and Cardiovascular Systems Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-395786 (URN)10.1016/j.resuscitation.2019.07.015 (DOI)000487197500028 ()31330199 (PubMedID)
    Available from: 2019-10-28 Created: 2019-10-28 Last updated: 2020-01-16Bibliographically approved
    4. A study comparing victims of out-of-hospital and in-hospital cardiac arrest admitted alive to the ICU.
    Open this publication in new window or tab >>A study comparing victims of out-of-hospital and in-hospital cardiac arrest admitted alive to the ICU.
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Cardiac arrest, OHCA, IHCA, CPR, coronary angiography, percutaneous coronary intervention, PCI
    National Category
    Anesthesiology and Intensive Care
    Research subject
    Internal Medicine
    Identifiers
    urn:nbn:se:uu:diva-402517 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-16
  • Public defence: 2020-03-06 09:00 H:son-Holmdahlsalen, Uppsala
    Bergfelt Lennmyr, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Registry-Based Studies in Adult Acute Lymphoblastic Leukemia in Sweden: Survival and Quality of Life2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL), a common child malignancy, also constitutes a minor fraction of adult cancer with approximately 50 new cases per year in Sweden. While the five-year overall survival (OS) in pediatric ALL is more than 90%, the prognosis in adults is dismal. Using the Swedish ALL quality registry, this thesis investigates treatment and outcome of adult ALL according to national guidelines. In addition, the introduction of patient-reported outcome in the ALL and Acute Myeloid Leukemia registries is evaluated. 

    In Paper I, measurement of minimal residual disease by flow cytometry was found to be feasible but not consistently applied in the 35 patients with Philadelphia (Ph)-negative B-ALL investigated. In Paper II, treatment, toxicity and outcome of 155 patients, 55-85 years (y) with ALL diagnosis between 2005 and 2012 were studied in detail by patient charts review. An age-adopted protocol recommended from 2009 did not result in better outcome. In Paper III, disease recurrence in the same cohort as Paper II was studied. The median overall survival (OS) after ALL relapse was 3.6 months. In Paper IV, the whole ALL registry was studied and OS was estimated in 930 adult patients diagnosed in the periods 1997-2006 and 2007-2015. Five year OS improved in patients 18-45y from 50% to 65%, in patients 46-65y from 25% to 46%, and in patients >65y from 7% to 11%. This demonstrates that young patients have the best prognosis, in part due to the introduction of a dose-intense “pediatric-like” chemotherapy protocol. Compared to women, middle-aged men were found to have a worse outcome.

    Historically, Philadelphia-positive (Ph-pos) ALL has a poor prognosis compared to Ph-negative ALL. In this material, the frequency of Ph-pos ALL was 34% of examined B-ALL. Analysis of the whole registry revealed that in 2007-2015, i.e. after the introduction of the tyrosine kinase inhibitor imatinib, Ph-pos ALL was no longer associated with inferior OS. In Paper V, ALL and Acute Myeloid Leukemia patients, six months after diagnosis, completed a web or paper questionnaire regarding quality of life, symptoms and experience with care. The response rate was 64%. Depression symptoms were frequent (18%), especially in young women who reported worrying about fertility.

    In summary, although OS in adult ALL has improved, more effective and less toxic therapies in upfront treatment are highly warranted. Collection of patient-reported outcome in a national quality registry is feasible and can add important aspects of cancer care that are not usually addressed.

    List of papers
    1. Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study
    Open this publication in new window or tab >>Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study
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    2015 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 135Article in journal (Refereed) Published
    Abstract [en]

    The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

    Keywords
    Acute lymphoblastic leukaemia, Adults, Minimal residual disease, Flow cytometry
    National Category
    Cancer and Oncology Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-258836 (URN)10.1007/s12032-015-0582-2 (DOI)000351474100049 ()25796502 (PubMedID)
    Available from: 2015-07-23 Created: 2015-07-20 Last updated: 2020-01-15Bibliographically approved
    2. Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden
    Open this publication in new window or tab >>Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden
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    2017 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 99, no 2, p. 141-149Article in journal (Refereed) Published
    Abstract [en]

    ObjectivesOlder/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials. MethodsUsing Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85years, diagnosed with ALL 2005-2012. ResultsOf 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype. Philadelphia chromosome positivity (Ph+) occurred in 35%. Of the 155 B- and T-ALL patients, 80% were treated with intensive protocols, and 20% with a palliative approach. Higher age and WHO performance status 2 influenced the choice of palliation. Intensive, palliative, and both approaches resulted in complete remission rate 83/16/70% and 3-year overall survival (OS) 32/3/26%. The age-adapted protocol did not improve outcome. With intensive treatment, platelet count 35x10(9)/L and age 75years were adverse prognostic factors for OS, Ph+ was not. Male sex was an adverse prognostic factor in the 55-64 year age-group. ConclusionsWe report a high frequency of Ph+ in older/elderly patients, with no evidence of poorer outcome compared to Ph-negative disease. Overall prognosis for elderly patients with ALL remains dismal, despite the use of age-adapted treatment.

    Place, publisher, year, edition, pages
    WILEY, 2017
    Keywords
    acute lymphoblastic leukemia, chemotherapy, elderly, epidemiology
    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-329913 (URN)10.1111/ejh.12896 (DOI)000404936400005 ()
    Available from: 2017-10-20 Created: 2017-10-20 Last updated: 2020-01-15Bibliographically approved
    3. Real-world data on first relapse of acute lymphoblastic leukemia in patients > 55 years
    Open this publication in new window or tab >>Real-world data on first relapse of acute lymphoblastic leukemia in patients > 55 years
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    2018 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 59, no 10, p. 2470-2473Article in journal, Letter (Other academic) Published
    Place, publisher, year, edition, pages
    Taylor & Francis Group, 2018
    National Category
    Cancer and Oncology Hematology
    Identifiers
    urn:nbn:se:uu:diva-374878 (URN)10.1080/10428194.2017.1416369 (DOI)000455166400026 ()29345172 (PubMedID)
    Funder
    Thuréus stiftelse för främjande av geriatrisk forskningErik, Karin och Gösta Selanders Foundation
    Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2020-01-15Bibliographically approved
    4. Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry
    Open this publication in new window or tab >>Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry
    Show others...
    2019 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 103, no 2, p. 88-98Article in journal (Refereed) Published
    Abstract [en]

    Objectives: As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care.

    Methods: We used the population-based Swedish ALL Registry to evaluate characteristics, treatment and long-term outcome in 933 patients with diagnosis between 1997 and 2015.

    Results: The median age was 53 years. The frequency of Philadelphia (Ph)-positive leukaemia was 34% of examined B-ALL with a peak incidence at 50-59 years. Five-year overall survival (OS) improved between 1997-2006 and 2007-2015; in patients 18-45 years from 50% (95% CI 43-57) to 65% (95% CI 58-72), 46-65 years from 25% (95% CI 18-32) to 46% (95% CI 37-55) and >65 years from 7% (95% CI 2.6-11) to 11% (95% CI 5.9-16) (P < 0.05). Men with Ph-neg B-ALL 46-65 years had inferior OS compared with women (P < 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0-6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph-positive disease was not associated with impaired prognosis but with lower risk of death in 2007-2015.

    Conclusions: In a population-based cohort, OS has improved in adult ALL, especially for Ph-positive disease but for middle-aged men with Ph-negative B-ALL outcome was poor. Cure without late toxicity or relapse is still desired.

    Place, publisher, year, edition, pages
    WILEY, 2019
    Keywords
    acute lymphoblastic leukaemia, adult, Philadelphia-positive
    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-390495 (URN)10.1111/ejh.13247 (DOI)000475475200003 ()31074910 (PubMedID)
    Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2020-01-15Bibliographically approved
    5. Introducing Patient Reported Outcome in the Acute Leukemia Quality Registries in Sweden
    Open this publication in new window or tab >>Introducing Patient Reported Outcome in the Acute Leukemia Quality Registries in Sweden
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-402409 (URN)
    Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-15
  • Public defence: 2020-03-06 09:15 A1:107a, Uppsala
    Adeyemi, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(0)-Catalyzed Synthesis of Spirocycles and Supercritical Chemistry using a Resistively Heated Flow Reactor2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This doctoral thesis focusses on an effective and selective approach to the synthesis of spirocycles using palladium(0)-catalyzed Mizoroki-Heck reactions. In addition, selective and efficient chemistry was highlighted by the design and evaluation of a novel resistively heated system for continuous flow (CF) synthesis for high-temperature and high-pressure applications.

    Paper I described the design and evaluation of a novel resistively heated CF system. The design of a low-cost, simple, robust, and effective CF system involving a resistively heated steel reactor capable of delivering 400 °C and 200 bar was reported. The reactor was evaluated with esterification, transesterification and direct carboxylic acid to nitrile conversions using supercritical ethanol, methanol and acetonitrile respectively. Diels-Alder reactions under neat conditions were also carried out at high temperature and pressure.

    Paper II reported the synthesis of spirooxindoles by a selective application of the palladium(0)-catalyzed Mizoroki-Heck spirocyclization. The precursors for the reaction were synthesized by coupling 2-iodoanilines with esters derived from enantiomerically pure (+)-Vince lactam decorated with the bulky, directing 2,5-dimethylpyrrole protecting group. Ten different spirooxindoles were reported with good yields and high regio- and stereoselectivity. Functionalization of a synthesized spirooxindole was done by a palladium(0)-catalyzed alkoxycarbonylation, followed by selective deprotections.

    In Paper III, ether precursors were synthesized from (+)-Vince lactam, via a Mitsunobu reaction with the corresponding iodophenols. The precursors were later subjected to conditions for intramolecular Mizoroki-Heck reaction. Overall, 12 spiroethers were synthesized in useable yields, regioselectivity up to 98% and with excellent diastereoselectivity (d.e.>98%). Further functionalization to mono-protected rigidified amino acids was also demonstrated.

    List of papers
    1. Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
    Open this publication in new window or tab >>Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
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    2017 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed) Published
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-333407 (URN)10.1021/acs.oprd.7b00063 (DOI)000406356200003 ()
    Funder
    EU, FP7, Seventh Framework Programme, 607517
    Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2020-01-16Bibliographically approved
    2. Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides
    Open this publication in new window or tab >>Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides
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    2019 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 1, p. 82-88Article in journal, Letter (Refereed) Published
    Abstract [en]

    A method for highly regio- and stereoselective intramolecular Mizoroki-Heck 5- exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O - and N -deprotections.

    Place, publisher, year, edition, pages
    GEORG THIEME VERLAG KG, 2019
    Keywords
    spirooxindoles, Mizoroki-Heck, cyclization, carbonylation
    National Category
    Medicinal Chemistry Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-372880 (URN)10.1055/s-0037-1611360 (DOI)000453250700013 ()
    Funder
    EU, FP7, Seventh Framework Programme, 607517
    Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2020-01-16Bibliographically approved
    3. Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck Reaction
    Open this publication in new window or tab >>Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck Reaction
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Palladium(0)-catalyzed intramolecular annulation of twelve 1,3-disubstituted cyclopentenes, derived from (+)-vince lactam, resulted in 5-exo cyclizations, furnishing a series of 2,5-dimethyl-1-((3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]-2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process, following the arylpalladium insertion, was controlled by fine-tuning of the reaction system, providing regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single diastereoisomers.

    National Category
    Organic Chemistry Pharmaceutical Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-402335 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-24
  • Public defence: 2020-03-06 09:15 Room B22, Uppsala
    Liljebäck, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The incidence of type 1 diabetes is increasing worldwide and therapies of islet transplantation and potential cell-based therapies are rapidly evolving. Choosing the optimal site for such therapies is crucial for safety and for obtaining the best possible outcome. The liver is currently the site of choice, but is unfortunately associated with disadvantages for graft survival.

    In paper I, intraportally transplanted human islets were evaluated for hypoxia, apoptosis, and beta-cell survival. This revealed a substantial graft loss of approximately 50 % of transplanted islet mass at one month posttransplantation. At the same time, revascularization was increased, yet still lower than that of native islets. The highest rate of apoptosis was associated with prolonged time in culture prior transplantation.

    Due to progressive loss of graft function, repeated islet transplantation is often performed. A mouse model, used in paper II, demonstrated an increased survival rate of islets transplanted one week after a first transplant. This finding may reflect an improved engraftment environment “primed” by the first islet injection. No difference in islet vascular density could be ascribed to it.   

    As stem cell-based therapies improve, graft monitoring possibilities and retrieval are of importance for safely introducing these techniques into the clinic. Islet grafts to omentum and muscle cured diabetic mice in paper III. Gene expression was unaltered or increased for genes important for beta-cell function.

    Decidual stromal cells (DSCs) have immunomodulatory properties that could prove useful for treatments of autoimmune or inflammatory conditions. In paper IV, DSCs were found to be easily isolated from human placenta. The cells were characterized by surface markers, differentiation capacity and gene expression during culture. Co-culture with human pancreatic islets was also conducted. DSCs were observed to be very similar to other types of mesenchymal stromal cells. Greatest change in gene expression was seen between passage 2 and 5. The effect on human islet function may depend on islet viability prior to co-culture.

    List of papers
    1. Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model
    Open this publication in new window or tab >>Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model
    2016 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 25, no 3, p. 481-489Article in journal (Refereed) Published
    Abstract [en]

    Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

    Keywords
    Islet transplantation, Diabetes, Amyloid, Engraftment
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-294600 (URN)10.3727/096368915X688902 (DOI)000372669200005 ()26264975 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Diabetes AssociationSwedish Child Diabetes FoundationNovo Nordisk
    Available from: 2016-05-26 Created: 2016-05-25 Last updated: 2020-02-04Bibliographically approved
    2. Fewer Islets Survive from a First Transplant than a Second Transplant: Evaluation of Repeated Intraportal Islet Transplantation in Mice
    Open this publication in new window or tab >>Fewer Islets Survive from a First Transplant than a Second Transplant: Evaluation of Repeated Intraportal Islet Transplantation in Mice
    2019 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, no 11, p. 1455-1460Article in journal (Refereed) Published
    Abstract [en]

    Beta cell replacement is an exciting field where new beta cell sources and alternative sites are widely explored. The liver has been the implantation site of choice in the clinic since the advent of islet transplantation. However, in most cases, repeated islet transplantation is needed to achieve normoglycemia in diabetic recipients. This study aimed to investigate whether there are differences in islet survival and engraftment between a first and a second transplantation, performed 1 week apart, to the liver. C57BL/6 mice were accordingly transplanted twice with an initial infusion of syngeneic islets expressing green fluorescent protein (GFP). The second islet transplant was performed 1 week later and consisted of islets isolated from non-GFP C57BL/6-mice. Animals were sacrificed either 1 day or 1 month after the second transplantation. A control group received a saline infusion instead of GFP-expressing islets, 1 week later obtained a standard non-GFP islet transplant, and was subsequently sacrificed 1 month later. Islet engraftment in the liver was assessed by immunohistochemistry and serum was analyzed for angiogenic factors induced by the first islet transplantation. Almost 70% of islets found in the liver following repeated islet transplantation originated from the second transplantation. The vascular density in the transplanted non-GFP-expressing islets did not differ depending on whether their transplantation was preceded by a primary islet transplantation or saline administration only nor did angiogenic factors in serum prior to the transplantation of non-GFP islets differ between animals that had received a previous islet transplantation or a saline infusion. We conclude that first islet transplantation creates, by unknown mechanisms, favorable conditions for the survival of a second transplant to the liver.

    Keywords
    GFP, engraftment, islet transplantation, type 1 diabetes
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-398599 (URN)10.1177/0963689719866685 (DOI)000479643300001 ()31359771 (PubMedID)
    Funder
    Swedish Child Diabetes FoundationSwedish Research Council, 2017-01343EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes Association
    Available from: 2019-12-07 Created: 2019-12-07 Last updated: 2020-01-17Bibliographically approved
    3. Function and Gene Expression of Islets Experimentally Transplanted to Muscle or Omentum
    Open this publication in new window or tab >>Function and Gene Expression of Islets Experimentally Transplanted to Muscle or Omentum
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Islet transplantation, muscle, omentum, engraftment, gene expression, laser capture microdissection
    National Category
    Cell and Molecular Biology
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-282952 (URN)
    Available from: 2016-04-08 Created: 2016-04-08 Last updated: 2020-01-17
    4. Alterations of Decidual Stromal Cells in Culture and their Effect on Human Pancreatic Islets in Vitro
    Open this publication in new window or tab >>Alterations of Decidual Stromal Cells in Culture and their Effect on Human Pancreatic Islets in Vitro
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Several studies have shown improved outcome of islet transplantation after co-culture or co-transplantation with mesenchymal stromal cells (MSCs). Since there is no standardized MSC source or protocol, studies revealing the mechanism behind these promising results are fundamental for further advances and for the implementation of this treatment in clinical practice. In this study, we investigated the features of decidual stromal cells (DSCs), a type of MSCs isolated from the decidual layer of human placentas, their alterations in culture and their effect on human beta-cells in vitro.

    Human DSCs were isolated after planned caesarian sections and characterized during culture up to passage 10. Inflammatory biomarkers were analyzed in culture medium and in lysates of DSCs and human islets. After 48 hours of co-culture, assessment of islet function by high glucose and forskolin perifusion and gene expression analysis of DSCs and islets were performed. Additionally, islets were co-cultured with pro-inflammatory cytokines to evaluate the cytoprotective ability of DSCs in different co-culture systems.

    DSCs were easily isolated and of maternal origin. The cells retained the typical MSC surface marker expression up to 10 passages and were to some extent able to differentiate into three mesenchymal lineages. Gene expression analysis, after culture, showed the highest number of altered genes between passage 2 and 5. DSCs had variable effect on human islet function after co-culture, where the impact appeared dependent on islet quality of the donor. DSCs increased human islet cell death when combined with cytokine stress.

    DSCs are an eligible MSC source, easily isolated and expanded in culture. We report on changes in gene expression during culture and an ambiguous effect on human islet function.

    Keywords
    Decidual stromal cells, Type 1 diabetes, Islets of Langerhans, Gene expression
    National Category
    Cell and Molecular Biology
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-402499 (URN)
    Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-02-04Bibliographically approved
  • Public defence: 2020-03-06 13:00 Enghoffsalen, Uppsala
    Engquist, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Clinical Bedside Studies of Cerebral Blood Flow in Severe Subarachnoid Hemorrhage Using Xenon CT2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aneurysmal subarachnoid hemorrhage (SAH) is frequently complicated by delayed cerebral ischemia (DCI), contributing to poor outcome. Particularly for patients in poor neurological state, prediction of the acute clinical course is difficult, as is the early detection of DCI. Repeated measurement of global and regional cerebral blood flow (CBF) could potentially identify patients at risk of deterioration and guide in the clinical management.

    The studies in this thesis are based on bedside measurements of CBF by xenon-enhanced CT with the aim to assess and characterize global and regional CBF disturbances at different phases in the acute course after severe SAH. Furthermore, the effects of hemodynamic augmentation by hypervolemia, hemodilution and hypertension (HHH-therapy) on CBF and cerebral energy metabolism in patients with DCI are addressed.

    In Paper I, CBF disturbances at the early phase (day 0–3) after SAH were found common and often heterogeneous with substantial regions of near ischemic CBF. Older age and more severe hemorrhage (graded according to Fisher from CT) were factors associated with more compromised CBF. In Paper II, exploring the temporal dynamics of CBF, low initial CBF was associated with a persistent low level of CBF at day 4–7. The association was more pronounced when patients receiving HHH-therapy were separated, and indicates that patients with low CBF, even without clinical signs of DCI, could benefit from careful surveillance and optimization of circulation. In Paper III, the effects on CBF from HHH-therapy in patients with DCI was assessed. Hematocrit decreased during treatment, while the increase in systemic blood pressure was modest. Global CBF and CBF of the worst perfused regions increased, and the proportion of regions with critically low flow decreased accordingly. In Paper IV, the effects of HHH was further assessed in patients also monitored with cerebral microdialysis (CMD). CBF improved during HHH-therapy, while the cerebral energy metabolic CMD parameters stayed statistically unchanged. None of the patients developed metabolic signs of severe ischemia, but a disturbed energy metabolic pattern was common, possibly explained by mitochondrial dysfunction.

    List of papers
    1. Hemodynamic Disturbances in the Early Phase After Subarachnoid Hemorrhage: Regional Cerebral Blood Flow Studied by Bedside Xenon-enhanced CT.
    Open this publication in new window or tab >>Hemodynamic Disturbances in the Early Phase After Subarachnoid Hemorrhage: Regional Cerebral Blood Flow Studied by Bedside Xenon-enhanced CT.
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    2018 (English)In: Journal of Neurosurgical Anesthesiology, ISSN 0898-4921, E-ISSN 1537-1921, Vol. 30, no 1, p. 49-58Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: The mechanisms leading to neurological deterioration and the devastating course of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) are still not well understood. Bedside xenon-enhanced computerized tomography (XeCT) enables measurements of regional cerebral blood flow (rCBF) during neurosurgical intensive care. In the present study, CBF characteristics in the early phase after severe SAH were explored and related to clinical characteristics and early clinical course outcome.

    MATERIALS AND METHODS: Patients diagnosed with SAH and requiring mechanical ventilation were prospectively enrolled in the study. Bedside XeCT was performed within day 0 to 3.

    RESULTS: Data from 64 patients were obtained. Median global CBF was 34.9 mL/100 g/min (interquartile range [IQR], 26.7 to 41.6). There was a difference in CBF related to age with higher global CBF in the younger patients (30 to 49 y). CBF was also related to the severity of SAH with lower CBF in Fisher grade 4 compared with grade 3. rCBF disturbances and hypoperfusion were common; in 43 of the 64 patients rCBF<20 mL/100 g/min was detected in more than 10% of the region-of-interest (ROI) area and in 17 patients such low-flow area exceeded 30%. rCBF was not related to the localization of the aneurysm; there was no difference in rCBF of ipsilateral compared with contralateral vascular territories. In patients who initially were in Hunt & Hess grade I to III, median global CBF day 0 to 3 was significantly lower for patients who were in poor neurological state at discharge compared with patients in good neurological state, 25.5 mL/100 g/min (IQR, 21.3 to 28.3) versus 37.8 mL/100 g/min (IQR, 30.5 to 47.6).

    CONCLUSIONS: CBF disturbances are common in the early phase after SAH. In many patients, CBF was heterogenic and substantial areas with low rCBF were detected. Age and CT Fisher grade were factors influencing global cortical CBF. Bedside XeCT may be a tool to identify patients at risk of deteriorating so they can receive intensified management, but this needs further exploration.

    National Category
    Anesthesiology and Intensive Care Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-312080 (URN)10.1097/ANA.0000000000000395 (DOI)000428161600009 ()27906765 (PubMedID)
    Available from: 2017-01-04 Created: 2017-01-04 Last updated: 2020-01-10Bibliographically approved
    2. Temporal Dynamics of Cerebral Blood Flow During the Acute Course of Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT
    Open this publication in new window or tab >>Temporal Dynamics of Cerebral Blood Flow During the Acute Course of Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT
    2019 (English)In: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 30, no 2, p. 280-290Article in journal (Refereed) Published
    Abstract [en]

    Background: Compromised cerebral blood flow (CBF) is a crucial factor in delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Repeated measurement of CBF may improve our understanding of the temporal dynamics following SAH. The aim of this study was to assess CBF at different phases of the acute course in poor-grade SAH patients, hypothesizing more pronounced disturbances at day 4-7, and that the initial level of CBF determines the following course of CBF.

    Methods: Mechanically ventilated SAH patients were scheduled for bedside measurement of regional and global cortical CBF at day 0-3, 4-7, and 8-12, using xenon-enhanced computed tomography in a mobile setup. Patients were dichotomized depending on high or low initial global cortical CBF and cutoff level 30ml/100g/min.

    Results: Eighty-one patients were included, and 51 had measurements at day 0-3 and 4-7. In patients with high initial CBF, the level was unchanged at day 4-7; 37.7 (IQR 32.6-46.7) ml/100g/min versus 36.8 (IQR 29.5-44.8). The low-CBF group showed a slight increase from 23.6 (IQR 21.0-28.1) ml/100g/min to 28.4 (IQR 22.7-38.3) (P=0.025), still markedly lower than the high-CBF group (P=0.016). In the low-CBF group, CBF increased in patients who received hypertension, hypervolemia, and hemodilution (HHH therapy) but remained low in standard treated patients. For the subset of 27 patients examined also at day 8-12, the differences depending on initial CBF level were no longer statistically significant. Among patients with still low CBF at day 4-7, the proportion who had poor short-term outcome was 55% compared to 35% (n.s.) for patients with high CBF.

    Conclusions: CBF studied in poor-grade SAH patients at large did not show any statistically significant changes over time. Stratifying patients by high or low initial CBF and whether HHH therapy was given revealed an association between low initial CBF and persistent low CBF at day 4-7. These findings may be of clinical relevance in managing SAH patients with low early CBF.

    Place, publisher, year, edition, pages
    HUMANA PRESS INC, 2019
    Keywords
    Subarachnoid hemorrhage, Delayed cerebral ischemia, Cerebral blood flow, Xenon-CT, XeCT, Temporal, Sequential
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-380427 (URN)10.1007/s12028-019-00675-x (DOI)000461380900008 ()30790226 (PubMedID)
    Available from: 2019-04-01 Created: 2019-04-01 Last updated: 2020-01-10Bibliographically approved
    3. Effect of HHH-Therapy on Regional CBF after Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT
    Open this publication in new window or tab >>Effect of HHH-Therapy on Regional CBF after Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT
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    2018 (English)In: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 28, no 2, p. 143-151Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Management of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) is difficult and still carries controversies. In this study, the effect of therapeutic hypervolemia, hemodilution, and hypertension (HHH-therapy) on cerebral blood flow (CBF) was assessed by xenon-enhanced computerized tomography (XeCT) hypothesizing an increase in CBF in poorly perfused regions.

    METHODS:

    Bedside XeCT measurements of regional CBF in mechanically ventilated SAH patients were routinely scheduled for day 0-3, 4-7, and 8-12. At clinical suspicion of DCI, patients received 5-day HHH-therapy. For inclusion, XeCT was required at 0-48 h before start of HHH (baseline) and during therapy. Data from corresponding time-windows were also collected for non-DCI patients.

    RESULTS:

    Twenty patients who later developed DCI were included, and twenty-eight patients without DCI were identified for comparison. During HHH, there was a slight nonsignificant increase in systolic blood pressure (SBP) and a significant reduction in hematocrit. Median global cortical CBF for the DCI group increased from 29.5 (IQR 24.6-33.9) to 38.4 (IQR 27.0-41.2) ml/100 g/min (P = 0.001). There was a concomitant increase in regional CBF of the worst vascular territories, and the proportion of area with blood flow below 20 ml/100 g/min was significantly reduced. Non-DCI patients showed higher CBF at baseline, and no significant change over time.

    CONCLUSIONS:

    HHH-therapy appeared to increase global and regional CBF in DCI patients. The increase in SBP was small, while the decrease in hematocrit was more pronounced, which may suggest that intravascular volume status and rheological effects are of importance. XeCT may be potentially helpful in managing poor-grade SAH patients.

    Keywords
    Cerebral blood flow (CBF), Delayed cerebral ischemia (DCI), HHH-therapy (Triple-H), Subarachnoid hemorrhage (SAH), Xenon CT (XeCT)
    National Category
    Anesthesiology and Intensive Care Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-330938 (URN)10.1007/s12028-017-0439-y (DOI)000431994700001 ()28983856 (PubMedID)
    Available from: 2017-10-07 Created: 2017-10-07 Last updated: 2020-01-10Bibliographically approved
    4. CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage
    Open this publication in new window or tab >>CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage
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    2020 (English)In: Journal of Neurosurgery, ISSN 0022-3085Article in journal (Refereed) Published
    Keywords
    subarachnoid hemorrhage, cerebral blood flow, delayed cerebral ischemia, xenon CT, XeCT
    National Category
    Clinical Medicine
    Research subject
    Neurosurgery
    Identifiers
    urn:nbn:se:uu:diva-400694 (URN)10.3171/2019.11.JNS192759 (DOI)
    Note

    The Journal of Neurosurgery, publ online Jan 10, 2020 (accepted for publ Nov 5, 2019)

    Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-02-05Bibliographically approved
  • Public defence: 2020-03-06 13:00 Rudbecksalen, Uppsala
    Almstedt, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University.
    New targeted therapies for malignant neural tumors: From systematic discovery to zebrafish models2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancers in the neural system presents a major health challenge. The most aggressive brain tumor in adults, glioblastoma, has a median survival of 15 months and few therapeutic options. High-risk neuroblastoma, a childhood tumor originating in the sympathetic nervous system, has a 5-year survival under 50%, despite extensive therapy. Molecular characterization of these tumors has had some, but so far limited, clinical impact. In neuroblastoma, patients with ALK mutated tumors can benefit from treatment with ALK inhibitors. In glioblastoma, molecular subgroups have not yet revealed any subgroup-specific gene dependencies due to tumor heterogeneity and plasticity. In this thesis, we identify novel treatment candidates for neuroblastoma and glioblastoma. 

    In paper I, we discover novel drug targets for high-risk neuroblastoma by integrating patient data, large-scale pharmacogenomic profiles, and drug-protein interaction maps. Using a novel algorithm, TargetTranslator, we identify more than 80 targets for this patient group. Activation of cannabinoid receptor 2 (CNR2) or inhibition of mitogen-activated protein kinase 8 (MAPK8) reduces tumor growth in zebrafish and mice models of neuroblastoma, establishing TargetTranslator as a useful tool for target discovery in cancer. 

    In paper II, we screen approximately 1500 compounds across 100 molecularly characterized cell lines from patients to uncover heterogeneous responses to drugs in glioblastoma. We identify several connections between pathway activities and drug response. Sensitivity to proteasome inhibition is linked to oxidative stress response and p53 activity in cells, and can be predicted using a gene signature. We also discover sigma receptors as novel drug targets for glioblastoma and find a synergistic vulnerability in targeting cholesterol homeostasis.

    In paper III, we systematically explore novel targets for glioblastoma using an siRNA screen. Downregulation of ZBTB16 decreases cell cycle-related proteins and transcripts in patient-derived glioblastoma cells. Using a zebrafish assay, we find that ZBTB16 promotes glioblastoma invasion in vivo

    In paper IV, we characterized the growth of seven patient-derived glioblastoma cell lines in orthotopic zebrafish xenografts. Using automated longitudinal imaging, we find that tumor engraftment strongly correlates with tumor initiation capacity in mice xenografts and that the heterogeneous response to proteasome inhibitors is maintained in vivo

    In summary, this thesis identifies novel targets for glioblastoma and neuroblastoma using systematic approaches. Treatment candidates are evaluated in novel zebrafish xenograft models that are developed for high-throughput glioblastoma and neuroblastoma drug evaluation. Together, this thesis provides promising evidence of new therapeutic options for malignant neural tumors.

    List of papers
    1. Integrative discovery of treatments for high-risk neuroblastoma.
    Open this publication in new window or tab >>Integrative discovery of treatments for high-risk neuroblastoma.
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    2020 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 71Article in journal (Refereed) Published
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

    National Category
    Cancer and Oncology Cell and Molecular Biology Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-402363 (URN)10.1038/s41467-019-13817-8 (DOI)31900415 (PubMedID)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-02-04Bibliographically approved
    2. A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic states
    Open this publication in new window or tab >>A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic states
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    (English)In: Article in journal (Other academic) Submitted
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-402456 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-02-04Bibliographically approved
    3. ZBTB16 orchestrates growth and invasion in glioblastoma
    Open this publication in new window or tab >>ZBTB16 orchestrates growth and invasion in glioblastoma
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    ZBTB16/PLZF, glioblastoma, siRNA, targeted therapy
    National Category
    Cancer and Oncology Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-402522 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-18
    4. Real-time evaluation of glioblastoma treatments in patient-specific zebrafish xenografts
    Open this publication in new window or tab >>Real-time evaluation of glioblastoma treatments in patient-specific zebrafish xenografts
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology Other Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-402416 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-27
  • Public defence: 2020-03-06 13:15 Humanistiska teatern, Uppsala
    Mickelsson, Martin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, SWEDESD - The Swedish International Centre of Education for Sustainable Development.
    Sharing Good Examples, Then What?: Investigations of Contingency and Continuity in the Scaling-of-ESD-Activities-as-Learning2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis aims to contribute to a deepened and nuanced understanding of scaling in environmental and sustainability education (ESE) research, specifically, to develop a conceptual framework for engaging with issues of scaling in policy and practice regarding education for sustainable development (ESD). Three research objectives are formulated.

    The first objective is to develop analytical methods drawing on transactional learning theory for conducting empirical investigations of meaning making concerning educational content in scaling processes. This objective is achieved through an iterative participatory research process including, scaling researchers and practitioners, resulting in the development of the conceptual framework of Scaling-ESD-Activities-as-Learning (SEAL).

    The second objective of the thesis is to examine how workshop participants’ experiences and agency create conditions for the scaling of educational content in ESE. The objective is achieved through analysis of written reflections from scaling practitioners, reports on scaling ESD-activities and participatory research workshop discussions.

    The third objective is to investigate how educational content interplay with environments, such as natural and social environments, when scaling educational activities in ESE. This objective is achieved through analysis of the initial stages of scaling an ESD-activity and analysis of ESD-activities that have progressed to later stages of scaling.

    Four studies address the three research objectives: in three of the studies, empirical data was generated through participatory research workshops in Sweden, South Africa and Ecuador (Paper I, II, IV), while in one study empirical data was generated through a case study of an ESD-course in Southern Africa (Paper III).

    Drawing for its theoretical foundation on John Dewey’s transactional approach to learning, the thesis emphasises the importance of considering experience and aspects of contingency and continuity in learning processes.

    The results of the thesis show that approaching the scaling of ESD-activities as learning enables the identification of conditions for scaling that is characterised by deep and meaningful improvement of practice, sustainability over time along with the ability to evolve when faced with changing circumstances.

    The thesis contributes to ESE research with temporal perspectives on the scaling of ESD-activities, i.e. by considering contingency and continuity in the scaling process, maintaining the relevance of ESD-activities over time and through changing circumstances. Furthermore, by considering multiple, on the face disparate, scaling efforts as part of the same scaling event, the thesis highlight how each iteration of scaling an ESD-activity can constitute learning opportunities for further developing the activity at hand.

    List of papers
    1. Consider the Unexpected: Scaling ESD as a matter of learning
    Open this publication in new window or tab >>Consider the Unexpected: Scaling ESD as a matter of learning
    2019 (English)In: Environmental Education Research, ISSN 1350-4622, E-ISSN 1469-5871, Vol. 25, no 1, p. 135-150Article in journal (Refereed) Published
    Abstract [en]

    This article aims to introduce a view of scaling as a learning process. In the article we discuss the concept of ‘scaling up’ or ‘scaling’ of Education for Sustainable Development (ESD) activities on the basis of how ‘scaling up’ ESD is highlighted in the UNESCO Global Action Programme (GAP) on ESD. Drawing on a Deweyan theory of learning as processes of transactional encounters, the article presents a conceptual framework of scaling-ESD- activities-as-learning. This conceptual framework is intended to have implications for ESD policy and ESE research. The theoretical specications and practical implications presented are results of data collected using a participatory research approach (Re-Solve) and an abductive analysis. In this article, we argue that viewing scaling as a learning process enables a nuanced notion of scaling ESD-activities. This should be seen in relation to (a) complex sustainability challenges, (b) ethical aspects, (c) a more attentive and strict approach to scaling in ESD policy and (d) addressing questions of signicant importance to scaling research.

    Keywords
    scaling, education for sustainable development, biosocial becomings, global action programme on education for sustainable development, expansive learning
    National Category
    Didactics
    Research subject
    Curriculum Studies
    Identifiers
    urn:nbn:se:uu:diva-327985 (URN)10.1080/13504622.2018.1429572 (DOI)000464582800009 ()
    Projects
    Scaling of Education for Sustainable Development
    Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2020-01-16Bibliographically approved
    2. Scaling and subjectification in an ESD educational project
    Open this publication in new window or tab >>Scaling and subjectification in an ESD educational project
    2018 (English)In: Journal of Education for Sustainable Development, ISSN 0973-4082, E-ISSN 0973-4074, Vol. 12, no 1, p. 28-46Article in journal (Refereed) Published
    Abstract [en]

    The aim of the article is to investigate, in light of the emphasis put on scaling by UNESCO (UNESCO, 2014), how subjectification of those involved in educational innovations both enables and constricts scaling understood as a learning process. This is done through a case study of the Alforja Educativa, an educational project in Ecuador on antibiotic resistance (ABR). ABR has been described as a sustainability challenge comparable to climate change. The way in which subjectification enables and constrict scaling as a learning process is analysed by drawing on educational scaling research and the article illustrates how the subject positions of those involved in scaling emerge as scaling subjects in transactional relationships, both with the sites where the educational project is to be scaled, and in relation to that, which will be scaled.

    Keywords
    Scaling, education for sustainable development, transaction, antibiotic resistance, global action programme on education for sustainable development
    National Category
    Didactics
    Research subject
    Curriculum Studies
    Identifiers
    urn:nbn:se:uu:diva-349783 (URN)10.1177/0973408218773268 (DOI)
    Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2020-01-16Bibliographically approved
    3. Projecting change: Scaling the change project approach in Southern Africa
    Open this publication in new window or tab >>Projecting change: Scaling the change project approach in Southern Africa
    2019 (English)In: Environmental Education Research, ISSN 1350-4622, E-ISSN 1469-5871Article in journal (Refereed) Submitted
    Abstract [en]

    This article aims to contribute with knowledge about how transactional learning encounters involved in the spreading of ESD-activities can both enable and limit scaling efforts. In this article, four series of assignments developed through the change project approach (CPA) from Southern Africa are studied as cases for exploring what a conceptualisation of scaling-ESD-activities-as-learning demonstrates enabling and limiting conditions for scaling ESD-activities.  By studying shifts in participants’ understandings as a result of transactional learning encounters the article constitutes a response to the assertion in ESD policy that the UN Decade of Education for Sustainable Development (DESD) was unsuccessful in up-scaling ESD-activities. The article illustrates how the inherent complexity of spreading ESD-activities can be explored and addressed. Through consideration and engagement with the environing conditions and environment(s) in action that are involved in the scaling of ESD-activities, the ‘scaling’ process can enable stakeholder participation as well as development and exercise of agency that has potential to support the sustainability of  ESD-activities.

    Keywords
    scaling, environmental and sustainability education, environmental education, change project approach, Southern Africa
    National Category
    Didactics
    Research subject
    Curriculum Studies
    Identifiers
    urn:nbn:se:uu:diva-401061 (URN)
    Available from: 2020-01-05 Created: 2020-01-05 Last updated: 2020-01-16Bibliographically approved
    4. I think it works better if we have an example to help us: experiences in collaboratively conceptualizing the scaling of Education for Sustainable Development practices in South Africa
    Open this publication in new window or tab >>I think it works better if we have an example to help us: experiences in collaboratively conceptualizing the scaling of Education for Sustainable Development practices in South Africa
    2019 (English)In: Environmental Education Research, ISSN 1350-4622, E-ISSN 1469-5871Article in journal (Refereed) In press
    Abstract [en]

    This article aims to contribute to the knowledge of how the ‘scaling’ of Education for Sustainable Development (ESD) activities is conceptualized in practice through transactional learning encounters. In the context of the UNESCO Global Action Programme (GAP) on ESD, I discuss the re-actualisation of experiences as part of these encounters. The study is a result of data collected as part of a Re-Solve participatory research workshop held in South Africa in 2016, involving researchers and practitioners with experiences of ESD-activities in the Southern African region. To identify and analyse the transactional learning encounters a practical epistemology analysis (PEA) is used. The article draws on a Deweyan theory of learning as transactional encounters supported with a tentative conceptual framework of scaling-ESD-activities-as-learning (SEAL). Throughout the study, I illustrate the transactional encounters, including the re-actualisation of participants' past experiences of ESD-activities. These encounters enabled the conceptualization of contextually relevant concepts of scaling, thus constituting an enabling condition for reflective scaling practices.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2019
    Keywords
    Environmental and sustainability education, scaling, scaling-up, Dewey, learning
    National Category
    Didactics
    Research subject
    Curriculum Studies
    Identifiers
    urn:nbn:se:uu:diva-401062 (URN)
    Available from: 2020-01-05 Created: 2020-01-05 Last updated: 2020-01-22Bibliographically approved
  • Public defence: 2020-03-13 02:15 sal IV, Uppsala
    Reyes Molina, Sebastián
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Philosophy.
    Legal Interpretation and Standards of Proof: Essays in Philosophy of Law and Evidence Law Theory2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This dissertation addresses the issues of the indeterminacy of law and judicial discretion in the decision of the quaestio facti. It is composed of four papers:

    In the first paper, I develop an account of legal indeterminacy called the ‘systemic indeterminacy’ thesis. This thesis claims that legal indeterminacy and judicial discretion are the results of features of the structure of typical rational legal systems such as interpretative codes with a plurality of interpretative directives, the non-redundancy clause, and the non-liquet rule. 

    In the second paper, I criticise two approaches that support the thesis that law ought to ascertain the truth of the quaestio facti: the motivation approach and the legal approach. First, I advance two objections to a version of the motivation approach that I call the ‘behaviour-guidance’ theory. The first objection claims that the appearance of ascertaining the truth is enough to produce the psychological state of compliance. The second objection claims that the indeterminacy of law brings about the impossibility of an ex ante knowledge of the content of the law, thus, the governed cannot gain knowledge of the law’s efforts to ascertain the truth. Second, I explore if the legal approach is plausible. I provide five different legal reasons to support the claim that the law ought to ascertain the truth of the quaestio facti. However, I show that none of these reasons are particularly convincing.

    In the third paper, I advance three objections to the idea of reducing the indeterminacy of the standard of proof rules by adding new legal rules for their interpretation. The first objection claims that these interpretative rules, do not provide any guidance to the trier of fact to set the quantum of evidence. The second objection claims that insofar as these interpretative rules are posited in a natural language they are also indeterminate. The third objection claims that these interpretative rules are redundant legal rules.

    In the fourth paper, I develop the thesis that standards of proof are competence norms that grant competence to triers of fact to set the quantum of evidence in a case-by-case manner. 

    List of papers
    1. Systemic Indeterminacy and Judicial Discretion
    Open this publication in new window or tab >>Systemic Indeterminacy and Judicial Discretion
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The main claim of this paper is the following: In a typical rational legal system, legal adjudication is necessarily discretional. Discretion is the result of what I call ‘systemic indeterminacy’. Systemic indeterminacy is the thesis that claims that typical rational legal systems that have an interpretative code with more than one interpretative directive and the non-redundancy clause are necessarily indeterminate. Since typical rational legal systems do not have redundant rules a plurality of interpretative directives will necessarily yield a plurality of interpretative results. Due to the non-liquet rule judges are obligated to choose among the different interpretative results provided by the interpretative code. In other words, by building a thesis on legal indeterminacy as the consequence of having a plurality of interpretative directives that necessarily yield different results, I proceed to provide an account of discretion as a necessary feature of legal adjudication.

    Keywords
    legal interpretation - law - indeterminacy - discretion
    National Category
    Law
    Research subject
    Philosophy
    Identifiers
    urn:nbn:se:uu:diva-402323 (URN)
    Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-21
    2. On Behaviour-guidance, Legal Reasons, and The Ascertainment of the Truth of the Quaestio Facti
    Open this publication in new window or tab >>On Behaviour-guidance, Legal Reasons, and The Ascertainment of the Truth of the Quaestio Facti
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In this essay, I advance two objections to the ‘behaviour-guidance’ theory that claims that for the law to motivate the behaviour of the governed, legal systems ought to ascertain the truth of the quaestio facti.  The first objection is based on what can cause the psychological state of being motivated to comply with the content of the law. The core claim is that the appearance of ascertaining the truth is enough to produce the psychological state of compliance. The second objection is based on the indeterminacy of law. It claims that if indeterminacy of law brings about the impossibility of an ex ante knowledge of the content of the law, then the governed cannot gain knowledge of the law’s efforts to ascertain the truth. Thus, the psychological state of compliance cannot be produced. I then provide five different legal reasons to support the claim that the law ought to ascertain the truth of the quaestio facti

    Keywords
    law - truth - interpretation - legal interpretation - indeterminacy - normativity
    National Category
    Law
    Research subject
    Philosophy
    Identifiers
    urn:nbn:se:uu:diva-402330 (URN)
    Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-21
    3. On Legal Interpretation and Second-Order Proof Rules
    Open this publication in new window or tab >>On Legal Interpretation and Second-Order Proof Rules
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In this essay, I explore how indeterminacy and discretion pose issues to a specific type of legal rule: the standard of proof rule. I advance three objections to the idea of reducing the indeterminacy of the standard of proof rules by adding new legal rules for their interpretation. Each objection is of a different kind. The first objection claims that these interpretative rules, in the way that they are posited, do not provide any guidance to the trier of fact to set the quantum of evidence. The second objection claims that insofar as these interpretative rules are posited in a natural language they are also indeterminate. The third objection claims that these interpretative rules are redundant legal rules because it is possible to obtain the same result using already existing interpretative rules contained in the interpretative code. 

    Keywords
    legal interpretation - norms - indeterminacy - ambiguity - vagueness - redundancy - standards of proof
    National Category
    Law
    Research subject
    Philosophy
    Identifiers
    urn:nbn:se:uu:diva-402712 (URN)
    Available from: 2020-01-18 Created: 2020-01-18 Last updated: 2020-01-21
    4. Standards of Proof as Competence Norms
    Open this publication in new window or tab >>Standards of Proof as Competence Norms
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In this essay, I develop the thesis that standards of proof are competence norms that grant competence to triers of fact to set the quantum of evidence in a case-by-case manner. One of the distinctive features of competence norms is that they provide a procedure for the competence-holder to follow for exercising her competence. However, since standards of proof are legal rules they are necessarily indeterminate -- that is, multiple norms can be ascribed to a standard of proof rule. From a practical perspective, an indeterminate standard of proof suggests that courts choose the quantum of evidence in a case-by-case manner. In other words, the trier of fact exercises discretion when setting the quantum of evidence. That triers of fact exercise discretion when setting the quantum of evidence brings about the following consequence: similar cases can have a different quantum of evidence. 

    Keywords
    law - standards of proof - evidential reasoning - competence norms - legal power - trier of fact - adjudication
    National Category
    Law
    Research subject
    Philosophy
    Identifiers
    urn:nbn:se:uu:diva-402331 (URN)
    Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-21
  • Public defence: 2020-03-13 09:00 H:son Holmdahl-salen, Uppsala
    Stattin, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Epidemiology of Physical Activity and Fragility Fractures2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fragility fractures mainly affect elderly individuals and often cause long term pain, loss of function and higher mortality rates. Physical activity improves balance, increases muscle strength and bone mineral density, and may reduce the risk of fragility fractures. The aim of this thesis is to investigate the association between physical activity and fragility fractures.

    In Paper I the risk of hip and any fracture was investigated across levels of habitual walking/bicycling and exercise in participants from the population-based Cohort of Swedish Men (COSM) and Swedish Mammography Cohort (SMC). Individuals walking/bicycling a maximum of 20 minutes per day had a lower risk of hip and any fracture than individuals who did not walk or bicycle. The risk of hip and any fracture was gradually lower with increasing levels of exercise. In Paper II participants in the cross-country skiing race Vasaloppet were compared to non-participants from the general population, and were found to have a higher risk of any and forearm fracture but a lower risk of hip, proximal humerus and lower leg fracture. There was no difference in the risk of vertebral fracture. In Paper III, the association between physical activity and cardiovascular candidate plasma protein concentrations were analyzed in participants from the EpiHealth cohort and the Swedish Mammography Cohort Clinical. Of 184 assayed proteins, 75 associations with physical activity were discovered and 28 subsequently replicated in multivariable adjusted models. In Paper IV the COSM, SMC and the Vasaloppet cohort were combined to achieve as wide a range of physical activity as possible and a common measure of physical activity was created using generalized structural equation modeling (GSEM). Low levels of physical activity were associated with higher risk of any and hip fracture but lower risk of wrist fracture. Individuals with physical activity close to the median of the combined cohort had the lowest risk of fracture, and higher levels of physical activity was associated with a higher risk of any fracture.

    In conclusion, physical activity is associated with a lower risk of major fractures such as hip fractures, but may in large quantities increase the risk of wrist and any fracture. Physical activity is associated with more beneficial concentrations of 28 cardiovascular plasma proteins.

    List of papers
    1. Leisure-Time Physical Activity and Risk of Fracture: A Cohort Study of 66,940 Men and Women
    Open this publication in new window or tab >>Leisure-Time Physical Activity and Risk of Fracture: A Cohort Study of 66,940 Men and Women
    Show others...
    2017 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, no 8, p. 1599-1606Article in journal (Refereed) Published
    Abstract [en]

    Physical activity has been associated with reduced risk of fracture, but it is not known how the intensity or frequency of physical activity influences this risk reduction. We aim to compare the risk of hip fracture and fracture of any locale between men and women with different levels of leisure-time walking/bicycling and exercise. A total of 37,238 women (born 1914-1948) from the Swedish Mammography Cohort and 45,906 men (born 1918-1952) from the Cohort of Swedish Men were followed for a maximum of 17 years. Exposure and covariate information was collected through a self-administered questionnaire in 1997. Incident fractures (5153 individuals with hip fracture and 15,043 with any type of fracture) and comorbidities were gathered from national and local patient registries. Hazard ratios (HRs) were calculated using Cox proportional hazards regression. Individuals who walked/bicycled less than 20 minutes per day had a lower rate of hip fracture (multivariable adjusted HR = 0.77; 95% confidence interval [CI] 0.70 to 0.85) and any fracture (HR = 0.87; 95% CI 0.82 to 0.92) compared with those who hardly ever walked/bicycled. These reduced rates were also evident in both sexes, in different age categories, for vertebral fractures and for non-hip, non-vertebral fractures. Those who reported exercise 1 hour per week had a lower rate of hip fracture (HR = 0.87; 95% CI 0.80 to 0.96) and any fracture (HR = 0.94; 95% CI 0.89 to 0.99) compared with those who exercised less than 1 hour per week. Only minor differences in HRs were observed in individuals with moderate compared with higher levels of walking/bicycling or exercise. Walking/bicycling and exercise showed almost equal reductions in rate of fracture when compared with those in a joint category with lowest activity. In conclusion, both moderate and high self-reported frequency of physical activity is associated with reduced future risk of fracture.

    Keywords
    EPIDEMIOLOGY, EXERCISE, FRACTURE PREVENTION, GENERAL POPULATION STUDY, OSTEOPOROSIS
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-334469 (URN)10.1002/jbmr.3161 (DOI)000407438800002 ()28460152 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2020-01-19Bibliographically approved
    2. Decreased Hip, Lower Leg, and Humeral Fractures but Increased Forearm Fractures in Highly Active Individuals
    Open this publication in new window or tab >>Decreased Hip, Lower Leg, and Humeral Fractures but Increased Forearm Fractures in Highly Active Individuals
    Show others...
    2018 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 10, p. 1842-1850Article in journal (Refereed) Published
    Abstract [en]

    It is not known how physical exercise affects the risk of different types of fractures, especially in highly active individuals. To investigate this association, we studied a cohort of 118,204 men and 71,757 women who from 1991 to 2009 participated in Vasaloppet, a long-distance cross-country skiing race in Sweden, and 505,194 nonparticipants frequency-matched on sex, age, and county of residence from the Swedish population. Participants ranged from recreational exercisers to world-class skiers. Race participation, distance of race run, number of races participated in, and finishing time were used as proxies for physical exercise. Incident fractures from 1991 to 2010 were obtained from national Swedish registers. Over a median follow-up of 8.9 years, 53,175 fractures of any type, 2929 hip, 3107 proximal humerus, 11,875 lower leg, 11,733 forearm, and 2391 vertebral fractures occurred. In a Cox proportional hazard regression analysis using time-updated exposure and covariate information, participation in the race was associated with an increased risk of any type of fracture (hazard ratio [HR], 1.02; 95% CI, 1.00 to 1.05); forearm fractures had an HR, 1.11 with a 95% CI, 1.06 to 1.15. There was a lower risk of hip (HR, 0.75; 95% CI, 0.67 to 0.83), proximal humerus (HR, 0.90; 95% CI, 0.82 to 0.98), and lower leg fractures (HR, 0.93; 95% CI, 0.89 to 0.97), whereas the HR of vertebral fracture was 0.97 with a 95% CI, 0.88 to 1.07. Among participants, the risk of fracture was similar irrespective of race distance and number of races run. Participants close to the median finishing time had a lower risk of fracture compared with faster and slower participants. In summary, high levels of physical exercise were associated with a slightly higher risk of fractures of any type, including forearm fractures, but a lower risk of hip, proximal humerus, and lower leg fractures. © 2018 American Society for Bone and Mineral Research.

    Keywords
    EPIDEMIOLOGY, EXERCISE, FRACTURE PREVENTION, ORTHOPEDICS, OSTEOPOROSIS
    National Category
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-367531 (URN)10.1002/jbmr.3476 (DOI)000448078300011 ()29933501 (PubMedID)