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  • Public defence: 2024-04-16 09:15 B22, Biomedical Centre, Uppsala
    Yang, Mingyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pitfalls in β-cell ion imaging with fluorescent indicators and their use for real-time detection of somatostatin secretion2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fluorescent ion indicators have become indispensable tools in cell physiology. Dye indicators can easily be loaded into most types of cells, while genetically encoded indicators are advantageous in allowing specific cellular or subcellular targeting. Comparing responses of dye and protein-based indicators may provide useful insights into indicator properties and cellular processes. Here, a few genetically encoded Ca2+ indicators and fluorescent Ca2+ dyes were compared in insulin-secreting β-cells. Recordings of depolarization-triggered changes of the cytoplasmic Ca2+ concentration ([Ca2+]i) beneath the plasma membrane with total internal reflection fluorescence microscopy demonstrated distinct [Ca2+]i spikes with protein-based indicators, while the dyes mainly reported stable [Ca2+]i elevations. The spikes reflected Ca2+ release from the endoplasmic reticulum, triggered by autocrine purinergic receptor activation from exocytotic release of ATP. The indicator-dependent differences were unrelated to Ca2+ binding affinity and buffering and probably reflected slower Ca2+ dissociation kinetics of the protein indicators. In glucose-stimulated mouse islets, the dye Fura-2 reported the characteristic [Ca2+]i response with an initial lowing followed by rapid increase, which was abolished by hyperpolarization with the K+-channel opener diazoxide. The simultaneously present genetically encoded indicator R-GECO1 failed to detect the lowering and reported a spurious [Ca2+]i elevation also in the presence of diazoxide, responses that could be ascribed to pH sensitivity of the indicator. Recordings with fluorescent H+ indicators demonstrated that glucose increases cytoplasmic pH in β-cells. Elevations of [Ca2+]i counteracted the alkalinization and [Ca2+]i oscillations in glucose-stimulated islets were associated with anti-phasic oscillations of [Ca2+]i and pH. A [Ca2+]i imaging-based reporter cell assay for real-time detection of the islet hormone somatostatin was generated by transfecting HeLa cells with somatostatin receptor 2, the G-protein Gα15 and R-GECO1. The reporter cells detected somatostatin secretion from islets imaged in the same view-field as dose-dependent [Ca2+]i elevations. Mouse and human islets released somatostatin in response to high K+, glucose, and the hormones GLP-1 and ghrelin. In glucose-stimulated mouse islets, bursts of somatostatin release were synchronized with islet [Ca2+]i oscillations. Analyses of islets from human donors indicated that type 2 diabetes is associated with hypersecretion of somatostatin. In conclusion, this thesis highlights potential pitfalls with fluorescent ion indicators in β-cell signalling studies and provides new insights into β-cell regulation of [Ca2+]i and pH. Moreover, it introduces an assay for real-time detection of somatostatin secretion from islets that holds promise for studies of the role of this hormone under normal conditions and in diabetes.

    List of papers
    1. Indicator-dependent differences in detection of local intracellular Ca2+release events evoked by voltage-gated Ca2+entry in pancreatic & beta;-cells
    Open this publication in new window or tab >>Indicator-dependent differences in detection of local intracellular Ca2+release events evoked by voltage-gated Ca2+entry in pancreatic & beta;-cells
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    2023 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 109, article id 110805Article in journal (Refereed) Published
    Abstract [en]

    Genetically encoded Ca2+ indicators have become widely used in cell signalling studies as they offer advantages over cell-loaded dye indicators in enabling specific cellular or subcellular targeting. Comparing responses from dye and protein-based indicators may provide information about indicator properties and cell physiology, but side-by-side recordings in cells are scarce. In this study, we compared cytoplasmic Ca2+ concentration ([Ca2+]i) changes in insulin-secreting & beta;-cells recorded with commonly used dyes and indicators based on circularly permuted fluorescent proteins. Total internal reflection fluorescence (TIRF) imaging of K+ depolarizationtriggered submembrane [Ca2+]i increases showed that the dyes Fluo-4 and Fluo-5F mainly reported stable [Ca2+]i elevations, whereas the proteins R-GECO1 and GCaMP5G more often reported distinct [Ca2+]i spikes from an elevated level. [Ca2+]i spiking occurred also in glucose-stimulated cells. The spikes reflected Ca2+ release from the endoplasmic reticulum, triggered by autocrine activation of purinergic receptors after exocytotic release of ATP and/or ADP, and the spikes were consequently prevented by SERCA inhibition or P2Y1-receptor antagonism. Widefield imaging, which monitors the entire cytoplasm, increased the spike detection by the Ca2+ dyes. The indicator-dependent response patterns were unrelated to Ca2+ binding affinity, buffering and mobility, and probably reflects the much slower dissociation kinetics of protein compared to dye indicators. Ca2+ dyes thus report signalling within the submembrane space excited by TIRF illumination, whereas the protein indicators also catch Ca2+ events originating outside this volume. The study highlights that voltage-dependent Ca2+ entry in & beta;-cells is tightly linked to local intracellular Ca2+ release mediated via an autocrine route that may be more important than previously reported direct Ca2+ effects on phospholipase C or on intracellular channels mediating calcium-induced calcium release.

    Place, publisher, year, edition, pages
    Elsevier BV, 2023
    Keywords
    Ca 2+oscillations, R-GECO1, Fluo-5F, Fluo-4, P2Y 1 receptor, Insulin secretion, TIRF microscopy
    National Category
    Cell and Molecular Biology Physiology
    Identifiers
    urn:nbn:se:uu:diva-509244 (URN)10.1016/j.cellsig.2023.110805 (DOI)001040163500001 ()37437828 (PubMedID)
    Funder
    Swedish Research Council, 2019-01456Swedish Research Council, 2021-02081
    Available from: 2023-08-21 Created: 2023-08-21 Last updated: 2024-02-26Bibliographically approved
    2. Detection of glucose-induced Ca2+ signals is perturbed by changes of cytoplasmic pH in β-cells
    Open this publication in new window or tab >>Detection of glucose-induced Ca2+ signals is perturbed by changes of cytoplasmic pH in β-cells
    (English)Manuscript (preprint) (Other academic)
    Keywords
    islets, cytoplasmic Ca2+, R-GECO1, Fura-2, cytoplasmic pH, oscillations
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-523018 (URN)
    Available from: 2024-02-26 Created: 2024-02-26 Last updated: 2024-02-26
    3. Real-time detection of somatostatin release from single islets reveals hypersecretion in type 2 diabetes
    Open this publication in new window or tab >>Real-time detection of somatostatin release from single islets reveals hypersecretion in type 2 diabetes
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-523599 (URN)
    Available from: 2024-02-26 Created: 2024-02-26 Last updated: 2024-02-26
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  • Public defence: 2024-04-16 09:15 Polhemsalen, Uppsala
    Andersson, Axel
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division Vi3.
    Computational Methods for Image-Based Spatial Transcriptomics2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Why does cancer develop, spread, grow, and lead to mortality? To answer these questions, one must study the fundamental building blocks of all living organisms — cells. Like a well-calibrated manufacturing unit, cells follow precise instructions by gene expression to initiate the synthesis of proteins, the workforces that drive all living biochemical processes.

    Recently, researchers have developed techniques for imaging the expression of hundreds of unique genes within tissue samples. This information is extremely valuable for understanding the cellular activities behind cancer-related diseases.  These methods, collectively known as image-based spatial transcriptomics (IST) techniques,  use fluorescence microscopy to combinatorically label mRNA species (corresponding to expressed genes) in tissue samples. 

    Here, automatic image analysis is required to locate fluorescence signals and decode the combinatorial code. This process results in large quantities of points, marking the location of expressed genes. These new data formats pose several challenges regarding visualization and automated analysis.

    This thesis presents several computational methods and applications related to data generated from IST methods. 

    Key contributions include: (i) A decoding method that jointly optimizes the detection and decoding of signals, particularly beneficial in scenarios with low signal-to-noise ratios or densely packed signals;  (ii) a computational method for automatically delineating regions with similar gene compositions — efficient, interactive, and scalable for exploring patterns across different scales;  (iii) a software enabling interactive visualization of millions of gene markers atop Terapixel-sized images (TissUUmaps);  (iv) a tool utilizing signed-graph partitioning for the automatic identification of cells, independent of the complementary nuclear stain;  (v) A fast and analytical expression for a score that quantifies co-localization between spatial points (such as located genes);  (vi) a demonstration that gene expression markers can train deep-learning models to classify tissue morphology.

    In the final contribution (vii), an IST technique features in a clinical study to spatially map the molecular diversity within tumors from patients with colorectal liver metastases, specifically those exhibiting a desmoplastic growth pattern. The study unveils novel molecular patterns characterizing cellular diversity in the transitional region between healthy liver tissue and the tumor. While a direct answer to the initial questions remains elusive, this study sheds illuminating insights into the growth dynamics of colorectal cancer liver metastases, bringing us closer to understanding the journey from development to mortality in cancer.

    List of papers
    1. ISTDECO: In Situ Transcriptomics Decoding by Deconvolution
    Open this publication in new window or tab >>ISTDECO: In Situ Transcriptomics Decoding by Deconvolution
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In Situ Transcriptomics (IST) is a set of image-based transcriptomics approaches that enables localisation of gene expression directly in tissue samples. IST techniques produce multiplexed image series in which fluorescent spots are either present or absent across imaging rounds and colour channels. A spot’spresence and absence form a type of barcoded pattern that labels a particular type of mRNA. Therefore, the expression of agene can be determined by localising the fluorescent spots and decode the barcode that they form. Existing IST algorithms usually do this in two separate steps: spot localisation and barcode decoding. Although these algorithms are efficient, they are limited by strictly separating the localisation and decoding steps. This limitation becomes apparent in regions with low signal-to-noise ratio or high spot densities. We argue that an improved gene expression decoding can be obtained by combining these two steps into a single algorithm. This allows for an efficient decoding that is less sensitive to noise and optical crowding. We present IST Decoding by Deconvolution (ISTDECO), a principled decoding approach combining spectral and spatial deconvolution into a single algorithm. We evaluate ISTDECOon simulated data, as well as on two real IST datasets, and compare with state-of-the-art. ISTDECO achieves state-of-the-art performance despite high spot densities and low signal-to-noise ratios. It is easily implemented and runs efficiently using a GPU.ISTDECO implementation, datasets and demos are available online at: github.com/axanderssonuu/istdeco

    Keywords
    Deconvolution, In situ sequencing, Decoding, Image-based spatial transcriptomics
    National Category
    Medical Image Processing Bioinformatics (Computational Biology)
    Research subject
    Computerized Image Processing; Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-524008 (URN)
    Funder
    EU, European Research Council, 682810
    Note

    De två sista författarna delar sistaförfattarskapet

    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
    2. Points2Regions: Fast, interactive clustering of imaging-based spatial transcriptomics data
    Open this publication in new window or tab >>Points2Regions: Fast, interactive clustering of imaging-based spatial transcriptomics data
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Imaging-based spatial transcriptomics techniques generate image data that, once processed, results in a set of spatial points with categorical labels for different mRNA species. A crucial part of analyzing downstream data involves the analysis of these point patterns. Here, biologically interesting patterns can be explored at different spatial scales. Molecular patterns on a cellular level would correspond to cell types, whereas patterns on a millimeter scale would correspond to tissue-level structures. Often, clustering methods are employed to identify and segment regions with distinct point-patterns. Traditional clustering techniques for such data are constrained by reliance on complementary data or extensive machine learning, limiting their applicability to tasks on a particular scale. This paper introduces 'Points2Regions', a practical tool for clustering spatial points with categorical labels. Its flexible and computationally efficient clustering approach enables pattern discovery across multiple scales, making it a powerful tool for exploratory analysis. Points2Regions has demonstrated efficient performance in various datasets, adeptly defining biologically relevant regions similar to those found by scale-specific methods. As a Python package integrated into TissUUmaps and a Napari plugin, it offers interactive clustering and visualization, significantly enhancing user experience in data exploration. In essence, Points2Regions presents a user-friendly and simple tool for exploratory analysis of spatial points with categorical labels. 

    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Bioinformatics; Immunology; Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-523994 (URN)
    Funder
    EU, European Research Council, 682810Science for Life Laboratory, SciLifeLab
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28
    3. TissUUmaps 3: Improvements in interactive visualization, exploration, and quality assessment of large-scale spatial omics data
    Open this publication in new window or tab >>TissUUmaps 3: Improvements in interactive visualization, exploration, and quality assessment of large-scale spatial omics data
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    2023 (English)In: Heliyon, E-ISSN 2405-8440, Vol. 9, no 5, article id e15306Article in journal (Refereed) Published
    Abstract [en]

    Background and objectives: Spatially resolved techniques for exploring the molecular landscape of tissue samples, such as spatial transcriptomics, often result in millions of data points and images too large to view on a regular desktop computer, limiting the possibilities in visual interactive data exploration. TissUUmaps is a free, open-source browser-based tool for GPU-accelerated visualization and interactive exploration of 107+ data points overlaying tissue samples.

    Methods: Herein we describe how TissUUmaps 3 provides instant multiresolution image viewing and can be customized, shared, and also integrated into Jupyter Notebooks. We introduce new modules where users can visualize markers and regions, explore spatial statistics, perform quantitative analyses of tissue morphology, and assess the quality of decoding in situ transcriptomics data.

    Results: We show that thanks to targeted optimizations the time and cost associated with interactive data exploration were reduced, enabling TissUUmaps 3 to handle the scale of today's spatial transcriptomics methods.

    Conclusion: TissUUmaps 3 provides significantly improved performance for large multiplex datasets as compared to previous versions. We envision TissUUmaps to contribute to broader dissemination and flexible sharing of largescale spatial omics data.

    Place, publisher, year, edition, pages
    Elsevier BV, 2023
    Keywords
    Interactive visualization, Spatial omics, Spatial transcriptomics
    National Category
    Bioinformatics and Systems Biology
    Identifiers
    urn:nbn:se:uu:diva-508867 (URN)10.1016/j.heliyon.2023.e15306 (DOI)001029211200001 ()37131430 (PubMedID)
    Funder
    Swedish Foundation for Strategic Research, BD150008Swedish Foundation for Strategic Research, SB160046EU, European Research Council, CoG682810
    Available from: 2023-08-11 Created: 2023-08-11 Last updated: 2024-02-28Bibliographically approved
    4. Cell Segmentation of in situ Transcriptomics Data using Signed Graph Partitioning
    Open this publication in new window or tab >>Cell Segmentation of in situ Transcriptomics Data using Signed Graph Partitioning
    2023 (English)In: Graph-Based Representations in Pattern Recognition / [ed] Mario Vento; Pasquale Foggia; Donatello Conte; Vincenzo Carletti, Cham: Springer, 2023, p. 139-148Conference paper, Published paper (Refereed)
    Abstract [en]

    The locations of different mRNA molecules can be revealed by multiplexed in situ RNA detection. By assigning detected mRNA molecules to individual cells, it is possible to identify many different cell types in parallel. This in turn enables investigation of the spatial cellular architecture in tissue, which is crucial for furthering our understanding of biological processes and diseases. However, cell typing typically depends on the segmentation of cell nuclei, which is often done based on images of a DNA stain, such as DAPI. Limiting cell definition to a nuclear stain makes it fundamentally difficult to determine accurate cell borders, and thereby also difficult to assign mRNA molecules to the correct cell. As such, we have developed a computational tool that segments cells solely based on the local composition of mRNA molecules. First, a small neural network is trained to compute attractive and repulsive edges between pairs of mRNA molecules. The signed graph is then partitioned by a mutex watershed into components corresponding to different cells. We evaluated our method on two publicly available datasets and compared it against the current state-of-the-art and older baselines. We conclude that combining neural networks with combinatorial optimization is a promising approach for cell segmentation of in situ transcriptomics data. The tool is open-source and publicly available for use at https://github.com/wahlby-lab/IS3G.

    Place, publisher, year, edition, pages
    Cham: Springer, 2023
    Series
    Lecture Notes in Computer Science (LNCS), ISSN 0302-9743, E-ISSN 1611-3349 ; 14121
    Keywords
    Cell segmentation, in situ transcriptomics, tissue analysis, mutex watershed
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Computerized Image Processing; Machine learning
    Identifiers
    urn:nbn:se:uu:diva-523993 (URN)10.1007/978-3-031-42795-4_13 (DOI)978-3-031-42794-7 (ISBN)978-3-031-42795-4 (ISBN)
    Conference
    13th IAPR-TC-15 International Workshop, GbRPR 2023, Vietri sul Mare, Italy, September 6–8, 2023
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
    5. An Analytical Neighborhood Enrichment Score for Spatial Omics
    Open this publication in new window or tab >>An Analytical Neighborhood Enrichment Score for Spatial Omics
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The neighborhood enrichment test is commonly used to quantify spatial enrichment or depletion between spatial points with categorical labels — a data type frequently occurring in spatial omics. Traditionally, it is performed via permutation-based Monte Carlo methods, which can be computationally expensive. This study presents an analytical solution to the neighborhood enrichment problem. This direct calculation strongly correlated with traditional tests, offering substantially faster processing times across eight spatial omics datasets. Further validation on an extensive Xenium dataset highlighted the method’s ability to rapidly analyze large-scale data, making it a valuable tool for advancing spatial omics research. The implementation is publicly available.

    Keywords
    Spatial statistics, Neighborhood enrichment, Spatial omics, Co-localization
    National Category
    Bioinformatics (Computational Biology) Probability Theory and Statistics
    Research subject
    Bioinformatics; Mathematical Statistics; Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-524007 (URN)
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
    6. Transcriptome-Supervised Classification of Tissue Morphology Using Deep Learning
    Open this publication in new window or tab >>Transcriptome-Supervised Classification of Tissue Morphology Using Deep Learning
    2020 (English)In: IEEE 17th International Symposium on Biomedical Imaging (ISBI), 2020, p. 1630-1633Conference paper, Published paper (Refereed)
    Abstract [en]

    Deep learning has proven to successfully learn variations in tissue and cell morphology. Training of such models typically relies on expensive manual annotations. Here we conjecture that spatially resolved gene expression, e.i., the transcriptome, can be used as an alternative to manual annotations. In particular, we trained five convolutional neural networks with patches of different size extracted from locations defined by spatially resolved gene expression. The network is trained to classify tissue morphology related to two different genes, general tissue, as well as background, on an image of fluorescence stained nuclei in a mouse brain coronal section. Performance is evaluated on an independent tissue section from a different mouse brain, reaching an average Dice score of 0.51. Results may indicate that novel techniques for spatially resolved transcriptomics together with deep learning may provide a unique and unbiased way to find genotype phenotype relationships

    Series
    IEEE International Symposium on Biomedical Imaging (ISBI), ISSN 1945-7928, E-ISSN 1945-8452
    Keywords
    In situ sequencing, Gene expression, Tissue classification, Deep learning
    National Category
    Bioinformatics and Systems Biology
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-420376 (URN)10.1109/ISBI45749.2020.9098361 (DOI)000578080300341 ()978-1-5386-9330-8 (ISBN)978-1-5386-9331-5 (ISBN)
    Conference
    2020 IEEE 17th International Symposium on Biomedical Imaging (ISBI), Iowa City, 3-7 april
    Projects
    TissUUmaps
    Funder
    EU, European Research Council, 682810
    Available from: 2020-09-24 Created: 2020-09-24 Last updated: 2024-02-28Bibliographically approved
    7. Spatial transcriptome mapping of the desmoplastic growth pattern of colorectal liver metastases by in situ sequencing reveals a biologically relevant zonation of the desmoplastic rim
    Open this publication in new window or tab >>Spatial transcriptome mapping of the desmoplastic growth pattern of colorectal liver metastases by in situ sequencing reveals a biologically relevant zonation of the desmoplastic rim
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Colorectal cancer liver metastasis, growth pattern, in situ sequencing, desmoplastic
    National Category
    Cell and Molecular Biology Bioinformatics (Computational Biology) Cancer and Oncology
    Research subject
    Microbiology; Computerized Image Processing; Molecular Cellbiology
    Identifiers
    urn:nbn:se:uu:diva-523995 (URN)
    Funder
    Swedish Cancer SocietyKnut and Alice Wallenberg Foundation, 2021/1726Region VästerbottenCancerforskningsfonden i NorrlandUmeå UniversitySwedish Research Council, 2019-01238EU, European Research Council, 682810Science for Life Laboratory, SciLifeLab
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
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    UUThesis_A-Andersson-2024
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  • Public defence: 2024-04-18 13:00 Gunnesalen, Uppsala
    Ölander, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Vestibular schwannoma: Clinical, Epidemiological and Biochemical perspectives2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vestibular schwannoma (VS) is a slow growing benign tumour originating in the Schwann cells surrounding the vestibulocochlear nerve. Over recent decades, the incidence rate for VS has steadily increased, with greater numbers of patients with smaller tumours being diagnosed. Today, it is estimated that around 1 in 500 people will suffer from VS in their lifetime. The most common symptom of VS is unilateral hearing loss, tinnitus or dizziness. The growth rate of the tumour is unpredictable and not related to degree of symptoms. The overall aim of this thesis was to provide new knowledge that could be used to improve routines for treatment and clinical guidelines for future patients with sporadic VS.

    A local clinical quality database was used to identify patients with VS treated at Uppsala University hospital. The information in the database of patients with VS was used to analyze postoperative complications after translabyrinthine surgery, hearing outcomes after hearing preservation middle cranial fossa surgery, both postoperative and after more than 10 years of follow up, and the risk of enduing a fall-related injury. The proteome of the human endolymphatic sac endolymph in six patients with VS was described. 

    13% of the translabyrinthine operated patients (93 of 700) suffered from one or more complications postoperatively. Increasing age and tumour size were both risk factors for postoperative facial nerve dysfunction. Greater tumour size increased the risk for intracranial hemorrhage. 60 out of 84 patients with VS operated on through middle fossa surgery had preserved hearing after surgery. After 10 years, the hearing had deteriorated symmetrically in the tumour ear and the contralateral ear. There was no increased risk for fall-related injuries among patient with VS compared to VS-free controls. Studying subgroups, an increased risk of fall-related injury was displayed among middle-aged patients before being diagnosed with VS and postoperatively in patients treated with middle fossa surgery. A total of 1,211 proteins were detected in the ES endolymph, of which 110 were unique for the endolymph. To further improve the knowledge regarding patients with VS, a joint national guideline program would be desirable.

    List of papers
    1. Complications in translabyrinthine surgery of vestibular schwannoma
    Open this publication in new window or tab >>Complications in translabyrinthine surgery of vestibular schwannoma
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    2018 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 138, no 7, p. 639-645Article in journal (Refereed) Published
    Abstract [en]

    Objective: To evaluate the risk of complications associated with tumor size and patient's age in translabyrinthine vestibular schwannoma surgery. Methods: 700 patients with vestibular schwannoma primarily underwent translabyrinthine surgery between 1988 and 2014. Pre- and postoperative data were collected in a database and incidence of the postoperative complications cerebrospinal fluid leakage, meningitis, intracranial hemorrhage (ICH), facial nerve function and mortality were assessed and related to the tumor size and patient's age and retrospectively evaluated. Results: The tumor size significantly influenced the incidence of ICH and facial nerve dysfunction whereas age was correlated to facial nerve outcome. Conclusions: The translabyrinthine approach is a safe surgical procedure with relatively low risks of complications. The tumor size was significantly associated with a higher risk of ICH and facial nerve dysfunction whereas age only influenced the facial nerve outcome.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2018
    Keywords
    Translabyrinthine surgery, complications, tumor size, age
    National Category
    Neurology Otorhinolaryngology
    Identifiers
    urn:nbn:se:uu:diva-356818 (URN)10.1080/00016489.2018.1427887 (DOI)000432629200008 ()29361875 (PubMedID)
    Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2024-02-22Bibliographically approved
    2. The proteome of the human endolymphatic sac endolymph
    Open this publication in new window or tab >>The proteome of the human endolymphatic sac endolymph
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    2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 11850Article in journal (Refereed) Published
    Abstract [en]

    The endolymphatic sac (ES) is the third part of the inner ear, along with the cochlea and vestibular apparatus. A refined sampling technique was developed to analyse the proteomics of ES endolymph. With a tailored solid phase micro-extraction probe, five ES endolymph samples were collected, and six sac tissue biopsies were obtained in patients undergoing trans-labyrinthine surgery for sporadic vestibular schwannoma. The samples were analysed using nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) to identify the total number of proteins. Pathway identification regarding molecular function and protein class was presented. A total of 1656 non-redundant proteins were identified, with 1211 proteins detected in the ES endolymph. A total of 110 proteins were unique to the ES endolymph. The results from the study both validate a strategy for in vivo and in situ human sampling during surgery and may also form a platform for further investigations to better understand the function of this intriguing part of the inner ear.

    Place, publisher, year, edition, pages
    Springer Nature, 2021
    National Category
    Otorhinolaryngology
    Identifiers
    urn:nbn:se:uu:diva-451426 (URN)10.1038/s41598-021-89597-3 (DOI)000687328100009 ()34088924 (PubMedID)
    Funder
    Swedish Research Council, 2015-4870Tysta Skolan Foundation
    Available from: 2021-09-07 Created: 2021-09-07 Last updated: 2024-02-22Bibliographically approved
    3. A Decade Later: Assessing Hearing Preservation in Vestibular Schwannoma Patients Post Middle Cranial Fossa Surgery: Long-term hearing outcomes of MCF surgery
    Open this publication in new window or tab >>A Decade Later: Assessing Hearing Preservation in Vestibular Schwannoma Patients Post Middle Cranial Fossa Surgery: Long-term hearing outcomes of MCF surgery
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Otorhinolaryngology
    Identifiers
    urn:nbn:se:uu:diva-523501 (URN)
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-02-22
    4. Fall-related injury among patients with vestibular schwannoma
    Open this publication in new window or tab >>Fall-related injury among patients with vestibular schwannoma
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Otorhinolaryngology
    Identifiers
    urn:nbn:se:uu:diva-523502 (URN)
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-02-22
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    UUThesis_C-Ölander-2024
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  • Public defence: 2024-04-19 09:00 Universitetshuset, Sal IX, Uppsala
    Ahlstedt, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Registered nurses' work motivation and intention to stay at the workplace2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is currently a shortage of registered nurses (RNs) and high turnover of RNs, both nationally and internationally. Work motivation is an important part of a healthy work environment and something we need to know more about from an RN perspective.

    The overarching aim of this thesis was to enhance our understanding of the organisational and social workplace factors that contribute to an attractive environment for RNs, by exploring factors associated with work motivation. Four research questions were posed. (i) What factors create the conditions for motivation in RNs’ daily work? (ii) What role does social support in the workplace play in RNs’ work motivation? (iii) What role does the opportunity to work with relevant tasks play in RNs’ work motivation? (iv) Are there differences between healthcare settings regarding RNs’ social support, illegitimate tasks, and associations with work motivation? Four empirical studies were performed to answer these questions. Two were qualitative studies based on an ethnographic approach and two were quantitative cross-sectional studies based on a stratified national sample of RNs. The results of the qualitative studies indicate that crucial factors for RNs' work motivation include a friendly and permissive atmosphere in daily work. Visible progress and receiving feedback from the work itself also positively contributed to motivation. Additionally, RNs' opportunities to learn and support each other through ongoing communication during daily work tended to have a positive impact on work motivation. Effective collaboration between physicians and RNs with mutual respect, understanding of each other's competencies, and creating an environment where RNs could seek clarification were also central to work motivation. The quantitative studies revealed that the opportunity for social support from the immediate manager or co-workers was significant for dimensions related to RNs’ work motivation and the willingness to stay in the workplace. The associations differed in strength between healthcare settings. Furthermore, the results indicated that a factor in RNs' work motivation was the ability to work with tasks perceived as relevant, not illegitimate. However, the results highlighted that a significant portion of RNs performed illegitimate tasks, and that illegitimate tasks were more prevalent for RNs in home healthcare than those in primary care and hospitals. This is something to consider as more complex care is being conducted outside of hospitals. The thesis adds new knowledge that can be useful to the development of attractive workplaces, which could contribute to more RNs choosing to remain in their position for a longer period.

    List of papers
    1. What makes registered nurses remain in work?: An ethnographic study
    Open this publication in new window or tab >>What makes registered nurses remain in work?: An ethnographic study
    2019 (English)In: International Journal of Nursing Studies, ISSN 0020-7489, E-ISSN 1873-491X, Vol. 89, p. 32-38Article in journal (Refereed) Published
    Abstract [en]

    Background: Registered nurses' work-related stress, dissatisfaction and burnout are some of the problems in the healthcare and that negatively affect healthcare quality and patient care. A prerequisite for sustained high quality at work is that the registered nurses are motivated. High motivation has been proved to lead to better working results. The theory of inner work life describes the dynamic interplay between a person's perceptions, emotions and motivation and the three key factors for a good working life: nourishment, progress and catalysts. Objectives: The aim of the study was to explore registered nurses' workday events in relation to inner work life theory, to better understand what influences registered nurses to remain in work. Design: A qualitative explorative study with an ethnographic approach. Methods: Participant observation over four months; in total 56 h with 479 events and 58 informal interviews during observation; all registered nurses employed at the unit (n = 10) were included. In addition, individual interviews were conducted after the observation period (n = 9). The dataset was analysed using thematic analysis and in the final step of the analysis the categories were reflected in relation to the three key factors in theory of inner work life. Results: Nourishment in a registered nurse context describes the work motivation created by the interpersonal support between colleagues. It was important to registered nurses that physicians and colleagues respected and trusted their knowledge in the daily work, and that they felt comfortable asking questions and supporting each other. Progress in the context of registered nurses' work motivation was the feeling of moving forward with a mix of small wins and the perception of solving more complex challenges in daily work. It was also fundamental to the registered nurses' development through new knowledge and learning during daily work. Catalysts, actions that directly facilitate the work, were highlighted as the possibility to work independently along with the opportunity to work together with other registered nurses. Conclusion: This study has a number of implications for future work and research on creating an attractive workplace for registered nurses. Working independently, with colleagues from the same profession, integrated with learning, visible progress, and receiving feedback from the work itself, contribute to work motivation.

    National Category
    Other Health Sciences
    Research subject
    Health Care Research
    Identifiers
    urn:nbn:se:uu:diva-364722 (URN)10.1016/j.ijnurstu.2018.09.008 (DOI)000454965700006 ()30339953 (PubMedID)
    Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2024-02-22Bibliographically approved
    2. Flourishing at work: Nurses' motivation through daily communication - An ethnographic approach
    Open this publication in new window or tab >>Flourishing at work: Nurses' motivation through daily communication - An ethnographic approach
    2020 (English)In: Nursing and Health Sciences, ISSN 1441-0745, E-ISSN 1442-2018, Vol. 22, no 4, p. 1169-1176Article in journal (Refereed) Published
    Abstract [en]

    Shortage and turnover of registered nurses are worldwide challenges, and work motiva-tion is one factor in retaining staff in the healthcare sector. The aim of this study was toexplore registered nurses' motivation expressed in daily communication, using the basicneeds in self-determination theory as a framework. A secondary analysis of ethno-graphic data, collected through participant observations, informal interviews duringobservations, and individual interviews, was used. A total sample of all registered nursesemployed at a hospital unit in Sweden (n = 10) participated. The data were analyzed the-matically through the lens of the basic needs in self-determination theory: autonomy,competence, and relatedness. Self-regulation of learning, the possibilities to discuss work-related challenges with colleagues, and having registered nurses lead dialogues with phy-sicians were factors connected to autonomy. Having a registered nurse and physiciansolve problems together was a factor connected to competence.Asenseofbelongingand security in a permissive climate between registered nurses was co nnected to relat-edness. This paper has implications for increased awareness of the three basic motiva-tional needs, which could be used in the development of attractive workplaces

    Place, publisher, year, edition, pages
    Australia: John Wiley & Sons, 2020
    Keywords
    Nurse, Motivation, Collegiality, Communication, Self-determination theory, SDT, Sjuksköterska, Kommunikation, Självbestämmande teori, SDT
    National Category
    Nursing
    Research subject
    Health Care Research
    Identifiers
    urn:nbn:se:uu:diva-427494 (URN)10.1111/nhs.12789 (DOI)000589631400001 ()33104296 (PubMedID)
    Available from: 2020-12-08 Created: 2020-12-08 Last updated: 2024-02-22Bibliographically approved
    3. Social support from manager and co-workers in relation to registered nurses' work motivation in three healthcare settings: A cross-sectional study of a Swedish national sample
    Open this publication in new window or tab >>Social support from manager and co-workers in relation to registered nurses' work motivation in three healthcare settings: A cross-sectional study of a Swedish national sample
    (English)Manuscript (preprint) (Other academic)
    National Category
    Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-523641 (URN)
    Available from: 2024-02-21 Created: 2024-02-21 Last updated: 2024-02-22
    4. Do illegitimate tasks matter for registered nurses' work motivation?: A cross-sectional study based on a nationally representative sample of Swedish nurses
    Open this publication in new window or tab >>Do illegitimate tasks matter for registered nurses' work motivation?: A cross-sectional study based on a nationally representative sample of Swedish nurses
    2023 (English)In: The International Journal of Nursing Studies Advances (IJNS Advances), E-ISSN 2666-142X, Vol. 5, article id 100159Article in journal (Refereed) Published
    Abstract [en]

    Background: A challenge in Western countries is the growing need for registered nurses (RNs') in hospitals, primary care and home healthcare. Decreasing illegitimate tasks and strengthening RNs' work motivation are some strategies to address this challenge.

    Objective: Our overall aim was to explore the association between RNs' experiences of illegitimate tasks and work motivation operationalised as four dimensions: work engagement, opportunities to provide high-quality care, employer satisfaction and intention to remain at the workplace. To address this aim, three specific research questions were asked: (1) Is there an association between illegitimate tasks and work motivation? (2) Do the levels of reported illegitimate tasks differ between RNs working in hospitals and those working in primary care or home healthcare settings? (3) Do associations between illegitimate work tasks and work motivation differ with type of workplace?

    Design: A cross-sectional design.

    Methods: We used responses from a stratified population of RNs in Sweden, n = 2,333, working either in hospitals, primary care or home healthcare. Calibrating weights were applied in all analyses to ascertain the generalisability of the findings. Illegitimate tasks were measured with the Bern Illegitimate Tasks Scale. Data were analysed using chi-squared tests and linear or logistic regression analysis. Interaction was measured on the multiplicative scale by adding an interaction term to the fully adjusted models.

    Results: Overall, approximately 25 % of RNs reported frequently experiencing illegitimate tasks. There were statistically significant associations between higher perceptions of illegitimate tasks and lower ratings in the four dimensions of work motivation: work engagement [beta coefficient [beta] = -0.14, confidence interval [CI] 95 % = -0.18; -0.10], opportunities to provide highquality care [beta = -0.46, CI 95 % = -0.51; -40] and employer satisfaction [beta = -0.60, CI 95 % = -0.67; -0.54]. Experiencing higher levels of illegitimate tasks also related to a decreased intention to remain at the workplace [illegitimate tasks: odds ratio = 0.32, CI 95 % = 0.27; 0.29]. RNs who worked in home healthcare reported higher levels of illegitimate tasks than RNs who worked in hospitals.

    Conclusions: Reducing the amount of illegitimate tasks may contribute to counteracting the shortage of RNs by increasing work motivation and willingness to remain at the workplace.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    Cross-sectional survey, Healthcare organisations, Motivation, Registered nurses, Work engagement
    National Category
    Nursing Applied Psychology
    Identifiers
    urn:nbn:se:uu:diva-517487 (URN)10.1016/j.ijnsa.2023.100159 (DOI)001102021300001 ()
    Available from: 2023-12-11 Created: 2023-12-11 Last updated: 2024-02-22Bibliographically approved
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  • Public defence: 2024-04-19 09:15 Polhemsalen, Uppsala
    Tidén, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström.
    Surface modification of inorganic materials with graphene oxide: From solution to high-temperature synthesis2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The use of graphene as an additive in materials is often challenging due to the agglomeration of the two-dimensional graphene sheets. An alternative additive is graphene oxide (GO), an oxidized form of graphene, which is easily dispersed in water. In this thesis, a method based on electrostatic interactions has been developed to coat powder particles with GO. The GO surface has a negative charge at most pH values, while most inorganic materials form a thin oxide surface layer with a pH-dependent surface charge. Below a certain pH, a powder surface can have a positively charged surface oxide, which can interact with the negatively charged GO sheets and form a coated particle. The pH range for a successful coating process can be predicted based on the ionic potential (z/r) of the surface oxides and the oxide stability regions seen in Pourbaix diagrams. In the thesis, GO-coatings were obtained on powders of Cu, Fe, 316L stainless steel, MnAl(C) and AlSi7Mg. The coated powders showed reduced reflectance, long-term oxidation stability and in most cases improved flowability.

    The effect of the GO-coating on the processability of Cu, MnAl(C), 316L stainless steel and AlSi7Mg in laser powder bed fusion (L-PBF) was also investigated. For Cu, the reduced reflectance at the wavelength of the laser led to printing of fully dense parts compared to a 10 % porosity of the printed uncoated Cu powder using the same printing parameters. L-PBF printing of MnAl(C) has a problem with cracking but printing with the GO-coated powder resulted in a 35 % crack reduction. Fully dense parts could also be printed with GO-coated AlSi7Mg and 316L stainless steel powders. Significant changes in texture compared to the uncoated reference as well as moderately improved mechanical properties were observed.

    TiB2-SiC composites can be formed by reactive hot pressing of a TiC-Si-B4C powder mixture. In agreement with predictions, it was very difficult to coat powders of Si and B4C due to their acidic surface oxides. In the thesis, the influence of reduced GO (rGO) and carbon black (CB) on the microstructure and properties of the TiB2-SiC composite was investigated using ball milled mixtures of the powders. After reactive hot pressing at 1850 °C, sheet-like structures could be observed at fractured surfaces suggesting that graphene-like sheets survive the high temperatures. The rGO containing samples showed increased thermal conductivity, hardness, and fracture toughness by 50 %, 16 % and 20 %, respectively. The improved properties were attributed to a good dispersion of the rGO additive, a change in the microstructure and a decreased oxygen content of the composite.

    List of papers
    1. Synthesis of graphene oxide coated metal powders with improved flowability and reduced reflectance
    Open this publication in new window or tab >>Synthesis of graphene oxide coated metal powders with improved flowability and reduced reflectance
    2022 (English)In: Surface & Coatings Technology, ISSN 0257-8972, E-ISSN 1879-3347, Vol. 444, article id 128644Article in journal (Refereed) Published
    Abstract [en]

    In this study, a method has been developed to coat metal powder particles (Fe, 316L stainless steel and Cu) with graphene oxide (GO). The method is based on using a pH window where opposite zeta potentials cause the GO sheets to be attracted to the passive oxide layer of the metal powder surface and a rotary evaporator mixing to achieve good dispersion and control the concentration of GO. The pH-dependent interactions of GO and Cu and Fe metal powders in solution have been investigated by mixing the metal powder with GO dispersions between pH 4.2 and 11.3, and it could be observed that GO attached to the metal powder surfaces up to pH ~8 for both Cu and Fe. At lower pH the zeta potential of GO becomes less negative and oxidation of the metal becomes more prominent. Based on these observations, a pH window just below the IEP of the surface metal oxides was used to adhere GO on metal powders in a rotary evaporator with controlled GO concentrations and good distribution of the GO sheets which was verified with SEM and Raman spectroscopy mapping. X-ray diffraction and Raman spectroscopy has been used to evaluate the GO and the metal oxides. Some relevant powder properties were investigated before and after coating of GO. The reflectance of Cu powders in the near-infrared 1070 nm wavelength range was reduced by up to 66 %, depending on the amount of GO coating. Flowability measurements showed that the flowability of the coated 316L powder could be improved significantly while the flowability of pure Fe powder was relatively unaffected by the coating. The results show that GO coated metal powder can be useful in additive manufacturing processes using a laser powder fusion technique where low reflectance and high flowability are important.

    Place, publisher, year, edition, pages
    ElsevierElsevier BV, 2022
    Keywords
    Metal powder, Graphene oxide, Coating, Reflectance, Flowability
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-481756 (URN)10.1016/j.surfcoat.2022.128644 (DOI)000822939100001 ()
    Available from: 2022-08-17 Created: 2022-08-17 Last updated: 2024-02-27Bibliographically approved
    2. Additive Manufacturing of Cu Using Graphene-Oxide-Treated Powder
    Open this publication in new window or tab >>Additive Manufacturing of Cu Using Graphene-Oxide-Treated Powder
    2023 (English)In: Materials, ISSN 1996-1944, E-ISSN 1996-1944, Vol. 16, no 15, article id 5216Article in journal (Refereed) Published
    Abstract [en]

    Additive manufacturing of Cu is interesting for many applications where high thermal and electric conductivity are required. A problem with printing of Cu with a laser-based process is the high reflectance of the powder for near-infrared wavelengths making it difficult to print components with a high density. In this study, we have investigated laser bed fusion (L-PBF) of Cu using graphene oxide (GO)-coated powder. The powder particles were coated in a simple wet-chemical process using electrostatic attractions between the GO and the powder surface. The coated powder exhibited a reduced reflectivity, which improved the printability and increased the densities from similar to 90% for uncoated powder to 99.8% using 0.1 wt% GO and a laser power of 500W. The coated Cu powders showed a tendency for balling using laser powers below 400 W, and increasing the GO concentration from 0.1 to 0.3 wt.% showed an increase in spattering and reduced density. Graphene-like sheet structures could be observed in the printed parts using scanning electron microscopy (SEM). Carbon-filled inclusions with sizes ranging from 10-200 nm could also be observed in the printed parts using transmission electron microscopy (TEM). The GO treatment yielded parts with higher hardness (75.7 HV) and electrical conductivity (77.8% IACS) compared to the parts printed with reference Cu powder.

    Place, publisher, year, edition, pages
    MDPI AG, 2023
    Keywords
    Cu, graphene oxide, GO, SLM, additive manufacturing, AM, laser powder bed fusion, LPBF
    National Category
    Manufacturing, Surface and Joining Technology Metallurgy and Metallic Materials
    Identifiers
    urn:nbn:se:uu:diva-510002 (URN)10.3390/ma16155216 (DOI)001045566700001 ()37569920 (PubMedID)
    Available from: 2023-08-28 Created: 2023-08-28 Last updated: 2024-02-27Bibliographically approved
    3. Crack reduction in laser powder bed fusion of MnAl(C) using graphene oxide coated powders
    Open this publication in new window or tab >>Crack reduction in laser powder bed fusion of MnAl(C) using graphene oxide coated powders
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    2024 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, article id 1142Article in journal (Refereed) Published
    Abstract [en]

    MnAl(C) is a promising candidate as a rare earth free magnet. When processing MnAl(C) in laser powder bed fusion (L-PBF) the high cooling rates can retain the high temperature epsilon-phase which can then be annealed at low temperatures to yield the ferromagnetic tau-phase. However, MnAl(C) has been shown to be difficult to print using L-PBF and the material is prone to severe cracking. In this study, we have investigated how the addition of a graphene oxide (GO) coating on the powders can affect the processability of MnAl(C) and properties of the printed parts. MnAl(C) powders were coated with 0.2 wt.% GO using a wet-chemical process. The addition of GO reduced crack formation in the printed parts, and also influenced the degree of < 001 > texture along the build direction. After printing, densities of 93% and 87% could be achieved for the reference and 0.2 wt.% GO, respectively. Furthermore, a 35% reduction of cracking was calculated from image analysis, comparing printed samples produced from coated and non-coated powders. Both powders formed mostly the e-phase but some two-phase regions with a mix of γ- and ε-phase could be observed in the as-printed parts, but seemed to be more prominent in the uncoated reference samples and could also be linked to cracks. The τ-phase together with smaller amounts of secondary phases was obtained after heat treatment at 560 degrees C for 5 min for both samples. Vibrating sample magnetometry was used to measure the magnetic properties, the reference had a remanence of 33Am2/ kg and a coercivity of 139 kA/m, and the 0.2 wt.% GO sample showed a similar remanence of 30Am2/ kg and coercivity of 130 kA/m. These results show that GO coating is a viable method to reduce detrimental cracking in L-PBF MnAl without reducing the magnetic performance of the material.

    Place, publisher, year, edition, pages
    Springer Nature, 2024
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-523948 (URN)10.1038/s41598-024-51283-5 (DOI)001142462100014 ()38212350 (PubMedID)
    Funder
    Swedish Research Council, 2022-03069
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-03-28Bibliographically approved
    4. Influence of reduced graphene oxide and carbon black on mechanical and thermal characteristics of TiB2-SiC ceramics
    Open this publication in new window or tab >>Influence of reduced graphene oxide and carbon black on mechanical and thermal characteristics of TiB2-SiC ceramics
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    2024 (English)In: Journal of the European Ceramic Society, ISSN 0955-2219, E-ISSN 1873-619XArticle in journal (Refereed) In press
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-523949 (URN)10.1016/j.jeurceramsoc.2024.02.029 (DOI)
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-27
    5. Oxidation protection of Cu powders using graphene oxide and oxalic acid
    Open this publication in new window or tab >>Oxidation protection of Cu powders using graphene oxide and oxalic acid
    (English)Manuscript (preprint) (Other academic)
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-523946 (URN)
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-27
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  • Public defence: 2024-04-19 09:15 Rosénsalen, Uppsala
    Ternby, Ellen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Information prior to prenatal diagnosis: Knowledge, informational needs and decision-making2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of this thesis was to explore different aspects of information relevant to decision-making regarding prenatal diagnosis (PND) for chromosomal anomalies (CA). 

    In Papers I–II, women and partners undergoing combined ultrasound and biochemistry (CUB) tests, invasive tests or declining PND for CAs answered a questionnaire. Overall, expectant parents had varying to low levels of knowledge about Down syndrome (DS), with few differences between women and partners, or between those accepting or declining PND. Thus, knowledge at these levels does not seem to influence the decision to accept or decline PND. Some seem to regard CUB as a routine test.

    Paper III explored midwives' perspectives with a questionnaire. The majority believed they had not received sufficient education about PND, and few felt knowledgeable enough to provide information about DS. Most midwives desired more education regarding tests and DS. Actual knowledge levels concerning DS varied, and in some cases, were low.

    Paper IV explored the factors influencing decisions concerning PND through interviews with pregnant women. The decision-making process is affected by individual factors (i.e. attitude towards anomalies, worry and need for reassurance, and self-perceived risk) and external factors (i.e. test characteristics and influence from others). The quality of life for an affected individual and the impact on the family is important for some women when making decisions about PND. Healthcare professionals can influence women’s decisions through their attitudes, how they present the tests, and the woman’s individual probability of CAs.

    Paper V used Q methodology to explore women’s views on what is important when receiving information about PND. Some women prefer receiving information gradually, while others prefer comprehensive information early in pregnancy. Some value information about the conditions tested for early in the process. The extent to which women wanted to involve their partner in the decision-making process varied. None preferred group information sessions.

    In conclusion, providing information and pre-test counselling to pregnant women is a complex task. There is room for improvement in the information provided to expectant parents, and in the education provided to midwives related to PND and DS. Women’s decisions regarding PND are influenced by both individual and external factors. Information about test characteristics and conditions tested for could be helpful for pregnant women when they make decisions. Healthcare professionals’ approach can influence women’s decisions. Women have varying informational needs, making individual and non-directive pre-test counselling with a competent healthcare professional essential to facilitate informed decision-making. 

    List of papers
    1. Information and knowledge about Down syndrome among women and partners after first trimester combined testing
    Open this publication in new window or tab >>Information and knowledge about Down syndrome among women and partners after first trimester combined testing
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    2015 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 3, p. 329-32Article in journal (Refereed) Published
    Abstract [en]

    We assessed reasons among women and partners for choosing combined ultrasound-biochemistry testing, information and knowledge about Down syndrome and decisions concerning invasive procedures and termination of pregnancy in a prospective cohort study in Uppsala County. In all 105 pregnant women and 104 partners coming for a combined ultrasound-biochemistry test answered a questionnaire. The most common reason for a combined ultrasound-biochemistry test was "to perform all tests possible to make sure the baby is healthy". Internet and midwives were the most common sources of information. Seventy-two percent had not received information on what it means to live with a child with Down syndrome. Many expectant parents perceived information as insufficient. Both women and partners had varying or low levels of knowledge about medical, cognitive and social consequences of Down syndrome. Twenty-five percent had not decided on an invasive test if indicated and only 42% would consider termination of pregnancy with a Down syndrome diagnosis.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-245332 (URN)10.1111/aogs.12560 (DOI)000349603600016 ()25582972 (PubMedID)
    Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2024-02-28Bibliographically approved
    2. Why do pregnant women accept or decline prenatal diagnosis for Down syndrome?
    Open this publication in new window or tab >>Why do pregnant women accept or decline prenatal diagnosis for Down syndrome?
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    2016 (English)In: Journal of community genetics, ISSN 1868-310X, Vol. 7, no 3, p. 237-242Article in journal (Refereed) Published
    Abstract [en]

    To investigate if actual knowledge of Down syndrome (DS), influences the decision to accept or decline prenatal diagnosis (PND). Secondary aims were to elucidate reasons for accepting or declining PND and investigate differences between the accepting and declining group in perceived information, knowing someone with DS and thoughts about decision-making. A questionnaire was completed by 76 pregnant women who underwent invasive testing and 65 women who declined tests for chromosomal aberrations in Uppsala, Sweden. Apart from one question no significant differences were found in knowledge of DS between women declining or accepting PND for DS. Both groups had varying and in several respects low levels of knowledge about DS and its consequences. Most common reasons to accept PND were 'to ease my worries' and 'to do all possible tests to make sure the baby is healthy'. Corresponding statements declining PND were 'termination of pregnancy is not an option' and 'because invasive tests increase the risk of miscarriage'. More women declining PND knew someone with DS. Knowledge of DS at these levels is not a major factor when women decide to accept or decline PND for DS. Their choice is mostly based on opinions and moral values.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-300828 (URN)10.1007/s12687-016-0272-6 (DOI)000386778700007 ()27438596 (PubMedID)
    Available from: 2016-08-15 Created: 2016-08-15 Last updated: 2024-02-28Bibliographically approved
    3. Midwives and information on prenatal testing with focus on Down syndrome
    Open this publication in new window or tab >>Midwives and information on prenatal testing with focus on Down syndrome
    2015 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 35, no 12, p. 1202-1207Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To investigate midwives' knowledge of prenatal diagnosis especially Down syndrome, information given by midwives to parents, expectant parents' requests for information and how midwives perceive their own competence to give information.

    METHOD: A cross-sectional, prospective study with a questionnaire was completed by 64 out of 70 midwives working in the outpatient antenatal care in Uppsala County, Sweden.

    RESULTS: The midwives had varying and in some areas low levels of knowledge about Down syndrome. Information about Down syndrome was most often given only when asked for or when there was an increased probability of a Down syndrome pregnancy. The most common questions from expectant parents concerned test methods and risk assessments while questions regarding symptoms of Down syndrome and consequences of having a child with Down syndrome were uncommon. The majority (83-89%) had insufficient or no education regarding different prenatal tests. Only 2 midwives (3%) had received education about Down syndrome and 10% felt they had sufficient knowledge to inform about the syndrome. More education about prenatal tests and Down syndrome was desired by 94%.

    CONCLUSION: It is important to ensure that midwives in antenatal care have sufficient knowledge to inform expectant parents about the conditions screened for.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-268688 (URN)10.1002/pd.4676 (DOI)000368442000007 ()26279318 (PubMedID)
    Available from: 2015-12-09 Created: 2015-12-09 Last updated: 2024-02-28Bibliographically approved
    4. Factors influencing pregnant women’s decision to accept or decline prenatal diagnosis – A qualitative study
    Open this publication in new window or tab >>Factors influencing pregnant women’s decision to accept or decline prenatal diagnosis – A qualitative study
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Information, informed choice, genetic counseling, decision making, prenatal diagnosis, chromosome aberrations
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-523706 (URN)
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-02-28
    5. Pregnant women's informational needs prior to decisions about prenatal diagnosis for chromosomal anomalies: A Q methodological study
    Open this publication in new window or tab >>Pregnant women's informational needs prior to decisions about prenatal diagnosis for chromosomal anomalies: A Q methodological study
    2024 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    Objective

    To study pregnant women's subjective viewpoints on what is important when receiving information prior to decision-making regarding prenatal testing for chromosomal anomalies.

    Method

    Data were collected using Q methodology. During January 2020—October 2021, 45 pregnant women in Sweden completed a 50-item Q sort. Statements regarding what is important when receiving information about prenatal screening and diagnosis were prioritized through ranking in a fixed sorting grid on an 11-point scale, from “most important” to “least important.” Socio-demographics and coping styles were surveyed through questionnaires.

    Results

    Three groups represented different viewpoints on what pregnant women consider important when receiving information about prenatal screening and diagnosis. Factor 1: Stepwise information and decision-making: viewing information and decision-making as a step-by-step process. Factor 2: Decision-making as a continuous process based on couple autonomy: Striving for an informed decision as a couple about tests, test results and conditions screened. Factor 3: As much information as early as possible—the importance of personal autonomy in decision-making: Prioritizing autonomous decision-making based on non-directive information early in the pregnancy.

    Conclusion

    This study highlights the complexities involved when providing information. As shown by the differing viewpoints in this study, pregnant women's informational needs differ, making individual and personalized information preferable.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2024
    Keywords
    prenatal diagnosis, informed choice
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-519893 (URN)10.1002/pd.6514 (DOI)001134912600001 ()38167810 (PubMedID)
    Funder
    Sjukvårdsregionala forskningsrådet Mellansverige, RFR-844621
    Available from: 2024-02-06 Created: 2024-02-06 Last updated: 2024-02-28Bibliographically approved
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  • Public defence: 2024-04-19 12:30 Rudbecksalen, Uppsala
    Vaccaro, Alessandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tertiary lymphoid structures in glioblastoma: Discovery, Characterization and Therapeutic Induction2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glioblastoma (GBM) is an incurable brain cancer with a median survival of less than two years from diagnosis. The tumor microenvironment plays a major role in GBM progression through sustaining immunosuppression and poor lymphocytic infiltration. Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that form in inflamed tissues and are associated with positive prognosis in numerous cancers outside the central nervous system. Prior to this work, TLS had not been reported or studied in GBM. In this thesis, we aimed to characterize TLS in glioma patients, and to investigate immunotherapeutic approaches that could reprogram the GBM microenvironment to induce these structures, promote anti-tumor responses and prolong survival.

    In Paper I, we discovered the presence of TLS in low grade and high grade glioma tissues, and found that they correlated with increased T cell infiltration inside the tumor. Moreover, we demonstrated that agonistic CD40 therapy (αCD40) induced the formation of TLS with a follicle-like organization in murine glioma models. αCD40 also promoted a population of CD11b+ regulatory B cells, which inhibited T cell activation. These cells were not present within the TLS, indicating that TLS formation and the induction of CD11b+ B cells were likely two independent processes.

    In Paper II, we employed murine glioma models to study the therapeutic effect of cytokines involved in lymphoid tissue development, and selected LIGHT as the most promising candidate. To therapeutically deliver LIGHT to the tumor microenvironment, we engineered an AAV vector targeted to the brain endothelial cells to express LIGHT (AAV-LIGHT). AAV-LIGHT promoted the formation of TLS and functional high endothelial venules. Moreover, AAV-LIGHT strengthened effector and memory CD8+ T cell responses, and boosted a population of TCF1+CD8+ stem-like T cells. This was associated with a prolonged survival, indicating that AAV-LIGHT is a promising therapeutic candidate for the treatment of GBM. 

    In Paper III, we coupled advanced spatial transcriptomics of human GBM tissue and time point experiments in murine glioma models to investigate the stages of TLS assembly. We found that TLS formation is a step-wise process, where each stage is characterized by specific cell components and pathways. Understanding the steps underlying TLS assembly will be critical to develop efficient TLS-inducing immunotherapies.

    List of papers
    1. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
    Open this publication in new window or tab >>Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
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    2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 4127Article in journal (Refereed) Published
    Abstract [en]

    Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

    Place, publisher, year, edition, pages
    Springer Nature, 2021
    National Category
    Immunology in the medical area Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-448896 (URN)10.1038/s41467-021-24347-7 (DOI)000672713500007 ()34226552 (PubMedID)
    Note

    These authors contributed equally: Luuk van Hooren, Alessandra Vaccaro

    Available from: 2021-07-11 Created: 2021-07-11 Last updated: 2024-02-28Bibliographically approved
    2. Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma
    Open this publication in new window or tab >>Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma
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    2023 (English)In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 41, no 6, p. 1134-1151Article in journal (Refereed) Published
    Abstract [en]

    Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted ad-eno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in aPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1+CD8+ stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regres-sion upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.

    Place, publisher, year, edition, pages
    Elsevier BV, 2023
    Keywords
    glioblastoma, TNFSF14, LIGHT, lymphotoxin αβ, tertiary lymphoid structures, stem-like T cells, high endothelial venules, antigen-presenting niches
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-508441 (URN)10.1016/j.ccell.2023.04.010 (DOI)001025445800001 ()37172581 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, 20 1008 PjFSwedish Cancer Society, 201010 UsFSwedish Cancer Society, 190184PjSwedish Research Council, 2016-02495Swedish Research Council, 2020-02563Swedish Research Council, 2019-01326Knut and Alice Wallenberg Foundation, KAW 2019.0088Swedish Childhood Cancer Foundation, TJ 2019-0014Swedish Cancer Society, CAN 2015/1216
    Available from: 2023-08-02 Created: 2023-08-02 Last updated: 2024-02-28Bibliographically approved
    3. A spatially-resolved journey through tertiary lymphoid structure formation in glioblastoma
    Open this publication in new window or tab >>A spatially-resolved journey through tertiary lymphoid structure formation in glioblastoma
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Immunology in the medical area Cancer and Oncology
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-523778 (URN)
    Available from: 2024-02-23 Created: 2024-02-23 Last updated: 2024-02-28
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  • Public defence: 2024-04-19 13:10 Fåhreussalen, Uppsala
    Österlund, Emerik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Prognostic and Predictive Factors in Metastatic Colorectal Cancer2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The outcome for metastatic colorectal cancer (mCRC) patients has improved substantially in recent decades. This has chiefly been observed in study populations, and predominantly in left-sided primary tumours, which is why we wanted to study if and how survival has improved in the background population. It has also been seen that certain molecular subtypes are more common in population-based materials, and, thus, we studied the prevalence and effects of different molecular alterations.

    Paper I is a national population-based material of all 19 566 Swedish patients with a diagnosis of mCRC 2007-2016, 55% were male and 70% had synchronous metastases. Median overall survival (OS) for all patients was 14.0 months. An improvement could be seen over time, also in stratified analyses. OS was influenced by presentation of metastases, age, primary tumour location, and sex. All except sex remained statistically significant in a multivariable analysis. Differences of about one month in median OS were seen between healthcare regions, but these diminished over time.

    Paper II included all 765 patients from the Uppsala Region with a mCRC diagnosis 2010-2020. Right colon primary tumours were seen in 38%, left colon in 27% and rectum in 34%. BRAF-V600E mutations (mt) and deficient mismatch repair (dMMR) had a poor OS and were more common in right colon primary tumours. Primary tumour location did not affect OS in subgroups according to mutations in RAS or BRAF, nor in a multivariable analysis. Molecular alterations seem to be more important than primary tumour location for prognosis.

    Paper III studied KRAS-G12Cmt in three population-based and one real-world material. KRAS-G12C was seen in 2-4% of all tested and in 4-8% of all KRASmt. No differences in patient characteristics were observed between KRAS-G12C and other KRASmt. No differences in OS were seen between KRAS-G12C and other KRASmt, neither for all patients, nor in different treatment groups.

    Paper IV studied atypical BRAFmt (aBRAFmt) in two population-based and one real-world cohort. aBRAFmt was seen in 1-4% of the adequately tested patients in the different cohorts. aBRAFmt patients were predominantly male, had dMMR less often, more rectal primary tumours, and less peritoneal metastases compared with BRAF-V600Emt. Serrated adenocarcinomas were seen in about half of the aBRAFmt. OS was significantly better for aBRAFmt than in BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt patients. Nine aBRAFmt received epidermal growth factor receptor inhibitors without responses.

    List of papers
    1. Temporal development in survival, and gender and regional differences in the Swedish population of patients with synchronous and metachronous metastatic colorectal cancer
    Open this publication in new window or tab >>Temporal development in survival, and gender and regional differences in the Swedish population of patients with synchronous and metachronous metastatic colorectal cancer
    2022 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, no 10, p. 1278-1288Article in journal (Refereed) Published
    Abstract [en]

    Background

    Survival in patients with metastatic colorectal cancer (mCRC) has markedly improved in patients included in clinical trials. In population-based materials, improvements were seen until about a decade ago, but it is unclear if survival has continued to improve. It is also unclear if regional or gender differences exist.

    Material and methods

    All patients with mCRC (N = 19,566) in Sweden between 2007 and 2016 were identified from the national quality register, SCRCR, with almost complete coverage. Overall survival (OS) from diagnosis of metastatic disease was calculated in two calendar periods, 2007–2011 and 2012–2016. Differences between groups were compared using Cox regression.

    Results

    Median age was 72 years, 55% were males, synchronous presentation was seen in 13,630 patients and metachronous in 5936. In synchronous disease, the primary tumour was removed more often during the first than the second period (51% vs 41%, p < 0.001). Median OS (mOS) was 14.0 months. It was longer in those with metachronous than synchronous disease (17.6 vs 13.1 months, p < 0.001) and in males (15.0 vs 12.8 months, p < 0.001), and markedly influenced by age and primary location. It was longer in patients diagnosed during the second period than during the first (14.9 vs 13.1 months, HR 0.89 (95% CI 0.86–0.92), p < 0.001). This difference was seen in all subgroups according to sex, age, presentation, and sidedness. mOS was about one month shorter in 1/6 healthcare regions, most pronounced during the first period. Differences in median of up to 5 months were seen between the region with the shortest and longest mOS.

    Conclusions

    Overall survival in Swedish patients with mCRC has improved during the past decade but is still substantially worse than reported from clinical trials/hospital-based series, reflecting the selection of patients to trials. Regional differences were seen, but they decreased with time. Women did not have a poorer prognosis in multivariable analyses.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2022
    Keywords
    Metastatic colorectal cancer, population, survival, regional differences, gender differences
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-496816 (URN)10.1080/0284186X.2022.2126327 (DOI)000859105800001 ()36152023 (PubMedID)
    Funder
    Swedish Cancer Society, 190382
    Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2024-02-25Bibliographically approved
    2. Primary tumor location, molecular alterations, treatment, and outcome in a population-based metastatic colorectal cancer cohort
    Open this publication in new window or tab >>Primary tumor location, molecular alterations, treatment, and outcome in a population-based metastatic colorectal cancer cohort
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-522640 (URN)
    Funder
    Swedish Cancer SocietyInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-Örebro, 2021-2022
    Available from: 2024-02-06 Created: 2024-02-06 Last updated: 2024-02-25
    3. KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer
    Open this publication in new window or tab >>KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer
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    2022 (English)In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 12, article id 826073Article in journal (Refereed) Published
    Abstract [en]

    Background

    KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.

    Methods

    Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan-Meier, and differences were compared using Cox regression, adjusted for baseline factors.

    Results

    The KRAS-G12C frequency was 2%-4% of all tested in the seven cohorts (mean 3%) and 4%-8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74-1.42, reference KRAS-G12C) nor within treatment groups defined as "systemic chemotherapy, alone or with biologics", "metastasectomy and/or ablations", or "best supportive care", RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.

    Conclusions

    In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.

    Place, publisher, year, edition, pages
    Frontiers Media S.A.Frontiers Media SA, 2022
    Keywords
    colorectal cancer, metastatic, KRAS mutation, KRAS-G12C mutation, population-based, real-world
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-470669 (URN)10.3389/fonc.2022.826073 (DOI)000769560100001 ()35251991 (PubMedID)
    Available from: 2022-03-29 Created: 2022-03-29 Last updated: 2024-02-25Bibliographically approved
    4. Atypical (non‐V600E) BRAF mutations in metastatic colorectal cancer in population and real‐world cohorts
    Open this publication in new window or tab >>Atypical (non‐V600E) BRAF mutations in metastatic colorectal cancer in population and real‐world cohorts
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    2024 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 154, no 3, p. 488-503Article in journal (Refereed) Published
    Abstract [en]

    BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2024
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-522631 (URN)10.1002/ijc.34733 (DOI)001072911600001 ()37724848 (PubMedID)
    Funder
    Eli Lilly and Company, 2012‐2017
    Available from: 2024-02-06 Created: 2024-02-06 Last updated: 2024-02-25Bibliographically approved
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  • Public defence: 2024-04-19 13:15 Universitetshuset sal X, Uppsala
    Waddling, Jennifer
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Playing with the Global: Family Dynamics and International Education in a Marketised Preschool Landscape2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The surge in popularity of international schools around the world has extended to the domain of Early Childhood Education and Care. In the past few decades, international preschools have be­come more commonplace in marketised educational contexts. This thesis studies families who enrol their children in international preschools in Stockholm, Sweden, framing the rise of these institu­tions as embedded within two aspects of globalisation: the growing worth of transnational assets and the increasing prevalence of transnational families, encompassing those raising their children in foreign countries and those composed of parents from different national backgrounds. 

    The study, departing from Pierre Bourdieu’s relational sociology, examines preschool choice from two angles. The first inspects the social recruitment of international preschools through sta­tistical analysis of individual-level register data concerning families. This analysis considers social characteristics such as education level, income, and migration histories. Secondly, through interviews with middle-class parents, it explores families’ choice-making processes, examining how they navigate their children’s preschool options and ultimately select international preschools. 

    The results show that international preschools cater to families with strong and weak social positions and those with Swedish and foreign backgrounds, which evidences a widespread belief in the value of transnational attributes. However, differences between international preschools’ spe­cific languages highlighted that some languages are more closely linked with social advantage than others. Preschool choice was found to be shaped by complex dynamics, wherein social class, gender, migration experiences, family structures, and parenting cultures intersected with the local context and supply of preschools, both international and not. This first encounter with institutionalised education emerged as a situation where families renegotiated their family identity and priorities. Due to preschool chil­dren’s young age, transnational assets were not always easily transmitted or acquired, especially when parents desired divergent international and national investments. Such acquisition demanded consid­erable efforts in parenting, commuting to international preschools, and altering family dynamics. Preschools were shown to serve as providers of transnational assets and as possible hindrances to the particular forms of internationality families wished to nurture in their children.

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  • Public defence: 2024-04-22 08:00 Alex Hambergsalen, Uppsala
    Medina-Jiménez, Brenda Irene
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Single-cell RNA sequencing provides novel insights into spider development and represents an innovative alternative to study the evolution and development of panarthropods2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Panarthropoda is a monophyletic group of invertebrate animals with a segmented body, paired appendages, dorsal brain, and ventral nerve cords. In order to study the mechanisms underpining their evolution, I study the genetic factors that drive their development. A typical research strategy is the candidate gene approach, in which orthologs of genes from a well established model organisms such as the fruit fly Drosophila melanogaster are studied in other more or less related species for comparison.

    Recently developed single-cell RNA sequencing technologies allow the profiling of gene expression on the level of individual cells, and thus provide a much more detailed insight into gene expression.

    In Paper-I, I applied the candidate gene approach to study the potential role of two transcription factors, called tiptop/teashirt and spalt, as trunk-selectors in panarthropods.

    In Paper-II, I applied single-cell RNA sequencing to obtain the transcriptome of embryonic cells from spiders at mid-to-late stage in development. This generated a gene expression/gene-cell matrix that I analyzed to define the identity of cell clusters.

    In Paper-III, I present an improved SCS data analysis based on the data presented in Paper-II. This revealed a number of new cell clusters including a cluster that is characterized by known eye-developmental genes, genes that have previously not been identified as eye-developmental genes, and hitherto un-investigated genes. My in-situ hybridization analyis shows that these genes are potential novel factors of eye development in the spider.

    This work constitutes a successful example of the advantages of applying scRNA-seq in the study of panarthropod evolution and development.

    List of papers
    1. Single-cell RNA sequencing of mid-to-late stage spider embryos: new insights into spider development
    Open this publication in new window or tab >>Single-cell RNA sequencing of mid-to-late stage spider embryos: new insights into spider development
    2024 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 25, article id 150Article in journal (Refereed) Published
    Abstract [en]

    Background

    The common house spider Parasteatoda tepidariorum represents an emerging new model organism of arthropod evolutionary and developmental (EvoDevo) studies. Recent technical advances have resulted in the first single-cell sequencing (SCS) data on this species allowing deeper insights to be gained into its early development, but mid-to-late stage embryos were not included in these pioneering studies.

    Results

    Therefore, we performed SCS on mid-to-late stage embryos of Parasteatoda and characterized resulting cell clusters by means of in-silico analysis (comparison of key markers of each cluster with previously published information on these genes). In-silico prediction of the nature of each cluster was then tested/verified by means of additional in-situ hybridization experiments with additional markers of each cluster.

    Conclusions

    Our data show that SCS data reliably group cells with similar genetic fingerprints into more or less distinct clusters, and thus allows identification of developing cell types on a broader level, such as the distinction of ectodermal, mesodermal and endodermal cell lineages, as well as the identification of distinct developing tissues such as subtypes of nervous tissue cells, the developing heart, or the ventral sulcus (VS). In comparison with recent other SCS studies on the same species, our data represent later developmental stages, and thus provide insights into different stages of developing cell types and tissues such as differentiating neurons and the VS that are only present at these later stages.

    Place, publisher, year, edition, pages
    BioMed Central (BMC), 2024
    Keywords
    Single-cell sequencing, Spider development, Nervous system, Genetic fingerprint, Parasteatoda tepidariorum
    National Category
    Developmental Biology Bioinformatics and Systems Biology
    Identifiers
    urn:nbn:se:uu:diva-523429 (URN)10.1186/s12864-023-09898-x (DOI)38326752 (PubMedID)
    Funder
    Uppsala UniversityEU, Horizon 2020, 766053Swedish National Infrastructure for Computing (SNIC)UPPMAXSwedish Research Council, 2018‑05973
    Available from: 2024-02-19 Created: 2024-02-19 Last updated: 2024-02-29Bibliographically approved
    2. Single-cell sequencing reveals novel insights into spider eye development
    Open this publication in new window or tab >>Single-cell sequencing reveals novel insights into spider eye development
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Spiders evolved different types of eyes, a pair of primary eyes that are usually forward pointing, and three pairs of secondary eyes that are typically situated more posterior and lateral on the spider's head. The best understanding of arthropod eye development comes from the vinegar fly Drosophila melanogaster, the main arthropod model organism that also evolved different types of eyes, the larval eyes and the ocelli and facet eyes of the imago. The gene regulatory networks (GRNs) that underlay eye development in this species are well investigated revealing a conserved core network, but also show a number of differences between the different types of eyes. Recent candidate gene approaches identified a number of conserved genes in arthropod eye development, but also revealed crucial differences including the apparent lack of some key factors in some groups of arthropods, including spiders. Here we use single cell sequencing (SCS) to overcome the bias of candidate gene approaches with the aim to identifying new genes involved in spider eye development, and thus to gain deeper insight into spider eye development, and arthropod eye development in general. Our main finding is that Hedgehog (Hh)-signalling is involved in eye development in the spider Parasteatoda tepidariorum, and by investigating embryonic gene expression in representatives of all main groups of spiders, we demonstrate that this involvement is conserved in spiders as a whole. 

    Keywords
    Arthropod Evolution, Arthropod Head Development, Eye Development, Visual system development
    National Category
    Zoology Evolutionary Biology
    Research subject
    Earth Science with specialization in Historical Geology and Palaeontology; Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-523433 (URN)
    Funder
    EU, Horizon 2020, 766053Swedish Research Council, 2022-03522
    Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
    3. Panarthropod tiptop/teashirt and spalt orthologs and their potential role as "trunk"-selector genes
    Open this publication in new window or tab >>Panarthropod tiptop/teashirt and spalt orthologs and their potential role as "trunk"-selector genes
    2021 (English)In: EvoDevo, E-ISSN 2041-9139, Vol. 12, article id 7Article in journal (Refereed) Published
    Abstract [en]

    Background: In the vinegar fly Drosophila melanogaster, the homeodomain containing transcription factor Teashirt (Tsh) appears to specify trunk identity in concert with the function of the Hox genes. While in Drosophila there is a second gene closely related to tsh, called tiptop (tio), in other arthropods species only one copy exists (called tio/tsh). The expression of tsh and tio/tsh, respectively, is surprisingly similar among arthropods suggesting that its function as trunk selector gene may be conserved. Other research, for example on the beetle Tribolium castaneum, questions even conservation of Tsh function among insects. The zinc-finger transcription factor Spalt (Sal) is involved in the regulation of Drosophila tsh, but this regulatory interaction does not appear to be conserved in Tribolium either. Whether the function and interaction of tsh and sal as potential trunk-specifiers, however, is conserved is still unclear because comparative studies on sal expression (except for Tribolium) are lacking, and functional data are (if at all existing) restricted to Insecta.

    Results: Here, we provide additional data on arthropod tsh expression, show the first data on onychophoran tio/tsh expression, and provide a comprehensive investigation on sal expression patterns in arthropods and an onychophoran.

    Conclusions: Our data support the idea that tio/tsh genes are involved in the development of "trunk" segments by regulating limb development. Our data suggest further that the function of Sal is indeed unlikely to be conserved in trunk vs head development like in Drosophila, but early expression of sal is in line with a potential homeotic function, at least in Arthropoda.

    Place, publisher, year, edition, pages
    BioMed Central (BMC)BMC, 2021
    Keywords
    Arthropod development, Hox, Homeotic gene, Trunk-selector, Panarthropoda, Onychophora
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:uu:diva-445423 (URN)10.1186/s13227-021-00177-y (DOI)000657313700001 ()34078450 (PubMedID)
    Funder
    Swedish Research Council, 621-201504726EU, Horizon 2020, 766053
    Available from: 2021-06-14 Created: 2021-06-14 Last updated: 2024-02-27Bibliographically approved
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  • Public defence: 2024-04-22 13:15 room 80101, Uppsala
    Garozzo, Lucia M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Physics.
    Exploring effective descriptions of gauge fields and strings: A Lagrangian approach with insights from color-kinematics duality2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The concept of a color-kinematics duality is an important driving force in advancing the modern understanding of scattering amplitudes, in both field theory and string theory. Yet, open questions remain that motivate the need for a deeper understanding of the duality. A central open question is: do the kinematic numerators admit a Lie-algebraic origin, just like the corresponding color factors? The answer may be intimately related to a detailed understanding of the duality at the level of the Lagrangian. For pure Yang-Mills theory, a cubic Lagrangian which directly computes color-dual numerators is not yet known. In this thesis, we make progress in this direction by constructing a cubic Lagrangian in terms of the ordinary gauge field and a set of auxiliary fields. The contributions to the numerators are split into independent sectors specified by the number of contractions between polarization vectors. We find a novel Lagrangian with a finite number of fields and interactions that computes color-dual Yang-Mills numerators to any multiplicity, valid for sectors with up to two polarization contractions. In the context of string theory, insights from the color-kinematics duality have revealed interesting relations between string and field theory amplitudes. The sector of open bosonic string amplitudes where transcendental numbers are absent is known to be described by a higher-derivative field theory. The spectrum of this theory includes a massless gauge field and extra massive modes: by integrating the latter out from the Lagrangian, we obtain an expansion in the inverse string tension, which is a low-energy effective description of the dynamics of the massless modes of the bosonic string. This thesis develops the general method and explicitly writes down the operators entering the effective Lagrangian through fourth order in the inverse string tension.

    List of papers
    1. Lagrangians manifesting color-kinematics duality in the NMHV sector of Yang-Mills
    Open this publication in new window or tab >>Lagrangians manifesting color-kinematics duality in the NMHV sector of Yang-Mills
    2023 (English)In: Journal of High Energy Physics (JHEP), ISSN 1126-6708, E-ISSN 1029-8479, Vol. 2023, no 8, article id 222Article in journal (Refereed) Published
    Abstract [en]

    Scattering amplitudes in Yang-Mills theory are known to exhibit kinematic structures which hint to an underlying kinematic algebra that is dual to the gauge group color algebra. This color-kinematics duality is still poorly understood in terms of conventional Feynman rules, or from a Lagrangian formalism. In this work, we present explicit Lagrangians whose Feynman rules generate duality-satisfying tree-level BCJ numerators, to any multiplicity in the next-to-MHV sector of pure Yang-Mills theory. Our Lagrangians make use of at most three pairs of auxiliary fields (2, 1, 0-forms) — surprisingly few compared to previous attempts of Lagrangians at low multiplicities. To restrict the Lagrangian freedom it is necessary to make several non-trivial assumptions regarding field content, kinetic terms, and interactions, which we discuss in some detail. Future progress likely hinges on relaxing these assumptions.

    Place, publisher, year, edition, pages
    Springer, 2023
    Keywords
    Scattering Amplitudes, Duality in Gauge Field Theories
    National Category
    Other Physics Topics
    Identifiers
    urn:nbn:se:uu:diva-524486 (URN)10.1007/JHEP08(2023)222 (DOI)001188238100001 ()
    Funder
    Knut and Alice Wallenberg Foundation, KAW 2018.0116Knut and Alice Wallenberg Foundation, KAW 2018.0162Ragnar Söderbergs stiftelse
    Available from: 2024-03-05 Created: 2024-03-05 Last updated: 2024-04-09Bibliographically approved
    2. Effective interactions of the open bosonic string via field theory
    Open this publication in new window or tab >>Effective interactions of the open bosonic string via field theory
    2024 (English)Manuscript (preprint) (Other academic)
    National Category
    Other Physics Topics
    Identifiers
    urn:nbn:se:uu:diva-524487 (URN)
    Available from: 2024-03-05 Created: 2024-03-05 Last updated: 2024-03-06
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  • Public defence: 2024-04-23 09:15 Lecture Hall 2, Uppsala
    Sundberg, Anton
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Essays in Labor Economics: Parenthood, Immigration, and Education2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay I: This paper examines the impact of parenthood on labor market outcomes for both men and women using population-wide annual income data from 1960 to 2021 in Sweden. First, I document the contemporary child penalties across several labor market outcomes. Second, I show that while the motherhood penalty in earnings declined significantly during the 1960s, 1970s, and early 1980s, the rate of decline slowed from the late 1980s onwards. Third, I identify a fatherhood penalty emerging since the 1980s, particularly pronounced among men in more gender-egalitarian households (proxied by the father's share of parental leave) and among fathers who have sons relative to daughters.

    Essay II (with Olof Åslund and Arizo Karimi): We explore the effect of gender equality norms and shared institutional and economic contexts on the size of the motherhood penalty, studying child migrants and children of immigrants in Sweden. While there are results pointing to a moderate but statistically robust negative association between source country gender equality and the labor market impact of motherhood, the overall picture is more one of similarity across highly diverse groups. All groups of mothers exhibit qualitatively comparable labor market trajectories following first childbirth, but penalties are somewhat greater among those descending from the most gender-unequal societies.       

    Essay III (with Demid Getik and Anna Sjögren): We examine how exposure to recent migrants and asylum seekers affects the academic performance of incumbent students in Sweden between 2008 and 2022, a period characterized by large migration inflows. To identify the effect, we exploit variation in contemporaneous and cumulative exposure to recent migrants between siblings and across cohorts within schools. We find a small but statistically significant positive impact on native students' test scores from cumulative exposure to recent migrants. However, students with immigrant backgrounds do not experience similar benefits. A closer look at the more acute 2015 refugee crisis corroborates our main findings.    

    Essay IV (with Mounir Karadja): We study the economic effects of gaining access to the taxi labor market. Comparing individuals who pass the required written exams for a taxi license with those who have not yet done so, we find that immigrants increase their monthly earnings by nearly 50 percent between 1 and 3 years later and reduce their reliance on social insurance programs. Natives experience smaller gains of about 10 percent. Recently arrived immigrants reap the largest gains, suggesting that their outside options are limited, leading to a larger impact of taxi driving on their earnings.

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  • Public defence: 2024-04-24 09:00 room A1:111a, Uppsala
    Héchard, Tifaine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Molecular mechanism of plasmid copy number control in Yersinia2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The ability of pathogenic bacteria to cause disease depends on various virulence mechanisms. The three pathogenic species of Yersinia use a type III secretion system (T3SS) to translocate effector proteins into host cells and disrupt the immune system. This T3SS is encoded on a 70kb, low-copy, virulence plasmid. A novel mechanism of virulence was identified in Y. pseudotuberculosis, where the plasmid copy number (PCN) increases during infection. The PCN needs to be tightly regulated, as it encodes important, but costly, virulence genes. This thesis expends our understanding of PCN regulation and its importance in Yersinia virulence.

    In Paper I, we demonstrate that PCN regulation as a virulence mechanism is a dynamic system capable of adapting to different host environments. We found that an increased PCN is important at the onset of infection, particularly during the colonization phase. In later stages, within different organs, the PCN decreases, suggesting a reduced need for the T3SS once the infection is established. This insight was enabled by the development of a novel method based on droplet digital PCR, allowing accurate PCN detection in sample with very little target DNA. 

    In Paper II, we studied the PCN regulation by YopD. We showed that YopD represses PCN through the regulation of copA transcription. This YopD-dependant PCN control is released when YopD is secreted outside the bacteria upon contact with the host cell. YopD is a multifunctional protein. It possesses different domains crucial for its different functions. We found that the domains important for T3SS regulation are also required for PCN regulation.  

    In Paper III, we used phenotypical approaches together with Nuclear Magnetic Resonance (NMR) method to study YmoA, a protein regulating gene expression in Yersinia in response to environmental stresses. YmoA’s ability to control gene expression requires its interaction with H-NS, a global DNA regulator. YmoA up-regulates a great number of genes, the T3SS and its effectors protein for instance. We observed that it also down-regulates many others, such as flagellar assembly genes. Our findings reveal that YmoA regulates PCN and senses temperature and osmotic stress resulting in a change of its conformation, which affects its ability to form a complex with H-NS. 

    In summary, the studies presented in this thesis show that PCN is a highly dynamic, tightly regulated mechanism, important for Yersinia pathogenesis.

    List of papers
    1. Spatiotemporal Variations in Growth Rate and Virulence Plasmid Copy Number during Yersinia pseudotuberculosis Infection
    Open this publication in new window or tab >>Spatiotemporal Variations in Growth Rate and Virulence Plasmid Copy Number during Yersinia pseudotuberculosis Infection
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    2021 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 89, article id e00710-20Article in journal (Refereed) Published
    Abstract [en]

    Pathogenic Yersinia spp. depend on the activity of a potent virulence plasmid-encoded ysc/yop type 3 secretion system (T3SS) to colonize hosts and cause disease. It was recently shown that Y. pseudotuberculosis up-regulates the virulence plasmid copy number (PCN) during infection and the resulting elevated gene dose of plasmid-encoded T3SS genes is essential for virulence. When and how this novel regulatory mechanism is deployed and regulates the replication of the virulence plasmid during infection is unknown. In the current study, we applied droplet digital PCR (ddPCR) to investigate the dynamics of Y. pseudotuberculosis virulence PCN variations and growth rates in infected mouse organs. We demonstrated that both PCN and growth varied in different tissues and over time throughout the course of infection, indicating that the bacteria adapted to discrete microenvironments during infection. The PCN was highest in Peyer’s Patches and caecum during the clonal invasive phase of the infection, while the fastest growth rates were found in the draining mesenteric lymph nodes. In deeper, systemic organs, the PCN was lower and more modest growth rates were recorded. Our study indicates that increased gene dosage of the plasmid-encoded T3SS genes is most important early in the infection during invasion of the host. The described ddPCR approach will greatly simplify analyses of PCN, growth dynamics, and bacterial loads in infected tissues, and will be readily applicable to other infection models.

    Place, publisher, year, edition, pages
    American Society for Microbiology, 2021
    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-437848 (URN)DOI: 10.1128/IAI.00710-20 (DOI)000637755500029 ()33495272 (PubMedID)
    Funder
    Swedish Research Council, 2018-02376Swedish Research Council, 2018-02855Swedish Society for Medical Research (SSMF)Carl Tryggers foundation
    Available from: 2021-03-16 Created: 2021-03-16 Last updated: 2024-02-23Bibliographically approved
    2. Calcium-responsive plasmid copy number regulation is dependent on discrete YopD domains in Yersinia pseudotuberculosis
    Open this publication in new window or tab >>Calcium-responsive plasmid copy number regulation is dependent on discrete YopD domains in Yersinia pseudotuberculosis
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    2023 (English)In: Plasmid, ISSN 0147-619X, E-ISSN 1095-9890, Vol. 126, article id 102683Article in journal (Refereed) Published
    Abstract [en]

    Yersinia pathogenicity depends mainly on a Type III Secretion System (T3SS) responsible for translocating effector proteins into the eukaryotic target cell cytosol. The T3SS is encoded on a 70 kb, low copy number virulence plasmid, pYV. A key T3SS regulator, YopD, is a multifunctional protein and consists of discrete modular domains that are essential for pore formation and translocation of Yop effectors. In Y. pseudotuberculosis, the temperature-dependent plasmid copy number increase that is essential for elevated T3SS gene dosage and virulence is also affected by YopD. Here, we found that the presence of intracellular YopD results in increased levels of the CopA-RNA and CopB, two inhibitors of plasmid replication. Secretion of YopD leads to decreased expression of copA and copB, resulting in increased plasmid copy number. Moreover, using a systematic mutagenesis of YopD mutants, we demonstrated that the same discrete modular domains important for YopD translocation are also necessary for both the regulation of plasmid copy number as well as copA and copB expression. Hence, Yersinia has evolved a mechanism coupling active secretion of a plasmid-encoded component of the T3SS, YopD, to the regulation of plasmid replication. Our work provides evidence for the cross-talk between plasmid-encoded functions with the IncFII replicon.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    Plasmid replication, T3SS, Yersinia, Plasmid copy number
    National Category
    Microbiology in the medical area
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-500989 (URN)10.1016/j.plasmid.2023.102683 (DOI)000988625100001 ()37075853 (PubMedID)
    Funder
    Swedish Society for Medical Research (SSMF), S18-0174Swedish Research Council, 2018-02376German Research Foundation (DFG), DE616/7-1,7-2
    Note

    De två första författarna delar förstaförfattarskapet

    Available from: 2023-04-30 Created: 2023-04-30 Last updated: 2024-02-23Bibliographically approved
    3. YmoA functions as a molecular stress sensor in Yersinia
    Open this publication in new window or tab >>YmoA functions as a molecular stress sensor in Yersinia
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-523709 (URN)
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-02-23
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  • Public defence: 2024-04-25 13:15 Rudbecksalen, Uppsala
    Kukka, Antti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, SWEDESD - Sustainability Learning and Research Centre. Department of Pediatrics, Gävle Regional Hospital, Region Gävleborg, Gävle, Sweden.
    Surviving Birth and Thriving: Identifying infants at risk of death and disability in low- and middle-income countries2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Ending preventable newborn deaths is an unfinished global health agenda. Infants surviving birth have a right to thrive and to reach their full developmental potential. The aim of this thesis was to evaluate methods for identification of infants in need of neonatal resuscitation and at risk of disability in low- and middle-income countries.

    Paper I was an observational study conducted in Pokhara, Nepal, comparing the heart rate in the first 3 minutes in infants who were quietly breathing (n=54) versus crying (n=1155) immediately after birth.  The median heart rate did not differ between the two groups, but both bradycardia and tachycardia were more common among non-crying but breathing newborns.

    Paper II was a systematic review and meta-analysis of studies examining the incidence and outcomes of intrapartum-related neonatal encephalopathy in low- and middle-income countries. Altogether 53 articles were identified. The incidence ranged from 1.5 to 20.3 per 1000 live births (5 studies), the mean neonatal mortality was 19.3 % (45 studies, 3307 infants), and the incidence of combined outcome of death or moderate to severe disability at follow-up was 44.6 % (19 studies, 1595 children).

    Paper III evaluated the feasibility of smartphone-aided remote General Movements Assessment for identification of children at risk of cerebral palsy in Kathmandu, Nepal. Children surviving birth asphyxia or neonatal seizures were filmed by parents using the NeuroMotion smartphone application at home at 3 months’ age. Altogether 31 children were enrolled, and 16 parents returned at least one video of approved technical quality. Usability of the app was good based on parental survey.

    In Paper IV, individual (n=4) and group interviews (n=2) were conducted with ten mothers participating in the smartphone aided follow-up of their infants. The data were analysed using deductive qualitative content analysis. The remote follow-up was acceptable with support from the research assistants. Some participants would have preferred a face-to-face evaluation.

    Conclusion: Not crying at birth is a potential indicator for need of neonatal resuscitation. Infants who survive resuscitation are at risk of intrapartum-related neonatal encephalopathy, which has persistently high burden particularly in low-income countries. All survivors of encephalopathy need follow-up and smartphone-aided remote General Movements Assessment could complement the assessments in settings similar to Kathmandu.

    List of papers
    1. Observational study comparing heart rate in crying and non-crying but breathing infants at birth
    Open this publication in new window or tab >>Observational study comparing heart rate in crying and non-crying but breathing infants at birth
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    2023 (English)In: BMJ Paediatrics Open, E-ISSN 2399-9772, Vol. 7, no 1, article id e001886Article in journal (Refereed) Published
    Abstract [en]

    Background: Stimulating infants to elicit a cry at birth is common but could result in unnecessary handling. We evaluated heart rate in infants who were crying versus non-crying but breathing immediately after birth.

    Methods: This was single-centre observational study of singleton, vaginally born infants at = 33 weeks of gestation. Infants who were crying or non-crying but breathing within 30 s after birth were included.

    Background: demographic data and delivery room events were recorded using tablet-based applications and synchronised with continuous heart rate data recorded by a dry-electrode electrocardiographic monitor. Heart rate centile curves for the first 3 min of life were generated with piecewise regression analysis. Odds of bradycardia and tachycardia were compared using multiple logistic regression.

    Results: 1155 crying and 54 non-crying but breathing neonates were included in the final analyses. There were no significant differences in the demographic and obstetric factors between the cohorts. Non-crying but breathing infants had higher rates of early cord clamping <60 s after birth (75.9% vs 46.5%) and admission to the neonatal intensive care unit (13.0% vs 4.3%). There were no significant differences in median heart rates between the cohorts. Non-crying but breathing infants had higher odds of bradycardia (heart rate <100 beats/min, adjusted OR 2.64, 95% CI 1.34 to 5.17) and tachycardia (heart rate = 200 beats/min, adjusted OR 2.86, 95% CI 1.50 to 5.47).

    Conclusion: Infants who are quietly breathing but do not cry after birth have an increased risk of both bradycardia and tachycardia, and admission to the neonatal intensive care unit.

    Place, publisher, year, edition, pages
    BMJ Publishing Group LtdBMJ PUBLISHING GROUP, 2023
    Keywords
    neonatology, physiology, resuscitation
    National Category
    Pediatrics Nursing
    Identifiers
    urn:nbn:se:uu:diva-501964 (URN)10.1136/bmjpo-2023-001886 (DOI)000974560200001 ()37028906 (PubMedID)
    Available from: 2023-05-22 Created: 2023-05-22 Last updated: 2024-03-04Bibliographically approved
    2. Incidence and outcomes of intrapartum-related neonatal encephalopathy in low-income and middle-income countries: a systematic review and meta-analysis
    Open this publication in new window or tab >>Incidence and outcomes of intrapartum-related neonatal encephalopathy in low-income and middle-income countries: a systematic review and meta-analysis
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    2022 (English)In: BMJ Global Health, E-ISSN 2059-7908, Vol. 7, no 12, article id e010294Article, review/survey (Refereed) Published
    Abstract [en]

    Aim: To examine the incidence of intrapartum-related neonatal encephalopathy, and neonatal mortality and neurodevelopmental outcomes associated with it in low-income and middle-income countries.

    Methods: Reports were included when neonatal encephalopathy diagnosed clinically within 24 hours of birth in term or near-term infants born after intrapartum hypoxia-ischaemia defined as any of the following: (1) pH <= 7.1 or base excess <=-12 or lactate >= 6, (2) Apgar score <= 5 at 5 or 10 min, (3) continuing resuscitation at 5 or 10 min or (4) no cry from baby at 5 or 10 min. Peer-reviewed articles were searched from Ovid MEDLINE, Cochrane, Web of Science and WHO Global Index Medicus with date limits 1 November 2009 to 17 November 2021. Risk of bias was assessed using modified Newcastle Ottawa Scale. Inverse variance of heterogenicity was used for meta-analyses.

    Results: There were 53 reports from 51 studies presenting data on 4181 children with intrapartum-related neonatal encephalopathy included in the review. Only five studies had data on incidence, which ranged from 1.5 to 20.3 per 1000 live births. Neonatal mortality was examined in 45 studies and in total 636 of the 3307 (19.2%) infants died. Combined outcome of death or moderate to severe neurodevelopmental disability was reported in 19 studies and occurred in 712 out of 1595 children (44.6%) with follow-up 1 to 3.5 years.

    Conclusion: Though there has been progress in some regions, incidence, case mortality and morbidity in intrapartum-related neonatal encephalopathy has been static in the last 10 years.PROSPERO registration numberCRD42020177928.

    Place, publisher, year, edition, pages
    BMJ Publishing Group Ltd, 2022
    Keywords
    epidemiology, paediatrics, indices of health and disease and standardisation of rates, systematic review
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-495635 (URN)10.1136/bmjgh-2022-010294 (DOI)000906427500001 ()36581333 (PubMedID)
    Available from: 2023-01-31 Created: 2023-01-31 Last updated: 2024-03-13Bibliographically approved
    3. NeuroMotion Smartphone Application for Remote General Movements Assessment: a Feasibility Study in Nepal
    Open this publication in new window or tab >>NeuroMotion Smartphone Application for Remote General Movements Assessment: a Feasibility Study in Nepal
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    2024 (English)In: BMJ Open, E-ISSN 2044-6055, Vol. 14, no 3, article id e080063Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To evaluate the feasibility of using the NeuroMotion smartphone application for remote General Movements Assessment for screening of infants for cerebral palsy in Kathmandu, Nepal. 

    METHOD: Thirty-one term born infants at risk of cerebral palsy due to birth asphyxia or neonatal seizures were recruited for the follow-up at Paropakar Maternity and Women’s Hospital, 1st October 2021 to 7th January 2022. Parents filmed their children at home using the app at 3 months’ age and the videos were assessed for technical quality using a standardized form and for fidgety movements by Prechtl’s General Movements Assessment. Usability of the app was evaluated through a parental survey. 

    RESULTS: Twenty families sent in altogether 46 videos out of which 35 had approved technical quality. Sixteen children had at least one video with approved technical quality. Three infants lacked fidgety movements. The level of agreement between assessors was acceptable (Krippendorf alpha 0.781). Parental answers to the usability survey were in general positive. 

    INTERPRETATION: Engaging parents in screening of cerebral palsy with the help of a smartphone-aided remote General Movements Assessment is possible in the urban area of a South Asian lower middle-income country.

    Place, publisher, year, edition, pages
    BMJ Publishing Group Ltd, 2024
    Keywords
    cerebral palsy, general movements assessment, neonatal follow-up, low- and middle income countries, pilot projects
    National Category
    Pediatrics
    Research subject
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-523703 (URN)10.1136/bmjopen-2023-080063 (DOI)001179427300001 ()38431302 (PubMedID)
    Funder
    Promobilia foundation, 21009Linnéa och Josef Carlssons stiftelseStiftelsen Folke Bernadottes minnesfondInsamlingsstiftelsen Födelsefonden - Perinatalmedicinska forskningsfonden i UppsalaRegion Stockholm, 2019-1138Knut and Alice Wallenberg Foundation
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-04-03Bibliographically approved
    4. 'We did everything by phone': a qualitative study of mothers' experience of smartphone-aided screening of cerebral palsy in Kathmandu, Nepal
    Open this publication in new window or tab >>'We did everything by phone': a qualitative study of mothers' experience of smartphone-aided screening of cerebral palsy in Kathmandu, Nepal
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    2024 (English)In: BMC Pediatrics, E-ISSN 1471-2431Article in journal (Refereed) Submitted
    Abstract [en]

    BACKGROUND: International guidelines recommend early intervention to all children at risk of cerebral palsy, but targeted screening programs are often lacking in low- and middle-income settings with the highest burden of disease. Smartphone applications have the potential to improve access to early diagnostics by empowering parents to film their children at home followed by centralized evaluation of videos with General Movements Assessment. We explored mothers’ perceptions about participating in a smartphone aided cerebral palsy screening program in Kathmandu, Nepal.

    METHODS: This is an explorative qualitative study that used focus group discussions (n=2) and individual interviews (n=4) with mothers of term-born infants surviving birth asphyxia or neonatal seizures. Parents used the NeuroMotion™ smartphone app to film their children at home and the videos were analysed using General Movements Assessment. Sekhon et al.’s framework on the acceptability of health care interventions guided the design of the interviews and the deductive qualitative content analysis.

    RESULTS: Mothers were interested in engaging with the programme and expressed hope it would benefit their children. Most felt use of the app was intuitive. They were, however, unclear about the way the analysis was performed. Support from the research team was often needed to overcome an initial lack of self-confidence in using the technology and to reduce anxiety related to the follow-up. The intervention was overall perceived as recommendable but should be supplemented by a face-to-face consultation.

    CONCLUSION: Smartphone aided remote screening of cerebral palsy is acceptable in a lower middle-income population but requires additional technical support.

    Place, publisher, year, edition, pages
    BioMed Central (BMC), 2024
    Keywords
    cerebral palsy, qualitative research, general movements assessment, neonatal follow-up, low- and middle-income countries, telemedicine
    National Category
    Pediatrics
    Research subject
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-523708 (URN)
    Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2024-03-05
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  • Public defence: 2024-04-26 09:00 Häggsalen, Uppsala
    Martinho Vieira, Rafael
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Uppsala University.
    Exploring magnetocaloric materials by ab-initio methods2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis explores the characterization of magnetocaloric materials from first-principles calculations, emphasizing entropy variation associated with the magnetocaloric effect. The study happens in the context of the search for new magnetocaloric materials to be applied in domestic magnetic refrigerators,  as environmentally friendly and energy-efficient alternatives to conventional vapor-compression devices.

    The study involves benchmarking entropy calculations in systems like FeRh, which exhibits a first-order metamagnetic transition, and Gd, with a second-order ferromagnetic-paramagnetic transition. Different levels of approximations are examined and compared against experimental data, highlighting the need to distinguish between first-order and second-order transitions in the approach taken. The tests underscore the necessity of calculating vibrational and elastic properties for both phases to accurately calculate the entropy variation. This insight is applied in the study of Mn0.5Fe0.5NiSi0.9Al0.05, with results consistent with experimental data.

    Furthermore, the relationship between structural changes and magnetic properties is investigated, in particular for pressure-induced polymorphs in Gd and the phase transition in Mn0.5Fe0.5NiSi0.95Al0.05. In the case of Gd, it was shown that variations in magnetic ordering temperature under pressure could be explained through a model based on the formation and accumulation of stacking faults. For the Mn0.5Fe0.5NiSi0.95Al0.05 system, the adoption of a magnetic composite model, in conjunction with experimental data, allowed to determine that the magnetostructural transition in these compounds is predominantly driven by the lattice subsystem. 

    The results positively confirm the feasibility of using first-principles entropy estimates as an effective screening tool in high-throughput studies for magnetocaloric materials. A promising workflow is proposed, demonstrating potential in its initial results. Through comparison with experimental data, the derived routes offer valuable insights for the further refinement of the workflow. This approach aims to enhance accuracy and systematically manage complex systems, highlighting a path forward for future advancements.

    Lastly, the introduction of a novel scaling scheme in Monte Carlo simulations enhancing accuracy across various temperatures, represents a potential advancement in the field of magnetic simulations.

    List of papers
    1. Realistic first-principles calculations of the magnetocaloric effect: applications to hcp Gd
    Open this publication in new window or tab >>Realistic first-principles calculations of the magnetocaloric effect: applications to hcp Gd
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    2022 (English)In: Materials Research Letters, E-ISSN 2166-3831, Vol. 10, no 3, p. 156-162Article in journal (Refereed) Published
    Abstract [en]

    We present an efficient computational approach to evaluate field-dependent entropy of magnetocaloric materials from ab-initio methods. The temperature dependence is reported for the entropy change, specific heat and magnetization for hcp Gd. To obtain optimal accuracy in the calculations, a mixed-scheme for magnetic Monte Carlo simulations is proposed and found to be superior to using pure quantum or classic statistics. It is demonstrated that lattice and magnetic contributions play a role in the entropy change and that the dominating contribution comes from the magnetic contribution. The total calculated entropy change agrees with measurements at room temperature. IMPACT STATEMENT Demonstration of the accuracy of ab-initio theory, coupled to statistical methods, for accurate calculations of the total entropy variation associated with the magnetic transition of Gd. Reproduction of experimental data of entropy change.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2022
    Keywords
    Magnetocaloric, Gd, entropy, Monte Carlo, mixed statistics
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-467898 (URN)10.1080/21663831.2022.2033866 (DOI)000752058000001 ()
    Funder
    Swedish Foundation for Strategic Research, EM16-0039Swedish Energy AgencySwedish Research CouncilSwedish Research Council, 2018-05973StandUp
    Available from: 2022-02-18 Created: 2022-02-18 Last updated: 2024-03-19Bibliographically approved
    2. High-throughput compatible approach for entropy estimation in magnetocaloric materials: FeRh as a test case
    Open this publication in new window or tab >>High-throughput compatible approach for entropy estimation in magnetocaloric materials: FeRh as a test case
    2021 (English)In: Journal of Alloys and Compounds, ISSN 0925-8388, E-ISSN 1873-4669, Vol. 857, article id 157811Article in journal (Refereed) Published
    Abstract [en]

    Aiming to predict new materials for magnetic refrigeration from high-throughput calculations asks for an accurate, transferable, and resource-wise balanced approach. Here, we analyze the influence of various approximations on the calculation of key properties of magnetocaloric materials, while revisiting the well-known FeRh system for benchmarking our approach. We focus on the entropy change and its contributions from the electronic, lattice, and magnetic degrees of freedom. All approximations considered are based on first-principles methods and have been tested, and compared for FeRh. In particular, we find that in this context, the Debye approximation for the lattice entropy fails, due to the presence of soft phonon modes in the AFM phase. This approximation is frequently used in the literature as a simple alternative to full phonon calculations. Since soft modes are likely to occur also among promising magnetocaloric materials where structural transformations are common, the use of the Debye approximation should be discarded for these systems treatment. This leaves the calculations of the lattice contribution the most demanding task from the computational point of view, while the remaining contributions can be approximated using more efficient approaches. The entropy change AS shows a peak around 370 K, for which the total entropy change is given by 24.8 JK(-1) kg(-1) (Delta S-ele = 7.38, Delta S-lat = 7.05, Delta S-mag = 10.36 JK(-1) kg(-1)) in good agreement with previous theoretical and experimental findings.

    Place, publisher, year, edition, pages
    ElsevierELSEVIER SCIENCE SA, 2021
    Keywords
    FeRh, Magnetocalorics, Entropy, Phase transition, DFT
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-437236 (URN)10.1016/j.jallcom.2020.157811 (DOI)000610867800099 ()
    Funder
    Swedish Research Council, 2016-07213Swedish Foundation for Strategic Research , EM16-0039StandUpSwedish Energy AgencyeSSENCE - An eScience Collaboration
    Available from: 2021-03-12 Created: 2021-03-12 Last updated: 2024-03-19Bibliographically approved
    3. The role of pressure-induced stacking faults on the magnetic properties of gadolinium
    Open this publication in new window or tab >>The role of pressure-induced stacking faults on the magnetic properties of gadolinium
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    2023 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Experimental data show that under pressure, Gd goes through a series of structural transitions hcp → Sm-type (close-packed rhombohedral)→ dhcp that is accompanied by a gradual decrease of the Curie temperature and magnetization till the collapse of a finite magnetization close to the dhcp structure. We explore theoretically the pressure-induced changes of the magnetic properties, by describing these structural transitions as the formation of fcc stackings faults. Using this approach, we are able to describe correctly the variation of the Curie temperature with pressure, in contrast to a static structural model using the hcp structure. 

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-525212 (URN)10.48550/arXiv.2309.01285 (DOI)
    Available from: 2024-03-19 Created: 2024-03-19 Last updated: 2024-03-20
    4. Giant magnetocaloric effect in the (Mn,Fe)NiSi-system
    Open this publication in new window or tab >>Giant magnetocaloric effect in the (Mn,Fe)NiSi-system
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    2023 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The search for energy-efficient and environmentally friendly cooling technologies is a key driver for the development of magnetic refrigeration based on the magnetocaloric effect (MCE). This phenomenon arises from the interplay between magnetic and lattice degrees of freedom that is strong in certain materials, leading to a change in temperature upon application or removal of a magnetic field. Here we report on a new material, Mn1−xFexNiSi0.95Al0.05, with an exceptionally large isothermal entropy at room temperature. By combining experimental and theoretical methods we outline the microscopic mechanism behind the large MCE in this material. It is demonstrated that the competition between the Ni2In-type hexagonal phase and the MnNiSi-type orthorhombic phase, that coexist in this system, combined with the distinctly different magnetic properties of these phases, is a key parameter for the functionality of this material for magnetic cooling.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-525213 (URN)10.48550/arXiv.2307.00128 (DOI)
    Available from: 2024-03-19 Created: 2024-03-19 Last updated: 2024-03-19
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  • Public defence: 2024-04-26 13:00 Geijersalen, Uppsala
    Kashuba, Natalija
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Archaeology and Ancient History, Archaeology.
    Mended by masticates: A study of archaeogenetic proxies of migration, settlement and health in North Eurasian Mesolithic2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A joint archaeogenetic perspective integrates diverse lines of evidence from archaeology and paleogenetics to advance our understanding of human prehistory. In this thesis I contribute to the corpus of archaeogenetic data by producing and analysing ancient genomic data from osseous and masticated material. 

    Masticated birch bark pitch (also called resin) is presented as a novel source for ancient DNA that contains an abundance of data from different species. The masticated lumps analysed in this work, which come from a Mesolithic site in western Scandinavia, encapsulated human genetic information (individual genomes and oral microbiomes) and environmental aDNA from species (plants and animals) consumed or used as raw material at the site. Ancient DNA from this archaeological material transpires as a direct link between a practised archaeological culture and the genotype of the practitioners, in this case a particular lithic technology (the eastern pressure blade concept) and Scandinavian hunter-gatherers (SHG). The paleopathological information obtained from the microbiomes from this masticated material suggests poor oral health in the Early Mesolithic population of Scandinavia.

    I use the genomic information obtained from various sources to examine hunter-gatherer populations in two opposite parts of northern Eurasia, the northeast Asia and the Scandinavian Peninsula. While the Mesolithic period in Europe has been subjected to intensive study, the paleogenetic history of northern Asia has remained only partially explored. I provide an overview of population dynamics in areas of northeast Asia and around Lake Baikal (Sakha republic, Cis-Baikal and Transbaikal) starting from the end of the Last Glacial Maximum (LGM). Additionally, the most northeastern occurrence of an early form of plague bacteria gets recorded, which is correlated with the population decline in the area during the Late Neolithic / Early Bronze Age periods. While this part of the world was occupied by humans through the LGM, the Scandinavian Peninsula was uninhabitable until the Holocene glacial retreat. By analysing new genomes from bones, teeth and masticated lumps, I also present a detailed study of demographic formation and change within the Mesolithic population in Scandinavia. Some of the demographic events presented in this thesis can be linked to changes in climate throughout the Holocene. 

    I conclude that information obtained from both osseous and masticated material depicts a vivid picture of human life in distant areas of prehistoric northern Eurasia and provides new insights into paleodemography, mobility, settlement and health in the post-glacial world.

    List of papers
    1. Ancient DNA from mastics solidifies connection between material culture and genetics of mesolithic hunter-gatherers in Scandinavia
    Open this publication in new window or tab >>Ancient DNA from mastics solidifies connection between material culture and genetics of mesolithic hunter-gatherers in Scandinavia
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    2019 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 2, article id 185Article in journal (Refereed) Published
    Abstract [en]

    Human demography research in grounded on the information derived from ancient DNA and archaeology. For example, the study on the early postglacial dual-route colonisation of the Scandinavian Peninsula is largely based on associating genomic data with the early dispersal of lithic technology from the East European Plain. However, a clear connection between material culture and genetics has been lacking. Here, we demonstrate that direct connection by analysing human DNA from chewed birch bark pitch mastics. These samples were discovered at Huseby Klev in western Sweden, a Mesolithic site with eastern lithic technology. We generated genome-wide data for three individuals, and show their affinity to the Scandinavian hunter-gatherers. Our samples date to 9880-9540 calBP, expanding the temporal range and distribution of the early Scandinavian genetic group. We propose that DNA from ancient mastics can be used to study environment and ecology of prehistoric populations.

    National Category
    Archaeology
    Identifiers
    urn:nbn:se:uu:diva-387279 (URN)10.1038/s42003-019-0399-1 (DOI)000468006400001 ()31123709 (PubMedID)
    Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2024-03-03Bibliographically approved
    2. Human population dynamics and Yersinia pestis in ancient northeast Asia
    Open this publication in new window or tab >>Human population dynamics and Yersinia pestis in ancient northeast Asia
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    2021 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 2, article id eabc4587Article in journal (Refereed) Published
    Abstract [en]

    We present genome-wide data from 40 individuals dating to c.16,900 to 550 years ago in northeast Asia. We describe hitherto unknown gene flow and admixture events in the region, revealing a complex population history. While populations east of Lake Baikal remained relatively stable from the Mesolithic to the Bronze Age, those from Yakutia and west of Lake Baikal witnessed major population transformations, from the Late Upper Paleolithic to the Neolithic, and during the Bronze Age, respectively. We further locate the Asian ancestors of Paleo-Inuits, using direct genetic evidence. Last, we report the most northeastern ancient occurrence of the plague-related bacterium, Yersinia pestis. Our findings indicate the highly connected and dynamic nature of northeast Asia populations throughout the Holocene.

    Place, publisher, year, edition, pages
    American Association for the Advancement of Science (AAAS)AMER ASSOC ADVANCEMENT SCIENCE, 2021
    National Category
    Archaeology
    Identifiers
    urn:nbn:se:uu:diva-435740 (URN)10.1126/sciadv.abc4587 (DOI)000606331400011 ()33523963 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, uppstore2018029Knut and Alice Wallenberg Foundation, SNIC-2018-8-43
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2021-03-01 Created: 2021-03-01 Last updated: 2024-03-03Bibliographically approved
    3. Metagenomic analysis of Mesolithic chewed pitch reveals poor oral health among stone age individuals
    Open this publication in new window or tab >>Metagenomic analysis of Mesolithic chewed pitch reveals poor oral health among stone age individuals
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    2024 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 22125Article in journal (Refereed) Published
    Abstract [en]

    Prehistoric chewed pitch has proven to be a useful source of ancient DNA, both from humans and their microbiomes. Here we present the metagenomic analysis of three pieces of chewed pitch from Huseby Klev, Sweden, that were dated to 9,890-9,540 before present. The metagenomic profile exposes a Mesolithic oral microbiome that includes opportunistic oral pathogens. We compared the data with healthy and dysbiotic microbiome datasets and we identified increased abundance of periodontitis-associated microbes. In addition, trained machine learning models predicted dysbiosis with 70-80% probability. Moreover, we identified DNA sequences from eukaryotic species such as red fox, hazelnut, red deer and apple. Our results indicate a case of poor oral health during the Scandinavian Mesolithic, and show that pitch pieces have the potential to provide information on material use, diet and oral health.

    Place, publisher, year, edition, pages
    Springer Nature, 2024
    National Category
    Bioinformatics and Systems Biology Bioinformatics (Computational Biology) Genetics
    Identifiers
    urn:nbn:se:uu:diva-522281 (URN)10.1038/s41598-023-48762-6 (DOI)001144707500001 ()38238372 (PubMedID)
    Funder
    Riksbankens JubileumsfondSwedish Research Council, 2019-00849The Research Council of Norway, 231305UPPMAX, snic-2018/150-9
    Available from: 2024-02-02 Created: 2024-02-02 Last updated: 2024-03-03Bibliographically approved
    4. Transformation of the Scandinavian hunter-fisher-gatherer population throughout the Mesolithic
    Open this publication in new window or tab >>Transformation of the Scandinavian hunter-fisher-gatherer population throughout the Mesolithic
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    aDNA, The Mesolithic, Population genomics, masticates / pitch / resin, Scandinavian hunter-gatherers
    National Category
    Archaeology Evolutionary Biology
    Research subject
    Archaeology; Biology with Specialisation in Human Evolution and Genetics
    Identifiers
    urn:nbn:se:uu:diva-524365 (URN)
    Available from: 2024-03-03 Created: 2024-03-03 Last updated: 2024-03-03
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    UUThesis_Kashuba,N-2024
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  • Public defence: 2024-04-26 13:15 Heinz-Otto Kreiss 101195, Uppsala
    Denoel, Fernand
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Solid State Physics.
    Frustrated magnetism in icosahedral structures: The influence of order-disorder in quasicrystals and approximant crystals2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This work will begin with an introduction to quasicrystals (QCs) and their structure, defining the unit cell-equivalent for icosahedral quasiperiodicity: a 3D tiling based on the golden ratio and aperiodic in all three dimensions. We briefly present the cut-and-project method used to generate QCs from a higher dimension hypercrystal, and how to build the 3D Penrose tilings, composed of the two golden rhombohedra. We introduce the atomic elementary units used to understand Tsai-type icosahedral QCs and their related approximant crystals (ACs). Approximants are conventional periodic crystals with local atomic environments very similar to their QC counterparts. Two methods for synthesis of Tsai-type QCs and approximants are introduced, the self-flux method as well as a rapid quench method. We describe briefly the differences between the two methods and aspect about phase stability for QCs and ACs obtained in binary and ternary systems. Various types of structural modulations can be induced in ACs which are absent from QCs. We present a new criterion discovered during the doctoral studies, which links the structure of existing ACs to the existence of stable QC counterparts. Basic concepts of magnetism relevant to Tsai systems are then introduced, with a description of the 4f shell magnetism in lanthanide elements, how it differs from transition metal magnetism, with localized (and relatively large) magnetic moments. In intermetallic systems such as Tsai-type QCs and ACs, the main type of magnetic interaction is of RKKY type. We link their structure to the magnetic behavior and phase transition that can occur in frustrated systems: spin glass, reentrant spin glass, spin ice, etc. and how they can be related to various Tsai systems.

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  • Public defence: 2024-04-27 10:15 Ihresalen, Engelska Parken, Hus 21, Uppsala
    Hurkens, Amélie