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  • Public defence: 2020-02-20 09:14 B41, Uppsala
    Sakthikumar, Sharadha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Characterizing the spectrum of somatic alterations in canine and human cancers2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancers arise as a result of deleterious somatic alterations accumulating in the genome during the process of cell division. These alterations arise either via exposure to mutagens or due to errors occurring during DNA replication. In this thesis, a systematic exploration, from discovery to analyses of somatic alterations in three diverse cancers that affect dogs and humans, was undertaken.

    In Studies I and II, whole-exome sequencing of dogs affected by the cancers of osteosarcoma and hemangiosarcoma were done to delineate coding mutations that can contribute to their carcinogenesis. Besides, as these cancers mirror the corresponding human disease in clinical manifestation and histological features, a secondary objective was to confirm the molecular drivers found in the canines were also influencing factors in the human cancer(s).

    In the osteosarcoma investigations with three breeds, we found that tumors show a high frequency of somatic copy-number alterations, affecting key cancer genes. TP53 was the most frequently altered gene, akin to human osteosarcoma. The second most mutated gene, histone methyltransferase SETD2, has known epigenetic roles in multiple cancers but not in osteosarcoma. Our study highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine disease may serve as an excellent model for developing treatment strategies in both species.

    In the hemangiosarcoma study in golden retrievers, putative driver alterations were identified in the tumor suppressor TP53 and in genes involved in the cell cycle regulating PI3K pathway, including PIK3CA and PIK3R1. Furthermore, we find several somatic alterations between the dog hemangiosarcoma and human angiosarcoma overlap, indicating we can use the canine model to apprise the infrequently occurring human disease.

    In Study III, we implemented whole-genome sequencing methodologies to define both coding and non-coding alterations in the glioblastoma cancer genome. We find the coding somatic alterations recapitulate what has been previously seen for the cancer, including driver alterations in the genes of EGFR, PTEN, and TP53. Significantly though, using the concept of evolutionary constraint, we find an enrichment of non-coding mutations in regulatory regions, around GBM-implicated genes. The mutated regions include splice sites, promoters, and transcription factor binding sites, suggesting the importance of regulatory mutations for the pathogenesis of glioblastoma.

    Overall, the insights garnered from the above exome- and genome-wide surveys provide novel insights into unraveling some of the complexities associated with somatic genomic alterations in cancer genomes. It also convincingly underscores the benefits of using sequencing technologies to comprehend complex biological diseases.

    List of papers
    1. SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
    Open this publication in new window or tab >>SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
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    2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13, p. 3421-3431Article in journal (Refereed) Published
    Abstract [en]

    Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease.

    Place, publisher, year, edition, pages
    AMER ASSOC CANCER RESEARCH, 2018
    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-360424 (URN)10.1158/0008-5472.CAN-17-3558 (DOI)000437214300003 ()29724721 (PubMedID)
    Funder
    EU, European Research CouncilSwedish Research Council FormasSwedish Research CouncilEU, European Research Council
    Available from: 2018-09-19 Created: 2018-09-19 Last updated: 2019-12-17Bibliographically approved
    2. Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma
    Open this publication in new window or tab >>Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma
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    2019 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 17, no 12, p. 2410-2421Article in journal (Refereed) Published
    Abstract [en]

    Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease. IMPLICATIONS: We characterize the genomic landscape of canine hemangiosarcoma and demonstrate its similarity to human angiosarcoma.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-399825 (URN)10.1158/1541-7786.MCR-19-0221 (DOI)000500951800006 ()31570656 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2020-01-13Bibliographically approved
    3. Whole Genome Sequencing of Glioblastoma Reveals Enrichment of Non-Coding Constraint Mutations in Known and Novel Genes
    Open this publication in new window or tab >>Whole Genome Sequencing of Glioblastoma Reveals Enrichment of Non-Coding Constraint Mutations in Known and Novel Genes
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Research subject
    Medical Genetics; Bioinformatics; Biology with specialization in Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-399886 (URN)
    Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2019-12-17Bibliographically approved
  • Public defence: 2020-02-21 09:15 Polhemsalen, Uppsala
    Zeng, Shuangshuang
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Electrical Engineering, Solid-State Electronics. Uppsala University.
    Solid-state nanopores: fabrication and applications2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Nanopores are of great interest in study of DNA sequencing, protein profiling and power generation. Among them, solid-state nanopores show obvious advantages over their biological counterparts in terms of high chemical stability and reusability as well as compatibility with the existing CMOS fabrication techniques. Nanopore sensing is most frequently based on measuring ionic current through a nanopore while applying a voltage across it. When an analyte passes through the pore, the ionic current temporarily changes, providing information of the analyte such as its size, shape and surface charge. Although many magnificent reports on using solid-state nanopores have appeared in the literature, several challenges still remain for their wider applications, which include improvement of fabrication reproducibility for mass production of ultra-small nanopores and minimization of measurement instability as well as control of translocation speed and reduction of background noise. This thesis work explores different techniques to achieve robust and high throughput fabrication of sub-10 nm nanopores for different applications.

    The thesis starts with presenting various fabrication techniques explored during my PhD studies. Focused ion beam method was firstly employed to drill nanopores in free-standing SiNx membranes. Sub-10 nm nanopores could be obtained with a focused helium ion beam. But the fabrication throughput was limited with this technique. A new fabrication process combing electron beam lithography (EBL) with reactive ion etching/ion beam etching, which is compatible with the existing CMOS fabrication technology, was developed to realize a high throughput, mass production of nanopores in free-standing SiNx membranes. However, the smallest size that could be controllably achieved with this process was around 40 nm, which is still far from sub-10 nm in size required for, e.g., DNA sequencing. Finally, by using anisotropic etching of single-crystal silicon in KOH solution, sub-5 nm truncated pyramidal nanopores were mass produced with good process controllability in a silicon-on-insulator (SOI) substrate. In addition, nanopore arrays were also successfully fabricated using a modified EBL based fabrication process.

    Then, several sensing application examples using either single nanopores or nanopore arrays were investigated. Translocation of nanoparticles, DNA and proteins were demonstrated using the fabricated single nanopores or nanopore arrays in a single freestanding membrane. Moreover, the kinetics and mechanism of the lipid bilayer formation in nanopore array, aiming to prevent non-specific adsorption, were studied using ionic current measurements. In addition, individual addressability of a solid-state nanopore array on separated freestanding membranes was realized by integrating microfluidics and a customized multiplexer.

    List of papers
    1. Generalized Noise Study of Solid-State Nanopores at Low Frequencies
    Open this publication in new window or tab >>Generalized Noise Study of Solid-State Nanopores at Low Frequencies
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    2017 (English)In: ACS Sensors, ISSN 2379-3694, Vol. 2, no 2, p. 300-307Article in journal (Refereed) Published
    Abstract [en]

    Nanopore technology has been extensively investigated for analysis of biomolecules, and a success story in this field concerns DNA sequencing using a nanopore chip featuring an array of hundreds of biological nanopores (BioNs). Solid-state nanopores (SSNs) have been explored to attain longer lifetime and higher integration density than what BioNs can offer, but SSNs are generally considered to generate higher noise whose origin remains to be confirmed. Here, we systematically study lowfrequency (including thermal and flicker) noise characteristics of SSNs measuring 7 to 200 nm in diameter drilled through a 20-nmthick SiNx membrane by focused ion milling. Both bulk and surface ionic currents in the nanopore are found to contribute to the flicker noise, with their respective contributions determined by salt concentration and pH in electrolytes as well as bias conditions. Increasing salt concentration at constant pH and voltage bias leads to increase in the bulk ionic current and noise therefrom. Changing pH at constant salt concentration and current bias results in variation of surface charge density, and hence alteration of surface ionic current and noise. In addition, the noise from Ag/AgCl electrodes can become predominant when the pore size is large and/or the salt concentration is high. Analysis of our comprehensive experimental results leads to the establishment of a generalized nanopore noise model. The model not only gives an excellent account of the experimental observations, but can also be used for evaluation of various noise components in much smaller nanopores currently not experimentally available.

    Keywords
    flicker noise, nanopore, electrical double layer, model, power spectrum density, low frequency range, Hooge’s theory
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-315230 (URN)10.1021/acssensors.6b00826 (DOI)000395047000017 ()
    Funder
    Swedish Research Council, 621-2014-6300Stiftelsen Olle Engkvist Byggmästare, 2016/39Swedish Foundation for Strategic Research
    Note

    Chenyu Wen and Shuangshuang Zeng contributed equally to this work.

    Available from: 2017-02-10 Created: 2017-02-10 Last updated: 2019-12-16Bibliographically approved
    2. Group behavior of nanoparticles translocating multiple nanopores
    Open this publication in new window or tab >>Group behavior of nanoparticles translocating multiple nanopores
    2018 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 22, p. 13483-13490Article in journal (Refereed) Published
    Abstract [en]

    Nanopores have been implemented as nanosensors for DNA sequencing, biomolecule inspection, chemical analysis, nanoparticle detection, etc. For high-throughput and parallelized measurement using nanopore arrays, individual addressability has been a crucial technological solution in order to enable scrutiny of signals generated at each and every nanopore. Here, an alternative pathway of employing arrayed nanopores to perform sensor functions is investigated by examining the group behavior of nanoparticles translocating multiple nanopores. As no individual addressability is required, fabrication of nanopore devices along with microfluidic cells and readout circuits can be greatly simplified. Experimentally, arrays of less than 10 pores are shown to be capable of analyzing translocating nanoparticles with a good signal-to-noise margin. According to theoretical predictions, more pores (than 10) per array can perform high-fidelity analysis if the noise level of the measurement system can be better controlled. More pores per array would also allow for faster measurement at lower concentration because of larger capture cross sections for target nanoparticles. By experimentally varying the number of pores, the concentration of nanoparticles, or the applied bias voltage across the nanopores, we have identified the basic characteristics of this multievent process. By characterizing average pore current and associated standard deviation during translocation and by performing physical modeling and extensive numerical simulations, we have shown the possibility of determining the size and concentration of two kinds of translocating nanoparticles over 4 orders of magnitude in concentration. Hence, we have demonstrated the potential and versatility of the multiple-nanopore approach for high-throughput nanoparticle detection.

    Place, publisher, year, edition, pages
    Washington: American Chemical Society (ACS), 2018
    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-369418 (URN)10.1021/acs.analchem.8b03408 (DOI)000451246100048 ()30372031 (PubMedID)
    Funder
    Swedish Research Council, 621-2014-6300Stiftelsen Olle Engkvist Byggmästare, 2016/39
    Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2019-12-16Bibliographically approved
    3. Rectification of protein translocation in truncated-pyramidal nanopores
    Open this publication in new window or tab >>Rectification of protein translocation in truncated-pyramidal nanopores
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    2019 (English)In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 14, p. 1056-1062Article in journal (Refereed) Published
    Abstract [en]

    Solid-state nanopore technology presents an emerging single-molecule-based analytical tool for the separation and analysis of nanoparticles. Different approaches have been pursued to attain the anticipated detection performance. Here, we report the rectification behaviour of protein translocation through silicon-based truncated pyramidal nanopores. When the size of translocating proteins is comparable to the smallest physical constriction of the nanopore, the frequency of translocation events observed is lower for proteins that travel from the larger to the small opening of the nanopore than for those that travel in the reverse direction. When the proteins are appreciably smaller than the nanopore, an opposite rectification in the frequency of translocation events is evident. The maximum rectification factor achieved is around ten. Numerical simulations reveal the formation of an electro-osmotic vortex in such asymmetric nanopores. The vortex–protein interaction is found to play a decisive role in rectifying the translocation in terms of polarity and amplitude. The reported phenomenon can be potentially exploitable for the discrimination of various nanoparticles.

    National Category
    Nano Technology Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-384656 (URN)10.1038/s41565-019-0549-0 (DOI)000495608700014 ()31591525 (PubMedID)
    Funder
    Swedish Research Council, 621-2014-6300Swedish Research Council, 2016/39
    Available from: 2019-06-07 Created: 2019-06-07 Last updated: 2019-12-16Bibliographically approved
    4. Controlled size reduction and its underlying mechanism to form solid-state nanopores via electron beam induced carbon deposition
    Open this publication in new window or tab >>Controlled size reduction and its underlying mechanism to form solid-state nanopores via electron beam induced carbon deposition
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    2019 (English)In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 30, no 45, article id 455303Article in journal (Refereed) Published
    Abstract [en]

    Solid-state nanopores have drawn considerable attention for their potential applications in DNA sequencing and nanoparticle analysis. However, fabrication of nanopores, especially those of diameter below 30 nm, requires sophisticated techniques. Here, a versatile method to controllably reduce the diameter of prefabricated large-size pores down to sub-30 nm without greatly increasing the effective pore depth from the original membrane thickness is shown. This method exploits carbon deposition achieved via hydrocarbon evaporation, induced by an incident beam of electrons, and subsequent dissociation of hydrocarbon to solid carbon deposits. The carbon deposition employs a conventional scanning electron microscope equipped with direct visual feedback, along with a stable hydrocarbon source nearby the sample. This work systematically studies how electron beam accelerating voltage, imaging magnification, initial pore size and membrane composition affect the process of pore size reduction. Secondary electrons generated in the membrane material are confirmed to be the main cause of the dissociation of hydrocarbon. Thicker carbon deposited on one side than on the other of the membrane results in an asymmetric nanopore shape and a rectifying ionic transport. A physico-phenomenological model combined with Monte Carlo simulations is proposed to account for the observed carbon deposition behaviors.

    Place, publisher, year, edition, pages
    IOP PUBLISHING LTD, 2019
    Keywords
    solid-state nanopore, pore size reduction, electron beam induced carbon deposition, secondary electrons, effective pore depth, rectifying behavior
    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-394045 (URN)10.1088/1361-6528/ab39a2 (DOI)000483100000001 ()31394513 (PubMedID)
    Funder
    Swedish Research Council, 621-2014-6300Swedish Foundation for Strategic Research , FFL15-0174
    Available from: 2019-10-04 Created: 2019-10-04 Last updated: 2020-01-08Bibliographically approved
    5. Mechanism and kinetics of lipid bilayer formation in solid-state nanopores
    Open this publication in new window or tab >>Mechanism and kinetics of lipid bilayer formation in solid-state nanopores
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    2020 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827Article in journal (Refereed) Published
    Abstract [en]

    Solid-state nanopores provide a highly versatile platform for rapid electrical detection and analysis of single molecules. Lipid bilayer coating of the nanopores can reduce non-specific analyte adsorption to the nanopore sidewalls and increase the sensing selectivity by providing possibilities for tethering specific ligands in a cell-membrane mimicking environment. However, mechanism and kinetics of lipid bilayer formation from vesicles remain unclear in the presence of nanopores. In this work, we used a silicon-based, truncated-pyramidal nanopore array as the support for lipid bilayer formation. Lipid bilayer formation in the nanopores was monitored in real-time by the change in ionic current through the nanopores. Statistical analysis revealed that a lipid bilayer is formed from instantaneous rupture of individual vesicle upon adsorption in the nanopores, differing from the generally agreed mechanism that lipid bilayers form at a high vesicle surface coverage on a planar support. The2dependence of the lipid-bilayer formation process as a function of applied bias, vesicle size and concentration was systematically studied. In addition, the non-fouling properties of the lipid bilayer coated nanopores were demonstrated during long single stranded DNA translocation through the nanopore array. The findings indicate that lipid bilayer formation process can be modulated by introducing nanocavities intentionally on the planar surface to create active sites or changing the vesicle size and concentration.

    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-399725 (URN)10.1021/acs.langmuir.9b03637 (DOI)
    Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2020-02-06Bibliographically approved
    6. A nanopore array of individual addressability enabled by integrating microfluidics and a multiplexer
    Open this publication in new window or tab >>A nanopore array of individual addressability enabled by integrating microfluidics and a multiplexer
    2019 (English)In: IEEE Sensors Journal, ISSN 1530-437X, E-ISSN 1558-1748, Vol. 20, no 3, p. 1558-1563Article in journal (Refereed) Published
    Abstract [en]

    Solid-state nanopores (SSN) are of significant potential as a versatile tool for chemical sensing, biomolecule inspection, nanoparticle detection, etc. High throughput characterization of SSN in an arrayed format is highly desired for a wide range of applications. Herein, we demonstrate a novel design to integrate an SSN array with microfluidics and a multiplexer. Ionic current measurement on each nanopore can then be individually addressed fluidically and/or electrically with minimum cross talk (electric leakage). This integration provides a scalable platform for automated high-throughput, low-cost, and rapid electrical characterization potentially of a large number of SSN.

    Keywords
    individual addressability, integration, microfluidics, multiplexer, solid-state nanopores
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:uu:diva-397405 (URN)10.1109/JSEN.2019.2947713 (DOI)
    Funder
    Swedish Research Council, 621-2014-6300
    Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2020-01-29Bibliographically approved
  • Public defence: 2020-02-21 13:00 Humanistiska teatern, Uppsala
    Risberg, Olle
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Philosophy, Ethics and Social Philosophy.
    Guiding Concepts: Essays on Normative Concepts, Knowledge, and Deliberation2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis addresses a range of questions about normativity, broadly understood. Recurring themes include (i) the idea of normative ‘action-guidance’, and the connection between normativity and motivational states, (ii) the possibility of normative knowledge and its role in deliberation, and (iii) the question of whether (and if so, how) normative concepts can themselves be evaluated.

    The first two papers, ‘The Entanglement Problem and Idealization in Moral Philosophy’ and ‘Weighting Surprise Parties: Some Problems for Schroeder’, critically examine various versions of the view that what we ought to do depends on some (actual or hypothetical) motivational states, such as desires. It is suggested that such views are, for different but interrelated reasons, extensionally inadequate.

    The third paper, ‘From Evolutionary Theory to Moral Skepticism, via Disagreement’ (co- authored with Folke Tersman), proposes that two arguments for moral skepticism can be combined in a mutually supportive way. A central role is played by the principle that a subject S knows that p only if S adherently believes that p, where this roughly means that S could not easily have failed to believe that p unless her epistemic position were worse or p were false. It is suggested that evolutionary considerations and facts about moral disagreement together indicate that moral beliefs violate this principle.

    The fourth paper, ‘Ethics and the Question of What to Do’, offers an account of the so- called ‘central deliberative question’ that is highlighted by several kinds of choice situations, including those that involve normative uncertainty and normative conflicts. It is proposed that this question is not best understood as the question of what one ought to do, not even in an ‘all things considered’ sense, but as the question of what to do. A meta-normative view that involves elements of both cognitivism and non-cognitivism is put forward as the best explanation of this fact.

    The fifth paper, ‘Meta-Skepticism’, develops a novel skeptical challenge to beliefs about the external world, the central idea being that even if beliefs about the external world can constitute knowledge, there are various other knowledge-like concepts that they cannot satisfy even if they are true. This raises the question of whether some of these concepts are epistemically more important than the others, and, in particular, the further question of how the relevant notion of ‘epistemic importance’ should be understood. Several answers to this question are considered and found wanting.

    List of papers
    1. The Entanglement Problem and Idealization in Moral Philosophy
    Open this publication in new window or tab >>The Entanglement Problem and Idealization in Moral Philosophy
    2018 (English)In: Philosophical quarterly (Print), ISSN 0031-8094, E-ISSN 1467-9213, Vol. 68, no 272, p. 542-559Article in journal (Refereed) Published
    Abstract [en]

    According to many popular views in normative ethics, meta-ethics, and axiology, facts about what we ought to do or what is good for us depend on facts about the attitudes that some agent would have in some relevant idealized circumstances. This paper presents an unrecognized structural problem for such views which threatens to be devastating.

    Place, publisher, year, edition, pages
    Oxford University Press, 2018
    Keywords
    Ought, value, ideal observer theory, subjectivism, response-dependence, attitude-dependence
    National Category
    Ethics
    Research subject
    Ethics
    Identifiers
    urn:nbn:se:uu:diva-334582 (URN)10.1093/pq/pqx064 (DOI)000434474900006 ()
    Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2019-12-14Bibliographically approved
    2. Weighting Surprise Parties: Some Problems For Schroeder
    Open this publication in new window or tab >>Weighting Surprise Parties: Some Problems For Schroeder
    2016 (English)In: Utilitas, ISSN 0953-8208, E-ISSN 1741-6183, Vol. 28, no 1, p. 101-107Article in journal (Refereed) Published
    Abstract [en]

    In this article I argue against Schroeder's account of the weight of normative reasons. It is shown that in certain cases an agent may have reasons she cannot know about without them ceasing to be reasons, and also reasons she cannot know about at all. Both possibilities are troubling for Schroeder's view.

    Place, publisher, year, edition, pages
    Cambridge University Press, 2016
    National Category
    Philosophy
    Research subject
    Practical Philosophy
    Identifiers
    urn:nbn:se:uu:diva-262064 (URN)10.1017/S0953820815000394 (DOI)000370688100007 ()
    Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2019-12-14Bibliographically approved
    3. From Evolutionary Theory to Moral Skepticism, via Disagreement
    Open this publication in new window or tab >>From Evolutionary Theory to Moral Skepticism, via Disagreement
    (English)Manuscript (preprint) (Other academic)
    National Category
    Ethics
    Research subject
    Philosophy
    Identifiers
    urn:nbn:se:uu:diva-398743 (URN)
    Available from: 2019-12-09 Created: 2019-12-09 Last updated: 2019-12-14
    4. Ethics and the Question of What to Do
    Open this publication in new window or tab >>Ethics and the Question of What to Do
    (English)Manuscript (preprint) (Other academic)
    National Category
    Philosophy
    Research subject
    Ethics; Philosophy
    Identifiers
    urn:nbn:se:uu:diva-398741 (URN)
    Available from: 2019-12-09 Created: 2019-12-09 Last updated: 2019-12-14
    5. Meta-Skepticism
    Open this publication in new window or tab >>Meta-Skepticism
    (English)Manuscript (preprint) (Other academic)
    National Category
    Philosophy
    Research subject
    Philosophy; Philosophy
    Identifiers
    urn:nbn:se:uu:diva-398742 (URN)
    Available from: 2019-12-09 Created: 2019-12-09 Last updated: 2019-12-14
  • Public defence: 2020-02-21 13:00 Room A1:111a, Uppsala
    Wäneskog, Marcus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Too close for comfort: The role of Contact-Dependent growth Inhibition (CDI) in interbacterial competition and cooperation2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Contact-Dependent growth inhibition (CDI) was discovered in 2005 in the E. coli isolate EC93. Since then our knowledge of CDI systems and their impact on bacterial communities have increased exponentially. Yet many biological aspects of CDI systems are still unknown and their impact on complex microbial communities have only just begun to be studied. CDI systems require the function of three proteins; CdiBAI. The outer-membrane transport protein, CdiB, allows for the transportation of the toxin delivery protein CdiA to the cell surface of an inhibitor cell. Through a contact- and receptor-dependent interaction with a target cell the toxic C-terminal domain of CdiA is cleaved off and delivered into the target cell were it mediates a growth arrest. Different CdiA-CT domains encodes for diverse toxic activities, such as nucleases and membrane ionophore toxins. Each unique CdiA-CT toxin has a cognate immunity protein (CdiI) that binds and neutralize against its toxic activity, thus preventing a possible self-inhibition.

    In this thesis I have studied the effect of CDI system(s) on both single cell and population level, within both intra- and interspecies bacterial communities. The findings presented here shows that multiple class I cdiBAI loci within a cell can function in a synergetic manner and act as versatile interbacterial warfare systems able to inhibit the growth of rival bacteria, even when CdiA expression is low. We also show that class II CdiA receptor-binding domains can mediate broad-range cross-species toxin delivery and growth inhibition, even when a non-optimal target cell receptor is expressed at a low level. Additionally, we show that the cdiA gene supports the expression of two separate proteins. The full-length CdiA protein, able to mediate an extracellular toxin delivery, but also the discrete CdiA-CT toxin domain. This stand-alone CdiA-CT expression was stress-dependent and together with its cognate CdiI immunity protein functioned as a selfish-genetic element. Moreover, we show that CDI systems can increase bacterial stress tolerance via an extracellular toxin delivery between kin-cells. This stress tolerance phenotype only occurred under conditions when we also observed a selective degradation of the CdiI immunity protein. Therefore, we suggest that a selective CdiI degradation allows for a sub-population of cells to self-intoxicate, thereby becoming transiently dormant, which confers an increase in stress tolerance. The findings presented in this thesis collectively suggest that CDI systems could function as a pseudo-quorum sensing system able to mediate behavioral changes and stress tolerance within a sub-population of cells in a bacterial community.

    List of papers
    1. The E. coli isolate EC93 utilizes two class I CDI systems for antagonistic bacterial interactions
    Open this publication in new window or tab >>The E. coli isolate EC93 utilizes two class I CDI systems for antagonistic bacterial interactions
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-400199 (URN)
    Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-19
    2. Contact-dependent growth inhibition induces high levels of antibiotic-tolerant persister cells in clonal bacterial populations
    Open this publication in new window or tab >>Contact-dependent growth inhibition induces high levels of antibiotic-tolerant persister cells in clonal bacterial populations
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    2018 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 37, no 9, article id UNSP e98026Article in journal (Refereed) Published
    Abstract [en]

    Bacterial populations can use bet-hedging strategies to cope with rapidly changing environments. One example is non-growing cells in clonal bacterial populations that are able to persist antibiotic treatment. Previous studies suggest that persisters arise in bacterial populations either stochastically through variation in levels of global signalling molecules between individual cells, or in response to various stresses. Here, we show that toxins used in contact-dependent growth inhibition (CDI) create persisters upon direct contact with cells lacking sufficient levels of CdiI immunity protein, which would otherwise bind to and neutralize toxin activity. CDI-mediated persisters form through a feedforward cycle where the toxic activity of the CdiA toxin increases cellular (p)ppGpp levels, which results in Lon-mediated degradation of the immunity protein and more free toxin. Thus, CDI systems mediate a population density-dependent bet-hedging strategy, where the fraction of non-growing cells is increased only when there are many cells of the same genotype. This may be one of the mechanisms of how CDI systems increase the fitness of their hosts.

    Place, publisher, year, edition, pages
    WILEY, 2018
    Keywords
    bet-hedging, contact-dependent growth inhibition, persisters, toxin
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356400 (URN)10.15252/embj.201798026 (DOI)000431279400003 ()29572241 (PubMedID)
    Funder
    Swedish Foundation for Strategic Research Swedish Research CouncilEU, European Research Council
    Note

    Anirban Ghosh and Özden Baltekin contributed equally to this work.

    Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2019-12-19Bibliographically approved
    3. CdiA C-terminal polymorphic toxin domains and their cognate immunity genes are stress induced Type II Toxin-Antitoxin systems
    Open this publication in new window or tab >>CdiA C-terminal polymorphic toxin domains and their cognate immunity genes are stress induced Type II Toxin-Antitoxin systems
    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-400200 (URN)
    Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-19
    4. Class II contact‐dependent growth inhibition (CDI) systems allow for broad‐range cross‐species toxin delivery within the Enterobacteriaceae family
    Open this publication in new window or tab >>Class II contact‐dependent growth inhibition (CDI) systems allow for broad‐range cross‐species toxin delivery within the Enterobacteriaceae family
    2019 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 111, no 4, p. 1109-1125Article in journal (Refereed) Published
    Abstract [en]

    Contact‐dependent growth inhibition (CDI) allows bacteria to recognize kin cells in mixed bacterial populations. In Escherichia coli, CDI mediated effector delivery has been shown to be species‐specific, with a preference for the own strain over others. This specificity is achieved through an interaction between a receptor‐binding domain in the CdiA protein and its cognate receptor protein on the target cell. But how conserved this specificity is has not previously been investigated in detail. Here, we show that class II CdiA receptor‐binding domains and their Enterobacter cloacae analog are highly promiscuous, and can allow for efficient effector delivery into several different Enterobacteriaceae species, including Escherichia, Enterobacter, Klebsiella and Salmonella spp. In addition, although we observe a preference for the own receptors over others for two of the receptor‐binding domains, this did not limit cross‐species effector delivery in all experimental conditions. These results suggest that class II CdiA proteins could allow for broad‐range and cross‐species growth inhibition in mixed bacterial populations.

    National Category
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-382983 (URN)10.1111/mmi.14214 (DOI)000464655800017 ()30710431 (PubMedID)
    Funder
    Swedish Foundation for Strategic Research Swedish Research CouncilÅke Wiberg FoundationWenner-Gren Foundations
    Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-12-19Bibliographically approved
  • Public defence: 2020-02-21 13:15 Enghoffsalen, Uppsala
    Edén, Desirée
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tissue Factor regulation, signaling and functions beyond coagulation with a focus on diabetes2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein best known for initiating the coagulation cascade upon binding of its ligand FVIIa. Apart from its physiological role in coagulation, TF and TF/FVIIa signaling has proved to be involved in diseases such as diabetes, cancer and cardiovascular diseases. Biological functions coupled to TF/FVIIa signaling include diet-induced obesity, apoptosis, angiogenesis and migration.

    Aim: The aim of this thesis was to investigate the role of TF/FVIIa in cells of importance in diabetes, to further investigate the mechanism behind TF/FVIIa anti-apoptotic signaling in cancer cells and lastly to examine the regulation of TF expression in monocytes by micro RNAs (miRNA).

    Results: In paper I we found that TF/FVIIa signaling augments cytokine-induced beta cell death and impairs glucose stimulated insulin secretion from human pancreatic islets. In paper II the relevance of TF/FVIIa in isolated human primary adipocytes was investigated. Adipocytes are a target cell for insulin and diabetics typically have increased lipolysis and impaired glucose uptake. No evidence was found for a role of TF/FVIIa in lipolysis or glucose uptake in adipocytes. However, adipocytes were found to express TF and FVII. The FVII produced was sufficient to initiate coagulation in the adipocytes. In paper III an anti-apoptotic TF/FVIIa induced signaling pathway in prostate and breast cancer cells was investigated in depth. Previous research has shown that TF/FVIIa signaling results in transactivation of insulin-like growth factor 1 receptor (IGF-1R) leading to subsequent protection from apoptosis induced by TNF-related apoptosis inducing ligand (TRAIL). The current results propose a mechanism where IGF-1R transactivation by TF/FVIIa is dependent on integrin β1 (ITGβ1) signaling. TF/FVIIa/ ITGβ1 signaling was found to result in phosphorylation of src and subsequent phosphorylation of caveolin 1 (Cav1). Once phosphorylated, the inhibitory effect of Cav1 on IGF-1R is cancelled, resulting in IGF-1R activation. In paper IV the role of miRNA regulation of TF expression in monocytic cells was investigated. The miRNA miR-223-3p was identified to be differentially expressed in U937 cells undergoing differentiation to a more monocyte-like phenotype and an anti-parallel correlation between TF and miR-223-3p expression in monocytes was proved. Hence, miR-223-3p regulates the inducible expression of TF in monocytes.

    Conclusions: The work in this thesis furthers the knowledge of molecular mechanisms behind TF regulation and TF/FVIIa signaling and some functional consequences as well as their biological relevance in diabetes. 

    List of papers
    1. Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets
    Open this publication in new window or tab >>Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets
    2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, p. 2563-2572Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis Patients diagnosed with type 1 or type 2 diabetes have elevated levels of coagulation factor VIIa (FVIIa) and its receptor tissue factor (TF) in their bloodstream. This may affect the fate of the beta cells. We aimed to study the effects of TF/FVIIa signalling on cytokine-induced beta cell death and islet function in vitro. Methods Human pancreatic islets and MIN-6 beta cells were used to study TF mRNA and protein expression using real-time PCR, immunoblotting and flow cytometry. The effects of TF/FVIIa on cytokine-induced beta cell death were studied in MIN-6 cells and human pancreatic islets using cell-death ELISA and propidium iodide and cleaved caspase-3 staining. Effects of TF/FVIIa on the phosphorylation of p38, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) were investigated by immunoblotting. Glucose-stimulated insulin secretion (GSIS) from human islets was measured with an insulin ELISA. Results A combination of the cytokines IL-1 beta, TNF-alpha and IFN-gamma induced TF expression in human pancreatic islets and in beta cells. TF/FVIIa did not affect basal beta cell death but, independently of downstream coagulation activity, augmented beta cell death in response to cytokines. The effect of TF/FVIIa on cytokine-induced beta cell death was found to be dependent on the stress kinase JNK, since FVIIa addition potentiated cytokine-induced JNK activation and JNK inhibition abolished the effect of TF/FVIIa on cytokine-induced beta cell death. Moreover, TF/FVIIa signalling resulted in inhibition of GSIS from human pancreatic islets. Conclusions/interpretation These results indicate that TF/FVIIa signalling has a negative effect on beta cell function and promotes beta cell death in response to cytokines.

    Keywords
    Beta cells, Cytokines, Diabetes, FVIIa, Glucose-stimulated insulin secretion, JNK, Pancreatic islets, Tissue factor
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-265663 (URN)10.1007/s00125-015-3729-y (DOI)000361993000013 ()26271343 (PubMedID)
    Funder
    Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyStiftelsen Olle Engkvist ByggmästareMagnus Bergvall FoundationSwedish Society of MedicineSwedish Child Diabetes FoundationSwedish Research Council
    Available from: 2015-11-05 Created: 2015-11-02 Last updated: 2019-12-19Bibliographically approved
    2. Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner
    Open this publication in new window or tab >>Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner
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    2019 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 3, p. 158-167Article in journal (Refereed) Published
    Abstract [en]

    Background: Tissue factor (TF) combined with its ligand FVII initiates blood coagulation and intracellular signaling. Obese and type 2 diabetic subjects have increased TF expression in their adipose tissue and an increased risk for thrombotic complications. Here we address the role of TF/FVII on adipocyte functions.

    Materials and methods: Subcutaneous fat was obtained by means of needle aspiration from healthy volunteers, and adipocytes were isolated after collagenase digestion. 3T3-L1 fibroblasts kept in culture were differentiated into adipocytes by addition of IBMX, dexamethasone, rosiglitazone, and insulin to the media. Proteins and mRNA were analyzed by western blot and RT-PCR. Coagulation activity was determined by a colorimetric FX-assay. Lipolysis was measured as free glycerol using a colorimetric method. Glucose uptake was evaluated by scintillation counting of D-[U-C-14] glucose.

    Results: In isolated human primary adipocytes we found expression of TF and FVII. TF expression was confirmed in 3T3-L1 adipocytes, and both cell types were found to be procoagulant in a TF/FVIIa-dependent manner. FXa was generated without FVIIa added to the coagulation assay, and active site-inhibited FVIIa blocked FXa formation, supporting our finding of FVII production by human primary adipocytes. There was no evidence for a role of TF in either lipolysis or glucose uptake in our experimental settings.

    Conclusion: Human primary adipocytes express active TF and FVII, and the TF/FVIIa complex formed on the adipocyte surface can activate substrate FX. Whether the TF/FVIIa complex conveys signaling pathways leading to biological functions and has any biological activity in adipocytes beyond coagulation remains to be elucidated.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2019
    Keywords
    Adipocytes, coagulation, FVII, lipolysis, tissue factor
    National Category
    Cardiac and Cardiovascular Systems Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-396115 (URN)10.1080/03009734.2019.1645248 (DOI)000481057900001 ()31407948 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Heart Lung FoundationErik, Karin och Gösta Selanders Foundation
    Available from: 2019-10-31 Created: 2019-10-31 Last updated: 2019-12-19Bibliographically approved
    3. Activation of β1 integrins and caveolin-1 by TF/FVIIa promotes IGF-1R signaling and cell survival
    Open this publication in new window or tab >>Activation of β1 integrins and caveolin-1 by TF/FVIIa promotes IGF-1R signaling and cell survival
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-399437 (URN)
    Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-19
    4. miR-223-3p regulates post-transcriptional tissue factor gene expression in human monocytic cells
    Open this publication in new window or tab >>miR-223-3p regulates post-transcriptional tissue factor gene expression in human monocytic cells
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-399598 (URN)
    Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-19
  • Public defence: 2020-02-22 13:00 Hall IV, Uppsala
    Muchitsch, Veronika
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Musicology.
    Vocal Figurations: Technique, Technology, and Mediation in the Gendering of Voice in Twenty-First-Century Pop Music2020Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis examines the gendering of voice in twenty-first-century pop music and music criticism through the concept of vocal figurations. Embodying a thoroughly relational understanding of voice, it articulates vocal technique, studio technology, and electronic mediation as three primary dimensions through which voices come to signal gender as it intersects with other vectors of social identity. The artistic trajectories of Lana Del Rey, Anohni and Beyoncé, whose voices are central to their performances and reception histories, form the analytical cases of this thesis. Substantiating the roles of technical, technological, and mediated dimensions of voices in the production and possible disruption of normative sonic discourses, the analyses of these voices advance knowledge about the specific interlockings of material, discursive, aesthetic, and political dimensions that gender voices in twenty-first-century popular music. The relational conceptualization of voice embodied in vocal figurations further leads to a multi-faceted analytical method that juxtaposes music analysis with analyses of critical reception and identifies the latter as a sphere of discursive production. Illuminating the ways in which music criticism produces and perpetuates sonic discourses that saturate vocal qualities with assumptions about gender as they intersect with sexuality, race, and class, this thesis seeks to initiate an extended critical examination of these processes.

  • Public defence: 2020-02-27 09:15 Room C8:301, Uppsala
    Paivandy, Aida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Induction of Mast Cell Apoptosis via Granule Permeabilization: A Novel Approach to Target Mast Cells2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mast cells are densely granulated tissue-resident immune cells that play an important role in orchestrating inflammatory responses. Dysregulated increases in the numbers and activation status of mast cells can have deleterious consequences for the body in various inflammatory diseases. Mast cells are best-known for their detrimental roles in allergic diseases, e.g., asthma. Thus, strategies that target mast cells and their harmful activities in such pathological conditions are potentially attractive therapeutic options. An efficient strategy to accomplish a full blockade of the harmful events mediated by various mast cell mediators is to locally eliminate mast cell populations altogether by inducing their apoptosis.

    Using in vitro-cultured mast cells, we identified that mefloquine, an antimalarial drug with lysosomotropic activity, causes permeabilization of secretory granules, increased production of reactive oxygen species (ROS), release of granule-localized proteases into the cytosol and apoptotic cell death (Paper I). Moreover, intraperitoneal injections of mefloquine in mice resulted in a reduced peritoneal mast cell population in vivo.

    To evaluate the possibility of using lysosomotropic agents for selectively depleting human lung mast cells by induction of apoptosis, human lung specimens were used. Exposure of either intact human lung tissue, purified lung mast cells or mixed populations of lung cells to mefloquine revealed that human lung mast cells are highly susceptible to ROS-induced apoptosis in this setting. In contrast, other cell populations of the lung were largely refractory (Paper II).

    Lastly, in an attempt to gain a deeper insight into the mechanism underlying ROS production and the downstream events in response to lysosomotropic challenge, we identified that the mast cell secretory granules comprise major subcellular compartments for ROS production in response to mefloquine (Paper III). Lysosomal iron, granzyme B and the ERK1/2 MAP kinase signaling pathway were found to contribute to production of ROS in response to mefloquine. Furthermore, granule acidification was shown to be essential for mefloquine-mediated effects in mast cells, i.e., granule permeabilization, ROS production and cell death. Collectively, the present thesis introduces the possibility of inducing selective mast cell apoptosis via granule permeabilization as a novel strategy to target mast cells. Thus, this strategy has a potential to be used therapeutically to ameliorate mast cell-mediated detrimental effects in inflammatory diseases, such as asthma.

    List of papers
    1. Mefloquine, an anti-malaria agent, causes reactive oxygen species-dependent cell death in mast cells via a secretory granule-mediated pathway.
    Open this publication in new window or tab >>Mefloquine, an anti-malaria agent, causes reactive oxygen species-dependent cell death in mast cells via a secretory granule-mediated pathway.
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    2014 (English)In: Pharmacology research & perspectives, ISSN 2052-1707, Vol. 2, no 6, article id e00066Article in journal (Refereed) Published
    Abstract [en]

    Mast cells are known to have a detrimental impact on a variety of pathological conditions. There is therefore an urgent need of developing strategies that limit their harmful effects. The aim of this study was to accomplish this by developing a means of inducing mast cell apoptosis. The strategy was to identify novel compounds that induce mast cell apoptosis by permeabilization of their secretory lysosomes (granules). As a candidate, we assessed mefloquine, an anti-malarial drug that has been proposed to have lysosome-permeabilizing activity. Mefloquine was added to mast cells and administered in vivo, followed by assessment of the extent and mechanisms of mast cell death. Mefloquine was cytotoxic to murine and human mast cells. Mefloquine induced apoptotic cell death of wild-type mast cells whereas cells lacking the granule compounds serglycin proteoglycan or tryptase were shown to undergo necrotic cell death, the latter finding indicating a role of the mast cell granules in mefloquine-induced cell death. In support of this, mefloquine was shown to cause compromised granule integrity and to induce leakage of granule components into the cytosol. Mefloquine-induced cell death was refractory to caspase inhibitors but was completely abrogated by reactive oxygen species inhibition. These findings identify mefloquine as a novel anti-mast cell agent, which induces mast cell death through a granule-mediated pathway. Mefloquine may thus become useful in therapy aiming at limiting harmful effects of mast cells.

    Keywords
    Apoptosis, granules, mast cells, mefloquine, mMCP-6, reactive oxygen species, serglycin, tryptase
    National Category
    Natural Sciences
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-401708 (URN)10.1002/prp2.66 (DOI)25505612 (PubMedID)
    Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-02-05Bibliographically approved
    2. Induction of Human Lung Mast Cell Apoptosis by Granule Permeabilization: A Novel Approach for Targeting Mast Cells
    Open this publication in new window or tab >>Induction of Human Lung Mast Cell Apoptosis by Granule Permeabilization: A Novel Approach for Targeting Mast Cells
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    2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1645Article in journal (Refereed) Published
    Abstract [en]

    Mast cells are implicated as detrimental players in inflammatory lung diseases, particularly asthma. Mast cells respond to activating stimuli by releasing a wide panel of pro-inflammatory compounds that can contribute profoundly to the pathology, and there is currently an unmet need for strategies that efficiently ameliorate harmful effects of mast cells under such conditions. Here, we sought to evaluate a novel concept for targeting human lung mast cells, by assessing the possibility of selectively depleting the lung mast cells by induction of apoptosis. For this purpose, we used lysosomotropic agents, i.e., compounds that are known to permeabilize the secretory granules of mast cells, thereby releasing the contents of the granules into the cytosol. Either intact human lung tissue, purified human lung mast cells or mixed populations of human lung cells were incubated with the lysosomotropic agents mefloquine or siramesine, followed by measurement of apoptosis, reactive oxygen species (ROS) production, and release of cytokines. We show that human lung mast cells were highly susceptible to apoptosis induced by this strategy, whereas other cell populations of the lung were largely refractory. Moreover, we demonstrate that apoptosis induced by this mode is dependent on the production of ROS and that the treatment of lung tissue with lysosomotropic agents causes a decrease in the release of pathogenic cytokines. We conclude that selective apoptosis of human lung mast cells can be accomplished by administration of lysosomotropic agents, thus introducing the possibility of using such drugs as novel therapeutics in the treatment of inflammatory lung disorders such as asthma.

    Keywords
    apoptosis, granules, lysosomotropic agents, mast cells, mefloquine
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-339681 (URN)10.3389/fimmu.2017.01645 (DOI)000416221900001 ()29230220 (PubMedID)
    Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2020-01-13Bibliographically approved
    3. Lysosomotropic challenge of mast cells causes intra-granular reactive oxygen species production
    Open this publication in new window or tab >>Lysosomotropic challenge of mast cells causes intra-granular reactive oxygen species production
    Show others...
    2019 (English)In: CELL DEATH DISCOVERY, ISSN 2058-7716, Vol. 5, article id 95Article in journal (Refereed) Published
    Abstract [en]

    Mast cells contribute to the pathology of allergic and other disorders. Strategies to interfere with harmful mast cell-related activities are therefore warranted. Previously we established a principle for inducing selective apoptosis of mast cells, by the use of lysosomotropic agents that cause secretory granule permeabilization, leading to production of reactive oxygen species (ROS). However, the mechanism of ROS production has not been known. Here we addressed this issue. Live microscopy analysis showed that the secretory granules comprise major subcellular compartments for ROS production in response to mefloquine. As further signs for the primary involvement of secretory granules, both ROS production and cell death was blunted in mast cells lacking serglycin, a secretory granule-restricted proteoglycan. Inhibition of granule acidification caused an essentially complete blockade of granule permeabilization, ROS production and cell death in response to mefloquine. ROS production was also attenuated in the presence of an iron chelator, and after inhibition of either granzyme B or the ERK1/2 MAP kinase signaling pathway. Together, our findings reveal that the mast cell secretory granules constitute major sites for ROS production in mast cells subjected to lysosomotropic challenge. Moreover, this study reveals a central role for granule acidification in ROS generation and the pro-apoptotic response triggered downstream of secretory granule permeabilization.

    National Category
    Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-387281 (URN)10.1038/s41420-019-0177-3 (DOI)000468005600001 ()31123601 (PubMedID)
    Funder
    Swedish Research CouncilKnut and Alice Wallenberg Foundation
    Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2020-01-13Bibliographically approved
  • Public defence: 2020-02-27 13:15 ITC 2446, Uppsala
    Löscher, Ida
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Aiming at Moving Targets: Applying Cognitive Work Analysis to Work Domains in Transition2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The design of IT systems for complex work environments is essential for workers to be able to operate more effectively and efficiently. To design a system that supports the workers' specific tasks we need to understand the work demands and the context in which the system operates. However, this is a difficult task because of the dynamic nature of complex systems. The thesis investigates how the cognitive work analysis (CWA) framework (Vicente, 1999) can be applied to understand a domain under transformation by (1) developing methods to manage challenges associated with applying CWA to real-world complex systems and (2) investigating how models from the CWA framework can be used to contend with the moving target for development. The studies are carried out within two quite different application domains: long-haul driving and health care. An activity prioritization method was suggested as a useful technique to focus the analyzing efforts during the analysis of tasks and strategies. However, adaption to practical constraints has to be done thoughtfully in order not to lose the value of the analysis. Moreover, workshops were proposed as a means to bridge the gap between the analysis and design by finding design metaphors and possible future work strategies from the domain knowledge of the drivers. Third, a study was done using the abstraction hierarchy (AH) to learn about digitization in health care, which is an example of ongoing change in a work domain. The AH was also adapted to model health IT systems as a means to provide an overview and consistent vision of strategic decisions. Using the AH as an overview of sub-systems that were developed by different organizations or organizational units would make it possible to identify collaboration needs or a lack of connectivity and integration between systems. The AH can therefore be applied to support the development of an IT system that is to be part of a transforming work domain.

    List of papers
    1. Activity prioritization to focus the control task analysis
    Open this publication in new window or tab >>Activity prioritization to focus the control task analysis
    2016 (English)In: Journal of Cognitive Engineering and Decision Making, ISSN 1555-3434, E-ISSN 2169-5032, Vol. 10, no 1, p. 91-104Article in journal (Refereed) Published
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-298003 (URN)10.1177/1555343416629307 (DOI)000374661200006 ()
    Projects
    MODAS
    Available from: 2016-03-01 Created: 2016-06-29 Last updated: 2020-01-08Bibliographically approved
    2. Rebuttal to Burns and Naikar
    Open this publication in new window or tab >>Rebuttal to Burns and Naikar
    2016 (English)In: Journal of Cognitive Engineering and Decision Making, ISSN 1555-3434, E-ISSN 2169-5032, Vol. 10, no 1, p. 109-110Article in journal, Editorial material (Other academic) Published
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-299392 (URN)10.1177/1555343416629179 (DOI)000374661200008 ()
    Available from: 2016-03-31 Created: 2016-07-18 Last updated: 2020-01-08Bibliographically approved
    3. Eliciting strategies in revolutionary design: exploring the hypothesis of predefined strategy categories
    Open this publication in new window or tab >>Eliciting strategies in revolutionary design: exploring the hypothesis of predefined strategy categories
    2018 (English)In: Theoretical Issues in Ergonomics Science, ISSN 1463-922X, E-ISSN 1464-536X, Vol. 19, no 1, p. 101-117Article in journal (Refereed) Published
    Abstract [en]

    Introducing automation in a human-machine system changes the tasks performed by human operators. It is difficult to analyse systems for which there are no experienced operators. This issue emerged within a project with the aim to develop a human–machine interface for a highly automated long-haul vehicle. To handle the problem, a formative strategies analysis method with promises to enable desktop analyses through predefined strategy categories was adopted. The method was used to investigate strategies for controlling the future long haul vehicle by conducting workshops with today's drivers. The method was shown to be a valuable asset in eliciting strategies for revolutionary design.

    Keywords
    Cognitive work analysis, strategies analysis, automation, revolutionary systems design, long haul trucks
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-292799 (URN)10.1080/1463922X.2017.1278805 (DOI)000428728900006 ()
    Projects
    MODAS
    Funder
    VINNOVA, 2012-03678
    Available from: 2017-01-27 Created: 2016-05-09 Last updated: 2020-01-08Bibliographically approved
    4. Work domain analysis of an intensive care unit: An Abstraction Hierarchy based on a bed-side approach
    Open this publication in new window or tab >>Work domain analysis of an intensive care unit: An Abstraction Hierarchy based on a bed-side approach
    2016 (English)In: Proc. Human Factors and Ergonomics Society Europe Chapter 2015 Annual Conference, 2016Conference paper, Published paper (Refereed)
    Abstract [en]

    Work in intensive care units requires interaction with several medical devices and interpretation of dynamic information from several sources. The aim of the current study was to gain understanding of the work domain to support the development of a holistic information environment and further analyses of risky situations. A total of 18 hours of bed-side observations at an intensive care unit and interviews with three experienced intensive care unit nurses were conducted in order to receive input data for the modelling of the work domain. The domain was modelled in an abstraction hierarchy, as according to the first phase of the cognitive work analysis framework. The results show that the ultimate purpose of the work carried out in an intensive care unit is keeping patients alive while gaining time for treatment, but also to perform treatment and relieve symptoms. The purpose is represented at the top level of the model, and lower levels include functions as supporting the patients’ vital functions and avoiding secondary complications. With this work domain analysis as a basis, three different design challenges identified can be dealt with systematically.

    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-335425 (URN)
    Conference
    Human Factors and Ergonomics Society Europe Chapter 2015 Annual Conference
    Available from: 2017-12-05 Created: 2017-12-05 Last updated: 2020-01-08
    5. Using Cognitive Work Analysis to Model the Impact of Digitalization on Intensive Care Nursing
    Open this publication in new window or tab >>Using Cognitive Work Analysis to Model the Impact of Digitalization on Intensive Care Nursing
    (English)In: Journal of Cognitive Engineering and Decision Making, ISSN 1555-3434, E-ISSN 2169-5032Article in journal (Refereed) Submitted
    Abstract [en]

    The continuous development of health IT fuels a process of ongoing digitalization that affects the work of hospital staff. A Cognitive Work Analysis methodology was used to investigate the impact of digitalization through a Clinical Information System (CIS), an addition to the basic Electronic Medical Record, on one intensive care unit (ICU). Both observations and semi-structured interviews were performed. The replacement of a paper charting system with a digital CIS that meant some of the administrative tasks could be automated and other tasks being performed on a computer screen instead of using paper. The nurses’ work domain was modeled and compared to a study performed prior to the implementation of the CIS. The study demonstrates the potential utility of the Cognitive Work Analysis approach (when applied both pre and post-implementation) to evaluate the impact of a CIS on ICU nurses.

    Place, publisher, year, edition, pages
    London: Sage Publications
    Keywords
    Cognitive Work Analysis, Work Domain Analysis, Intensive Care, Nursing, Digitalization
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-401122 (URN)
    Projects
    The effects of digitalization on the work environment of nurses (DISA)
    Funder
    Forte, Swedish Research Council for Health, Working Life and Welfare, 2016-07153
    Available from: 2020-01-06 Created: 2020-01-06 Last updated: 2020-02-06Bibliographically approved
    6. Supporting industrial uptake of cognitive work analysis
    Open this publication in new window or tab >>Supporting industrial uptake of cognitive work analysis
    2015 (English)In: Proc. Human Factors and Ergonomics Society 59th Annual Meeting, Thousand Oaks, CA: Sage Publications, 2015, p. 170-174Conference paper, Published paper (Refereed)
    Abstract [en]

    As part of a broader industrial project, the first two stages of a Cognitive Work Analysis (CWA, Work Domain Analysis [WDA] and Control Task Analysis [ConTA]) were completed for Long Haul Commercial Road Transport. To support the potential uptake of CWA by different stakeholders within the industrial organization, parts of the ConTA Contextual Activity Template (CAT) were truncated. The goal of the current, exploratory study, was to identify which stakeholders within the industrial organization could benefit from using the WDA or CAT for either their Strategic (Research) or Product (Development) planning, and over what time horizon. We observed differences in the perceived usefulness of the WDA and the CAT between the different stakeholders. Innovative solutions to the issues raised should significantly enhance the industrial use of Cognitive Work Analysis.

    Place, publisher, year, edition, pages
    Thousand Oaks, CA: Sage Publications, 2015
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-268730 (URN)978-0-945289-47-0 (ISBN)
    Conference
    HFES 2015, October 26–30, Los Angeles, CA
    Available from: 2015-10-30 Created: 2015-12-09 Last updated: 2020-01-08Bibliographically approved
    7. Visualizing Purpose and Functionality Overlaps of Health IT Systems using an Abstraction Hierarchy
    Open this publication in new window or tab >>Visualizing Purpose and Functionality Overlaps of Health IT Systems using an Abstraction Hierarchy
    2019 (English)In: Proceedings of the Human Factors and Ergonomics Society Annual Meeting, Newbury Park, California: Sage Publications, 2019, Vol. 63, p. 317-321Conference paper, Published paper (Refereed)
    Abstract [en]

    The development of health IT fuels a digitalization process that affects the work of hospital staff negatively in the case of poor integration of IT systems. A challenge lies in keeping track of the existing IT systems and possible overlapping functions. The Abstraction Hierarchy model from the Cognitive Work Analysis framework describes how parts of a complex system relate to the over-arching goals of the system, which could work as an overview of the IT systems. In this study, we explore how an Abstraction Hierarchy can be used to visualize how IT systems’ functions overlap, interfere with, or depend on each other. The Abstraction Hierarchy was developed based on documentation, interviews, and a study visit at a hospital ward. The overlaps in functionality visualized in the Abstraction Hierarchy could serve as indicators for the need for further investigation of effects on the hospital staff’s work.

    Place, publisher, year, edition, pages
    Newbury Park, California: Sage Publications, 2019
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-398112 (URN)10.1177/1071181319631463 (DOI)
    Conference
    Human Factors and Ergonomics Society Annual Meeting
    Projects
    The effects of digitalization on the work environment of nurses (DISA)
    Funder
    Forte, Swedish Research Council for Health, Working Life and Welfare, 2016-07153
    Available from: 2019-12-02 Created: 2019-12-02 Last updated: 2020-01-08
    8. Cognitive Work Analysis to support development of health IT in a complex organization
    Open this publication in new window or tab >>Cognitive Work Analysis to support development of health IT in a complex organization
    (English)In: Applied Ergonomics, ISSN 0003-6870, E-ISSN 1872-9126Article in journal (Refereed) Submitted
    Abstract [en]

    The continuous development of health IT fuels a process of ongoing digitalization that can affect the work of hospital staff negatively with respect to the poor integration of IT systems. One aim is to understand challenges associated with the work of implementing health IT systems within a complex organization. Another aim is to explore how an abstraction hierarchy, a modeling tool from the cognitive work analysis framework, can be used for development of health IT by visualizing how IT systems’ functions overlap, interfere with or depend on each other. We interviewed decision makers holding different positions at a large university hospital in Sweden and the possible use of the abstraction hierarchy was evaluated during a workshop. Multiple challenges are associated with the development of health IT systems, including difficulties in usability work, various work roles and use cases, the complexity of the organization, external development and technical and legal barriers to system integration. The abstraction hierarchy could indicate the need for further investigation of functionality overlap and reveal collaboration needs between development projects.

    Place, publisher, year, edition, pages
    Amsterdam: Elsevier
    Keywords
    Digitalization, Cognitive Work Analysis, Work Domain Analysis, Abstraction Hierarchy
    National Category
    Human Computer Interaction
    Identifiers
    urn:nbn:se:uu:diva-401125 (URN)
    Projects
    The effects of digitalization on the work environment of nurses (DISA)
    Funder
    Forte, Swedish Research Council for Health, Working Life and Welfare, 2016-07153
    Available from: 2020-01-06 Created: 2020-01-06 Last updated: 2020-02-05Bibliographically approved
  • Public defence: 2020-02-28 09:00 Gunnesalen, Uppsala
    Brüggemann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hip Revision Surgery: Identification of Genetic Markers and Evaluation of Novel Treatment Strategies2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Total hip arthroplasty (THA) is, despite its overall good outcome, for some patients followed by hip revision surgery. This seems in parts to be because of genetic susceptibility to revision surgery. The most common reason for revision surgery is aseptic loosening followed by periprosthetic joint infection and dislocation. Cups made of porous tantalum (TM cups) were thought to be favorable in revision surgery to address aseptic loosening, but they seem to confer an increased risk of dislocation. The effectiveness and biocompatibility in vivo of TM cups have not been researched. Dual mobility cups (DMCs) with two articulating surfaces are proposed to prevent dislocation to a higher degree than standard polyethylene liners.

    Our hypotheses were that TM cups are superior to their historical treatment alternative in terms of re-revision rates; that the combination of DMC cemented into TM cups would decrease the risk for dislocation after revision surgery; that tantalum ion liberation is marginal after the use of TM cups; and that certain risk genes are associated with an increased risk for revision surgery after total joint arthroplasty.

    Studies I&II were register-based cohort studies comparing the implant survival of TM cups and conventional acetabular reinforcement rings (study I), and the combination of TM cups/DMC with TM cups/standard polyethylene liners (study II). We found that TM cups perform equally well as reinforcement rings, but that the two implants differ in their failure mechanisms. Cementing a DMC into TM cups adequately addressed the issue of recurrent dislocation. In study III we investigated whether tantalum ion liberation does occur after implantation of a TM cups and how this affects patients’ immunological response by comparison of three groups: primary non-tantalum THA, primary tantalum THA and revision tantalum THA. We found the highest concentration of tantalum ions in the revision cases, yet tantalum ions were not associated with an immunological response, and we found no signs of alteration in the investigated lymphocyte subsets. Study IV aimed to identify possible risk genes for revision surgery after total hip or knee replacement by a genome wide association study. We found six significant risk genes for the endpoint revision surgery for any reason, and three for the endpoint revision due to aseptic loosening. We found a variety of suggestive risk genes within the region coding for the ABO-system.

    In conclusion, the novel treatment options TM cups and DMC show good results in hip revision surgery, but longer follow-up is warranted. The use of porous tantalum seems not to be associated with the immunological activation that can be observed in metallosis. The risk for revision surgery is associated with certain risk genes.

    List of papers
    1. Are porous tantalum cups superior to conventional reinforcement rings?: A retrospective cohort study of 207 acetabular revisions
    Open this publication in new window or tab >>Are porous tantalum cups superior to conventional reinforcement rings?: A retrospective cohort study of 207 acetabular revisions
    2017 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 88, no 1, p. 35-40Article in journal (Refereed) Published
    Abstract [en]

    Background and purpose - Porous tantalum cups have been introduced as an alternative to various reinforcement rings in revision hip surgery. We hypothesized that porous tantalum cups would be superior to muller acetabular roof reinforcement rings (MARRs) in revision hip surgery with re-revision for aseptic loosening as the primary outcome measure. Patients and methods - 207 hips operated with either a porous tantalum cup (TM cup, n = 111) or a MARR (n = 96) at index procedure were identified in our local arthroplasty register. Acetabular defects were classified according to Paprosky. There were 96 men and 111 women with a median age of 71 (35-95) years, presenting acetabular defect size type I in 39 cases, IIA in 22, IIB in 27, IIC in 43, IIIA in 32, and IIIB in 37 cases. Analysis of medical records identified all patients with subsequent re-revision and reasons for re-revisions. Kaplan-Meier survival functions were used to estimate implant survival. Results - With re-revision for aseptic loosening as the end-point, the 6-year unadjusted cumulative survival was 97% (95% CI: 94-100) for TM cups and 96% (CI: 92-100) for MARR (p = 0.6). Using re-revision for any reason as the endpoint, 6-year survival was 87% (CI: 81-94) for TM cups and 95% (CI: 90-99) for MARR (p = 0.06). The main reason for re-revision in the TM group was dislocation (n = 10), followed by loosening (n = 3), whereas the main reason for re-revision in the MARR group was aseptic loosening (n = 8). Duration of the index procedure and perioperative blood loss were lower in the TM group. Interpretation - Both TM and MARR lead to good 6-year results in acetabular revision surgery. The methods differ in their respective failure mechanisms. We conclude that TM cups are a valuable treatment option in acetabular revision surgery, but the reasons underlying dislocations after the use of TM cups must be analyzed further.

    National Category
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-316408 (URN)10.1080/17453674.2016.1248315 (DOI)000392736200007 ()27892748 (PubMedID)
    Available from: 2017-03-02 Created: 2017-03-02 Last updated: 2020-01-09Bibliographically approved
    2. Do dual-mobility cups cemented into porous tantalum shells reduce the risk of dislocation after revision surgery?: A retrospective cohort study on 184 patients
    Open this publication in new window or tab >>Do dual-mobility cups cemented into porous tantalum shells reduce the risk of dislocation after revision surgery?: A retrospective cohort study on 184 patients
    2018 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 2, p. 156-162Article in journal (Refereed) Published
    Abstract [en]

    Background and purpose Dual-mobility cups (DMCs) reduce the risk of dislocation and porous tantalum (TM) shells show favorable osseointegration after acetabular revision surgery, yet the combination of these implants has not been studied. We hypothesized that (1) cementing a DMC into a TM shell decreases the risk of dislocation; (2) DMCs cemented into TM shells are not at greater risk of re-revision; (3) liberation of tantalum ions is marginal after use of this combined technique.Patients and methods We investigated the outcome in 184 hips (184 patients) after acetabular revision surgery with TM shells, fitted either with DMCs (n = 69), or with standard polyethylene (PE) liners (n = 115). Chart follow-up was complete for all patients, and the occurrence of dislocations and re-revisions was recorded. 20 were deceased, 50 were unable to attend follow-up, leaving 114 for assessment of hip function after 4.9 (0.5-8.9) years, radiographs were obtained in 99, and tantalum concentrations in 84 patients.Results 1 patient with a DMC had a dislocation, whereas 14 patients with PE liners experienced at least 1 dislocation. 11 of 15 re-revisions in the PE group were necessitated by dislocations, whereas none of the 2 re-revisions in the DMC group was performed for this reason. Hence, dislocation-free survival after 4 years was 99% (95% CI 96-100) in the DMC group, whereas it was 88% (CI 82-94, p = 0.01) in the PE group. We found no radiographic signs of implant failure in any patient. Mean tantalum concentrations were 0.1 mu l/L (CI 0.05-0.2) in the DMC group and 0.1 mu g/L (CI 0.05-0.2) in the PE group.Interpretation Cementing DMCs into TM shells reduces the risk of dislocation after acetabular revision surgery without jeopardizing overall cup survival, and without enhancing tantalum release.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2018
    National Category
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-353002 (URN)10.1080/17453674.2018.1432927 (DOI)000429335700004 ()29400106 (PubMedID)
    Available from: 2018-07-13 Created: 2018-07-13 Last updated: 2020-01-09Bibliographically approved
    3. Safety of Use of Tantalum in Total Hip Arthroplasty
    Open this publication in new window or tab >>Safety of Use of Tantalum in Total Hip Arthroplasty
    (English)In: Journal of Bone and Joint Surgery. American volume, ISSN 0021-9355, E-ISSN 1535-1386Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    Background:

    Tantalum implants have been used in >500,000 orthopaedic patients. Although the risks of metallosis and aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) after total hip arthroplasty (THA) are being debated, we are not aware of any studies investigating the liberation of tantalum ions and their potential effects on the immune system. We evaluated whether tantalum concentrations are elevated after THA with acetabular tantalum implants and assessed potential alterations in T-cell subpopulations.

    Methods:

    After a mean follow-up of 4 years (range, 0.5 to 8.9 years) of 144 patients who had undergone THA, blood samples were analyzed regarding blood tantalum concentrations, total white blood-cell counts, and lymphocyte subsets in 3 groups of patients: those treated with non-tantalum primary THA (“primary non-tantalum,” n = 30), those treated with primary THA with a tantalum cup (“primary tantalum,” n = 30), and those who underwent revision surgery with a tantalum shell (“revision tantalum,” n = 84). Blood donors served as controls for immunological parameters (n = 59). Correlations between tantalum concentrations and human leukocyte antigen (HLA)-DR+ T cells were calculated, radiographic signs of implant loosening were assessed, and the Harris hip score (HHS) was used to evaluate hip function.

    Results:

    The median tantalum concentration was similar to the detection limit both in the primary non-tantalum group (0.05 µg/L, 95% confidence interval [CI] = 0.05 to 0.05 µg/L) and in the primary tantalum group (0.051 µg/L, 95% CI = 0.050 to 0.055 µg/L), and it was 0.091 µg/L (95% CI = 0.083 to 0.112 µg/L) in the revision tantalum group (p < 0.0001 in the group-wise comparison with both primary non-tantalum and primary tantalum). We found a weak negative correlation of higher tantalum concentration with the concentration of HLA-DR+/CD8+ T cells (r = −0.22, 95% CI = −0.35 to −0.05, p = 0.01) but no correlation of tantalum concentration with the concentration of HLA-DR+/CD4+ T cells (r = −0.11, 95% CI = −0.27 to 0.06, p = 0.24). The values for all lymphocyte subgroups were within normal ranges. No implants were deemed loose. The median HHS was good to excellent.

    Conclusions:

    Exposure to stable tantalum cups is associated with low blood concentrations of tantalum. Signs of T-cell activation typical of ALVAL seem to be lacking.

    Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence

    National Category
    Medical and Health Sciences
    Research subject
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-401793 (URN)10.2106/JBJS.19.00366 (DOI)
    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-02-05Bibliographically approved
    4. Is the risk of revision after arthroplasty surgery associated with specific gene loci? A genome-wide association study of single nucleotide polymorphisms in 1,130 arthroplasty-treated twins.
    Open this publication in new window or tab >>Is the risk of revision after arthroplasty surgery associated with specific gene loci? A genome-wide association study of single nucleotide polymorphisms in 1,130 arthroplasty-treated twins.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background:

    We aimed to identify single nucleotide polymorphisms (SNPs) associated with an increased risk of revision surgery following total joint replacement (TJR) within the setting of a genome-wide association study.

    Patients and Methods

    Genetic information was present on 1,130 twins in the Swedish Twin Registry’s TwinGene dataset who had been treated with TJR of the hip or knee. Of these, 94 underwent revision surgery for any reason, our primary outcome, and 75/94 underwent revision due to aseptic loosening, our secondary outcome. Genetic information was collected using the Illumina OmniExpress and Psych arrays and the Haplotype Reference Consortium served as the reference for gene imputation. Adjusted Cox regression models with a robust sandwich estimator were fitted to calculate hazard ratios (HRs) with 95% confidence intervals (CI) at a significance level of p<5*10-8.

    Results

    Six SNPs were statistically significantly associated with an increased risk for revision due to any reason, with the leading four located in a gene region coding for the sodium-dependent taurine and beta-alanine transporter. The first SNP, rs62233562, conferred a HR of undergoing revision surgery of 3.1 (95%CI 2.2-4.4, p=1.74*10-10). Similar HR were attained for the SNPs 3:14506680 (p=1.8*10-10), rs2289129 (p=1.8*10-10), and rs17309567 (p=3.16*10-10). The fifth SNP was located in the calmodulin-binding transcription activator 1 gene (rs11120968, HR 2.3; 95%CI 1.7-3.1, p=1.45*10-8), and the sixth, rs13081679, in an intron region (HR 2.9; 95%CI 2.0-4.1, p=2.63*10-8). When investigating aseptic loosening as the outcome, three SNP reached statistical significance: The previously identified rs17309567 remained significant (HR 3.35; 95%CI: 2.31-4.86, p=1.69*10-10), followed by two SNPs within the region coding for the ABO-system: rs7853989 (HR: 3.46; 95%CI 2.33-5.13, p=6.91*10-10), and 9:136126631 (HR: 2.82; 95%CI 1.95-4.07, p=3.35*10-8).

    Conclusions

    We identified novel SNPs conferring an increased risk of revision surgery after TJR, some with a potential connection to the pathophysiology underlying TJR loosening. Given the association of ABO-variants with complications after TJR, our findings of risk-SNPs within gene regions encoding for the ABO-system merit further investigation and replication.

    National Category
    Orthopaedics
    Identifiers
    urn:nbn:se:uu:diva-401795 (URN)
    Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-09
  • 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
    Show others...
    (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
    Show others...
    (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