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  • Public defence: 2018-10-19 09:00 E10:1307-1309 (Trippelrummet), Uppsala
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Genetic Cartography at Massively Parallel Scale2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Massively parallel sequencing (MPS) is revolutionizing genomics. In this work we use, refine, and develop new tools for the discipline.

    MPS has led to the discovery of multiple novel subtypes in Acute Lymphoblastic Leukemia (ALL). In Study I we screen for fusion genes in 134 pediatric ALL patients, including patients without an assigned subtype. In approximately 80% of these patients we detect novel or known fusion gene families, most of which display distinct methylation and expression patterns. This shows the potential for improvements in the clinical stratification of ALL. Large sample sizes are important to detect recurrent somatic variation. In Study II we investigate if a non-index overlapping pooling schema can be used to increase sample size and detect somatic variation. We designed a schema for 172 ALL samples and show that it is possible to use this method to call somatic variants.

    Around the globe there are many ongoing and completed genome projects. In Study III we sequenced the genome of 1000 Swedes to create a reference data set for the Swedish population. We identified more than 10 million variants that were not present in publicly available databases, highlighting the need for population-specific resources. Data, and the tools developed during this study, have been made publicly available as a resource for genomics in Sweden and abroad.

    The increased amount of sequencing data has created a greater need for automation. In Study IV we present Arteria, a computational automation system for sequencing core facilities. This system has been adopted by multiple facilities and has been used to analyze thousands of samples. In Study V we developed CheckQC, a program that provides automated quality control of Illumina sequencing runs. These tools make scaling up MPS less labour intensive, a key to unlocking the full future potential of genomics.

    The tools, and data presented here are a valuable contribution to the scientific community. Collectively they showcase the power of MPS and genomics to bring about new knowledge of human health and disease.

    List of papers
    1. Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
    Open this publication in new window or tab >>Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
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    2017 (English)In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 10, article id 148Article in journal (Refereed) Published
    Abstract [en]

    Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

    Keywords
    Pediatric acute lymphoblastic leukemia, RNA sequencing, Fusion genes, BCP-ALL, T-ALL, Translocation
    National Category
    Cancer and Oncology Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-332658 (URN)10.1186/s13045-017-0515-y (DOI)000408001300001 ()28806978 (PubMedID)
    Funder
    Swedish Foundation for Strategic Research , RBc08-008Swedish Cancer Society, 130440, 160711Swedish Childhood Cancer Foundation, 11098Swedish Research Council, C0524801, 2016-03691_3
    Note

    De 2 sista författarna delar sistaförfattarskapet.

    Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2018-08-27Bibliographically approved
    2. Identification of somatic variants by targeted sequencing of pooled cancer samples
    Open this publication in new window or tab >>Identification of somatic variants by targeted sequencing of pooled cancer samples
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical Genetics
    Research subject
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-269752 (URN)
    Available from: 2015-12-18 Created: 2015-12-18 Last updated: 2018-08-27
    3. SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population
    Open this publication in new window or tab >>SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population
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    2017 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 11, p. 1253-1260Article in journal (Refereed) Published
    Abstract [en]

    Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2017
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-337314 (URN)10.1038/ejhg.2017.130 (DOI)000412823800012 ()28832569 (PubMedID)
    Funder
    Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg Foundation, 2014.0272Swedish Research CouncilSwedish National Infrastructure for Computing (SNIC), sens2016003EU, European Research Council, 282330
    Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-08-27Bibliographically approved
    4. Arteria: An automation system for a sequencing core facility
    Open this publication in new window or tab >>Arteria: An automation system for a sequencing core facility
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Bioinformatics (Computational Biology) Computer Systems
    Identifiers
    urn:nbn:se:uu:diva-357972 (URN)
    Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-27
    5. CheckQC: Quick quality control of Illumina sequencing runs
    Open this publication in new window or tab >>CheckQC: Quick quality control of Illumina sequencing runs
    2018 (English)In: The Journal of Open Source Software, ISSN 2475-9066, Vol. 3, no 22, article id 556Article in journal (Refereed) Published
    Keywords
    bioinformatics, sequencing
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-349255 (URN)10.21105/joss.00556 (DOI)
    Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-08-27Bibliographically approved
  • Public defence: 2018-10-19 09:15 B42, Uppsala
    Sundell, Gustav
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Using peptide-phage display to capture conditional motif-based interactions2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis explores the world of conditional protein-protein interactions using combinatorial peptide-phage display and proteomic peptide-phage display (ProP-PD). Large parts of proteins in the human proteome do not fold in to well-defined structures instead they are intrinsically disordered. The disordered parts are enriched in linear binding-motifs that participate in protein-protein interaction. These motifs are 3-12 residue long stretches of proteins where post-translational modifications, like protein phosphorylation, can occur changing the binding preference of the motif. Allosteric changes in a protein or domain due to phosphorylation or binding to second messenger molecules like Ca2+ can also lead conditional interactions. Finding phosphorylation regulated motif-based interactions on a proteome-wide scale has been a challenge for the scientific community.

    Through combinatorial peptide phage display selections against the calcium binding protein Sorcin we discovered the Φ-Φ-X-P motif that preferentially interacts with calcium bound Sorcin. Through C-terminal ProP-PD we discovered that the engineered L391F, K329M Ø9 mutant of the second PDZ domain of DLG1 has a reduced specificity and increased affinity towards proteomic targets as compared to the wild type DLG1 PDZ2 domain.

    Finally a novel application of ProP-PD that allows us to capture phospho-regulated interactions by combining it with glutamic phosphomimetic substitution is presented. We created a phosphomimetic ProP-PD library of C-terminal sequences of known and putative serine/threonine phospho-sites, and their phosphomimetic counterparts. The library was used in selection against PDZ 1, 2 and 3 of Scribble and DLG1.  We found site-specific phosphorylation events that either enable or disable interactions. Selectivity towards phosphopeptide binding was confirmed for Scribble PDZ1 through biophysical experiments, supporting the viability of the phosphomimetic ProP-PD. Through structural and mutational analysis we found that the gate-keeping residue for phosphopeptide binding in Scribble PDZ1 is arginine 762. With this proof-of-concept study we have introduced phosphomimetic ProP-PD as a viable method to discover phospho-regulated protein-peptide interactions.

    Taken together, this work has contributed with methods to capture selectivity differences in motif-based interactions of proteins depending on allosteric binding of calcium, protein engineering and on ligand modification by phosphorylation. 

     

    List of papers
    1. Structural basis of Sorcin-mediated calcium-dependent signal transduction
    Open this publication in new window or tab >>Structural basis of Sorcin-mediated calcium-dependent signal transduction
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    2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 16828Article in journal (Refereed) Published
    Abstract [en]

    Sorcin is an essential penta-EF hand calcium binding protein, able to confer the multi-drug resistance phenotype to drug-sensitive cancer cells and to reduce Endoplasmic Reticulum stress and cell death. Sorcin silencing blocks cell cycle progression in mitosis and induces cell death by triggering apoptosis. Sorcin participates in the modulation of calcium homeostasis and in calcium-dependent cell signalling in normal and cancer cells. The molecular basis of Sorcin action is yet unknown. The X-ray structures of Sorcin in the apo (apoSor) and in calcium bound form (CaSor) reveal the structural basis of Sorcin action: calcium binding to the EF1-3 hands promotes a large conformational change, involving a movement of the long D-helix joining the EF1-EF2 sub-domain to EF3 and the opening of EF1. This movement promotes the exposure of a hydrophobic pocket, which can accommodate in CaSor the portion of its N-terminal domain displaying the consensus binding motif identified by phage display experiments. This domain inhibits the interaction of sorcin with PDCD6, a protein that carries the Sorcin consensus motif, co-localizes with Sorcin in the perinuclear region of the cell and in the midbody and is involved in the onset of apoptosis.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-269971 (URN)10.1038/srep16828 (DOI)000364903100002 ()26577048 (PubMedID)
    Funder
    Swedish Research CouncilÅke Wiberg Foundation
    Available from: 2015-12-19 Created: 2015-12-19 Last updated: 2018-09-02Bibliographically approved
    2. Improved affinity at the cost of decreased specificity: a recurring theme in PDZ-peptide interactions.
    Open this publication in new window or tab >>Improved affinity at the cost of decreased specificity: a recurring theme in PDZ-peptide interactions.
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    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 34269Article in journal (Refereed) Published
    Abstract [en]

    The E6 protein from human papillomavirus (HPV) plays an important role during productive infection and is a potential drug target. We have previously designed a high affinity bivalent protein binder for the E6 protein, a fusion between a helix from the E6 associated protein and PDZØ9, an engineered variant (L391F/K392M) of the second PDZ domain from synapse associated protein 97 (SAP97 PDZ2). How the substitutions improve the affinity of SAP97 PDZ2 for HPV E6 is not clear and it is not known to what extent they affect the specificity for cellular targets. Here, we explore the specificity of wild type SAP97 PDZ2 and PDZØ9 through proteomic peptide phage display. In addition, we employ a double mutant cycle of SAP97 PDZ2 in which the binding kinetics for nine identified potential cellular peptide ligands are measured and compared with those for the C-terminal E6 peptide. The results demonstrate that PDZØ9 has an increased affinity for all peptides, but at the cost of specificity. Furthermore, there is a peptide dependent coupling free energy between the side chains at positions 391 and 392. This corroborates our previous allosteric model for PDZ domains, involving sampling of intramolecular energetic pathways.

    National Category
    Natural Sciences
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-306579 (URN)10.1038/srep34269 (DOI)000384758300001 ()27694853 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2016-10-29 Created: 2016-10-29 Last updated: 2018-09-02Bibliographically approved
    3. Proteome‐wide analysis of phospho‐regulated PDZ domain interactions
    Open this publication in new window or tab >>Proteome‐wide analysis of phospho‐regulated PDZ domain interactions
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    2018 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 14, no 8, article id e8129Article in journal (Refereed) Published
    Abstract [en]

    A key function of reversible protein phosphorylation is to regulate protein–protein interactions, many of which involve short linear motifs (3–12 amino acids). Motif‐based interactions are difficult to capture because of their often low‐to‐moderate affinities. Here, we describe phosphomimetic proteomic peptide‐phage display, a powerful method for simultaneously finding motif‐based interaction and pinpointing phosphorylation switches. We computationally designed an oligonucleotide library encoding human C‐terminal peptides containing known or predicted Ser/Thr phosphosites and phosphomimetic variants thereof. We incorporated these oligonucleotides into a phage library and screened the PDZ (PSD‐95/Dlg/ZO‐1) domains of Scribble and DLG1 for interactions potentially enabled or disabled by ligand phosphorylation. We identified known and novel binders and characterized selected interactions through microscale thermophoresis, isothermal titration calorimetry, and NMR. We uncover site‐specific phospho‐regulation of PDZ domain interactions, provide a structural framework for how PDZ domains accomplish phosphopeptide binding, and discuss ligand phosphorylation as a switching mechanism of PDZ domain interactions. The approach is readily scalable and can be used to explore the potential phospho‐regulation of motif‐based interactions on a large scale.

    Keywords
    PDZ domainphage displayphosphorylationprotein–protein interactionScribble
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-358712 (URN)10.15252/msb.20178129 (DOI)
    Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-09-02
    4. The Sign of Nuclear Magnetic Resonance Chemical Shift Difference as a Determinant of the Origin of Binding Selectivity: Elucidation of the Position Dependence of Phosphorylation in Ligands Binding to Scribble PDZ1
    Open this publication in new window or tab >>The Sign of Nuclear Magnetic Resonance Chemical Shift Difference as a Determinant of the Origin of Binding Selectivity: Elucidation of the Position Dependence of Phosphorylation in Ligands Binding to Scribble PDZ1
    2018 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, no 1, p. 66-71Article in journal (Refereed) Published
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-359433 (URN)10.1021/acs.biochem.7b00965 (DOI)
    Available from: 2018-09-02 Created: 2018-09-02 Last updated: 2018-09-02
  • Public defence: 2018-10-19 10:15 Lindahlsalen, Uppsala
    Talla, Venkat
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Uppsala University.
    Speciation genetics of recently diverged species: 2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Species differentiation can be a consequence of evolutionary forces including natural selection and random genetic drift. Patterns of genomic differentiation vary across the tree of life. This variation seems to be dependent on, for example, differences in genomic architecture and molecular mechanisms. However, the knowledge we currently possess, both regarding the processes driving speciation and the resulting genomic signatures, is from a very small subset of the overall biodiversity that resides on the planet. Therefore, characterization of the architecture of genomic divergence from more organism groups will be important to understand the effects of molecular mechanisms and evolutionary forces driving divergence between lineages. Hence it has not been possible to come to a consensus on the relative importance of genetic drift and natural selection on divergence processes in general. In this thesis, I use genomic approaches to investigate the forces underlying species and population differentiation in the European cryptic wood white butterflies (Leptidea sinapisL. reali and L. juvernica) and two closely related bird species, the chiffchaff (Phylloscopus collybita abietinus) and the Siberian chiffchaff (P. tristis). Both these groups contain recently diverged species, a prerequisite for investigating initial differentiation processes. However, the study systems also differ in several respects, allowing for applying distinct approaches to understand the divergence process in each system.

    In summary, by applying a suite of genomic approaches, my thesis work gives novel insights into the speciation history of wood whites and chiffchaff. I identify candidate genes for local adaptation in both systems and concludes that genome differentiation in wood white butterflies have been driven by a combination of random genetic drift and week directional selection in allopatry. In the chiffchaff, the general differentiation landscape seems to have been shaped by recurrent background selection (and potentially selective sweeps), likely as a consequence of regional variation in the recombination rate which has also been observed in other genome-scans in birds. Potentially, some of the highly differentiated regions contain barriers to gene-flow as these regions are still present in sympatry, where species exchange genetic material at a high rate.

    List of papers
    1. Rapid Increase in Genome Size as a Consequence of Transposable Element Hyperactivity in Wood-White (Leptidea) Butterflies
    Open this publication in new window or tab >>Rapid Increase in Genome Size as a Consequence of Transposable Element Hyperactivity in Wood-White (Leptidea) Butterflies
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    2017 (English)In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 9, no 10, p. 2491-2505Article in journal (Refereed) Published
    Abstract [en]

    Characterizing and quantifying genome size variation among organisms and understanding if genome size evolves as a consequence of adaptive or stochastic processes have been long-standing goals in evolutionary biology. Here, we investigate genome size variation and association with transposable elements (TEs) across lepidopteran lineages using a novel genome assembly of the common wood-white (Leptidea sinapis) and population re-sequencing data from both L. sinapis and the closely related L. reali and L. juvernica together with 12 previously available lepidopteran genome assemblies. A phylogenetic analysis confirms established relationships among species, but identifies previously unknown intraspecific structure within Leptidea lineages. The genome assembly of L. sinapis is one of the largest of any lepidopteran taxon so far (643Mb) and genome size is correlated with abundance of TEs, both in Lepidoptera in general and within Leptidea where L. juvernica from Kazakhstan has considerably larger genome size than any other Leptidea population. Specific TE subclasses have been active in different Lepidoptera lineages with a pronounced expansion of predominantly LINEs, DNA elements, and unclassified TEs in the Leptidea lineage after the split from other Pieridae. The rate of genome expansion in Leptidea in general has been in the range of four Mb/Million year (My), with an increase in a particular L. juvernica population to 72Mb/My. The considerable differences in accumulation rates of specific TE classes in different lineages indicate that TE activity plays a major role in genome size evolution in butterflies and moths.

    Keywords
    butterfly, Lepidoptera, Leptidea, genome expansion, transposable elements, population
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-341668 (URN)10.1093/gbe/evx163 (DOI)000414778600001 ()28981642 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council, VR 2013-4508EU, FP7, Seventh Framework Programme, 625997Swedish National Infrastructure for Computing (SNIC), b2014034
    Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2018-08-28Bibliographically approved
    2. Lack of parallelism: lineage-specific directional selection drives genome differentiation across a triplet of cryptic butterfly species
    Open this publication in new window or tab >>Lack of parallelism: lineage-specific directional selection drives genome differentiation across a triplet of cryptic butterfly species
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Speciation, wood-white butterflies, Leptidea, Lepidoptera, cryptic species, genome-scan
    National Category
    Genetics
    Research subject
    Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-358288 (URN)
    Available from: 2018-08-27 Created: 2018-08-27 Last updated: 2018-08-28
    3. Heterogeneous Patterns of Genetic Diversity and Differentiation in European and Siberian Chiffchaff (Phylloscopus collybita abietinus/P. tristis)
    Open this publication in new window or tab >>Heterogeneous Patterns of Genetic Diversity and Differentiation in European and Siberian Chiffchaff (Phylloscopus collybita abietinus/P. tristis)
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    2017 (English)In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 7, no 12, p. 3983-3998Article in journal (Refereed) Published
    Abstract [en]

    Identification of candidate genes for trait variation in diverging lineages and characterization of mechanistic underpinnings of genome differentiation are key steps toward understanding the processes underlying the formation of new species. Hybrid zones provide a valuable resource for such investigations, since they allow us to study how genomes evolve as species exchange genetic material and to associate particular genetic regions with phenotypic traits of interest. Here, we use whole-genome resequencing of both allopatric and hybridizing populations of the European (Phylloscopus collybita abietinus) and the Siberian chiffchaff (P. tristis)-two recently diverged species which differ in morphology, plumage, song, habitat, and migration-to quantify the regional variation in genome-wide genetic diversity and differentiation, and to identify candidate regions for trait variation. We find that the levels of diversity, differentiation, and divergence are highly heterogeneous, with significantly reduced global differentiation, and more pronounced differentiation peaks in sympatry than in allopatry. This pattern is consistent with regional differences in effective population size and recurrent background selection or selective sweeps reducing the genetic diversity in specific regions prior to lineage divergence, but the data also suggest that post-divergence selection has resulted in increased differentiation and fixed differences in specific regions. We find that hybridization and backcrossing is common in sympatry, and that phenotype is a poor predictor of the genomic composition of sympatric birds. The combination of a differentiation scan approach with identification of fixed differences pinpoint a handful of candidate regions that might be important for trait variation between the two species.

    Keywords
    chiffchaff, speciation, genome-scan, divergence islands, Z-chromosome, autosomes
    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-344216 (URN)10.1534/g3.117.300152 (DOI)000417073900015 ()29054864 (PubMedID)
    Funder
    Swedish Research Council, 2013-4508Swedish National Infrastructure for Computing (SNIC), b2013146
    Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-08-28Bibliographically approved
    4. Dissecting the effects of natural selection and mutation on genetic diversity in three recently diverged cryptic butterfly species
    Open this publication in new window or tab >>Dissecting the effects of natural selection and mutation on genetic diversity in three recently diverged cryptic butterfly species
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Adaptation, speciation, Leptidea, Lepidoptera, cryptic species, selection
    National Category
    Genetics
    Research subject
    Biology with specialization in Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-358291 (URN)
    Available from: 2018-08-27 Created: 2018-08-27 Last updated: 2018-08-28
    5. Gene expression profiling across ontogenetic stages in the wood white (Leptidea sinapis) reveals pathways linked to butterfly diapause regulation
    Open this publication in new window or tab >>Gene expression profiling across ontogenetic stages in the wood white (Leptidea sinapis) reveals pathways linked to butterfly diapause regulation
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    2018 (English)In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 27, no 4, p. 935-948Article in journal (Refereed) Published
    Abstract [en]

    In temperate latitudes, many insects enter diapause (dormancy) during the cold season, a period during which developmental processes come to a standstill. The wood white (Leptidea sinapis) is a butterfly species distributed across western Eurasia that shows photoperiod-induced diapause with variation in critical day-length across populations at different latitudes. We assembled transcriptomes and estimated gene expression levels at different developmental stages in experimentally induced directly developing and diapausing cohorts of a single Swedish population of L. sinapis to investigate the regulatory mechanisms underpinning diapause initiation. Different day lengths resulted in expression changes of developmental genes and affected the rate of accumulation of signal molecules, suggesting that diapause induction might be controlled by increased activity of monoamine neurotransmitters in larvae reared under short-day light conditions. Expression differences between light treatment groups of two monoamine regulator genes (DDC and ST) were observed already in instar III larvae. Once developmental pathways were irreversibly set at instar V, a handful of genes related to dopamine production were differentially expressed leading to a significant decrease in expression of global metabolic genes and increase in expression of genes related to fatty acid synthesis and sequestration. This is in line with a time-dependent (hour-glass) model of diapause regulation where a gradual shift in the concentration of monoamine neurotransmitters and their metabolites during development of larvae under short-day conditions leads to increased storage of fat, decreased energy expenditures, and ultimately developmental stasis at the pupal stage.

    Place, publisher, year, edition, pages
    WILEY, 2018
    Keywords
    developmental plasticity, diapause, gene expression, hour-glass model, Lepidoptera, monoamine neurotransmitter
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-351766 (URN)10.1111/mec.14501 (DOI)000428797100010 ()29411442 (PubMedID)
    Funder
    Swedish Research Council, 2013-4508]Science for Life Laboratory - a national resource center for high-throughput molecular bioscience, Backstrom_2014Knut and Alice Wallenberg Foundation
    Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-08-28Bibliographically approved
  • Public defence: 2018-10-19 10:15 Polhemsalen, Uppsala
    Ekholm, Victor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Ion pairing and Langmuir-like adsorption at aqueous surfaces studied by core-level spectroscopy2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Surface-bulk equilibria for solutes in aqueous solutions are studied using X-ray Photoelectron Spectroscopy (XPS) with high surface and chemical sensitivity. In the first part, the results show a reduction of the biochemically relevant guanidinium ions’ surface propensity with the addition of disodium sulphate due to ion pairing with the strongly hydrated sulphate ion, which could have implications for protein folding. Thereafter, the work considers amphiphilic organic compounds related to atmospheric science where the surface propensities, orientations at the surface and solute-solute and solute-solvent interactions are investigated. In the second part, two linear organic ions are investigated both as single solutes and in mixture. Both organic ions are surface enriched on their own and even more in the mixed solute solution. Due to hydrophobic expulsion of the alkyl chains, ion pairing between the organic ions and van der Waals interaction, the organic ions seem to assemble in clusters with their alkyl chains pointing out of the surface. The third part also covers linear organic compounds but one at a time probing the surface concentration as a function of bulk concentration. A Langmuir-like adsorption behavior was observed and Gibb’s free energy of surface adsorption (ΔGAds) values were extracted. An empiric model for deriving values for ΔGAds is proposed based upon the seemingly linear change in ΔGAds per carbon when comparing alcohols of different chain lengths. The fourth part investigates the acid/base fraction at the surface as function of bulk pH. The most important factor for this fraction seems to be how the surface propensity varies with the charge state of the acid or base instead of a possible difference in pH or pKa value at the surface. In the fifth part the oxygen K-edge of aqueous carbonate and bicarbonate is probed with the bulk-sensitive Resonant Inelastic X-ray Scattering (RIXS) technique.

    List of papers
    1. Anomalous surface behavior of hydrated guanidinium ions due to ion pairing
    Open this publication in new window or tab >>Anomalous surface behavior of hydrated guanidinium ions due to ion pairing
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    2018 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 148, no 14, article id 144508Article in journal (Refereed) Published
    Abstract [en]

    Surface affinity of aqueous guanidinium chloride (GdmCl) is compared to that of aqueous tetrapropylammonium chloride (TPACl) upon addition of sodium chloride (NaCl) or disodium sulfate (Na2SO4). The experimental results have been acquired using the surface sensitive technique X-ray photoelectron spectroscopy on a liquid jet. Molecular dynamics simulations have been used to produce radial distribution functions and surface density plots. The surface affinities of both TPA(+) and Gdm(+) increase upon adding NaCl to the solution. With the addition of Na2SO4, the surface affinity of TPA(+) increases, while that of Gdm(+) decreases. From the results of MD simulations it is seen that Gdm(+) and SO42- ions form pairs. This finding can be used to explain the decreased surface affinity of Gdm(+) when co-dissolved with SO42- ions. Since SO42- ions avoid the surface due to the double charge and strong water interaction, the Gdm(+)-SO42- ion pair resides deeper in the solutions' bulk than the Gdm(+) ions. Since TPA(+) does not form ion pairs with SO42-, the TPA(+) ions are instead enriched at the surface.

    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-353201 (URN)10.1063/1.5024348 (DOI)000430128600034 ()29655316 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-09-02Bibliographically approved
    2. Strong Enrichment of Atmospherically Relevant Organic Ions at the Aqueous Interface: The Role of Ion Pairing and Cooperative Effects
    Open this publication in new window or tab >>Strong Enrichment of Atmospherically Relevant Organic Ions at the Aqueous Interface: The Role of Ion Pairing and Cooperative Effects
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    (English)In: Article in journal (Other academic) Submitted
    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-357368 (URN)
    Available from: 2018-08-15 Created: 2018-08-15 Last updated: 2018-09-02
    3. Surface propensity of atmospherically relevant carboxylates and alkyl ammonium ions studied by XPS: towards a building-block model of surface propensity based on Langmuir adsorption
    Open this publication in new window or tab >>Surface propensity of atmospherically relevant carboxylates and alkyl ammonium ions studied by XPS: towards a building-block model of surface propensity based on Langmuir adsorption
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-358541 (URN)
    Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-09-02
    4. Surface behavior of amphiphiles in aqueous solution: a comparison between different pentanol isomers
    Open this publication in new window or tab >>Surface behavior of amphiphiles in aqueous solution: a comparison between different pentanol isomers
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    2015 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 21, p. 14036-14044Article in journal (Refereed) Published
    Abstract [en]

    Position isomerism is ubiquitous in atmospheric oxidation reactions. Therefore, we have compared surface-active oxygenated amphiphilic isomers (1- and 3-pentanol) at the aqueous surface with surface- and chemically sensitive X-ray photoelectron spectroscopy (XPS), which reveals information about the surface structure on a molecular level. The experimental data are complemented with molecular dynamics (MD) simulations. A concentration-dependent orientation and solvation of the amphiphiles at the aqueous surface is observed. At bulk concentrations as low as around 100 mM, a monolayer starts to form for both isomers, with the hydroxyl groups pointing towards the bulk water and the alkyl chains pointing towards the vacuum. The monolayer (ML) packing density of 3-pentanol is approx. 70% of the one observed for 1-pentanol, with a molar surface concentration that is approx. 90 times higher than the bulk concentration for both molecules. The molecular area at ML coverage (approximate to 100 mM) was calculated to be around 32 +/- 2 angstrom(2) per molecule for 1-pentanol and around 46 +/- 2 angstrom(2) per molecule for 3-pentanol, which results in a higher surface concentration (molecules per cm(2)) for the linear isomer. In general we conclude therefore that isomers - with comparable surface activities - that have smaller molecular areas will be more abundant at the interface in comparison to isomers with larger molecular areas, which might be of crucial importance for the understanding of key properties of aerosols, such as evaporation and uptake capabilities as well as their reactivity.

    National Category
    Physical Chemistry Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-256562 (URN)10.1039/c5cp01870f (DOI)000354946200029 ()25953683 (PubMedID)
    Available from: 2015-06-24 Created: 2015-06-24 Last updated: 2018-09-02Bibliographically approved
    5. Alcohols at the Aqueous Surface: Chain Length and Isomer Effects
    Open this publication in new window or tab >>Alcohols at the Aqueous Surface: Chain Length and Isomer Effects
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    2016 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 9, p. 6648-6656Article in journal (Refereed) Published
    Abstract [en]

    Surface-active organic molecules at the liquid-vapor interface are of great importance in atmospheric science. Therefore, we studied the surface behavior of alcohol isomers with different chain lengths (C4-C6) in aqueous solution with surface- and chemically sensitive X-ray photoelectron spectroscopy (XPS), which reveals information about the surface structure on a molecular level. Gibbs free energies of adsorption and surface concentrations are determined from the XPS results using a standard Langmuir adsorption isotherm model. The free energies of adsorption, ranging from around -15 to -19 kJ/mol (C4-C6), scale linearly with the number of carbon atoms within the alcohols with ΔGAds/CH2 ≈ -2 kJ/mol. While for the linear alcohols, surface concentrations lie around 2.4 x 1014 molecules/cm2 at the bulk concentrations where monolayers are formed, the studied branched alcohols show lower surface concentrations of around 1.6 x 1014 molecules/cm2, both of which are in line with the molecular structure and their orientation at the interface. Interestingly, we find that there is a maximum in the surface enrichment factor for linear alcohols at low concentrations, which is not observed for the shorter branched alcohols. This is interpreted in terms of a cooperative effect, which we suggest to be the result of more effective van der Waals interactions between the linear alcohol alkyl chains at the aqueous surface, making it energetically even more favorable to reside at the liquid-vapor interface. 

    National Category
    Physical Chemistry Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-265221 (URN)10.1039/c5cp06463e (DOI)000371139400030 ()26868637 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Foundation for Strategic Research Carl Tryggers foundation
    Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2018-09-02Bibliographically approved
    6. Shifted Equilibria of Organic Acids and Bases in the Aqueous Surface Region
    Open this publication in new window or tab >>Shifted Equilibria of Organic Acids and Bases in the Aqueous Surface Region
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    (English)In: Article in journal (Other academic) Epub ahead of print
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-341965 (URN)10.1039/C8CP01898G (DOI)
    Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-09-09
    7. Aqueous carbonate and bicarbonate ions studied by RIXS at the O K-edge
    Open this publication in new window or tab >>Aqueous carbonate and bicarbonate ions studied by RIXS at the O K-edge
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-359428 (URN)
    Available from: 2018-09-02 Created: 2018-09-02 Last updated: 2018-09-02
  • Public defence: 2018-10-19 13:00 Auditorium Minus, Gustavianum, Uppsala
    Bakker, Marta
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    How hands shape the mind: The P400 as an index of manual actions and gesture perception2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Being able to perform and understand actions is crucial for proper functioning in the social world. From birth, we use our bodies to act and to promote learning about ourselves, our environment and other people’s actions and intentions. Our mind is embodied; thus, our actions play a crucial role in cognitive and social development.

    This thesis focuses on the close interrelation between action and perception and the role of our hands in this link. Three empirical studies on action processing are presented in a framework of embodied cognition that emphasises the role of bodily experience in social development. All three studies were designed to measure event-related potentials (ERPs) in infants 4 to 9 months old, when they observed manual actions, grasping and the give-me gesture.

    Study I demonstrates the neural underpinnings of infants’ action–perception link at the age when their ability to grasp for objects in a functional manner emerges. Neural processing has been found to be influenced by infants’ own manual experience of exactly the same grasping action.

    Study II reveals that brief active motor training with goal-directed actions, even before the solid motor plans for grasping are developed, facilitates processing of others’ goal-directed actions.

    Study III shows that the same neural correlate that indexes processing of reaching actions is involved in encoding of the give-me gesture, a type of non-verbal communication that conveys a request. This ability was found not to be directly dependent on the infants’ own ability to respond behaviourally to another person’s gesture.

    This thesis pinpoints the neural correlate, P400, involved in the processing of goal-directed actions and gestures. The findings highlight the importance of motor experience, as well as the involvement of attentional processes in action processing. Additionally, the data from Study III may suggest a possible involvement of grasping skills in encoding non-verbal communicative gestures.

    List of papers
    1. Neural correlates of action perception at the onset of functional grasping
    Open this publication in new window or tab >>Neural correlates of action perception at the onset of functional grasping
    2015 (English)In: Social Cognitive & Affective Neuroscience, ISSN 1749-5016, E-ISSN 1749-5024, Vol. 10, no 6, p. 769-796Article in journal (Refereed) Published
    Abstract [en]

    Event-related potentials were recorded while infants observe congruent or incongruent grasping actions at the age when organized grasping first emerges (4-6 months of age). We demonstrate that the event-related potential component P400 encodes the congruency of power grasps at the age of 6 months (Experiment 1) and in 5-month-old infants that have developed the ability to use power grasps (Experiment 2). This effect does not extend to precision grasps, which infants cannot perform (Experiment 3). Our findings suggest that infants' encoding of the relationship between an object and a grasping hand (the action-perception link) is highly specialized to actions and manual configurations of actions that infants are able to perform.

    Keywords
    grasping, experience, infant, P400, event-related potential
    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-258358 (URN)10.1093/scan/nsu119 (DOI)000356272800002 ()25193947 (PubMedID)
    Available from: 2015-07-13 Created: 2015-07-13 Last updated: 2018-08-29Bibliographically approved
    2. Enhanced neural processing of goal-directed actions during active training in 4-month-old infants
    Open this publication in new window or tab >>Enhanced neural processing of goal-directed actions during active training in 4-month-old infants
    2016 (English)In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 28, no 3, p. 472-482Article in journal (Refereed) Published
    Abstract [en]

    The current study explores the neural correlates of action perception and its relation to infants' active experience performing goal-directed actions. Study 1 provided active training with sticky mittens that enables grasping and object manipulation in prereaching 4-month-olds. After training, EEG was recorded while infants observed images of hands grasping toward (congruent) or away from (incongruent) objects. We demonstrate that brief active training facilitates social perception as indexed by larger amplitude of the P400 ERP component to congruent compared with incongruent trials. Study 2 presented 4-month-old infants with passive training in which they observed an experimenter perform goal-directed reaching actions, followed by an identical ERP session to that used in Study 1. The second study did not demonstrate any differentiation between congruent and incongruent trials. These results suggest that (1) active experience alters the brains' response to goal-directed actions performed by others and (2) visual exposure alone is not sufficient in developing the neural networks subserving goal processing during action observation in infancy.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-270101 (URN)10.1162/jocn_a_00909 (DOI)000369760000009 ()26679217 (PubMedID)
    Funder
    EU, European Research Council, CACTUS 312292Knut and Alice Wallenberg Foundation, KWA 2012.0120
    Available from: 2015-12-21 Created: 2015-12-21 Last updated: 2018-08-29Bibliographically approved
    3. The neural basis of non-verbal communication - enhanced processing of perceived give-me gestures in 9-month-old girls
    Open this publication in new window or tab >>The neural basis of non-verbal communication - enhanced processing of perceived give-me gestures in 9-month-old girls
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    2015 (English)In: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 6, p. 59-Article in journal (Refereed) Published
    Abstract [en]

    This study investigated the neural basis of non-verbal communication. Event-related potentials were recorded while 29 nine-month-old infants were presented with a give me gesture (experimental condition) and the same hand shape but rotated 90 degrees, resulting in a non-communicative hand configuration (control condition). We found different responses in amplitude between the two conditions, captured in the P400 ERR component. Moreover, the size of this effect was modulated by participants' sex, with girls generally demonstrating a larger relative difference between the two conditions than boys.

    Keywords
    give-me gesture, ERP, P400, sex differences, non-verbal communication, social perception, infancy
    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-246336 (URN)10.3389/fpsyg.2015.00059 (DOI)000348913300001 ()25705196 (PubMedID)
    Available from: 2015-03-10 Created: 2015-03-05 Last updated: 2018-08-29
  • Public defence: 2018-10-19 13:15 Sal IV, Uppsala
    Johansson, Gustaf
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History.
    När man skär i nuet faller framtiden ut: Den globala krisens bildvärld i Sverige under 1970-talet2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The aim of this dissertation is to investigate how this notion of a threatening global crisis was visualized in Swedish public media during the 1970s. The study has two main areas of interest. The first one entails an examination of how the visualizations relate to the present as a mode of time: how are temporal and spatial categories configured to make the “now” of global crisis visible? The second area of focus is the relationship between the visualizations and the imperative of change. This imperative was articulated in terms of concern for the global future: how did the visualizations guide, organize, and structure the ability to see the present from the perspective of global crisis?

    The study is based on a wide selection of media sources: newspapers, magazines, art exhibitions, popular science books, and television programs. I also look at how concerns for the global future surfaced in educational materials for use in school and in ideas for social reform articulated within the emerging discipline of Future Studies.

    In the dissertation, I show how the image-world that was created by the public circulation of global crisis narratives contained a broad range of images. Iconic ones, like photographs of the Earth from space and the J-curve diagrams, were no doubt important in the Swedish context. But they were not the only way to visualize notions of crisis on a global scale. Rather, it was the combination of many different types of visual material, providing different perspectives and possibilities, which defined the image-world that made global crisis visible from a Swedish point of view. Configurations of different times and places played an especially important role, giving visual form to the negative universal history of global crisis perception, and establishing a transhistorical space from which lessons could be learned and points of crisis brought into view.

    This montage-like quality of the image-world of global crisis is particularly important when trying to understand how the imperative of change, widely articulated when these topics were discussed in the Swedish public sphere, were related to the visualizations. Through the configuration of different images and perspectives, they guided the viewers to certain examples and showed how they connected with other points of importance. They visualized a structure for perceiving the “now” of global crisis. An outline of how to comprehend these connections, and how to realize where and when it was possible to act in order to counteract them, was thus made visually present in the images.

  • Public defence: 2018-10-20 09:36 Sal X, Uppsala
    Stenwall, Anton
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transcriptional and morphological analysis of organ donor pancreata2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The diabetes disease panorama affects more than 400 million people world wide – a number projected to rise above 640 million in the next 20 years. Type 1 and type 2 diabetes are associated with adverse complications, resulting in severe morbidity and high healthcare costs exerting substantial strain on society. Type 1 diabetes results from the destruction of the insulin producing beta-cells, while type 2 diabetes is a multifactorial combination of a decreased ability of the beta cells to secrete sufficient insulin and a peripheral resistance to insulin-mediated glucose uptake. The cause of diabetes is unknown, as are the possibly sequential cellular events resulting in overt disease. In this thesis, organ-donor pancreata from donors with or without diabetes are analysed in order to deepen our understanding of the Islets of Langerhans, the beta cells and the pancreas. 

    In Paper I, islets from a donor that died at onset of type 1 diabetes, showing morphological signs of hydropic degeneration are analyzed on a gene-expression level, and the results are compared to islets from a donor without diabetes. We find no signs of ongoing inflammation, apoptosis or ER stress. In Paper IIwe compare the expression levels of genes related to cellular stress, in islets from donors with type 2 diabetes and from donors with high pre-mortal HbA1c levels but without a diabetes diagnosis, to the expression levels in islets from donors with normal HbA1c levels. We report that islets from donors with type 2 diabetes show signs of cellular stress on a transcriptional level compared with islets from donors without diabetes. In Paper III we performed a transcriptional analysis of the islets from organ donors aged between 1 and 81 years in order to elucidate whether age induces specific changes in the islet transcriptome. We found 20 genes that co-varied with increasing age. In Paper IV,the pancreatic expression of host-defense molecules is characterized, and we report the expression of several host-defense molecules not previously described in the human pancreas. Together, these results deepen our understanding of the effects of ageing and prolonged exposure to high blood sugar levels on the islets, as well as our knowledge about the innate immunity of the human pancreas. 

     

    List of papers
    1. Gene expression analysis of human islets in a subject at onset of type 1 diabetes
    Open this publication in new window or tab >>Gene expression analysis of human islets in a subject at onset of type 1 diabetes
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    2014 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 51, no 2, p. 199-204Article in journal (Refereed) Published
    Abstract [en]

    Swollen islet cells have been repeatedly described at onset of type 1 diabetes, but the underlying mechanism of this observation, termed hydropic degeneration, awaits characterization. In this study, laser capture microdissection was applied to extract the islets from an organ donor that died at onset of type 1 diabetes and from an organ donor without pancreatic disease. Morphologic analysis revealed extensive hydropic degeneration in 73 % of the islets from the donor with type 1 diabetes. Expression levels of genes involved in apoptosis, ER stress, beta cell function, and inflammation were analyzed in isolated and laser-captured islets by qPCR. The chemokine MCP-1 was expressed in islets from the donor with type 1 diabetes while undetectable in the control donor. No other signs of inflammation were detected. There were no signs of apoptosis on the gene expression level, which was also confirmed by negative immunostaining for cleaved caspase-8. There was an increased expression of the transcription factor ATF4, involved in transcription of ER stress genes, in the diabetic islets, but no further signs of ER stress were identified. In summary, on the transcription level, islets at onset of type 1 diabetes in which many beta cells display hydropic degeneration show no obvious signs of apoptosis, ER stress, or inflammation, supporting the notion that these cells are responding normally to high glucose and eventually succumbing to beta cell exhaustion. Also, this study validates the feasibility of performing qPCR analysis of RNA extracted from islets from subjects with recent onset of T1D and healthy controls by laser capture microdissection.

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-202844 (URN)10.1007/s00592-013-0479-5 (DOI)000334054200004 ()23624551 (PubMedID)
    Available from: 2013-06-28 Created: 2013-06-28 Last updated: 2018-08-30Bibliographically approved
    2. Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
    Open this publication in new window or tab >>Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
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    2018 (English)In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 10, no 2, p. 69-79Article in journal (Refereed) Published
    Abstract [en]

    It is currently unknown how the islet transcriptional pattern changes as glucose metabolism deteriorates and progresses to fulminant type 2 diabetes (T2D). In this study, we hypothesized that islets from donors with elevated HbA1c levels, but not yet diagnosed with T2D, would show signs of cell stress on a transcriptional level. Laser capture microdissection and qPCR arrays including 330 genes related to mitochondria, oxidative stress, or the unfolded protein response were used to extract and analyze islets from organ donors with HbA1c <5.5% (37 mmol/mol), elevated HbA1c (6.0-6.5% (42-48 mmol/mol)), high HbA1c (>6.5% (48 mmol/mol)) or established T2D. Principal component analysis and hierarchical clustering based on the expression of all 330 genes displayed no obvious separation of the four different donor groups, indicating that the inter-donor variations were larger than the differences between groups. However, 44 genes were differentially expressed (P < 0.05, false discovery rate <30%) between islets from donors with HbA1c <5.5% (37 mmol/mol) compared with islets from T2D subjects. Twelve genes were differentially expressed compared to control islets in both donors with established T2D and donors with elevated HbA1c (6.0-6.5% (42-48 mmol/mol)). Overexpressed genes were related mainly to the unfolded protein response, whereas underexpressed genes were related to mitochondria. Our data on transcriptional changes in human islets retrieved by LCM from high-quality biopsies, as pre-diabetes progresses to established T2D, increase our understanding on how islet stress contributes to the disease development.

    Keywords
    HbA1c, laser capture, transcriptome, type 2 diabetes
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-342882 (URN)10.1080/19382014.2018.1433980 (DOI)000428814700003 ()29446696 (PubMedID)
    Funder
    Swedish Research Council, 65X-12219-15-6, K2015-54X-12219-19-4Novo NordiskÅke Wiberg FoundationTore Nilsons Stiftelse för medicinsk forskningMagnus Bergvall FoundationErnfors FoundationSwedish Child Diabetes FoundationSwedish Diabetes Association
    Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-08-30Bibliographically approved
    3. Transcriptional analysis of islets of Langerhans from organ donors of different ages
    Open this publication in new window or tab >>Transcriptional analysis of islets of Langerhans from organ donors of different ages
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    2018 (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    Background: The incidence of type 2 diabetes increases with age because of impaired glucose homeostasis. In this study, we hypothesized that aging induces specific transcriptional changes in human islets.

    Results: Full transcriptome analysis of laser-captured islets from 26 deceased organ donors aged 1-81 years revealed 20 genes that co-varied significantly with age; SGIP1, HIST1H3E, UST, LAD1, RORB, SSTR5-AS1, LDHB, KCNJ15, TRABD2B, GLUL, MBPL1P, EFCAB4B, PHLDA3, MAFB, DGKB, TNFRSF10C, C1ORF16B, CDKN2A, MAT1A and ITGB4. However, principal component analysis and hierarchical clustering of the full transcriptomes showed no obvious separation of donors based on age, and the expression of genes in key pathways of beta-cell function, replication, and senescence were not significantly affected by aging.

    Conclusions: Our data from laser-captured islets confirm only partly the age-related differences reported from islets isolated by enzymatic digestion. The largely preserved transcriptomes and function of islets in elderly are surprising considering the enormous metabolic activity exerted by endocrine cells, and our data could be in line with a continuous renewal of islet cells.

    Keywords
    Diabetes, Islet of Langerhans, Beta-cell, Ageing
    National Category
    Medical and Health Sciences
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-358716 (URN)
    Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-08-30
    4. Characterization of host defense molecules in the human pancreas
    Open this publication in new window or tab >>Characterization of host defense molecules in the human pancreas
    2018 (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    The gut microbiota can play a role in pancreatitis and, likely, in the development of type 1 diabetes (T1D). Anti-microbial peptides and secretory proteins are important mediators of the innate immune response against bacteria but their expression in the human pancreas is not fully known. In this study, immunohistochemistry was used to analyze the expression of seven anti-microbial peptides (Defensin α1, α4, β1-4 and Cathelicidin) and two secretory proteins with known antimicrobial properties (REG3A and GP2) in pancreatic and duodenal biopsies from 10 non-diabetic organ donors and one organ donor that died at onset of T1D. Immunohistochemical data was compared with previously published whole-transcriptome data sets. Seven (α1, β2, β3, α4, GP2, Cathelicidin, and REG3A) host defense molecules showed positive staining patterns in most non-diabetic organ donors, whereas two (β1 and β4) were negative in all non-diabetic donors. Two molecules (α1 and GP2) were restricted to the exocrine pancreas whereas two (β3, α4) were only expressed in islet tissue. Cathelicidin, β2, and REG3A were expressed in both islets and exocrine tissue. The donor that died at onset of T1D had generally less positivity for the host defense molecules, but, notably, this pancreas was the only one where defensin β1 was found. Neither donor age, immune-cell infiltration, nor duodenal expression correlated to the pancreatic expression of host defense molecules. In conclusion, these findings could have important implications for the inflammatory processes in diabetes and pancreatitis as we find several host defense molecules expressed by the pancreatic tissue.

    Keywords
    Pancreas, Islet of Langerhans, Diabetes, Defensin
    National Category
    Medical and Health Sciences
    Research subject
    Biology with specialization in Molecular Immunology
    Identifiers
    urn:nbn:se:uu:diva-358717 (URN)
    Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-08-30
  • Public defence: 2018-10-23 09:00 Gunnesalen, Uppsala
    Kitutu, Freddy Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Towards a functioning retail health market: Evaluating the integrated Community Case Management Intervention for Pediatric Febrile Illness in Drug Shops in Rural South Western Uganda2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Objectives: This thesis examined the health systems effects of implementing the integrated Community Case Management (iCCM) intervention for paediatric febrile illnesses in a retail health market in South Western Uganda. More specifically, it evaluated drug seller interpretation of malaria Rapid Diagnostics Test (RDT) results (study I), adherence to iCCM guidelines (study II) and the intervention effect on households’ perceived quality of drug seller fever care and care-seeking choice. Study IV qualitatively analysed the iCCM intervention implementation and causal mechanisms for observed effects. Improved understanding of such retail health markets will inform policy decisions and interventions for Universal Health Coverage.

    Methods: The study used mixed-methods design with an intervention and comparison arm, and pre-test assessment in both study arms. Data collection methods included care-seeker drug shop exit interviews and household surveys using structured questionnaires, focus group discussions, in-depth interviews, review of secondary data and a laboratory analysis of finger-prick capillary blood samples.

    Results: Among those tested for malaria parasites, there was 93% (95% CI 88.3, 96.2) agreement between drug sellers and laboratory scientist re-reading and with a kappa value of 0.84 (95% CI 0.75, 0.92) (Study I). The drug seller compliance with the reported malaria RDT results was 92.5% (95% CI 87.9, 95.7) (Study I). The iCCM intervention improved appropriate treatment for uncomplicated malaria by 34.5% (95% CI 8.6, 60.4), for pneumonia symptoms by 54.7% (95% CI 28.4, 81.0) and reduced appropriate treatment for non-bloody diarrhoea -11.2% (95% CI -65.5, 43.1), after adjusting for extraneous variables (Study II). Implementing the iCCM intervention in drug shops decreased the odds of households perceiving drug seller fever care as good but increased the household odds of choosing to seek care from private health facilities versus within the community (Study III). Drug sellers operated in a retail market system influenced by knowledge and actions of care-seekers, CHWs, government health workers and regulators, and also how formal and informal rules and norms were applied (Study IV). Implementation of the iCCM intervention at drug shops was modified and shaped by the emerging actor perceptions and behaviours (Study IV).

    Conclusions: This thesis demonstrates the implementation, causal mechanisms and contextual factors of the iCCM intervention in a rural retail health market. Fidelity and quality of iCCM intervention by drug sellers was acceptably high, probably as a result of co-interventions. Interventions in retail health markets should comprise of components that target the multiple actors or influences that shape that market. Multi-component health system interventions are complex to implement and also create complexity in their evaluation. When technologies are involved, their analysis should go beyond their substance as products and view them as items that encapsulate interests of different actors, some of which maybe converging with or competing against societal goals.

    List of papers
    1. Can malaria rapid diagnostic tests by drug sellers under field conditions classify children five years old or less with or without Plasmodium falciparum malaria? Comparison with nested PCR analysis.
    Open this publication in new window or tab >>Can malaria rapid diagnostic tests by drug sellers under field conditions classify children five years old or less with or without Plasmodium falciparum malaria? Comparison with nested PCR analysis.
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    (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    Background

    Malaria rapid diagnostic tests (RDTs) available as dipsticks or strips, are simple to perform, easily interpretable and do not require electricity nor infrastructural investment. Correct interpretation of and compliance with the malaria RDT results is a challenge to drug sellers. Thus, drug seller interpretation of malaria RDT strips was compared with laboratory scientist re-reading, and PCR analysis of Plasmodium DNA extracted from malaria RDT nitrocellulose strips and Fast Transient Analysis (FTA) cards. Malaria RDT cassettes are also assessed as potential source of Plasmodium DNA.

    Methods

    A total of 212 children aged between 2 and 60 months, 199 of whom had complete records at two study drug shops in south west Uganda participated in the study. Duplicate 5μL samples of capillary blood were picked from the 212 children, dispensed onto the sample well of the CareStartTM Pf-HRP2 RDT cassette and a fast transient analysis (FTA), WhatmanTM 3MM filter paper in parallel. The malaria RDT strip was interpreted by the drug seller within 15 to 20 minutes, visually re-read centrally by laboratory scientist and from it; Plasmodium DNA was recovered and detected by PCR, and compared with FTA recovered P. falciparum DNA PCR detection.

    Results

    Malaria positive samples were 62/199 (31.2% 95% CI 24.9 - 38.3) by drug seller interpretation of malaria RDT strip, 59/212 (27.8% 95% CI 22.2 – 34.3) by laboratory scientist, 55/212 (25.9% 95% CI 20.0 – 32.6) by RDT nitrocellulose strip PCR and 64/212 (30.2% 95% CI 24.4 – 37.7). The overall agreement between the drug seller interpretation and laboratory scientist re-reading of the malaria RDT strip was 93% with kappa value of 0.8 (95 % CI 0.7, 0.9). The drug seller compliance with the reported malaria RDT results and kappa value were 92.5% and 0.8 (95% CI 0.7, 0.9), respectively. The performance of the three diagnostic strategies compared with FTA PCR as the gold standard had sensitivity between 76.6% and 86.9%, specificity above 90%, positive predictive value ranging from 79% to 89.8% and negative predictive value above 90%.

    Conclusion:

    Drug sellers can use of malaria RDTs in field conditions and achieve acceptable accuracy for malaria diagnosis, and they comply with the malaria RDT results. Plasmodium DNA can be recovered from malaria RDT nitrocellulose strips even in the context of drug shops. Future malaria surveillance and diagnostic quality control studies with malaria RDT cassette as a source of Plasmodium DNA are recommended.

    Keywords
    Integrated case management, Rapid diagnostic test, Polymerase chain reaction, Drug seller, Febrile Illness, Malaria, Private sector, Compliance, External quality assurance
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:uu:diva-359581 (URN)
    Available from: 2018-09-04 Created: 2018-09-04 Last updated: 2018-09-07
    2. Integrated community case management by drug sellers influences appropriate treatment of paediatric febrile illness in South Western Uganda: a quasi-experimental study.
    Open this publication in new window or tab >>Integrated community case management by drug sellers influences appropriate treatment of paediatric febrile illness in South Western Uganda: a quasi-experimental study.
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    2017 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, no 1, article id 425Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Fever case management is a major challenge for improved child health globally, despite existence of cheap and effective child survival health technologies. The integrated Community Case Management (iCCM) intervention of paediatric febrile illnesses though adopted by Uganda's Ministry of Health to be implemented by community health workers, has not addressed the inaccess to life-saving medicines and diagnostics. Therefore, the iCCM intervention was implemented in private drug shops and evaluated for its effect on appropriate treatment of paediatric fever in a low malaria transmission setting in South Western Uganda.

    METHODS: From June 2013 to September 2015, the effect of the iCCM intervention on drug seller paediatric fever management and adherence to iCCM guidelines was assessed in a quasi-experimental study in South Western Uganda. A total of 212 care-seeker exit interviews were done before and 285 after in the intervention arm as compared to 216 before and 268 care-seeker interviews at the end of the study period in the comparison arm. The intervention effect was assessed by difference-in-difference analysis of drug seller treatment practices against national treatment recommendations between the intervention and comparison arms. Observed proportions among care-seeker interviews were compared with corresponding proportions from 5795 child visits recorded in patient registries and 49 direct observations of drug seller-care-seeker encounters in intervention drug shops.

    RESULTS: The iCCM intervention increased the appropriate treatment of uncomplicated malaria, pneumonia symptoms and non-bloody diarrhoea by 80.2% (95% CI 53.2-107.2), 65.5% (95% CI 51.6-79.4) and 31.4% (95% CI 1.6-61.2), respectively. Within the intervention arm, drug seller scores on appropriate treatment for pneumonia symptoms and diagnostic test use were the same among care-seeker exit interviews and direct observation. A linear trend (negative slope, - 0.009 p value < 0.001) was observed for proportions of child cases prescribed any antimicrobial medicine in the intervention arm drug shops.

    CONCLUSIONS: The iCCM intervention improved appropriate treatment for uncomplicated malaria, pneumonia symptoms and diarrhoea. Drug seller adherence to iCCM guidelines was high, without causing excessive prescription of antimicrobial medicines in this study. Further research should assess whether this effect is sustained over time and under routine supervision models.

    Keywords
    Appropriate treatment, Diagnostics, Drug sellers, Febrile illness, Integrated case management, Malaria, Pneumonia, Private sector, Uganda
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-332597 (URN)10.1186/s12936-017-2072-9 (DOI)000413685400004 ()29061148 (PubMedID)
    Available from: 2017-10-30 Created: 2017-10-30 Last updated: 2018-09-07Bibliographically approved
    3. Perceived quality of paediatric fever care from private drug shops and care-seeking choice in South Western Uganda: data from household surveys.
    Open this publication in new window or tab >>Perceived quality of paediatric fever care from private drug shops and care-seeking choice in South Western Uganda: data from household surveys.
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    (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    Background

    Child mortality is influenced by interventions beyond the health sector such as adequate access to education, quality water and sanitation, transport and general socio-economic wellbeing. Child mortality due to febrile illnesses remains unevenly distributed within countries. The role of context and variables that act at a higher level such as a geographical location has been largely under-examined. Factors that act at group level are commonly described in literature as neighbourhood factors. The aim of the study was to investigate whether contextual differences in choice of childhood fever care-seeking in South Western Uganda remain after relevant individual and household characteristics have been taken into account, for three outcome variables, namely, choice of care-seeking in private versus government health facilities, choice of care-seeking in private health facilities versus community level and perceived quality of childhood fever care at drug shops, among households in Mbarara and Bushenyi districts.

    Methods

    Two household surveys were conducted at different time periods in Bushenyi and Mbarara districts. The first survey of 2261 households was conducted from July to October 2013 before implementation of an adapted integrated Community Case Management (iCCM) intervention for paediatric febrile illness in drug shops in Mbarara district. The second survey of 3073 households was done from April to May 2015 after the intervention. These data were analysed for effect of contextual factors, the iCCM intervention and other predictors on choice of care-seeking and perceived quality of care among the households in Mbarara and Bushenyi.

     

    Results:

    In the pre-intervention survey , more households in both Mbarara and Bushenyi reported time required to travel to either a private clinic (31%) or drug shop (43%) of 15 minutes or less as compared to a government health facility (12%). The crude second level (neighbourhood) variance of the odds ratio for care-seeking in private versus government health facility was 0.446 (SE, 0.089). The intra-neighbourhood correlation and median odds ratio were 11.9% and 1.89, respectively, for the crude model. After adjusting for covariates that were kept in the prediction model, the estimates of neighbourhood variance, intra-neighbourhood correlation and mean odds ratio decreased to 0.241 (0.069), 6.8% and 1.6, respectively.

     

    Conclusion:         

    In addition to individual factors, contextual characteristics of the neighbourhoods predict the choice of care-seeking from private versus government health facilities, private health facilities versus in the community and perceived quality of pediatric fever care at drug shops.

    Keywords
    Care-seeking, Child health, Febrile illness, Under-five, Perceived quality, Drug shops, Malaria, Uganda, Household survey.
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Research subject
    International Health
    Identifiers
    urn:nbn:se:uu:diva-359582 (URN)
    Available from: 2018-09-07 Created: 2018-09-07 Last updated: 2018-09-07
    4. Health system effects of implementing integrated community case management (iCCM) intervention in private retail drug shops in South Western Uganda: a qualitative study
    Open this publication in new window or tab >>Health system effects of implementing integrated community case management (iCCM) intervention in private retail drug shops in South Western Uganda: a qualitative study
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    2017 (English)In: BMJ Global Health, ISSN 2059-7908, Vol. 2, no e000334Article in journal (Refereed) Published
    Abstract [en]

    Background Intervening in private drug shops to improve quality of care and enhance regulatory oversight may have health system effects that need to be understood before scaling up any such interventions. We examine the processes through which a drug shop intervention culminated in positive unintended effects and other dynamic interactions within the underlying health system.

    Methods A multifaceted intervention consisting of drug seller training, supply of diagnostics and subsidised medicines, use of treatment algorithms, monthly supervision and community sensitisation was implemented in drug shops in South Western Uganda, to improve paediatric fever management. Focus group discussions and in-depth interviews were conducted with stakeholders (drug sellers, government officials and community health workers) at baseline, midpoint and end-line between September 2013 and September 2015. Using a health market and systems lens, transcripts from the interviews were analysed to identify health system effects associated with the apparent success of the intervention.

    Findings Stakeholders initially expressed caution and fears about the intervention's implications for quality, equity and interface with the regulatory framework. Over time, these stakeholders embraced the intervention. Most respondents noted that the intervention had improved drug shop standards, enabled drug shops to embrace patient record keeping, parasite-based treatment of malaria and appropriate medicine use. There was also improved supportive supervision, and better compliance to licensing and other regulatory requirements. Drug seller legitimacy was enhanced from the community and client perspective, leading to improved trust in drug shops.

    Conclusion The study showed how effectively using health technologies and the perceived efficacy of medicines contributed to improved legitimacy and trust in drug shops among stakeholders. The study also demonstrated that using a combination of appropriate incentives and consumer empowerment strategies can help harmonise common practices with medicine regulations and safeguard public health, especially in mixed health market contexts.

    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-335586 (URN)
    Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2018-09-07
  • Public defence: 2018-10-25 09:00 Room 80101, Ångstrom Laboratory, Uppsala
    Pszczel, Damian
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Search for a new light boson in meson decays2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The subject of the presented work lies in the field of experimental particle physics. The main topic is the study of e+ e pairs from η meson decays. The data sample used in this work was collected by the WASA-at-COSY collaboration in proton-proton collisions at 1.4 GeV kinetic beam energy. The experiment took place in 2012 at Forschungzentrum Jülich in Germany at the COSY storage ring. An internal proton beam interacted with a pellet target of frozen hydrogen.

    We implemented a set of selection criteria in order to extract the η → e+ e γ event candidates. This is a rare electromagnetic decay of the η meson with branching ratio equal to 6.9·10−3. The resulting set of events served as the basis for three analyses.

    First, we extracted the η transition form factor that is a function depending on the inner quark and gluon structure of the meson. We implemented a specific method to reduce the contribution of background channels from direct pion production.

    The second analysis was the search for a narrow structure on the e+ e invariant mass in the selected sample of η → e+ e γ candidates. Many theoretical models and some astrophysical and particle physics measurements suggest the existence of a new boson, also called the dark photon, that couples to both dark and to Standard Model particles. This particle would decay to e+ e pairs of well-defined mass and therefore could be detected by looking for narrow peaks in the e+ e invariant mass spectra. Since no statistically significant signal was observed, we set an upper limit on the coupling parameter ε2.

    The third objective of this work was to select a sample of η → e+ e candidates. This is a very rare decay and therefore sensitive to physics beyond the Standard Model. No signal from η → e+ e was observed, therefore we were able to set an upper limit on the branching ratio for this decay.

  • Public defence: 2018-10-25 10:00 Polhemsalen, Uppsala
    Eriksson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Swedish Institute of Space Physics, Uppsala Division. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Electron energization in near-Earth space: Studies of kinetic scales using multi-spacecraft data2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plasma, a gas of charged particles exhibiting collective behavior, is everywhere in the Universe. The heating of plasma to millions of degrees and acceleration of charged particles to very high energies has been observed in many astrophysical environments. How and where the heating and acceleration occur is in many cases unclear. In most astrophysical environments, plasma consists of negative electrons and positive ions. In this thesis we focus on understanding the heating and acceleration of electrons. Several plasma processes have been proposed to explain the observed acceleration. However, the exact heating and acceleration mechanisms involved and their importance are still unclear. This thesis contributes toward a better understanding of this topic by using observations from two multi-spacecraft missions, Cluster and the Magnetospheric MultiScale (MMS), in near-Earth space.

    In Article I we look at magnetic nulls, regions of vanishing magnetic field B believed to be important in particle acceleration, in the Earth's nightside magnetosphere. We find that nulls are common at the nightside magnetosphere and that the characterization of the B geometry around a null can be affected by localized B fluctuations. We develop and present a method for determining the effect of the B fluctuation on the null's characterization.

    In Article II we look at a thin (a few km) current sheet (CS) in the turbulent magnetosheath. Observations suggest local electron heating and beam formation parallel to B inside the CS. The electron observations fits well with the theory of electron acceleration across a shock due to a potential difference. However, in our case the electron beams are formed locally inside the magnetosheath that is contrary to current belief that the beam formation only occurs at the shock.

    In Article III we present observations of electron energization inside a very thin (thinner than Article II) reconnecting CS located in the turbulent magnetosheath. Currently, very little is know about electron acceleration mechanisms at these small scales. MMS observe local electron heating and acceleration parallel to B when crossing the CS. We show that the energized electrons correspond to acceleration due to a quasi-static potential difference rather than electrostatic waves. This energization is similar to what has been observed inside ion diffusion regions at the magnetopause and magnetotail. Thus, despite the different plasma conditions a similar energization occurs in all these plasma regions.

    In Article IV we study electron acceleration by Fermi acceleration, betatron acceleration, and acceleration due to parallel electric fields inside tailward plasma jets formed due to reconnection, the so called tailward outflow region. We show that most observations are consistent with local electron heating and acceleration from a simplified two dimensional picture of Fermi acceleration and betatron acceleration in an outflow region. We find that Fermi acceleration is the dominant electron acceleration mechanism.

    List of papers
    1. Statistics and accuracy of magnetic null identification in multispacecraft data
    Open this publication in new window or tab >>Statistics and accuracy of magnetic null identification in multispacecraft data
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    2015 (English)In: Geophysical Research Letters, ISSN 0094-8276, E-ISSN 1944-8007, Vol. 42, p. 6883-6889Article in journal (Refereed) Published
    Abstract [en]

    Complex magnetic topologies are ubiquitous in astrophysical plasmas. Analyzing magnetic nulls, regions of vanishing magnetic field, is one way to characterize 3-D magnetic topologies. Magnetic nulls are believed to be important in 3-D reconnection and turbulence. In the vicinity of a null, plasma particles become unmagnetized and can be accelerated to high energies by electric fields. We present the first statistical study of the occurrence of magnetic nulls and their types in the Earth's nightside magnetosphere. We are able to identify the nulls both in the tail and in the magnetopause current sheets. On average, we find one null for every few current sheet crossings. We show that the type identification of magnetic nulls may be sensitive to local fluctuations in the magnetic field. We develop and demonstrate a method to estimate the reliability of the magnetic null type identification.

    National Category
    Geophysics Fusion, Plasma and Space Physics
    Identifiers
    urn:nbn:se:uu:diva-267334 (URN)10.1002/2015GL064959 (DOI)000363411200002 ()
    Funder
    Swedish Research Council, 2013-4309
    Available from: 2015-11-24 Created: 2015-11-20 Last updated: 2018-09-06Bibliographically approved
    2. Strong current sheet at a magnetosheath jet: Kinetic structure and electron acceleration
    Open this publication in new window or tab >>Strong current sheet at a magnetosheath jet: Kinetic structure and electron acceleration
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    2016 (English)In: Journal of Geophysical Research - Space Physics, ISSN 2169-9380, E-ISSN 2169-9402, Vol. 121, no 10, p. 9608-9618Article in journal (Refereed) Published
    Abstract [en]

    Localized kinetic-scale regions of strong current are believed to play an important role in plasma thermalization and particle acceleration in turbulent plasmas. We present a detailed study of a strong localized current, 4900 nA m(-2), located at a fast plasma jet observed in the magnetosheath downstream of a quasi-parallel shock. The thickness of the current region is similar to 3 ion inertial lengths and forms at a boundary separating magnetosheath-like and solar wind-like plasmas. On ion scales the current region has the shape of a sheet with a significant average normal magnetic field component but shows strong variations on smaller scales. The dynamic pressure within the magnetosheath jet is over 3 times the solar wind dynamic pressure. We suggest that the current sheet is forming due to high velocity shears associated with the jet. Inside the current sheet we observe local electron acceleration, producing electron beams, along the magnetic field. However, there is no clear sign of ongoing reconnection. At higher energies, above the beam energy, we observe a loss cone consistent with part of the hot magnetosheath-like electrons escaping into the colder solar wind-like plasma. This suggests that the acceleration process within the current sheet is similar to the one that occurs at shocks, where electron beams and loss cones are also observed. Therefore, electron beams observed in the magnetosheath do not have to originate from the bow shock but can also be generated locally inside the magnetosheath.

    National Category
    Fusion, Plasma and Space Physics
    Identifiers
    urn:nbn:se:uu:diva-312116 (URN)10.1002/2016JA023146 (DOI)000388965900020 ()
    Available from: 2017-01-09 Created: 2017-01-04 Last updated: 2018-09-06Bibliographically approved
    3. Electron Energization at a Reconnecting Magnetosheath Current Sheet
    Open this publication in new window or tab >>Electron Energization at a Reconnecting Magnetosheath Current Sheet
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    2018 (English)In: Geophysical Research Letters, ISSN 0094-8276, Vol. 45, no 16Article in journal, Letter (Refereed) Published
    Abstract [en]

    We present observations of electron energization within a sub-ion-scale magnetosheath current sheet (CS). A number of signatures indicate ongoing reconnection, including the thickness of the CS (∼0.7 ion inertial length), nonzero normal magnetic field, Hall magnetic fields with electrons carrying the Hall currents, and electron heating. We observe localized electron acceleration and heating parallel to the magnetic field at the edges of the CS. Electrostatic waves observed in these regions have low phase velocity and small wave potentials and thus cannot provide the observed acceleration and heating. Instead, we find that the electrons are accelerated by a parallel potential within the separatrix regions. Similar acceleration has been reported based on magnetopause and magnetotail observations.Thus, despite the different plasma conditions in magnetosheath, magnetopause, and magnetotail,the acceleration mechanism and corresponding heating of electrons is similar.

    Keywords
    magnetic reconnection, magnetosheath, electron heating, electron acceleration, Magnetospheric Multiscale
    National Category
    Other Physics Topics
    Research subject
    Physics with specialization in Space and Plasma Physics
    Identifiers
    urn:nbn:se:uu:diva-359592 (URN)10.1029/2018GL078660 (DOI)
    Funder
    Swedish Research Council, 2013-4309Swedish National Infrastructure for Computing (SNIC), m.2017-1-422 and m.2016 -457
    Available from: 2018-09-04 Created: 2018-09-04 Last updated: 2018-09-06
    4. Electron acceleration in a magnetotail reconnection outflow region using Magnetospheric MultiScale data
    Open this publication in new window or tab >>Electron acceleration in a magnetotail reconnection outflow region using Magnetospheric MultiScale data
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Physics Topics
    Research subject
    Physics with specialization in Space and Plasma Physics
    Identifiers
    urn:nbn:se:uu:diva-359593 (URN)
    Funder
    Swedish Research Council, 2013-4309
    Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-06
  • Public defence: 2018-10-26 09:15 Polhemsalen, 10134, Uppsala
    Keshavarz Hedayati, Samara
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Magnetism in Transition Metal Systems: Interplay between structure, dimensionality and electron correlation2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, an ab initio study of electronic structures and magnetic properties of transition metal systems has been presented, covering bulk, interface and surface geometries. Among them are Fe, Co, Ni, CaMnO3, Co2MnSi, a ferromagnetic Heusler alloy, as well as double-perovskites oxides such as Sr3(Fe1.25Ni0.75)O6 and Nd2NiMnO6.

    Their electronic structures have been obtained within the framework of the density functional theory (DFT) in combination with Hubbard type interaction such as the static correction evaluated within the Hartree-Fock method (DFT+U) or within the more sophisticated method of dynamical mean-field theory (DFT+DMFT). Using many-body approaches enables us to treat the correlation effects such as non-quasiparitcle states above the Fermi level for Co2MnSi and in the half-metallic side of the Co2MnAl/CoMnVAl heterostructure.

    Based on the converged electronic structure, the magnetic excitations were mapped onto the Heisenberg Hamiltonian. Among various ways to extract exchange parameters, in this Thesis the method of infinitesimal rotation of the spins has been applied in the framework of the local magnetic force approach. It is shown that the exchange interactions on the surface of transition metals can be substantially different from those in the corresponding bulk. At the same time, the dynamical correlations lead to a slight renormalization of the magnetic couplings. For CaMnO3, we demonstrated the crucial role of the atomic relaxations defining the magnetic order on the surface atoms. We were also able to extract the orbital decompositions, which helped identify the main contributions to the total exchange. For the double-perovskite systems, the extracted exchange parameters were then used to evaluate the ordering temperature using Monte-Carlo simulations, and the calculated critical temperatures were found to be in good agreement with our experimental measurements.

    In a more technical investigation, the influence of the spin polarization of the DFT exchange-correlation functional on the extracted exchange parameters has been investigated. We found a very good correspondence between the computed total energies and the parametrized Heisenberg model for LDA+U calculations, but not for LSDA+U. This means that for the extraction of the exchange parameters based on total energy differences, LDA+U is more appropriate.

    Finally, a systematic study of the emergence of the local minima in DFT+U calculations has been performed for the bulk of NiO, FeO, CoO and UO2. We extended the use of the occupation matrix control method to randomly generate density matrices which help better monitor the local minima and explore the energy landscape. The effect of the Hubbard U and the double-counting in introducing the local minima are discussed.

    List of papers
    1. Layer-resolved magnetic exchange interactions of surfaces of late 3d elements: Effects of electronic correlations
    Open this publication in new window or tab >>Layer-resolved magnetic exchange interactions of surfaces of late 3d elements: Effects of electronic correlations
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    2015 (English)In: Physical Review B. Condensed Matter and Materials Physics, ISSN 1098-0121, E-ISSN 1550-235X, Vol. 92, no 16, article id 165129Article in journal (Refereed) Published
    Abstract [en]

    We present the results of an ab initio study of the magnetic properties of Fe, Co, and Ni surfaces. In particular, we discuss their electronic structure and magnetic exchange interactions (J(ij)), as obtained bymeans of a combination of density functional theory and dynamical mean-field theory. All studied systems have a pronounced tendency to ferromagnetism both for bulk and surface atoms. The presence of narrowband surface states is shown to enhance the magnetic moment as well as the exchange couplings. The most interesting results were obtained for the Fe surface where the atoms have a tendency to couple antiferromagnetically with each other. This interaction is relatively small when compared to interlayer ferromagnetic interaction, and it depends strongly on the lattice parameter. Local correlation effects are shown to lead to strong changes of the overall shape of the spectral functions. However, they seem not to play a decisive role in the overall picture of magnetic couplings studied here. We have also investigated the influence of correlations on the spin and orbital moments of bulklike and surface atoms. We found that dynamical correlations in general lead to enhanced values of the orbital moment.

    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-267192 (URN)10.1103/PhysRevB.92.165129 (DOI)000363524200003 ()
    Funder
    Swedish Research CouncilSwedish Energy AgencyKnut and Alice Wallenberg FoundationSwedish e‐Science Research CentereSSENCE - An eScience Collaboration
    Available from: 2015-11-19 Created: 2015-11-19 Last updated: 2018-08-24Bibliographically approved
    2. Exchange interactions of CaMnO3 in the bulk and at the surface
    Open this publication in new window or tab >>Exchange interactions of CaMnO3 in the bulk and at the surface
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    2017 (English)In: Physical Review B Condensed Matter, ISSN 0163-1829, E-ISSN 1095-3795, Vol. 95, article id 115120Article in journal (Refereed) Published
    Abstract [en]

    We present electronic and magnetic properties of CaMnO3 (CMO) as obtained from ab initio calculations. We identify the preferable magnetic order by means of density functional theory plus Hubbard U calculations and extract the effective exchange parameters (Jij ' s) using the magnetic force theorem. We find that the effects of geometrical relaxation at the surface as well as the change of crystal field are very strong and are able to influence the lower-energymagnetic configuration. In particular, our analysis reveals that the exchange interaction between the Mn atoms belonging to the surface and the subsurface layers is very sensitive to the structural changes. An earlier study [A. Filippetti and W. E. Pickett, Phys. Rev. Lett. 83, 4184 (1999)] suggested that this coupling is ferromagnetic and gives rise to the spin-flip (SF) process on the surface of CMO. In our work, we confirm their finding for an unrelaxed geometry, but once the structural relaxations are taken into account, this exchange coupling changes its sign. Thus, we suggest that the surface of CMO should have the same G-type antiferromagnetic order as in the bulk. Finally, we show that the suggested SF can be induced in the system by introducing an excess of electrons.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-319934 (URN)10.1103/PhysRevB.95.115120 (DOI)000396008300003 ()
    Funder
    Swedish Research CouncileSSENCE - An eScience CollaborationKnut and Alice Wallenberg Foundation
    Available from: 2017-04-11 Created: 2017-04-11 Last updated: 2018-08-24Bibliographically approved
    3. First principles studies of the Gilbert damping and exchange interactions for half-metallic Heuslers alloys
    Open this publication in new window or tab >>First principles studies of the Gilbert damping and exchange interactions for half-metallic Heuslers alloys
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    2016 (English)In: Physical Review B. Condensed Matter and Materials Physics, ISSN 1098-0121, E-ISSN 1550-235X, Vol. 93, no 21, article id 214439Article in journal (Refereed) Published
    Abstract [en]

    Heusler alloys have been intensively studied due to the wide variety of properties that they exhibit. One of these properties is of particular interest for technological applications, i.e., the fact that some Heusler alloys are half-metallic. In the following, a systematic study of the magnetic properties of three different Heusler families Co(2)MnZ, Co(2)FeZ, and Mn(2)VZ with Z = (Al, Si, Ga, Ge) is performed. A key aspect is the determination of the Gilbert damping from first-principles calculations, with special focus on the role played by different approximations, the effect that substitutional disorder and temperature effects. Heisenberg exchange interactions and critical temperature for the alloys are also calculated as well as magnon dispersion relations for representative systems, the ferromagnetic Co2FeSi and the ferrimagnetic Mn2VAl. Correlation effects beyond standard density-functional theory are treated using both the local spin density approximation including the Hubbard U and the local spin density approximation plus dynamical mean field theory approximation, which allows one to determine if dynamical self-energy corrections can remedy some of the inconsistencies which were previously reported for these alloys.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-291375 (URN)10.1103/PhysRevB.93.214439 (DOI)000378809800001 ()
    Funder
    Swedish Research CouncilGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyKnut and Alice Wallenberg Foundation, 2013.0020; 2012.0031
    Available from: 2016-05-02 Created: 2016-05-02 Last updated: 2018-08-24Bibliographically approved
    4. Half-metallicity and magnetism in the Co2MnAl/CoMnVAl heterostructure
    Open this publication in new window or tab >>Half-metallicity and magnetism in the Co2MnAl/CoMnVAl heterostructure
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    2018 (English)In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 97, no 3, article id 035105Article in journal (Refereed) Published
    Abstract [en]

    We present a study of the electronic structure and magnetism of Co2MnAl, CoMnVAl, and their heterostructure. We employ a combination of density-functional theory and dynamical mean-field theory (DFT+DMFT). We find that Co2MnAl is a half-metallic ferromagnet, whose electronic and magnetic properties are not drastically changed by strong electronic correlations, static or dynamic. Nonquasiparticle states are shown to appear in the minority spin gap without affecting the spin polarization at the Fermi level predicted by standard DFT. We find that CoMnVAl is a semiconductor or a semimetal, depending on the employed computational approach. We then focus on the electronic and magnetic properties of the Co2MnAl/CoMnVAl heterostructure, predicted by previous first-principle calculations as a possible candidate for spin-injecting devices. We find that two interfaces, Co-Co/V-Al and Co-Mn/Mn-Al, preserve the half-metallic character, with and without including electronic correlations. We also analyze the magnetic exchange interactions in the bulk and at the interfaces. At the Co-Mn/Mn-Al interface, competing magnetic interactions are likely to favor the formation of a noncollinear magnetic order, which is detrimental for the spin polarization.

    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-341501 (URN)10.1103/PhysRevB.97.035105 (DOI)000419230600004 ()
    Available from: 2018-02-13 Created: 2018-02-13 Last updated: 2018-08-24Bibliographically approved
    5. Magnetic properties of Ruddlesden-Popper phases Sr3-&: A combined experimental and theoretical investigation
    Open this publication in new window or tab >>Magnetic properties of Ruddlesden-Popper phases Sr3-&: A combined experimental and theoretical investigation
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    2018 (English)In: Physical Review Materials, ISSN 2475-9953, Vol. 2, no 4, article id 044005Article in journal (Refereed) Published
    Abstract [en]

    We present a comprehensive study of the magnetic properties of Sr3-xYx(Fe1.25Ni0.75)O-7(-delta )(0 <= x <= 0.75). Experimentally, the magnetic properties are investigated using superconducting quantum interference device (SQUID) magnetometry and neutron powder diffraction (NPD). This is complemented by a theoretical study based on density functional theory as well as the Heisenberg exchange parameters. Experimental results show an increase in the Ned temperature (T-N) with an increase of Y concentrations and O occupancy. The NPD data reveal that all samples are antiferromagnetically ordered at low temperatures, which has been confirmed by our theoretical simulations for the selected samples. Our first-principles calculations suggest that the three-dimensional magnetic order is stabilized due to finite interlayer exchange couplings. The latter give rise to finite interlayer spin-spin correlations, which disappear above T-N.

    National Category
    Condensed Matter Physics Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-354116 (URN)10.1103/PhysRevMaterials.2.044005 (DOI)000430385300001 ()
    Funder
    Swedish Research CouncilKnut and Alice Wallenberg Foundation
    Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-08-24Bibliographically approved
    6. Curious magnetic states in double perovskite Nd2NiMnO6
    Open this publication in new window or tab >>Curious magnetic states in double perovskite Nd2NiMnO6
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Research subject
    Physics; Physics with spec. in Atomic, Molecular and Condensed Matter Physics; Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-357521 (URN)
    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-24
    7. Electronic structure, magnetism, and exchange integrals in transition-metal oxides: Role of the spin polarization of the functional in DFT+U calculations
    Open this publication in new window or tab >>Electronic structure, magnetism, and exchange integrals in transition-metal oxides: Role of the spin polarization of the functional in DFT+U calculations
    2018 (English)In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 97, no 18, article id 184404Article in journal (Refereed) Published
    Abstract [en]

    Density functional theory augmented with Hubbard-U corrections (DFT+U) is currently one of the most widely used methods for first-principles electronic structure modeling of insulating transition-metal oxides (TMOs). Since U is relatively large compared to bandwidths, the magnetic excitations in TMOs are expected to be well described by a Heisenberg model. However, in practice the calculated exchange parameters J(ij) depend on the magnetic configuration from which they are extracted and on the functional used to compute them. In this work we investigate how the spin polarization dependence of the underlying exchange-correlation functional influences the calculated magnetic exchange constants of TMOs. We perform a systematic study of the predictions of calculations based on the local density approximation plus U (LDA+U) and the local spin density approximation plus U (LSDA+U) for the electronic structures, total energies, and magnetic exchange interactions Jij extracted from ferromagnetic (FM) and antiferromagnetic (AFM) configurations of several transition-metal oxide materials. We report that for realistic choices of Hubbard U and Hund's J parameters, LSDA+U and LDA+U calculations result in different values of the magnetic exchange constants and band gap. The dependence of the band gap on the magnetic configuration is stronger in LDA+U than in LSDA+U and we argue that this is the main reason why the configuration dependence of Jij is found to be systematically more pronounced in LDA+U than in LSDA+U calculations. We report a very good correspondence between the computed total energies and the parametrized Heisenberg model for LDA+U calculations, but not for LSDA+U, suggesting that LDA+U is a more appropriate method for estimating exchange interactions.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-356500 (URN)10.1103/PhysRevB.97.184404 (DOI)000431989000004 ()
    Funder
    Swedish Research CouncilKnut and Alice Wallenberg FoundationeSSENCE - An eScience Collaboration
    Available from: 2018-07-30 Created: 2018-07-30 Last updated: 2018-10-10Bibliographically approved
    8. A systematic study of the local minima in L(S)DA+U
    Open this publication in new window or tab >>A systematic study of the local minima in L(S)DA+U
    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Research subject
    Materials Science
    Identifiers
    urn:nbn:se:uu:diva-357299 (URN)
    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-24
    9. Magnetism at the surface of Heusler semiconductors
    Open this publication in new window or tab >>Magnetism at the surface of Heusler semiconductors
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-357524 (URN)
    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-24
    10. Surface magnons and critical temperatures of Ni surfaces on Cu
    Open this publication in new window or tab >>Surface magnons and critical temperatures of Ni surfaces on Cu
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-319991 (URN)
    Available from: 2017-04-12 Created: 2017-04-12 Last updated: 2018-08-24
  • Public defence: 2018-10-26 09:15 Häggsalen, Uppsala
    Miao, Rui
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Metabolic Engineering of Synechocystis PCC 6803 for Butanol Production2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is an urgent demand for renewable alternatives to fossil fuels since the extraction and utilization cause a series of environmental problems in the world. Thus, the utilization of solar energy has attracted much attention in the last decades since there is excess amount of light on Earth. Photosynthetic microorganisms, such as cyanobacteria, can be a good biological chassis to convert solar energy directly to chemical energy. It has been demonstrated that cyanobacteria can produce various compounds which can be used asfourth-generation biofuels. This thesis focuses on the photo-autotrophic production of two biofuel compounds, isobutanol and 1-butanol, in the unicellular cyanobacterial strain Synechocystis PCC 6803. In the studies of isobutanol production, the endogenous alcohol dehydrogenase of Synechocystis encoded by slr1192 showed impressive activity in isobutanol formation. In addition, a-ketoisovalerate decarboxylase (Kivd) was identified as the only heterologous enzyme needed to be introduced for isobutanol production in Synechocystis. Kivd was further recognized as a bottleneck in the isobutanol production pathway. Therefore, Kivd was engineered via rational design to shift the preferential activity towards the production of isobutanol instead of the by-product 3-methyl-1-butanol. The best strain pEEK2-ST expressing KivdS286T showed dramatically increased productivity, and the activity of Kivd was successfully shifted further towards isobutanol production. A cumulative isobutanol titer of 911 mg L-1 was observed from this strain after 46 days growth under 50 μmol photons m−2 s−1 with pH adjusted to between 7 and 8. A maximum production rate of nearly 44 mg L-1d-1was reached between days 4 and 6. Similar metabolic engineering strategies were employed to generate 1-butanol producing Synechocystis strains and then to stepwise enhance the production. By selecting the best enzymes and promotors, 836 mg L-1 in-flask 1-butanol was produced. By optimizing the cultivation condition, an in-flask titer of 2.1 g L-1 and a maximal cumulative titer of 4.7 g L-1 were observed in the long-term cultivation. This thesis demonstrates different metabolic engineering strategies for producing valuable compounds in Synechocystis, exemplified with butanol, and how to enhance production systematically. 

    List of papers
    1. Metabolic Engineering of Synechocystis sp. PCC 6803 for Production of the Plant Diterpenoid Manoyl Oxide
    Open this publication in new window or tab >>Metabolic Engineering of Synechocystis sp. PCC 6803 for Production of the Plant Diterpenoid Manoyl Oxide
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    2015 (English)In: ACS Synthetic Biology, E-ISSN 2161-5063, Vol. 4, no 12, p. 1270-1278Article in journal (Refereed) Published
    Abstract [en]

    Forskolin is a high value diterpenoid with a broad range of pharmaceutical applications, naturally found in root bark of the plant Coleus forskohlii. Because of its complex molecular structure, chemical synthesis of forskolin is not commercially attractive. Hence, the labor and resource intensive extraction and purification from C. forskohlii plants remains the current source of the compound. We have engineered the unicellular cyanobacterium Synechocystis sp. PCC 6803 to produce the forskolin precursor 13R-manoyl oxide (13R-MO), paving the way for light driven biotechnological production of this high value compound. In the course of this work, a new series of integrative vectors for use in Synechocystis was developed and used to create stable lines expressing chromosomally integrated CfTPS2 and CfTPS3, the enzymes responsible for the formation of 13R-MO in C. forskohlii. The engineered strains yielded production titers of up to 0.24 mg g(-1) DCW 13R-MO. To increase the yield, 13R-MO producing strains were further engineered by introduction of selected enzymes from C. forskohlii, improving the titer to 0.45 mg g(-1) DCW. This work forms a basis for further development of production of complex plant diterpenoids in cyanobacteria.

    Keywords
    Synechocystis; manoyl oxide; forskolin; diterpenoid; MEP-pathway; genetic tools
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-259966 (URN)10.1021/acssynbio.5b00070 (DOI)000366884700002 ()26133196 (PubMedID)
    Funder
    Swedish Energy AgencyKnut and Alice Wallenberg FoundationEU, European Research Council, ERC-2012-ADG_20120314EU, European Research Council, 323034
    Available from: 2015-08-13 Created: 2015-08-13 Last updated: 2018-09-09Bibliographically approved
    2. Isobutanol production in Synechocystis PCC 6803 using heterologous and endogenous alcohol dehydrogenases
    Open this publication in new window or tab >>Isobutanol production in Synechocystis PCC 6803 using heterologous and endogenous alcohol dehydrogenases
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    2017 (English)In: Metabolic Engineering Communications, ISSN 2214-0301, Vol. 5, p. 45-53Article in journal (Refereed) Published
    Abstract [en]

    Isobutanol is a flammable compound that can be used as a biofuel due to its high energy density and suitable physical and chemical properties. In this study, we examined the capacity of engineered strains of Synechocystis PCC 6803 containing the α-ketoisovalerate decarboxylase from Lactococcus lactis and different heterologous and endogenous alcohol dehydrogenases (ADH) for isobutanol production. A strain expressing an introduced kivdwithout any additional copy of ADH produced 3 mg L−1 OD750−1 isobutanol in 6 days. After the cultures were supplemented with external addition of isobutyraldehyde, the substrate for ADH, 60.8 mg L−1 isobutanol was produced after 24 h when OD750 was 0.8. The in vivo activities of four different ADHs, two heterologous and two putative endogenous in Synechocystis, were examined and the Synechocystis endogenous ADH encoded by slr1192 showed the highest efficiency for isobutanol production. Furthermore, the strain overexpressing the isobutanol pathway on a self-replicating vector with the strong Ptrc promoter showed significantly higher gene expression and isobutanol production compared to the corresponding strains expressing the same operon introduced on the genome. Hence, this study demonstrates that Synechocystis endogenous AHDs have a high capacity for isobutanol production, and identifies kivd encoded α-ketoisovalerate decarboxylase as one of the likely bottlenecks for further isobutanol production.

    Keywords
    Cyanobacteria, Alcohol dehydrogenase, α-ketoisovalerate decarboxylase, Synechocystis PCC 6803, Isobutanol production
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-359893 (URN)10.1016/j.meteno.2017.07.003 (DOI)29188183 (PubMedID)
    Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-09Bibliographically approved
    3. Protein engineering of α-ketoisovalerate decarboxylase for improved isobutanol production in Synechocystis PCC 6803
    Open this publication in new window or tab >>Protein engineering of α-ketoisovalerate decarboxylase for improved isobutanol production in Synechocystis PCC 6803
    2018 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 47, p. 42-48Article in journal (Refereed) Published
    Abstract [en]

    Protein engineering is a powerful tool to modify e.g. protein stability, activity and substrate selectivity. Heterologous expression of the enzyme α-ketoisovalerate decarboxylase (Kivd) in the unicellular cyanobacterium Synechocystis PCC 6803 results in cells producing isobutanol and 3-methyl-1-butanol, with Kivd identified as a potential bottleneck. In the present study, we used protein engineering of Kivd to improve isobutanol production in Synechocystis PCC 6803. Isobutanol is a flammable compound that can be used as a biofuel due to its high energy density and suitable physical and chemical properties. Single replacement, either Val461 to isoleucine or Ser286 to threonine, increased the Kivd activity significantly, both in vivo and in vitro resulting in increased overall production while isobutanol production was increased more than 3-methyl-1-butanol production. Moreover, among all the engineered strains examined, the strain with the combined modification V461I/S286T showed the highest (2.4 times) improvement of isobutanol-to-3M1B molar ratio, which was due to a decrease of the activity towards 3M1B production. Protein engineering of Kivd resulted in both enhanced total catalytic activity and preferential shift towards isobutanol production in Synechocystis PCC 6803.

    Keywords
    Cyanobacteria, Isobutanol, alpha-ketoisovalerate decarboxylase, Site mutagenesis, Substrate pocket, Enzyme activity
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-357581 (URN)10.1016/j.ymben.2018.02.014 (DOI)000433423600005 ()29501927 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, 2011.0067Swedish Energy Agency, 44728-1NordForsk, 82845EU, Horizon 2020, 640720
    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-09-09Bibliographically approved
    4. Enhancement of photosynthetic isobutanol production in engineered cells of Synechocystis PCC 6803
    Open this publication in new window or tab >>Enhancement of photosynthetic isobutanol production in engineered cells of Synechocystis PCC 6803
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-359862 (URN)
    Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-17
    5. Metabolic engineering of Synechocystis PCC 6803 for photosynthetic 1-butanol production
    Open this publication in new window or tab >>Metabolic engineering of Synechocystis PCC 6803 for photosynthetic 1-butanol production
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-359891 (URN)
    Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-17
    6. Engineering Cyanobacteria for Biofuel Production
    Open this publication in new window or tab >>Engineering Cyanobacteria for Biofuel Production
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    2017 (English)In: Modern Topics in the Phototrophic Prokaryotes: Environmental and Applied Aspects / [ed] Hallenbeck, Patrick, USA: Springer, 2017, p. 351-393Chapter in book (Refereed)
    Place, publisher, year, edition, pages
    USA: Springer, 2017
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-338078 (URN)978-3-319-46259-2 (ISBN)978-3-319-46261-5 (ISBN)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-09-09Bibliographically approved
  • Public defence: 2018-10-26 10:15 Hörsal 2, Uppsala
    Aalto, Aino-Maija
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Incentives and Inequalities in Family and Working Life2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay I: Same-gender teachers may affect educational preferences by acting as role models for their students. I study the importance of the gender composition of teachers in math and science during lower secondary school on the likelihood to continue in math-intensive tracks in the next levels of education. I use population wide register data from Sweden and control for family fixed effects to account for sorting into schools. According to my results, the gender gap in graduating with a math-intensive track in upper secondary school would decrease by 16 percent if the share of female math and science teachers would be changed from none to all at lower secondary school. The gap in math-related university degrees would decrease by 22 percent from the same treatment. The performance is not affected by the higher share of female science teachers, only the likelihood to choose science, suggesting that the effects arise because female teachers serve as role models for female students.

  • Public defence: 2018-10-26 13:00 Ihresalen, Uppsala
    Ackermann-Boström, Constanze
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Modern Languages, German.
    Gelebte Mehrsprachigkeit im Plattenbau: Untersuchungen von Narrativen und Praktiken russlanddeutscher junger Erwachsener2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis focuses on the lived multilingualism of a group of young Russian-German adults who as children migrated together with their families from post-Soviet states to the Federal Republic of Germany during the 1990s. Today these adults live in a ‘Plattenbau’ housing estate in a small town in one of the new federal states of Germany. The large pre-fabricated concrete-slab system-built housing estates that were built during the GDR-era are today generally considered as deprived areas due a combination of decreasing population and high unemployment.

    This thesis shows how young Russian-Germans create a multilingual community of practice and use various aspects of language and non-linguistic resources for identity construction. The data analysed in this thesis comes from ethnographic studies conducted during three phases of fieldwork between Spring 2011 and Spring 2012. The data was collected at a youth centre where the group of young Russian-German adults regularly met.

    Combining intensive participant observation, field notes, photos, and narrative interviews the thesis is a mixed-method investigation. Underpinning the analysis of the research data are theoretical models of the relationship between language, identity, and space. Methodologically this study combines linguistic ethnography, narrative analysis, and membership categorization analysis.

    The thesis argues that an ethnographical-narrative approach is a powerful tool that is able to highlight the role of language(s) and non-linguistic resources for identity construction in social spaces, illustrates how young Russian-Germans construct a web of multilingual identities by using social categories to position themselves and others, and shows how the lived multilingualism of  young Russian-German adults influences all aspects of their social lives. For example, the thesis shows the maintenance of Russian as a heritage language within Russian-German families, yet and an avoidance of visible signs of the Russian-German heritage in public spaces.

  • Public defence: 2018-10-30 13:12 Häggsalen
    Žguns, Pjotrs A.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Configurational Thermodynamics of the CeO2-Gd2O3 System: A Combined DFT, Cluster Expansion and Monte Carlo Approach to Bulk and Interfaces2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, we study the configurational thermodynamics of Ce1-xGdxO2-x/2 x ≤ 1 or CGO. We apply a combined Density Functional Theory (DFT), cluster expansion and Monte Carlo (MC) approach in which the configurational energy of CGO is described by means of the Ising-type Hamiltonian. The interactions are determined by the cluster expansion of total energies calculated with DFT for a set of various cation–anion configurations. This allows one to perform on- the-fly calculations of the configurational energies in MC simulations of cation and anion ordering.

    The cluster interactions are essentially electrostatic and long-range, and describe the configurational energetics in the entire range of concentrations rather well.

    The phase diagram obtained in the MC simulations allows one to rationalise existing experimental data and is largely in agreement with that. We observe the phase separation into pure oxides, in equilibrium, below ca. 1000 K for x ≤ 1 (however it is kinetically hindered as diffusion of cations below ca. 1500 K is slow). We also observe the C-type oxygen–vacancy ordering in the x = 0.3–1 range below ca. 1200–3300 K (C phase), and a largely disordered, fluorite (F) phase in the x ≤ 0.3 range and above the ordering temperature.

    The DFT supercell calculations of the F and C phase configurations obtained in MC simulations allow us to study the effect of concentration and ordering on the lattice relaxations, lattice parameter and elastic moduli, providing insights into relation between preparation conditions, structure and properties.

    The bulk cluster interactions appear to be applicable also to coherent CeO2/C- type Gd2O3 interfaces, hence we examine a configurational energy landscape of the oxygen vacancy migration therein.

    This combined approach can be applied to study configurational thermodynamics of similar materials as well as the influence of configurational state on ionic conductivity and other properties.

    List of papers
    1. Ordering and phase separation in Gd-doped ceria: a combined DFT, cluster expansion and Monte Carlo study
    Open this publication in new window or tab >>Ordering and phase separation in Gd-doped ceria: a combined DFT, cluster expansion and Monte Carlo study
    2017 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 39, p. 26606-26620Article in journal (Refereed) Published
    Abstract [en]

    Ordering of dopants and oxygen vacancies is studied for Gd-doped ceria (x(Gd) <= 0.25) by means of a combined density functional theory (DFT) and cluster expansion approach, where the cluster interactions derived from DFT calculations are further used in Monte Carlo simulations. The methodology is meticulously tested and the stability of the obtained solutions with respect to the volume change, applied exchange-correlation approximation and other modelling parameters is carefully analysed. We study Gd and vacancy ordering in the case of thermodynamic equilibrium and vacancy ordering for quenched Gd configurations. We find that at the thermodynamic equilibrium there exists a transition temperature (T-C) below which phase separation into C-type Gd2O3 and pure CeO2 occurs. The phase separation is observed in the whole studied concentration range and the transition temperature increases with concentration from ca. 600 (x(Gd) = 0.03) to 1000 K (x(Gd) = 0.25). Above T-C the distribution of Gd is random, oxygen vacancies tend to cluster in the coordination shells along < 1, 1/2, 0 > and < 1, 1, 1 >, and the nearest neighbour position is preferred for Gd-vacancy. In the quenched Gd case, where Gd atoms are immobilised below 1500 K, the vacancy ordering is significantly frustrated. In fact, we observe an oxygen freezing transition below temperature T-F approximate to T-C - 350 K, which is close to temperatures at which a change in the conductivity slope is observed experimentally.

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2017
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-337327 (URN)10.1039/c7cp04106c (DOI)000412763700014 ()28949350 (PubMedID)
    Funder
    Swedish Research Council, VR 348-2012-6196
    Available from: 2018-01-02 Created: 2018-01-02 Last updated: 2018-09-03
    2. Phase diagram and oxygen–vacancy ordering in the CeO2–Gd2O3 system: a theoretical study
    Open this publication in new window or tab >>Phase diagram and oxygen–vacancy ordering in the CeO2–Gd2O3 system: a theoretical study
    2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 17, p. 11805-11818Article in journal (Refereed) Published
    Abstract [en]

    We present the phase diagram of Ce1-xGdxO2-x/2 (CGO), calculated by means of a combined Density Functional Theory (DFT), cluster expansion and lattice Monte Carlo approach. We show that this methodology gives reliable results for the whole range of concentrations (x ≡ xGd ≤ 1). In the thermodynamic equilibrium, we observe two transitions: the onset of oxygen-vacancy (O-Va) ordering at ca. 1200-3300 K for concentrations xGd = 0.3-1, and a phase separation into CeO2 and C-type Gd2O3 occurring below ca. 1000 K for all concentrations. We also model 'quenched' systems, with cations immobile below 1500 K, and observe that the presence of random-like cation configurations does not prevent C-type vacancy ordering. The obtained transition temperatures for Va ordering agree rather well with existing experimental data. We analyse the effect of vacancy ordering and composition on the lattice parameters and relaxation pattern of cations.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2018
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-353404 (URN)10.1039/c8cp01029c (DOI)000431824000034 ()29658037 (PubMedID)
    Funder
    Swedish Research Council, VR 348-2012-6196 2015-05538EU, European Research Council
    Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2018-09-26Bibliographically approved
    3. Influence of composition and oxygen-vacancy ordering on lattice parameter and elastic moduli of Ce1-xGdxO2-x/2: A theoretical study
    Open this publication in new window or tab >>Influence of composition and oxygen-vacancy ordering on lattice parameter and elastic moduli of Ce1-xGdxO2-x/2: A theoretical study
    2019 (English)In: Scripta Materialia, ISSN 1359-6462, E-ISSN 1872-8456, Vol. 158, p. 126-130Article in journal (Refereed) Published
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-359573 (URN)
    Funder
    Swedish Research Council, VR 348-2012-6196
    Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2018-09-19
    4. Configurational energy landscape of oxygen vacancy migration at coherent (111) CeO2/C-type Gd2O3 interface: DFT and cluster expansion study
    Open this publication in new window or tab >>Configurational energy landscape of oxygen vacancy migration at coherent (111) CeO2/C-type Gd2O3 interface: DFT and cluster expansion study
    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-359574 (URN)
    Funder
    Swedish Research Council, VR 348-2012-6196
    Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2018-09-19
  • Public defence: 2018-10-31 13:15 B21, BMC, Uppsala
    Jonsson, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Confined Compression of Single Particles: Development of a Novel Triaxial Testing Instrument and Particle-Scale Modelling2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    When predicting the performance of a powder compaction process, assessing the behaviour of the particles comprising the powder bed is of central relevance. Currently, however, no experimental methods are available for mimicking the multiaxial loading conditions imposed on the individual particles in a powder bed during compaction, and such analyses are therefore usually performed in silico. Thus, the purpose of this thesis is to introduce a novel experimental method that enables experimental evaluation of confined triaxial loading conditions on individual particles in the mm-scale.

    The work underlying the thesis consists of three major parts. Firstly, the triaxial instrument was designed and developed, after which its performance was evaluated using nominally ideal elastic-plastic spheres as model materials. These initial experiments showed that the instrument was able to successfully impose confined triaxial conditions on the particles, something that was verified by finite element method (FEM) simulations.

    Secondly, the triaxial instrument was used to investigate differences in deformation characteristics under uniaxial and triaxial loading conditions for four different microcrystalline cellulose (MCC)-based granules. It was shown that fragmentation, associated with unconfined uniaxial compression, was impeded under confined triaxial conditions, despite the emergence of cracks. In addition, it was observed that the primary crack always occurs in a plane parallel to the most deformed direction, and that the location of the largest pore has a pronounced influence on the path of the crack.

    Thirdly, the influence of different triaxial loading ratios were evaluated on polymer spheres, after which a unified description of contact pressure development was devised. Data from these experiments were then successfully used to calibrate a contact model for simulating bulk powder compression with the discrete element method (DEM).

    All in all, a novel experimental method has been established, which has proven useful as an alternative and complement to numerical studies when studying single particle deformation under confined triaxial conditions.

    List of papers
    1. An apparatus for confined triaxial testing of single particles
    Open this publication in new window or tab >>An apparatus for confined triaxial testing of single particles
    Show others...
    2015 (English)In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 270, p. 121-127Article in journal (Refereed) Published
    Abstract [en]

    A novel triaxial apparatus employing overlapping rigid boundaries has been designed and constructed for experimental measurement of contact forces under confined compression of single granules in the mm-scale. The performance of the apparatus was evaluated by performing uniaxial and triaxial compression experiments on ideal elastic-plastic materials. Compression curves were compared with the fully plastic Abbott-Firestone contact model and with results from FEM simulations. The increase in contact force associated with confined conditions was observed in the compression curves from triaxial compression experiments, as supported by predictions from simulations using single particle contact models. Hence, a new method for the assessment of mechanical behaviour of single particles under confined compression can be considered as established.

    Keywords
    Compression, Triaxial, Single particles, Confined conditions, Apparatus design, Contact mechanics
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-239203 (URN)10.1016/j.powtec.2014.10.016 (DOI)000347579300014 ()
    Funder
    Swedish Research Council, 621-2011-4049
    Available from: 2014-12-19 Created: 2014-12-19 Last updated: 2018-04-12Bibliographically approved
    2. Investigations of single microcrystalline cellulose-based granules subjected to confined triaxial compression
    Open this publication in new window or tab >>Investigations of single microcrystalline cellulose-based granules subjected to confined triaxial compression
    2016 (English)In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 289, p. 79-87Article in journal (Refereed) Published
    Abstract [en]

    Confined triaxial compression of single granules was performed in order to assess the contact force development and modes of granule deformation under these conditions. In the study, four microcrystalline cellulose-based granule types of different characteristics were investigated. Results from triaxial single-granule compression experiments were evaluated using an analytical model as well as by comparison to unconfined single-granule compression and to confined bulk compression experiments. It was observed that single granules deform and densify, but tend to keep their integrity during confined triaxial compression, as evident from both compression data and from morphological analysis. Results from confined single granule compression were well represented by the analytical model. These results also largely reflected those from bulk compression experiments, including features of the force-displacement curves as well as rank order between the granule types in terms of contact stiffness. Furthermore, it was shown that intragranular porosity to a high extent governs the onset of plastic incompressibility.

    Keywords
    Compression, Triaxial, Hydrostatic, Single granules, Confined conditions, Contact mechanics
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-280895 (URN)10.1016/j.powtec.2015.11.051 (DOI)000370095400012 ()
    Funder
    Swedish Research Council, 621-2011-4049
    Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2018-04-12Bibliographically approved
    3. Mechanical behaviour of ideal elastic-plastic particles subjected to different triaxial loading conditions
    Open this publication in new window or tab >>Mechanical behaviour of ideal elastic-plastic particles subjected to different triaxial loading conditions
    2017 (English)In: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 315, p. 347-355Article in journal (Refereed) Published
    Abstract [en]

    The contact force development for two types of polymeric elastoplastic particles subjected to different triaxial loading conditions was studied experimentally utilising a unique triaxial testing apparatus. In order to evaluate the experimental results, a finite element analysis was performed. The experimental findings highlighted the importance of contact dependence, which manifested itself in two principally different ways. Firstly, a reduced stiffness was observed when plastic deformation ceased to be fully contained, which, depending on the loading conditions, occurred at an engineering strain of about 5-10%. Secondly, a markedly increased stiffness was observed when particle confinement inhibited further plastic deformation, making elastic volume reduction the predominant deformation mode. The experimental results could be well reproduced by the numerical simulations, provided that isotropic hardening was included in the elastoplastic model. In an attempt to invariantly describe the data, a nominal contact pressure was determined as a function of the volumetric constraint of the particle. This resulted in an adequate collapse of results obtained for different loading conditions onto a single master curve at large volumetric constraint. In summary, this paper should be considered as a step along the pathway towards our long term goal of introducing novel and improved contact models.

    Keywords
    Particle mechanics, Triaxial, Compression, Spatial confinement, Contact dependence
    National Category
    Applied Mechanics
    Identifiers
    urn:nbn:se:uu:diva-323755 (URN)10.1016/j.powtec.2017.04.005 (DOI)000401593600041 ()
    Funder
    Swedish Research Council, 621-2011-4049
    Available from: 2017-06-13 Created: 2017-06-13 Last updated: 2018-04-12Bibliographically approved
    4. Crack nucleation and propagation in microcrystalline-cellulose based granules subject to uniaxial and triaxial load
    Open this publication in new window or tab >>Crack nucleation and propagation in microcrystalline-cellulose based granules subject to uniaxial and triaxial load
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Cracking patterns of four kinds of granules, based on the common pharmaceutical excipient microcrystalline cellulose (MCC) and subject to compressive load, were examined. The initial pore structure and the location of initial failure under uniaxial compression were assessed using X-ray micro-computed tomography, whereas contact force development and onset of cracking under more complex compressive load were examined using a triaxial testing apparatus. Smoothed particle hydrodynamics (SPH) simulations were employed for numerical analysis of the stress distributions prior to cracking. For granules subject to uniaxial compression, initial cracking always occurred along the meridian and the precise location of the crack depended on the pore structure. Likewise, for granules subject to triaxial compression, the fracture plane of the primary crack was generally parallel to the dominant loading direction. The occurrence of cracking was highly dependent on the triaxiality ratio, i.e. the ratio between the punch displacements in the secondary and dominant loading directions. Compressive stresses in the lateral directions, induced by triaxial compression, prevented crack opening and fragmentation of the granule, something that could be verified in the SPH simulations. These results provide corroboration as well as further insights into previously observed differences between confined and unconfined compression of granular media.

    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-347457 (URN)
    Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2018-04-12
    5. Evaluation of bulk compression using a discrete element procedure calibrated with data from triaxial experiments on single particles
    Open this publication in new window or tab >>Evaluation of bulk compression using a discrete element procedure calibrated with data from triaxial experiments on single particles