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  • Beckman, Lena
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Art History.
    THE GROTESQUE IN EL GRECO: BETWEEN FORM - BEYOND LANGUAGE - BESIDE THE SUBLIME2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    This study attempts to investigate the grotesque in four paintings of the artist Domenikos Theotokopoulos or El Greco as he is most commonly called. The concept of the grotesque originated from the finding of Domus Aurea in the 1480s. These grottoes had once been part of Nero’s palace, and the images and paintings that were found on its walls were to result in a break with the formal and naturalistic ideals of the Quattrocento and the mid-renaissance. By the end of the Cinquecento, artists were working in the mannerist style that had developed from these new ideas of innovativeness, where excess and artificiality were praised, and artists like El Greco worked from the standpoint of creating art that were  more perfect than perfect. The grotesque became an end to reach this goal. While Mannerism is a style, the grotesque is rather an effect of the ‘fantastic’.By searching for common denominators from earlier and contemporary studies of the grotesque, and by investigating the grotesque origin and its development through history, I have summarized the grotesque concept into three categories: between form, beyond language and beside the sublime. By applying these categories to four works of El Greco I set out to get a more nuanced and deepened understanding of the art of El Greco and the grotesque.

  • Munther, Liselott
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Cultural Anthropology and Ethnology.
    Återbruk 1750-1850: Återanvändning av soldatuniformers ylletyg i Västbo härad2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    This bachelor’s thesis in ethnology serves the purpose of showing how the shape of objects are influenced by human and non-human partakers. This essay will consist of how to unite the knowledge created during the registration at museums with the existing knowledge we have about the societies where these items were produced and used. 

     

    In farming communities textiles were used over long periods of time and were given new areas of use, in some cases far from their original purpose. When these new objects landed in a museum collection in the early 1900’s it could have been hard to understand and interpret the meaning of them and decipher what their purpose was to begin with as opposed to what it ended up as. The information created during registration is terse due to the fact that it mainly mentions from whom it was acquired and around what time it was crafted. Despite the lack of information about the objects one can understand the different elements to them and how they work together, one can also identify the meaning they had in their specific time. 

    The theoretical starting points for this essay are based around Bruno Latour’s theory “Actor-network theory”, or “ANT”. ANT equalizes the subsequent actors and enables the researcher to study how the actors change and influence each other. To understand the cultures that people have created Börje Hansen’s theory about rural and urban societies is used. The economical presumptions for those that live in the examined areas between 1750-1850 are scares and to reuse materials is both necessary and accepted. The soldier/tailor has learned to be frugal by reusing fabrics from the croft soldier’s uniform.  Frugality is an actor that affects the shape and form of the cover with a knotted pile and wedding pad that were fabricated in the Västbo district. 

     

     

     

    Keywords: Ethnology, actor-network, reuse, cover with a knotted pile, wedding pad

  • Linda Maria, Öberg
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Cultural Anthropology and Ethnology.
    När en popstjärna dör: – en etnologisk studie om hur den offentliga sorgen tog sig uttryck efter beskedet om David Bowies bortgång2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Public grief reactions is a recurrent phenomena that can seem incomprehensible to the onlooker and sometimes even to the mourners themselves. This case study on the death of David Bowie discusses what takes place when fans mourn an idol with the object to gain more insight into what these reactions are, say and do along with how these public grief reactions are connected to form, space and time. The results show that in the initial stages there is an outpouring of personal grief reactions in public spaces amplified by the intense news coverage of the event. After a couple of days a shift occurs amongst the fans where the heaviest emotions are replaced by gratitude and collectedness.

  • Svan Edelsvärd, Merja
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology, Studies in Faith and Ideologies.
    Eskatologiska bilder i Kristian Gidlunds bogg: När döden tar plats i livet2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • Hubert, Madlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Umea Univ, Dept Integrat Med Biol, SE-90187 Umea, Sweden.
    Larsson, Elin
    Umea Univ, Dept Integrat Med Biol, SE-90187 Umea, Sweden.
    Lundmark, Richard
    Umea Univ, Dept Integrat Med Biol, SE-90187 Umea, Sweden.
    Keeping in touch with the membrane: protein- and lipid-mediated confinement of caveolae to the cell surface2020In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 48, p. 155-163Article, review/survey (Refereed)
    Abstract [en]

    Caveolae are small Omega-shaped invaginations of the plasma membrane that play important roles in mechanosensing, lipid homeostasis and signaling. Their typical morphology is characterized by a membrane funnel connecting a spherical bulb to the membrane. Membrane funnels (commonly known as necks and pores) are frequently observed as transient states during fusion and fission of membrane vesicles in cells. However, caveolae display atypical dynamics where the membrane funnel can be stabilized over an extended period of time, resulting in cell surface constrained caveolae. In addition, caveolae are also known to undergo flattening as well as short-range cycles of fission and fusion with the membrane, requiring that the membrane funnel closes or opens up, respectively. This mini-review considers the transition between these different states and highlights the role of the protein and lipid components that have been identified to control the balance between surface association and release of caveolae.

  • Public defence: 2020-04-24 10:15 Ekmansalen, Uppsala
    Vicente, Mário
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Demographic History and Adaptation in African Populations2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Africa is the continent where modern humans originated and yet, African demographic history remains largely unknown. Through analyzing the genetic composition of extant and extinct individuals, it is possible to reveal signals of past demographic history and adaptation. In this thesis, I applied population genetic methods to investigate both deep African history and demographic changes associated with the migrations of farmers in Africa. While Paper I and II assess the genomic landscape before the arrival farming groups, Paper III, IV and V focus on the demographic patterns associated with the emergence of various African agro-pastoral societies and how shifts in ways of subsistence resulted in different selective pressures on the genomic level. The genomes from Southern African San hunter-gatherers harbor the earliest diverging lineages and represent the first population divergence event within the modern human phylogeny. However, gene-flow from farming groups has complicated the investigation of genetic relationships between different San groups. In Paper I, I established that Southern African hunter-gatherer genetic diversity fitted an isolation-by-distance model when genomic segments that trace their ancestry to farming groups were excluded. Paper II confirmed that all extant Southern African hunter-gatherers received admixture from farming groups, through comparison with ancient DNA data from three 2,000-year-old southern African Stone Age individuals. New date estimates for the first population divergence event in the modern human phylogeny, based on the Stone Age individuals, coincided with a period in the fossil record associated with transition between archaic humans into anatomically modern humans. Paper III assesses the genetic variation of four ancient Iron Age women from current-day South Africa. I was able to further refine their genetic profiles, which were closest related to southeast Bantu-speaking farmers from current-day South Africa. In Paper IV, I propose that the emergence of pastoralism in Southern Africa arrived through a male-driven migration of East African Afro-Asiatic related groups, who introduced their pastoral subsistence practices and livestock into Southern Africa. In Paper V, I investigated the history of the Fulani population and demonstrated how a shift in subsistence practice triggered different selective pressures in the Fulani. The pastoral Fulani from the Western Sahel show relatively high frequencies of the European-associated Lactase Persistence (LP) variant. Here, I propose that the LP mutation were introduced into Fulani genomes through contact with a North African group(s) who themselves carried European admixture. Additionally, by performing the first genome wide association study (GWAS) on the lactose digestion phenotype, I confirmed the association with the MCM6/LCT locus and identified a possible association between glycemic levels after lactose intake and the SPRY2 gene. Furthermore, in addition to the LP trait, I also identified other potential signals of local adaption related to the pastoralism lifeway of the Fulani. This thesis provided further insights on how the African genomic landscape was shaped through time, influenced by the environment, interactions between different groups and adaptations to different lifeways.

    List of papers
    1. Population history and genetic adaptation of the Fulani nomads: inferences from genome-wide data and the lactase persistence trait
    Open this publication in new window or tab >>Population history and genetic adaptation of the Fulani nomads: inferences from genome-wide data and the lactase persistence trait
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    2019 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 20, no 1, article id 915Article in journal (Refereed) Published
    Abstract [en]

    Background

    Human population history in the Holocene was profoundly impacted by changes in lifestyle following the invention and adoption of food-production practices. These changes triggered significant increases in population sizes and expansions over large distances. Here we investigate the population history of the Fulani, a pastoral population extending throughout the African Sahel/Savannah belt.

    Results

    Based on genome-wide analyses we propose that ancestors of the Fulani population experienced admixture between a West African group and a group carrying both European and North African ancestries. This admixture was likely coupled with newly adopted herding practices, as it resulted in signatures of genetic adaptation in contemporary Fulani genomes, including the control element of the LCT gene enabling carriers to digest lactose throughout their lives. The lactase persistence (LP) trait in the Fulani is conferred by the presence of the allele T-13910, which is also present at high frequencies in Europe. We establish that the T-13910 LP allele in Fulani individuals analysed in this study lies on a European haplotype background thus excluding parallel convergent evolution. We furthermore directly link the T-13910 haplotype with the Lactase Persistence phenotype through a Genome Wide Association study (GWAS) and identify another genomic region in the vicinity of the SPRY2 gene associated with glycaemic measurements after lactose intake.

    Conclusions

    Our findings suggest that Eurasian admixture and the European LP allele was introduced into the Fulani through contact with a North African population/s. We furthermore confirm the link between the lactose digestion phenotype in the Fulani to the MCM6/LCT locus by reporting the first GWAS of the lactase persistence trait. We also explored other signals of recent adaptation in the Fulani and identified additional candidates for selection to adapt to herding life-styles.

    Keywords
    Fulani people, Pastoralism, Lactase persistence, Adaptive gene-flow, GWAS
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-400745 (URN)10.1186/s12864-019-6296-7 (DOI)000501323300001 ()31791255 (PubMedID)
    Funder
    Swedish Research Council, 621-2014-5211EU, European Research Council, 759933
    Note

    Mário Vicente, Edita Priehodová, ViktorČerný and Carina M. Schlebusch contributed equally to this work.

    Available from: 2020-01-03 Created: 2020-01-03 Last updated: 2020-03-05Bibliographically approved
    2. Genetic Affinities among Southern Africa Hunter-Gatherers and the Impact of Admixing Farmer and Herder Populations
    Open this publication in new window or tab >>Genetic Affinities among Southern Africa Hunter-Gatherers and the Impact of Admixing Farmer and Herder Populations
    2019 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 36, no 9, p. 1849-1861Article in journal (Refereed) Published
    Abstract [en]

    Southern African indigenous groups, traditionally hunter-gatherers (San) and herders (Khoekhoe), are commonly referred to as "Khoe-San" populations and have a long history in southern Africa. Their ancestors were largely isolated up until similar to 2,000 years ago before the arrival of pastoralists and farmers in southern Africa. Assessing relationships among regional Khoe-San groups has been challenging due to admixture with immigrant populations that obscure past population affinities and gene flow among these autochthonous communities. We re-evaluate a combined genome-wide data set of previously published southern Africa Khoe-San populations in conjunction with novel data from Khoe-San individuals collected in Xade (Central Kalahari Game Reserve, Botswana) prior to their resettlement outside the reserve. After excluding regions in the genome that trace their ancestry to recent migrant groups, the genetic diversity of 20 Khoe-San groups fitted an isolation-by-distance model. Even though isolation-by-distance explained most genetic affinities between the different autochthonous groups, additional signals of contact between Khoe-San groups could be detected. For instance, we found stronger genetic affinities, than what would be explained by isolation-by-distance gene flow, between the two geographically separated Khoe-San groups, who speak branches of the Kx'a-language family (double dagger Hoan and Ju). We also scanned the genome-wide data for signals of adaptive gene flow from farmers/herders into Khoe-San groups and identified a number of genomic regions potentially introduced by the arrival of the new groups. This study provides a comprehensive picture of affinities among Khoe-San groups, prior to the arrival of recent migrants, and found that these affinities are primarily determined by the geographic landscape.

    Keywords
    Khoe-San, southern Africa, population structure, isolation-by-distance, adaptive gene-flow
    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-397127 (URN)10.1093/molbev/msz089 (DOI)000493043800001 ()31288264 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council, 621-2014-5211Swedish Research Council, 6422013-8019EU, European Research Council, 759933Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
    Available from: 2019-11-29 Created: 2019-11-29 Last updated: 2020-03-05Bibliographically approved
    3. Male-biased migration from East Africa introduced pastoralism into southern Africa
    Open this publication in new window or tab >>Male-biased migration from East Africa introduced pastoralism into southern Africa
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Hunter-gatherer lifestyles dominated the southern African landscape up to ~2,000 years ago, when herding and farming groups started to arrive into the area. First, herding and livestock of (possible) East African origin appeared in southern Africa, preceding the arrival of the large-scale Bantu-speaking agropastoral expansion. Modern-day Khoekhoe speaking Namaqua (or Nama in short) pastoralists show high proportions of East African admixture, linking the East African ancestry with Khoekhoe herders. Most of the other historical Khoekhoe populations have, however, disappeared over the last few centuries. In our study we analyzed genome-wide autosomal and full mitochondrial data from a population who trace their ancestry to the Khoekhoe-speaking herder groups from the southern Cape region of current-day South Africa. With the help of comparative data, we were able to align genetic date estimates and admixture proportions to archaeological proposed dates and routes for the arrival of the East African pastoralists in southern Africa. We also identified several Afro-Asiatic speaking pastoralist groups from Ethiopia and Tanzania who share high affinities with the East African ancestry present in southern Africa. Furthermore, we detect that the East African pastoralist expansion was heavily male-biased. We propose that pastoralism in southern Africa arrived through a male-biased migration of an East African Afro-Asiatic related group(s) who introduced the new subsistence practice to local southern African hunter-gatherers.

    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-406232 (URN)
    Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-03-05
    4. Four Iron Age women from KwaZulu-Natal: biological anthropology, genetics and archaeological context
    Open this publication in new window or tab >>Four Iron Age women from KwaZulu-Natal: biological anthropology, genetics and archaeological context
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    2019 (English)In: Southern African Humanities, ISSN 1681-5564, Vol. 32, no 1, p. 23-56Article in journal (Refereed) Published
    Abstract [en]

    We report further details on four partial human skeletons from KwaZulu-Natal previously selected for genetic analysis. Dating and genetic results indicate that they derived from agriculturist communities of the mid-second millennium AD. Morphological and genetic analysis shows that three individuals were female; identification of the fourth as female comes from genetic analysis only. All four were adults at death, three older adults and one younger. Genetically, all four individuals cluster strongly with Bantu-speaking populations with West African roots, a result supported by craniometric data for the one individual with a complete and well-preserved cranium. All nevertheless display some admixture with Khoe-San populations. We show that three of the women, and probably the fourth, carried genetic resistance to the Plasmodium vivax malaria parasite, while two had some protection against Trypanosoma brucei gambiense-induced sleeping sickness. The unusual rock-shelter burial locations of three of the women suggest that their deaths required ritual ‘cooling’. Lightning and violence are possible causes. We argue that this multipronged approach is necessary for the development of detailed and nuanced understandings of the past and of the individuals who lived in the region centuries ago.

    Place, publisher, year, edition, pages
    South Africa: Council of the Natal Museum, 2019
    Keywords
    Ancient DNA, Bantu-speaker expansion, Palaeopathology, Physical anthropology, Iron Age
    National Category
    Genetics Archaeology
    Identifiers
    urn:nbn:se:uu:diva-406231 (URN)
    Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-03-05
    5. Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago
    Open this publication in new window or tab >>Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago
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    2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 358, no 6363, p. 652-655Article in journal (Refereed) Published
    Abstract [en]

    Southern Africa is consistently placed as a potential region for the evolution of Homo sapiens We present genome sequences, up to 13x coverage, from seven ancient individuals from KwaZulu-Natal, South Africa. The remains of three Stone Age hunter-gatherers (about 2000 years old) were genetically similar to current-day southern San groups, and those of four Iron Age farmers (300 to 500 years old) were genetically similar to present-day Bantu-language speakers. We estimate that all modern-day Khoe-San groups have been influenced by 9 to 30% genetic admixture from East Africans/Eurasians. Using traditional and new approaches, we estimate the first modern human population divergence time to between 350,000 and 260,000 years ago. This estimate increases the deepest divergence among modern humans, coinciding with anatomical developments of archaic humans into modern humans, as represented in the local fossil record.

    National Category
    Archaeology Evolutionary Biology Genetics
    Identifiers
    urn:nbn:se:uu:diva-334636 (URN)10.1126/science.aao6266 (DOI)000414240500038 ()28971970 (PubMedID)
    Funder
    Swedish Research Council, 642-2013-8019; 621-2014-5211Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyThe Wenner-Gren Foundation
    Note

    Carina M. Schlebusch and Helena Malmström contributed equally to this work

    Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2020-03-05Bibliographically approved
  • Pergolizzi, Joseph V., Jr.
    et al.
    NEMA Res Inc, Naples, FL 34108 USA.
    Christo, Paul J.
    Johns Hopkins Med, Dept Anesthesiol & Crit Care Med, Div Pain Med, Baltimore, MD USA.
    LeQuang, Jo Ann
    NEMA Res Inc, Naples, FL 34108 USA.
    Magnusson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Med, Cardiol Res Unit, Stockholm, Sweden.
    The Use of Peripheral mu-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety2020In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 14, p. 1009-1025Article, review/survey (Refereed)
    Abstract [en]

    Peripherally acting mu-opioid receptor antagonists (PAMORAs) constitute a class of drugs which reverse opioid-induced constipation (OIC) with similar opioid analgesic effects. OIC differs from other forms of constipation in that it is an iatrogenic condition that occurs when an opioid acts on the dense network of mu-opioid receptors in the enteric system, which affect a variety of functions including gastrointestinal motility, secretion, and other factors that can cause bowel dysfunction. Unfortunately, laxative products, bowel regimens, dietary changes, and lifestyle modifications have limited effectiveness in preventing OIC, Opioid-associated adverse effect which occurs in 40% to 80% of opioid patients and may led to cessation of the treatment. PAMORAs are mu-receptor opioid antagonists specifically developed so that they have very limited ability to cross the blood-brain barrier and thus they are able to antagonize peripheral but not central mu-opioid receptors. PAMORAs are designed to have no effect on the analgesic benefits of opioid pain relievers but to relieve but antagonizing the effects of the opioid in the gastrointestinal system. The three main PAMORAS are methyl-trexone (oral or parenteral), naldemedine (oral only), and naloxegol (oral only). Clinical studies demonstrate the safety and efficacy of these agents for alleviating constipation without diminishing the analgesic effect of opioid therapy. The aim of this narrative review to update the current status of PAMORAs for treating OIC in terms of safety and efficacy.

  • Public defence: 2020-04-24 13:15 Room B41, Uppsala
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Inhibitors Targeting Insulin-Regulated Aminopeptidase (IRAP): Identification, Synthesis and Evaluation2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insulin-regulated aminopeptidase (IRAP) has emerged as a potential new therapeutic target for treatment of cognitive disorders. Inhibition of the enzymatic activity facilitates cognition in rodents. Potent and selective peptide and pseudopeptide based inhibitors have been developed, but most of them suffer from poor pharmacokinetics and blood-brain-barrier penetration. Hence, development of less-complex inhibitors with good pharmacokinetic properties are of great importance.

    The aim of this thesis was to identify and optimize new small-molecule based IRAP inhibitors for use as research tools to investigate the cognitive effects of IRAP inhibition. Adaptation of an existing enzymatic assay into a screening compatible procedure allowed the evaluation of 10,500 compounds as IRAP inhibitors. The screening campaign resulted in 23 compounds displaying more than 60% inhibition. Two of these compounds, a spiro-oxindole dihydroquinazolinone and an imidazo[1,5-α]pyridine, were further investigated in terms of structure-activity relationship, physicochemical properties, metabolic stability, and mechanism of inhibition.

    Spiro-oxindole dihydroquinazolinone based IRAP inhibitors were synthesized via fast and simple microwave-promoted reactions, either in batch or in a continuous flow approach. The most potent compounds displayed sub-µM affinity, and interestingly an uncompetitive mode of inhibition with the synthetic substrate used in the assay. Molecular modeling confirmed the possibility of simultaneous binding of the compounds and the substrate. Furthermore, the molecular modeling suggested that the S-enantiomer accounts for the inhibitory effect observed with this compound series. The compounds also proved inactive on the closely related enzyme aminopeptidase N. Unfortunately, the spiro-oxindole based inhibitors suffered from poor solubility and metabolic stability.

    Imidazo[1,5-α]pyridine based IRAP inhibitors were synthesized via a five step procedure, providing inhibitors in the low-µM range. The stereospecificity of a methyl group proved important for inhibition. The compound series displayed no inhibitory activity on aminopeptidase N. Intriguing, these compounds exhibit a noncompetitive inhibition mechanism with the model substrate. As observed for the spiro-compounds, the imidazopyridines suffered from both poor solubility and metabolic stability.  

    In summary, the work presented in this thesis provide synthetic procedures, initial structure-activity relationship, and pharmacological evaluation of two distinct inhibitors classes. The compounds are among the first non-peptidic IRAP inhibitors presented, serving as interesting starting points in the development of research tools for use in models of cognition.

    List of papers
    1. Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening
    Open this publication in new window or tab >>Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening
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    2016 (English)In: Assay and drug development technologies, ISSN 1540-658X, E-ISSN 1557-8127, Vol. 14, no 3, p. 180-193Article in journal (Refereed) Published
    Abstract [en]

    Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-297122 (URN)10.1089/adt.2016.708 (DOI)000374641700005 ()27078680 (PubMedID)
    Funder
    The Karolinska Institutet's Research FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council
    Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2020-03-07Bibliographically approved
    2. Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors
    Open this publication in new window or tab >>Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors
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    2020 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 9, no 3, p. 325-337Article in journal (Refereed) Published
    Abstract [en]

    Insulin‐regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non‐peptide IRAP inhibitors derived from a spiro‐oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)‐promoted three‐component reaction, or by a two‐step one‐pot procedure. For decoration of the oxindole ring system, rapid MW‐assisted Suzuki‐Miyaura cross‐couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S‐configuration of the spiro‐oxindole dihydroquinazolinones accounts for the inhibition of IRAP.

    Place, publisher, year, edition, pages
    John Wiley & Sons, Ltd, 2020
    Keywords
    enzymes, inhibitors, insulin, preclinical profiling, regulated aminopeptidases, spiro compounds
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-406132 (URN)10.1002/open.201900344 (DOI)
    Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-03-07
    3. Inhibition of Insulin-Regulated Aminopeptidase by Imidazo[1,5-α]pyridines; Synthesis and Evaluation
    Open this publication in new window or tab >>Inhibition of Insulin-Regulated Aminopeptidase by Imidazo[1,5-α]pyridines; Synthesis and Evaluation
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Inhibition of Insulin-regulated Aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign identifying novel small-molecule based compounds acting as inhibitors of the enzymatic activity IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of imidazo[1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an pIC50 values of 6.0. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound´s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding.

    Keywords
    Insulin-regulated aminopeptidase, IRAP, inhibitors
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-406413 (URN)
    Available from: 2020-03-07 Created: 2020-03-07 Last updated: 2020-03-07
    4. Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors
    Open this publication in new window or tab >>Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors
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    2014 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 18, no 11, p. 1582-1588Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthetic route towards spiro-oxindole dihydroquinazolinones as novel and drug-like insulin-regulated aminopeptidase (IRAP) inhibitors is reported. The synthesis is performed using a MW heated continuous flow system employing 200 mm X 3 mm i MW absorbing silicon carbide (SiC) or MW transparent borosilicate tubular reactors. A three-component MW-flow reaction to build up the spiro compounds (9 examples, 4087% yield), using the SiC reactor, as well as a SuzukiMiyaura cross-coupling reaction (71%), employing the borosilicate reactor, are presented with residence times down to 168 s. The continuous MW-flow routes provide a smooth and scalable synthetic methodology towards this class of IRAP inhibitors.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-240315 (URN)10.1021/op500237k (DOI)000345552100043 ()
    Available from: 2015-01-07 Created: 2015-01-07 Last updated: 2020-03-07Bibliographically approved
  • Westerinen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Optimization of a Methodology for Cell Based Untargeted Metabolomics with UHPLC-Q-ToF-MS2020Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Metabolomics is the study of small molecules (molecular weight < 1500 Da) in a biological system and can provide relevant information about endpoints of biochemical pathways by establishing metabolic profiles for different sample cohorts and comparing these through multivariate data analysis. The aim of this thesis was to establish and test a suitable methodology for cell-based untargeted metabolomics, utilizing UHPLC-MS. Two different system setups were established, using one C18 column and one HILIC column. Parameter optimization was carried out with a reference solution, containing a diverse set, with regards to their physical and chemical properties, of seven substances. Cultured HCT 116 cells were chosen as model system. Three different sample preparation procedures were evaluated, based on number of detected unique markers and relative degree of reproducibility. Two of the procedures were based on liquid extraction, Dual Layer Fractionation (DLF) and Consecutive Extraction (CE), and the third was a dilution (DI) of the cell samples. The HILIC system did not achieve an adequate number of detected unique markers for any of the sample preparation procedures and further optimization is required. For the C18 system, CE proved to have the highest degree of reproducibility, while retrieving the next greatest set of detected unique markers.

  • Public defence: 2020-04-28 13:00 Aula Gunnesalen, Uppsala
    Granström, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Patient-reported and medical outcomes in patients treated for diabetic macular edema: A real-world longitudinal study2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Diabetes mellitus can lead to complications, when the complication affects the eyes it is called retinopathy. This can affect the macula and lead to severe loss of vision, diabetic macular edema (DME). This condition has traditionally been treated with laser. However, in 2011, anti-vascular endothelial growth factor (anti-VEGF) injections in the eye were approved as a treatment for diabetic macular edema, and started to be used in eye clinics.

    Aim The overall aim of this thesis was to describe patient-reported outcomes and medical outcomes (PRO) in people treated for diabetic macular edema in a real-world setting in a long-time follow-up study in Sweden.

    Methods Participants were enrolled at two eye clinics at two county hospitals in Sweden between 2012 and 2014. Patient-reported outcomes were measured using a vision-specific questionnaire, the 25-question National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and a generic questionnaire, the Short Form-36 Health Survey (SF-36). Completed questionnaires, medical data such as visual acuity (EDRS), macula swelling (OCT) and social background characteristics were collected before treatment start, at one-year and four-year follow up points. The data was analyzed, descriptive statistics developed and comparative analyses were performed. Interviews were performed before treatment start and were analyzed using qualitative content analysis.

    Results A total of 59 participants were included at baseline. The mean age was 69 years, with an equal gender distribution. At baseline, the participants scored a low general health with the vision-specific questionnaire. In total, 21 participants were interviewed, and a theme emerged of ‘being at a crossroads and a crucial phase in life with an uncertain outcome’. The participants expressed thoughts and concerns at different levels, including practical concerns about the treatment procedure and more existential thoughts about hope for improved visual acuity or fear of deterioration. The results at the one-year follow up showed that 30 patients had improved visual acuity and reported an improvement in several subscales in the NEI VFQ-25. The remaining 27 participants had no improvement in visual acuity or in the vision specific questionnaire. The four-year follow-up involved 37 people, and the result showed significant improvement in subjective near-vision activities and improved distance visual acuity.

    Conclusion: Before treatment, the participants reported low general health and expressed concerns about the injection treatment and their vision. One year after treatment started, the results showed significant improvement in several NEI VFQ-25 subscales, decreased macula swelling and improved visual acuity. These positive results remained at the four-year follow-up point.

    List of papers
    1. Visual functioning and health-related quality of life in diabetic patients about to undergo anti-vascular endothelial growth factor treatment for sight-threatening macular edema
    Open this publication in new window or tab >>Visual functioning and health-related quality of life in diabetic patients about to undergo anti-vascular endothelial growth factor treatment for sight-threatening macular edema
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    2015 (English)In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 29, no 8, p. 1183-1190Article in journal (Refereed) Published
    Abstract [en]

    Purpose: To examine patient-reported outcome (PRO) in a selected group of Swedish patients about to receive anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME). Material and methods: In this cross-sectional study, 59 patients with diabetes mellitus, who regularly visited the outpatient eye-clinics, were included. Sociodemographic and clinical data were collected and the patients completed PRO measures before starting anti-VEGF treatment. PRO measures assessed eye-specific outcomes (NEI-VFQ-25) and generic health-related quality of life (SF-36). Results: The participants consisted of 30 men and 29 women (mean age, 68.5 years); 54 (92%) patients had type 2 diabetes; 5 (9%) patients had moderate or severe visual impairment; 28 (47%) were classified as having mild visual impairment. Some of the patients reported overall problems in their daily lives, such as with social relationships, as well as problems with impaired sight as a result of reduced distance vision. Conclusions: Further studies are needed to investigate PRO factors related to low perceived general health in this patient population. It is important to increase our understanding of such underlying mechanisms to promote improvements in the quality of patient care.

    Keywords
    Patient-reported measurements, Health-related quality of life, Visual function, Diabetic macula edema, Anti-VEGF treatment
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-274708 (URN)10.1016/j.jdiacomp.2015.07.026 (DOI)000366884900036 ()26318959 (PubMedID)
    Funder
    Magnus Bergvall Foundation
    Available from: 2016-02-02 Created: 2016-01-25 Last updated: 2020-03-10Bibliographically approved
    2. Patients’ experiences before starting anti-VEGF treatment for sight-threatening diabetic macular oedema: A qualitative interview study
    Open this publication in new window or tab >>Patients’ experiences before starting anti-VEGF treatment for sight-threatening diabetic macular oedema: A qualitative interview study
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    2018 (English)In: Nordic journal of nursing research, ISSN 2057-1585, E-ISSN 2057-1593, Vol. 38, no 1, p. 11-17Article in journal (Refereed) Published
    Keywords
    anti-VEGF treatment, diabetic macular oedema, qualitative research, visual impairment
    National Category
    Endocrinology and Diabetes
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-406418 (URN)10.1177/2057158517709409 (DOI)
    Available from: 2020-03-08 Created: 2020-03-08 Last updated: 2020-03-19Bibliographically approved
    3. Patient-reported outcomes and visual acuity after 12 months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting
    Open this publication in new window or tab >>Patient-reported outcomes and visual acuity after 12 months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting
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    2016 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 121, p. 157-165Article in journal (Refereed) Published
    Abstract [en]

    Aims: To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), patient reported outcome and describe levels of glycated hemoglobin and its association with the effects on visual acuity in patients treated with anti-VEGF for visual impairment due to diabetic macular edema (DME) during 12 months in a real world setting.

    Methods: In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68 years) with type 1 and type 2 diabetes diagnosed with DME were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used.

    Results: The total patient group had significantly improved visual acuity and reduced retinal thickness at 4 months and remains at 12 months follow up. Thirty patients had significantly improved visual acuity, and 27 patients had no improved visual acuity at 12 months. The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health, general vision, near activities, distance activities, and composite score, but no significant changes in scores were found in the group without improvements in visual acuity.

    Conclusions: Our study revealed that anti-VEGF treatment improved visual acuity and central retinal thickness as well as patient-reported outcome in real world 12 months after treatment start.

    Keywords
    Patient-reported measurements, Diabetic macular edema, Anti-VEGF treatment, Visual function
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-313411 (URN)10.1016/j.diabres.2016.09.015 (DOI)000390460100020 ()27718374 (PubMedID)
    Funder
    Magnus Bergvall Foundation
    Available from: 2017-01-30 Created: 2017-01-19 Last updated: 2020-03-10Bibliographically approved
    4. Long-term follow-up of antivacular endothelial growth factor treatment for diabetic macular oedema: a four year real-world study
    Open this publication in new window or tab >>Long-term follow-up of antivacular endothelial growth factor treatment for diabetic macular oedema: a four year real-world study
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    2019 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768Article in journal (Refereed) Published
    National Category
    Endocrinology and Diabetes
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-406419 (URN)10.1111/aos.14290 (DOI)
    Available from: 2020-03-08 Created: 2020-03-08 Last updated: 2020-03-12Bibliographically approved
  • Ablikim, M.
    et al.
    Adlarson, Patrik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Biernat, Jacek
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Ikegami Andersson, Walter
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Johansson, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Kupsc, Andrzej
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Li, Cui
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Papenbrock, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Pettersson, Joachim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Schönning, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Thorén, Viktor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Wolke, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Zou, J. H.
    Partial wave analysis of psi(3686) -> K+ K- eta2020In: Physical Review D: covering particles, fields, gravitation, and cosmology, ISSN 2470-0010, E-ISSN 2470-0029, Vol. 101, no 3, article id 032008Article in journal (Refereed)
    Abstract [en]

    Using a sample of (448.1 +/- 2.9) x 10(6) psi(3686) events collected with the BESIII detector, we perform the first partial wave analysis of psi(3686) -> K+K- eta. In addition to the well established states, phi(1020), phi(1680), and K-3(*)(1780), contributions from X(1750), rho(2150), rho(3)(2250), and K-2* (1980) are also observed. The X(1750) state is determined to be a 1(--) resonance. The simultaneous observation of the phi(1680) and X(1750) indicates that the X(1750), with previous observations in photoproduction, is distinct from the phi(1680). The masses, widths, branching fractions of psi(3686) -> K+K- eta, and the intermediate resonances are also measured.

  • Carl, Klang
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Christian, von Bothmer
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    En redovisningsbaserad investeringsstrategi viktad mot bransch – C_Score2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Piotroski skapade år 2000 en redovisningsbaserad investeringsstrategi F_Score. Genom att investera i förväntade vinnare och blanka aktier som förväntas vara kortsiktiga förlorare resulterar strategin i en genomsnittlig årsavkastning på 23%. I den här studien syftar vi till att testa om en modifierad version av Piotroskis modell F_Score kan finna marknadsanomalier i utvalda branscher mellan åren 2015 och 2018. Baserat på Piotroskis modell utvecklar vi en ny modell C_Score som normaliserar samtliga investeringssignaler (ROA, CFO, ΔROA, ACCRUALS, LEVER, ΔLiquid, ΔMargin, ΔTurn, EQ_Offer) genom att vikta signalen mot branschmedianen för respektive signal. Baserat på om företagen uppfyller kriterierna eller inte delas de in i portföljer. Resultat visar att medianen för de olika signalerna skiljer sig mellan branscherna. Vidare finner vi även att C_Score genererar abnormal avkastning, dock ej statistiskt signifikant. Baserat på resultatet drar vi slutsatsen att investeringsstrategier som inte viktas mot bransch kan missa viktig data som är specifik för olika branscher.

  • Aaboud, M.
    et al.
    Asimakopoulou, Eleni M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bergeås Kuutmann, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bokan, Petar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Gradin, P. O. Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Isacson, Max
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Mårtensson, Mikael U. F.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Sales De Bruin, Pedro
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zwalinski, L.
    Measurement of Azimuthal Anisotropy of Muons from Charm and Bottom Hadrons in pp Collisions at root s=13 TeV with the ATLAS Detector2020In: Physical Review Letters, ISSN 0031-9007, E-ISSN 1079-7114, Vol. 124, no 8, article id 082301Article in journal (Refereed)
    Abstract [en]

    The elliptic flow of muons from the decay of charm and bottom hadrons is measured in pp collisions at root s = 13 TeV using a data sample with an integrated luminosity of 150 pb(-1) recorded by the ATLAS detector at the LHC. The muons from heavy-flavor decay are separated from light-hadron decay muons using momentum imbalance between the tracking and muon spectrometers. The heavy-flavor decay muons are further separated into those from charm decay and those from bottom decay using the distance-of-closest-approach to the collision vertex. The measurement is performed for muons in the transverse momentum range 4-7 GeV and pseudorapidity range vertical bar eta vertical bar < 2.4. A significant nonzero elliptic anisotropy coefficient nu(2) is observed for muons from charm decays, while the nu(2) value for muons from bottom decays is consistent with zero within uncertainties.

  • Public defence: 2020-04-24 13:15 Eva Netzelius 10:K102, Uppsala
    Lundesjö Kvart, Susanne
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Konsten att undervisa ryttare: En studie om ridlärares pedagogiska praktik2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis concerns how riding teachers’ reflect upon their teaching and how they teach. The overall aim of the thesis is to contribute with knowledge about how riding lessons are organized, regarding both the accomplishment of lessons as activity systems and the interactional organization of instructional work. Horseback riding can be understood as an embodied and practical knowledge, and includes communication and collaboration between horse and rider, sometimes referred to as equestrian feel (Dashper, 2016). Two different theoretical perspectives were applied to explore how such knowledge is taught. Activity theory (Engeström, 1987) was used to analyze interviews with and observations of ten riding teachers about their understanding and implementation of their pedagogical practice. Teachers’ and students’ interactions during riding lessons were examined using an ethnomethodological and conversation analytic approach (Goodwin, 2000; Schegloff, 1996). The analyses were based on video-recordings of ten group lessons and 40 one-on-one riding lessons.

    The results show that riding lessons can be conceptualized as activity systems where the focus of teaching constantly changes; from horse to student to routine. Traditions and safety regulations are shown to generate contradictions that may hinder the teachers from developing their teaching. However, the teachers express a wish to use more student collaborative methods, and display an intention to communicate with students about equestrian feel. Another result unveils how the teacher and the individual students, within the mobile context of riding lessons, make instructional sequences possible by co-creating instructional spaces. A third result illuminates the participants’ collaborative work to make equestrian feel available for instruction. The teacher molds equestrian feel through online instructions, i.e., instructions produced during the students’ active riding. These instructions shift focus between the students’ seat and influence, the horse’s actions and the student’s embodied feel. Moreover, the teachers are shown to use visual, verbal and embodied resources as they interpret equestrian feel for the student. In sum, the studies shed light on the complex art of teaching practical and embodied knowledge of riding.

    List of papers
    1. Ridlärares pedagogiska praktik: En verksamhetsteoretisk studie
    Open this publication in new window or tab >>Ridlärares pedagogiska praktik: En verksamhetsteoretisk studie
    2013 (Swedish)Licentiate thesis, monograph (Other academic)
    Alternative title[en]
    Riding Instructors´ Pedagogical Practice : An activity-theoretical study
    Abstract [en]

    The riding lesson situation is complex and dynamic. Riding instructors must look at both the horse’s and the rider’s actions in order to provide useful and relevant instruction. The aim of this study is to describe and understand riding instructors’ pedagogical practice when giving riding lessons. The theoretical basis for the study is Engeström’s model for studying activity. His analytical model consists of six interrelated ”knots”. The activity system is continuously active through contradictions between the knots, ”knotworking”. These contradictions can occur at four different levels. By studying them we can arrive at an understanding of the structure of an activity system, in this case riding lessons.

    Ten riding instructors were interviewed and a number of riding lessons were observed. In collecting data, it was important to capture the use of language in pedagogical terms. The themes that formed the basis of interviews and observations were the concepts of communication, feeling and communication of feeling, as well as the roles of the riding instructor, the pupil and the horse. When the activity model was applied to the data, a number of knots could be observed, with the riding instructor as the subject and the pupil as the object. For example, the tools were horses and instructions. Parents and the riding hall were identified as rules and other riding instructors were the community. Finally, young people assisting the instructors and the pupils with grooming were identified as division of labour.

    Many of the statements and actions observed during riding lessons can be summarised in that they reflect a focus on the horse. Some riding instructors state unequivocally that what is most important to them is what is best for the horse. I call this an ”activity system with horse focus”. Another variety of statements and actions from the instructors shows an orientation towards the pupils. The instructors say that they have ambitions to support pupils in their learning. This is what I call an ”activity system with pupil focus”. Finally, there are statements and actions by instructors that can be explained by such things as ignorance, indifference or incompetence. One riding instructor says that there is a considerable amount of routine in her lessons. I call this an ”activity system with routine focus”. In this activity system the objects and goals often change places, unlike what happens in the other two activity systems. For different reasons, occasionally the routine focus switches into the other two activity systems.

    Contradictions were seen at four different levels within the three activity systems identified, e.g.: (1) riding instructors wanting to communicate with their pupils about the feeling of riding but lacking the words for it; (2) parents expecting that their child will get the opportunity to ride at every lesson and riding instructors feeling a pressure to meet these expectations even though they believe that the pupils need theory as well as practice; (3) the instructor wanting to improve her teaching but being inhibited by old traditions; and (4) modern teaching methods having developed within the general school system that require pupils to assume a degree of responsibility for their own learning. This stands in contradiction to the controlled riding lesson where pupils do not have much scope for acting on their own.

    Riding instructors give priority to the pupils or the horses to different degrees. They often act more or less subconsciously when they give pupils instruction or give them feedback. The horses are at the centre of the riding school and the riding lesson. The horses are a large part of the riding instructors’ everyday life and influential on their thinking about riding instruction. From an educational perspective, however, it would be desirable for instructors to place pupils and their learning at the centre. The need for and importance of pedagogical and didactic education for riding instructors ought to be emphasised. It is a challenge to develop riding lessons with an emphasis on optimising the conditions for pupils’ learning without taking the focus away from the horse and its wellbeing.

    Place, publisher, year, edition, pages
    Uppsala: Hippologenheten, SLU, 2013. p. 164
    Series
    Pedagogisk forskning i Uppsala, ISSN 0348-3630 ; 164
    Keywords
    Riding instructor, riding lesson, activity theory, pedagogical practice, communication
    National Category
    Pedagogy
    Research subject
    Education
    Identifiers
    urn:nbn:se:uu:diva-206769 (URN)978-91-506-2362-8 (ISBN)
    Presentation
    2013-06-04, Blåsenhus, Eva Netzelius-salen, von Kraemers Allé 1, Uppsala, 15:00 (Swedish)
    Supervisors
    Available from: 2013-09-10 Created: 2013-09-04 Last updated: 2020-03-05Bibliographically approved
    2. Instructions in horseback riding - The collaborative achievement of an instructional space
    Open this publication in new window or tab >>Instructions in horseback riding - The collaborative achievement of an instructional space
    (English)In: Learning, Culture and Social Interaction, ISSN 2210-6561, E-ISSN 2210-657XArticle in journal (Refereed) In press
    Abstract [en]

    In this study, the interactional organization of multimodal instructions and instructed actions during mobile horseback riding lessons in groups will be analyzed. The theoretical and analytical point of departure is the ethnomethodological and conversation analytic research tradition and the expanding “multimodal interaction analysis” that derives from this area of research. The data in this study consist of video recordings of riding lessons with groups of four to eight students. The results show that there are moments, limited in time and space, when the instructor and the individual students collaboratively establish what are here called “instructional spaces.” These spaces are co-created through addressivity work made by both instructor and student. Within each instructional space an instructional sequence is accomplished. They often begin with an instruction towards a specific student that comes close. The student directly performs an instructed action followed up by further instructions – either immediately or when next opportunity for an instructional space can be co-created. Students also initiate instructional spaces by riding close to the instructor. This article highlights the importance of collaboration, addressivity, timing, and space during mobile group lessons in horseback riding.

    Keywords
    Instruction; multimodality; addressivity; timing; space; horseback riding
    National Category
    Social Sciences
    Research subject
    Education
    Identifiers
    urn:nbn:se:uu:diva-406137 (URN)10.1016/j.lcsi.2018.10.002 (DOI)
    Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-03-11Bibliographically approved
    3. Instructing equestrian feel: on the art of teaching embodied knowledge
    Open this publication in new window or tab >>Instructing equestrian feel: on the art of teaching embodied knowledge
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    This study explores the instruction of equestrian feel as an interactional accomplishment. Equestrian feel is an embodied knowledge encompassing riders’ ability to feel the horse’s actions and to act appropriately. Building on ethnomethodological and conversation analytic analyses of video-recordings of riding lessons, we explore how equestrian feel is instructed in interaction between riding teachers and students. The results show how teachers use verbal resources, e.g. metaphors and similes, to describe embodied feel, as well as perceptual resources that are made relevant by orienting to the horse’s body as a semiotic field. Moreover, the teachers produce online instructions in the shape of directives, metaphorical vocal descriptions, and embodied demonstrations, thus molding the equipage by bringing attention to different aspects that together shape an embodied experience. In all, the study sheds light on communicative practices during riding lessons and on the interactional work involved in the art of instructing embodied knowledge.

    Keywords
    embodied knowledge, equestrian feel, ethnomethodological conversation analysis, instruction, molding, multimodality
    National Category
    Social Sciences
    Research subject
    Education
    Identifiers
    urn:nbn:se:uu:diva-406226 (URN)
    Available from: 2020-03-05 Created: 2020-03-05 Last updated: 2020-03-05
  • Halvarson, Tor
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Noring, Otto
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Pensionsåldern påverkan på BNP: En analys av effekten på Real BP då Danmark sänkte pensionsåldern 20042020Independent thesis Basic level (degree of Bachelor), 180 HE creditsStudent thesis
    Abstract [sv]

    En åldrande befolkning och behovet av höjd pensionsålder är ett omdebatterat ämne i industrialiserade länder. Den genomsnittliga förväntade livslängden har ökat samtidigt som pensionsåldern inte höjts i samma takt. Mot bakgrund av detta syftar studien till att deskriptivt visa hur Sverige, Danmark och Finlands pensionssystem är uppbyggda och hur befolkningsunderlaget förändrats under tidsperioden 2000-2008. Huvudsyftet är att undersöka hur Real BNP förändrades då Danmark genomförde en pensionsreform 2004 och då pensionsåldern sänktes från 67 till 65 år. I denna studie görs en difference-in-difference beräkning för att undersöka hur dansk Real BNP utvecklades jämfört med svensk Real BNP efter sänkt pensionsålder 2004. Vid inkludering av år och invandringsandel som kontrollvariabler ger vår difference-in-difference ett statistiskt signifikant estimat för pensionsreformen i Danmark på -4,1 % jämfört med Sverige. Det betyder att Danmarks Real BNP-utveckling var 4,1% lägre än svensk Real BNP-utveckling efter 2004. Detta är i linje med livscykelmodellens teori om förväntad konsumtion. Ett problem med vår undersökning är att Sverige också genomförde en pensionsreform under den studerade tidsperioden. Det går därmed inte att avgöra om det endast är den danska pensionsreformen som estimerar resultatet i difference-in-difference. Eftersom förutsättningar för difference-in-difference inte är uppfyllda kan vi inte tolka resultatet kausalt men sambanden kan diskuteras deskriptivt.

  • Sadri, Djuljsina
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Sociology.
    Elever som vill, men inte kan gå till skolan: En kvalitativ studie om skolkuratorers upplevelser och erfarenheter med hemmasittande elever som lider av psykisk ohälsa2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    In the Swedish school system there are many pupils who are not always able to attend school. The term for these students is “home sitters” and they have different reasons for not attending. Many “home sitters” actually have a desire to go to school but are hindered by, among other things, mental illness. The present study aims to investigate the experiences school counselors have with these home-based students, by interviewing school professionals about their experiences with these students. The study is thus based on a qualitative method with emphasis on interviews with a phenomenographic approach. The study's results clearly illustrate that there are different ways in which school counselors work with “home sitters”. The experiences also differ, but all respondents’ who have been interviewed have a background working with home-sitting students who have some form of mental illness. Lastly, the study concludes that the school counselors describe themselves as a collaborative link between parents and other professionals. School counselors believe that the hierarchical structure within society, where the authorities at the highest level make decisions, is an important foundation that creates security. The respondents point out that this important foundation however is flawed and in need of oversight. Also, they stress that schools suffer internally from a lack of knowledge about the factors that contribute to children staying at home.

  • Rosli, Nur Adiera Hanna
    et al.
    Univ Kebangsaan Malaysia, Fuel Cell Inst, Ukm Bangi 43600, Selangor, Malaysia.
    Loh, Kee Shyuan
    Univ Kebangsaan Malaysia, Fuel Cell Inst, Ukm Bangi 43600, Selangor, Malaysia.
    Wong, Wai Yin
    Univ Kebangsaan Malaysia, Fuel Cell Inst, Ukm Bangi 43600, Selangor, Malaysia.
    Yunus, Rozan Mohamad
    Univ Kebangsaan Malaysia, Fuel Cell Inst, Ukm Bangi 43600, Selangor, Malaysia.
    Lee, Tian Khoon
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Ahmad, Azizan
    Univ Kebangsaan Malaysia, Fac Sci & Technol, Ukm Bangi 43600, Selangor, Malaysia.
    Chong, Seng Tong
    Univ Tenaga Nas, Coll Energy Econ & Social Sci, Jalan IKRAM UNITEN, Kajang 43000, Selangor, Malaysia.
    Review of Chitosan-Based Polymers as Proton Exchange Membranes and Roles of Chitosan-Supported Ionic Liquids2020In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 21, no 2, article id 632Article, review/survey (Refereed)
    Abstract [en]

    Perfluorosulphonic acid-based membranes such as Nafion are widely used in fuel cell applications. However, these membranes have several drawbacks, including high expense, non-eco-friendliness, and low proton conductivity under anhydrous conditions. Biopolymer-based membranes, such as chitosan (CS), cellulose, and carrageenan, are popular. They have been introduced and are being studied as alternative materials for enhancing fuel cell performance, because they are environmentally friendly and economical. Modifications that will enhance the proton conductivity of biopolymer-based membranes have been performed. Ionic liquids, which are good electrolytes, are studied for their potential to improve the ionic conductivity and thermal stability of fuel cell applications. This review summarizes the development and evolution of CS biopolymer-based membranes and ionic liquids in fuel cell applications over the past decade. It also focuses on the improved performances of fuel cell applications using biopolymer-based membranes and ionic liquids as promising clean energy.

  • Aaboud, M.
    et al.
    Asimakopoulou, Eleni M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bergeås Kuutmann, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bokan, Petar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellajosyula, Venugopal
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Gradin, P. O. Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Isacson, Max
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Mårtensson, Mikael U. F.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Sales De Bruin, Pedro
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zwalinski, L.
    Fluctuations of anisotropic flow in Pb plus Pb collisions at root s(NN)=5.02 TeV with the ATLAS detector2020In: Journal of High Energy Physics (JHEP), ISSN 1126-6708, E-ISSN 1029-8479, no 1, article id 51Article in journal (Refereed)
    Abstract [en]

    Multi-particle azimuthal cumulants are measured as a function of centrality and transverse momentum using 470 mu b(-1) of Pb+Pb collisions at root s(NN) = 5.02TeV with the ATLAS detector at the LHC. These cumulants provide information on the event-by-event fluctuations of harmonic flow coefficients v(n) and correlated fluctuations between two harmonics v(n) and v(m). For the first time, a non-zero four-particle cumulant is observed for dipolar flow, v(1). The four-particle cumulants for elliptic flow, v(2), and triangular flow, v(3), exhibit a strong centrality dependence and change sign in ultra-central collisions. This sign change is consistent with significant non-Gaussian fluctuations in v(2) and v(3). The four-particle cumulant for quadrangular flow, v(4), is found to change sign in mid-central collisions. Correlations between two harmonics are studied with three- and four-particle mixed-harmonic cumulants, which indicate an anti-correlation between v(2) and v(3), and a positive correlation between v(2) and v(4). These correlations decrease in strength towards central collisions and either approach zero or change sign in ultra-central collisions. To investigate the possible flow fluctuations arising from intrinsic centrality or volume fluctuations, the results are compared between two different event classes used for centrality definitions. In peripheral and mid-central collisions where the cumulant signals are large, only small differences are observed. In ultra-central collisions, the differences are much larger and transverse momentum dependent. These results provide new information to disentangle flow fluctuations from the initial and final states, as well as new insights on the influence of centrality fluctuations.

  • Aaboud, M.
    et al.
    Asimakopoulou, Eleni M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bergeås Kuutmann, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bokan, Petar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Gradin, P. O. Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Isacson, Max
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Mårtensson, Mikael U. F.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Sales De Bruin, Pedro
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zwalinski, L.
    Search for electroweak production of charginos and sleptons decaying into final states with two leptons and missing transverse momentum in root s=13 TeV pp collisions using the ATLAS detector2020In: European Physical Journal C, ISSN 1434-6044, E-ISSN 1434-6052, Vol. 80, no 2, article id 123Article in journal (Refereed)
    Abstract [en]

    A search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented. The analysis is based on 139 fb(-1) of proton-proton collisions recorded by the ATLAS detector at the Large Hadron Collider at v s = 13 TeV. Three R-parity-conserving scenarios where the lightest neutralino is the lightest supersymmetric particle are considered: the production of chargino pairs with decays via eitherW bosons or sleptons, and the direct production of slepton pairs. The analysis is optimised for the first of these scenarios, but the results are also interpreted in the others. No significant deviations from the Standard Model expectations are observed and limits at 95% confidence level are set on the masses of relevant supersymmetric particles in each of the scenarios. For a massless lightest neutralino, masses up to 420 GeV are excluded for the production of the lightest-chargino pairs assuming W-boson-mediated decays and up to 1 TeV for slepton-mediated decays, whereas for slepton-pair production masses up to 700 GeV are excluded assuming three generations of mass-degenerate sleptons.

  • Vybornov, Aleksandr A.
    et al.
    Samara State Univ Social Sci & Educ, Dept Russian Hist & Archaeol, M Gorkogo St 65-67, Samara 443099, Russia.
    Vasilyeva, Irina N.
    Samara State Univ Social Sci & Educ, Lab Archaeol, M Gorkogo St 65-67, Samara 443099, Russia.
    Kulkova, Marianna A.
    Herzen State Pedag Univ Russia, Sci Geol & Mineral, R Moyki Emb 48-1, St Petersburg 191186, Russia;Herzen State Pedag Univ Russia, Dept Geol & Geoecol, R Moyki Emb 48-1, St Petersburg 191186, Russia.
    Oinonen, Markku
    Univ Helsinki, Radiocarbon Lab, Gustaf Hallstremin St 2, FL-00014 Helsinki, Finland.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Nesterova, Larisa A.
    Herzen State Pedag Univ Russia, Sci Geog, R Moyki Emb 48-1, St Petersburg 191186, Russia;Herzen State Pedag Univ Russia, Dept Phys Geog & Nat Management, R Moyki Emb 48-1, St Petersburg 191186, Russia.
    About ancient ceramic traditions of the population of the northern Caspian region2020In: VOLGOGRADSKII GOSUDARSTVENNYI UNIVERSITET-VESTNIK-SERIYA 4-ISTORIYA REGIONOVEDENIE MEZHDUNARODNYE OTNOSHENIYA, ISSN 1998-9938, Vol. 25, no 1, p. 141-151Article in journal (Refereed)
    Abstract [en]

    Introduction: The territory of the Northern Caspian region plays an important role in the study of the Neolithic of Eastern Europe. The main criterion of this period is clay pottery. One of the difficult issues is the time of the ceramic technology appearance.

    Methods and materials: The study of the pottery technology of the Neolithic population of the Northern Caspian region is carried out in the framework of the historical and cultural approach to the study of ceramics, according to the method of A. Bobrinsky. The technique is based on binocular microscopy, tracology and experiment in the form of physical modeling. The basis for identifying technological traces on ceramics is the comparative analysis of the vessels under study with the base of standards. It is made by means of physical modeling in field and laboratory conditions. The age of the Neolithic monuments was determined using traditional methods in radiocarbon laboratories in Russia and Ukraine, as well as using AMS at universities in Sweden and Finland.

    Analysis: Over the past 10 years, more than 68 radiocarbon dates on different materials such as charcoal, bones, organics from ceramics, charred crusts, humus have been obtained. They give the possibility to determine the time of appearance and spread of the earliest pottery in the Northern Caspian region. This is the middle 7th millennium BC. The chronological framework for the development of the Neolithic in the Northern Caspian region is ca. 6600-5500 BC. The paper establishes the main and specific features of ceramic traditions.

    Results: The technical and technological analysis allows to reveal the genesis, the features of dynamics and further development of pottery in this region. The complex of results obtained allows to attribute the Neolithic sites of the Caspian region to the earliest pottery areal in Eastern Europe.

  • Ciemala, M.
    et al.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Ziliani, S.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Crespi, F. C. L.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Leoni, S.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Fornal, B.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Maj, A.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Bednarczyk, P.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Benzoni, G.
    Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Bracco, A.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Boiano, C.
    Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Bottoni, S.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Brambilla, S.
    Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Bast, M.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Beckers, M.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Braunroth, T.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Camera, F.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Cieplicka-Orynczak, N.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Clement, E.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Coelli, S.
    Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Dorvaux, O.
    CNRS IN2P3, IPHC UMR 7178, F-67037 Strasbourg, France.
    Erturk, S.
    Nigde Omer Halisdemir Univ, Sci & Art Fac, Dept Phys, Nigde, Turkey.
    de France, G.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Fransen, C.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Goldkuhle, A.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Grebosz, J.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Harakeh, M. N.
    KVI Ctr ForAdv Radiat Technol, Groningen, Netherlands.
    Iskra, L. W.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Jacquot, B.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Karpov, A.
    JINR, FLNR, Dubna 141980, Russia.
    Kicinska-Habior, M.
    Univ Warsaw, Fac Phys, Warsaw, Poland.
    Kim, Y.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Kmiecik, M.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Lemasson, A.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Lenzi, S. M.
    Ist Nazl Fis Nucl, Sez Padova, I-35131 Padua, Italy;Univ Padua, Dipartimento Fis & Astron, I-35131 Padua, Italy.
    Lewitowicz, M.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Li, H.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Matea, I
    IPN Orsay Lab, Orsay, France.
    Mazurek, K.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Michelagnoli, C.
    ILL Grenoble, Grenoble, France.
    Matejska-Minda, M.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland;Univ Warsaw, Heavy Ion Lab, PL-02093 Warsaw, Poland.
    Million, B.
    Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Mueller-Gatermann, C.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Nanal, V
    Tata Inst Fundamental Res, Mumbai 400005, Maharashtra, India.
    Napiorkowski, P.
    Univ Warsaw, Heavy Ion Lab, PL-02093 Warsaw, Poland.
    Napoli, D. R.
    Ist Nazl Fis Nucl, Lab Nazl Legnaro, I-35020 Legnaro, Italy.
    Palit, R.
    Tata Inst Fundamental Res, Mumbai 400005, Maharashtra, India.
    Rejmund, M.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Schmitt, Ch
    CNRS IN2P3, IPHC UMR 7178, F-67037 Strasbourg, France.
    Stanoiu, M.
    IFIN HH, Bucharest, Romania.
    Stefan, I
    IPN Orsay Lab, Orsay, France.
    Vardaci, E.
    Univ Napoli, Naples, Italy;Ist Nazl Fis Nucl, Sez Napoli, Naples, Italy.
    Wasilewska, B.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Wieland, O.
    Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Zieblinski, M.
    Inst Nucl Phys, PAN, PL-31342 Krakow, Poland.
    Zielinska, M.
    Ctr CEA Saclay, CEA DRF, IRFU, F-91191 Gif Sur Yvette, France.
    Atac, A.
    Royal Inst Technol KTH, Dept Phys, SE-10691 Stockholm, Sweden.
    Barrientos, D.
    CERN, CH-1211 Geneva 23, Switzerland.
    Birkenbach, B.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Boston, A. J.
    Univ Liverpool, Oliver Lodge Lab, Liverpool L69 7ZE, Merseyside, England.
    Cederwall, B.
    Royal Inst Technol KTH, Dept Phys, SE-10691 Stockholm, Sweden.
    Charles, L.
    CNRS IN2P3, IPHC UMR 7178, F-67037 Strasbourg, France.
    Collado, J.
    Univ Valencia, Dept Ingn Elect, Valencia, Spain.
    Cullen, D. M.
    Univ Manchester, Schuster Lab, Nucl Phys Grp, Manchester M13 9PL, Lancs, England.
    Desesquelles, P.
    Univ Paris Sud, Univ Paris Saclay, CSNSM, CNRS,IN2P3, Batiment 104, F-91405 Orsay, France.
    Domingo-Pardo, C.
    Univ Valencia, Inst Fis Corpuscular, CSIC, E-46071 Valencia, Spain.
    Dudouet, J.
    Univ Lyon 1, UMR5822, CNRS, IPNL,IN2P3, F-69622 Villeurbanne, France.
    Eberth, J.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Gonzalez, V
    Univ Valencia, Dept Ingn Elect, Valencia, Spain.
    Goupil, J.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Harkness-Brennan, L. J.
    Univ Liverpool, Oliver Lodge Lab, Liverpool L69 7ZE, Merseyside, England.
    Hess, H.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Judson, D. S.
    Univ Liverpool, Oliver Lodge Lab, Liverpool L69 7ZE, Merseyside, England.
    Jungclaus, A.
    CSIC, Inst Estruct Mat, Madrid, Spain.
    Korten, W.
    Ctr CEA Saclay, CEA DRF, IRFU, F-91191 Gif Sur Yvette, France.
    Labiche, M.
    STFC Daresbury Lab, Warrington WA4 4AD, Cheshire, England.
    Alexis, L.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Menegazzo, R.
    Ist Nazl Fis Nucl, Sez Padova, I-35131 Padua, Italy.
    Mengoni, D.
    Ist Nazl Fis Nucl, Sez Padova, I-35131 Padua, Italy;Univ Padua, Dipartimento Fis & Astron, I-35131 Padua, Italy.
    Nyberg, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Perez-Vidal, R. M.
    Univ Valencia, Inst Fis Corpuscular, CSIC, E-46071 Valencia, Spain.
    Podolyak, Zs
    Univ Surrey, Dept Phys, Guildford GU2 7XH, Surrey, England.
    Pullia, A.
    Univ Milan, Dipartimento Fis, I-20133 Milan, Italy;Ist Nazl Fis Nucl, Sez Milano, Via Celoria 16, I-20133 Milan, Italy.
    Recchia, F.
    Ist Nazl Fis Nucl, Sez Padova, I-35131 Padua, Italy;Univ Padua, Dipartimento Fis & Astron, I-35131 Padua, Italy.
    Reiter, P.
    Univ Cologne, Inst Kernphys, D-50937 Cologne, Germany.
    Saillant, F.
    CEA IDRF CNRS IN2P3, GANIL, Blvd Henri Becquerel,Boite Postale 55027, F-14076 Caen, France.
    Salsac, M. D.
    Ctr CEA Saclay, CEA DRF, IRFU, F-91191 Gif Sur Yvette, France.
    Sanchis, E.
    Univ Valencia, Dept Ingn Elect, Valencia, Spain.
    Stezowski, O.
    Univ Lyon 1, UMR5822, CNRS, IPNL,IN2P3, F-69622 Villeurbanne, France.
    Theisen, C.
    Ctr CEA Saclay, CEA DRF, IRFU, F-91191 Gif Sur Yvette, France.
    Valiente-Dobon, J. J.
    Ist Nazl Fis Nucl, Lab Nazl Legnaro, I-35020 Legnaro, Italy.
    Holt, J. D.
    TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada;McGill Univ, Dept Phys, 3600 Rue Univ, Montreal, PQ H3A 2T8, Canada.
    Menendez, J.
    Univ Tokyo, Ctr Nucl Study, Tokyo 113003, Japan;Dept Fis Quant & Astrofis, Marti I Franques 1, Barcelona 08028, Spain.
    Schwenk, A.
    Tech Univ Darmstadt, Inst Kemphys, D-64289 Darmstadt, Germany;GSI Helmholtzzentrum Schwerionenforsch GmbH, ExtreMe Matter Inst EMMI, D-64291 Darmstadt, Germany;Max Planck Inst Kemphys, Saupfercheckweg 1, D-69117 Heidelberg, Germany.
    Simonis, J.
    Johannes Gutenberg Univ Mainz, Inst Kernphys & PRISMA Cluster Excellence, D-55128 Mainz, Germany.
    Testing ab initio nuclear structure in neutron-rich nuclei: Lifetime measurements of second 2(+) state in C-16 and O-202020In: Physical Review C: Covering Nuclear Physics, ISSN 2469-9985, E-ISSN 2469-9993, Vol. 101, no 2, article id 021303Article in journal (Refereed)
    Abstract [en]

    To test the predictive power of ab initio nuclear structure theory, the lifetime of the second 2(+) state in neutron-rich O-20, tau(2(2)(+)) = 150(-30)(+80) fs, and an estimate for the lifetime of the second 2(+) state in C-16 have been obtained for the first time. The results were achieved via a novel Monte Carlo technique that allowed us to measure nuclear state lifetimes in the tens-to-hundreds of femtoseconds range by analyzing the Doppler-shifted gamma-transition line shapes of products of low-energy transfer and deep-inelastic processes in the reaction O-18 (7.0 MeV/u) + Ta-181. The requested sensitivity could only be reached owing to the excellent performances of the Advanced gamma-Tracking Array AGATA, coupled to the PARIS scintillator array and to the VAMOS++ magnetic spectrometer. The experimental lifetimes agree with predictions of ab initio calculations using two- and three-nucleon interactions, obtained with the valence-space in-medium similarity renormalization group for O-20 and with the no-core shell model for C-16. The present measurement shows the power of electromagnetic observables, determined with high-precision gamma spectroscopy, to assess the quality of first-principles nuclear structure calculations, complementing common benchmarks based on nuclear energies. The proposed experimental approach will be essential for short lifetime measurements in unexplored regions of the nuclear chart, including r-process nuclei, when intense beams, produced by Isotope Separation On-Line (ISOL) techniques, become available.

  • Aalhuizen, Christoffer
    Potential of V2G in a Rural Low-Voltage Grid on Gotland for Voltage and Power Capacity Control2019Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The Swedish transportation sector needs to undergo major changes in order to achieve the established goals for climate and environment. The largest change is the replacement of fossil-fuelled vehicles to vehicles propelled by renewable energy sources, such as biofuels and electricity. To account for an increase in local electric power consumption, the electric power infrastructure of Sweden needs to adapt through expansion and reconstruction of the electric power grid. However, changes in infrastructure are usually expensive. It is therefore suitable to also examine alternative solutions, which could potentially be more cost efficient. One of these solutions are vehicle-to-grid (V2G), where electric vehicles acts as local electric power control and provides auxiliary services to the electric power grid. This thesis is a case study of a part of a low-voltage electric power grid on Gotland, with the goal of analysing the potential of V2G in the investigated area. The study focused on utilizing V2G for balancing electric power consumption and generation, and for adjusting voltage levels. Simulations of the area were executed in PSS®E for three different cases; one high-load case, low-load case and average-load case. It was found that by utilizing V2G a ramp up of electric power during mornings was delayed by approximately one hour, making the electric power grid potentially more compatible with photovoltaics (PV). However, the overall effects from V2G was fairly low. This outcome can partly be explained by the assumptions made in the report, and also due to some odd behaviour of the system model. 

  • Gunnarsson, Beatrice
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Onsbjer, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Vad sjuksköterskor anser ger arbetsrelaterad stress och dess påverkan på omvårdnadsarbetet och mötet med patienten2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: Underlag visar att sjukvården idag ställs inför ett hårdare samhällsklimat med ökad arbetsbelastning som påverkar den grundläggande omvårdnaden. Belägg visar hur arbetsrelaterad stress kan riskera patientsäkerheten. Därmed behövs en sammanställning av hur omvårdnadsarbetet och mötet med patienten berörs vid arbetsrelaterad stress hos sjuksköterskor. Syfte: Syftet med studien var att undersöka vad sjuksköterskor anser ger arbetsrelaterad stress samt sjuksköterskors uppfattningar om hur det påverkar omvårdnadsarbetet och mötet med patienten. Metod: En allmän litteraturstudie användes som metod där elva vetenskapliga och kvalitativa artiklar analyserades. Resultat: Resultatet visade att omvårdnadsarbetet och mötet med patienten påverkades negativt av den arbetsrelaterade stressen som främst berodde på övergripande problem på sjukhusnivå, avbrott i arbetet, tidsbrist, moralisk stress och sjuksköterskan som mer eller mindre erfaren. Omvårdnadsarbetet och mötet med patienten påverkades i sin tur negativt genom att patientens säkerhet riskerades samt brister i samarbetet mellan kollegor försvårade omvårdnaden. Även när relationen mellan sjuksköterskan och patienten uteblev påverkade det patienten negativt. Slutsats: Sjuksköterskor ansåg att flera faktorer bidrog till en arbetsrelaterad stress som påverkade omvårdnaden och mötet med patienten negativt. Vidare forskning bör utföras från ett patientperspektiv för att kunna klargöra vårdens möjlighet till förbättring och kartlägga de brister som finns.

  • Mauri, Davide
    et al.
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;PACMeR Athens, Evidence Based Dept, Athens, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Kalopita, Konstantina
    Alexandra Gen Hosp, Dept Anaesthesiol & Pain Med, Athens, Greece.
    Tsali, Lampriani
    PACMeR Athens, Evidence Based Dept, Athens, Greece.
    Polyzos, Nikolaos P.
    Hosp Univ Dexeus, Barcelona, Spain.
    Valachis, Antonis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Filis, Panagiotis
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Zarkavelis, Georgios
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Georgopoulos, Christos
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Zafeiri, Georgia
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Yerolatsite, Melina
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Papaioannou, Nikolaos
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Kapoulitsa, Fani
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Valsamidis, Dimitrios
    Alexandra Gen Hosp, Dept Anaesthesiol & Pain Med, Athens, Greece.
    Peponi, Evangelia
    Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece;Univ Hosp Ioannina, Dept Radiotherapy, Ioannina, Greece.
    Vrekoussis, Thomas
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece.
    Ntellas, Panagiotis
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Tzamachou, Eleftheria
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Pentheroudakis, Georgios
    Univ Hosp Ioannina, Dept Med Oncol, S Niarchos Ave, Ioannina 45500, Greece;Soc Study Clonal Heterogene Neoplasia EMEKEN, Ioannina, Greece.
    Cancer pain ... who cares?: International and national patterns of evidence-based global guide-lines recommendations for physicians on the Web (2011 vs. 2018)2020In: Journal of B.U.ON. (JBUON), ISSN 1107-0625, Vol. 25, no 1, p. 62-73Article in journal (Refereed)
    Abstract [en]

    Purpose: Although pain is a common event during treatment of cancer, its assessment and management remains suboptimal in everyday clinical practice at global level.

    Methods: Considering both the important role of Internet in daily life and that clinical guidelines are important for translating evidence in clinical practice, we performed a prospective study to scrutinize the magnitude of updated evidence-based cancer-pain guideline recommendation for physicians on the web. Changes over-time at a global level were scrutinized at two time points: 2011 for baseline and 2018 at first follow-up. Both anesthesiology and oncology societies were analyzed.

    Results: In 2011 we scrutinized 181,00 WebPages and 370 eligible societies were identified; 364 of these were eligible for analyses both in 2011 and 2018. The magnitude of cancer pain updated and evidence-based guideline recommendations on the web for health care providers was extremely low at global level and at any time point considered 1.1% (4/364) in 2011 and 4.7% (17364) in 2018. Continental and intercontinental patterns, National's highest developmental index, oncology tradition and economic-geographic areas were not found to influence cancer pain web-guideline provision. In 2018, pain & supportive care societies provided the highest rate of updated evidence-based cancer-pain guidelines for clinicians. Only 3/25 medical oncology societies and 1/34 radiation oncology societies, provided own or e-link (to other societies) evidence-based guidelines in their websites.

    Conclusions: Major medical oncology and radiation oncology societies - at global level - fail to produce updated cancer pain recommendations for their physicians, with most of these providing no or inconsistent or outdated guidelines.

  • Salles, Arleen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Evers, Kathinka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Farisco, Michele
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Anthropomorphism in AI2020In: AJOB Neuroscience, ISSN 2150-7740, E-ISSN 2150-7759, Vol. 11, no 2, p. 88-95Article in journal (Refereed)
    Abstract [en]

    AI research is growing rapidly raising various ethical issues related to safety, risks, and other effects widely discussed in the literature. We believe that in order to adequately address those issues and engage in a productive normative discussion it is necessary to examine key concepts and categories. One such category is anthropomorphism. It is a well-known fact that AI’s functionalities and innovations are often anthropomorphized (i.e., described and conceived as characterized by human traits). The general public’s anthropomorphic attitudes and some of their ethical consequences (particularly in the context of social robots and their interaction with humans) have been widely discussed in the literature. However, how anthropomorphism permeates AI research itself (i.e., in the very language of computer scientists, designers, and programmers), and what the epistemological and ethical consequences of this might be have received less attention. In this paper we explore this issue. We first set the methodological/theoretical stage, making a distinction between a normative and a conceptual approach to the issues. Next, after a brief analysis of anthropomorphism and its manifestations in the public, we explore its presence within AI research with a particular focus on brain-inspired AI. Finally, on the basis of our analysis, we identify some potential epistemological and ethical consequences of the use of anthropomorphic language and discourse within the AI research community, thus reinforcing the need of complementing the practical with a conceptual analysis.

  • Kuyvenhoven, Tim Collin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Philosophy, Logic and Metaphysics.
    On how we acquire knowledge of first principles (archai) in Aristotle: A defense of intuition (nous) understood as integral to induction (epagoge)2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    In this essay I consider from various perspectives the question of whether, for Aristotle, intuition (nous) is part of the process of induction (epagoge) helping to reach the first principles (archai) or whether nous is rather a state of knowing first brought about through a successful induction alone.

    I have argued we should be careful of drawing conclusions about the nature of the involvement of nous in the grasping of first principles on the basis of APo alone. The main reasons I give for this are to be found in the connections that can be drawn between Aristotle’s account of the grasping of the first principles from Met. I.1, the account of the intellectual grasp of the forms in DA II & III and the process of induction described in APo II.19. These texts, I argue, should all be understood as parallel accounts, describing from different points of view, one and the same intuitive process of knowledge acquisition. The unified picture emerging from this reading provides the basis for a view that nous should be understood as an integral part of the process of induction and not, as some scholars have argued, only as a result of it. Aristotle’s version of induction, unlike a common contemporaneous conception of it, is not a matter of generalization about a sample of a given population, the conclusion of which is then extrapolated to all or part of the total population, but rather relies on a form of mental insight or intuition which is to be understood as an ability to grasp a certain sort of universal features of things called, 'the why' or first principles, which, as well as epistemic concepts, constitute the principles which organize the natural world. It is precisely this correspondence between the first principles of reason and those of the natural world that for Aristotle explains the type of intuitive induction herein attributed to him.

  • Sepers, Bernice
    et al.
    Netherlands Inst Ecol NIOO KNAW, Dept Anim Ecol, Wageningen, Netherlands;Wageningen Univ & Res, Behav Ecol Grp, Wageningen, Netherlands.
    van den Heuvel, Krista
    Netherlands Inst Ecol NIOO KNAW, Dept Anim Ecol, Wageningen, Netherlands;Wageningen Univ & Res, Behav Ecol Grp, Wageningen, Netherlands.
    Lindner, Melanie
    Netherlands Inst Ecol NIOO KNAW, Dept Anim Ecol, Wageningen, Netherlands;Univ Groningen, Groningen Inst Evolutionary Life Sci GELIFES, Chronobiol Unit, Groningen, Netherlands.
    Viitaniemi, Heidi
    Univ Helsinki, Organismal & Evolutionary Biol Res Programme, Helsinki, Finland.
    Husby, Arild
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Norwegian Univ Sci & Technol, Dept Biol, Ctr Biodivers Dynam, N-7491 Trondheim, Norway.
    van Oers, Kees
    Netherlands Inst Ecol NIOO KNAW, Dept Anim Ecol, Wageningen, Netherlands;Wageningen Univ & Res, Behav Ecol Grp, Wageningen, Netherlands.
    Avian ecological epigenetics: pitfalls and promises2019In: Journal of Ornithology, ISSN 2193-7192, E-ISSN 2193-7206, Vol. 160, no 4, p. 1183-1203Article in journal (Refereed)
    Abstract [en]

    Epigenetic mechanisms can alter gene expression without a change in the nucleotide sequence and are increasingly recognized as important mechanisms that can generate phenotypic diversity. Most of our current knowledge regarding the origin and role of epigenetic variation comes from research on plants or mammals, often in controlled rearing conditions. Epigenetic research on birds in their natural habitats is still in its infancy, but is needed to answer questions regarding the origin of epigenetic marks and their role in phenotypic variation and evolution. Here we review the potential for studying epigenetic variation in natural bird systems. We aim to provide insights into (1) the origin of epigenetic variation, (2) the relationship between epigenetic variation and trait variation, and (3) the possible role of epigenetic variation in adaptation to changing environments. As there is currently little research on epigenetics in wild birds, we examine how findings on other taxa such as plants and mammals relate to birds. We also examine some of the pros and cons of the most commonly used methods to study patterns of DNA methylation in birds, and suggest some topics we believe need to be addressed to develop the field of wild avian epigenetics further.

  • Elmeskog, Kristian
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Government.
    "För att lära oss om samhället, typ...": en studie om skillnaderna i hur elever och deras lärare uppfattar samhällskunskap2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Kandidatuppsatsen bygger på en enkätstudie som frågat samhällskunskapslärare om deras uppfattningar av ämnet, samma frågor ställdes till lärarnas elever och resultaten jämfördes.

  • Aad, G.
    et al.
    Asimakopoulou, Eleni M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bergeås Kuutmann, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bokan, Petar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellajosyula, Venugopal
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Isacson, Max
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Mårtensson, Mikael U. F.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Sales De Bruin, Pedro
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zwalinski, L.
    Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector2020In: Physical Review D: covering particles, fields, gravitation, and cosmology, ISSN 2470-0010, E-ISSN 2470-0029, Vol. 101, no 3, article id 032009Article in journal (Refereed)
    Abstract [en]

    A search for the direct production of the supersymmetric partners of tau-leptons (staus) in final states with two hadronically decaying tau-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of 139 fb(-1), recorded with the ATLAS detector at the Large Hadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected Standard Model background is observed. Limits are derived in scenarios of direct production of stau pairs with each stau decaying into the stable lightest neutralino and one tau-lepton in simplified models where the two stau mass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidence level for a massless lightest neutralino.

  • Public defence: 2020-04-24 10:15 Sal XI, Uppsala
    Hjorth, Olof
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Imaging serotonin and dopamine transporters in social anxiety disorder: Characterization, treatment and expectancy effects2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The monoamines serotonin and dopamine are likely to be involved in the pathophysiology of social anxiety and other affective disorders, but their respective contributions and putative interactions in the causes and cures of these disorders are still not well understood. It is also largely unknown if and how expectations of treatment success affect brain neurochemistry and neural activations, and if expectations interact with antidepressants like selective serotonin reuptake inhibitors (SSRIs). In this thesis some of these issues were addressed by use of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Using the highly selective radiotracers [11C]DASB and [11C]PE2I to characterize the availability of serotonin (SERT) and dopamine (DAT) transporter proteins, study I compared non-displaceable binding potentials (BPND), probing the transporters, between patients with social anxiety disorder and healthy controls. Increased SERT binding was observed in the reward related region nucleus accumbens (NAcc), in the social anxiety group. Moreover, increased DAT binding was associated with severity of the disorder and social anxiety was also associated with higher SERT-DAT co-expression in fear- and reward-related areas, including the amygdala and NAcc. Study II showed that verbal instructions regarding expected treatment efficacy strongly affected the clinical outcome of SSRI-treatment. Overt treatment, when patients with social anxiety disorder were correctly informed, was vastly superior to covert SSRI treatment, when patients expected an ineffective placebo. Groups were also differentiated on objective brain activity measures. Study III further demonstrated different SERT and DAT binding changes in limbic and striatal areas with overt as compared to covert SSRI-treatment. Decreased DAT BPND in the striatum, as assessed with PET, correlated with improvement in the overt group, suggesting increased dopaminergic signalling. Study IV compared treatment-induced changes in SERT and DAT binding after cognitive-behavior therapy (CBT) combined with an SSRI or placebo in patients with social anxiety disorder. Both groups showed initial co-expression similar to study I. The SSRI+CBT and placebo+CBT combinations yielded dissimilar transporter change patterns. Higher SERT occupancy in the NAcc correlated with reduced symptoms and this relationship was moderated by the change in DAT BPND. The results of this thesis support that functional interactions between serotonin and dopamine modulate social anxiety symptomatology and are important brain targets for successful treatment. Further it demonstrates that the treatment success of SSRIs in social anxiety disorder depends on how the treatment is presented. These results can be informative for the practice of clinicians, but also highlights an ethical dilemma because a large portion of the total treatment effects is elicited by processes within the patient itself.

    List of papers
    1. Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder: a multitracer positron emission tomography study.
    Open this publication in new window or tab >>Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder: a multitracer positron emission tomography study.
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    2019 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BPND) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [11C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [11C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BPND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-400349 (URN)10.1038/s41380-019-0618-7 (DOI)31822819 (PubMedID)
    Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2020-03-06Bibliographically approved
    2. Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial
    Open this publication in new window or tab >>Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial
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    2017 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, no 24, p. 179-188, article id S2352-3964(17)30385-7Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).

    METHODS: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.

    FINDINGS: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n=24) as compared to covert (n=22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p<0.0001) with more than three times higher response rate (50% vs. 14%; χ(2)(1)=6.91, p=0.009) and twice the effect size (d=2.24 vs. d=1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p≤0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p=0.0006) and attenuated amygdala (z threshold 2.70, p=0.003) activity.

    INTERPRETATION: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.

    FUNDING RESOURCES: The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).

    Keywords
    Expectancies, Neuroimaging, Placebo effect, SSRI, Social anxiety disorder, fMRI
    National Category
    Psychology General Practice
    Identifiers
    urn:nbn:se:uu:diva-331755 (URN)10.1016/j.ebiom.2017.09.031 (DOI)000414392900030 ()29033138 (PubMedID)
    Funder
    Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-1368Swedish Research Council, 421-2013-1366Riksbankens Jubileumsfond, P13-1270:1
    Note

    Vanda Faria and Malin Gingnell contributed equally

    Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2020-03-06Bibliographically approved
    3. Response expectancies shape the effect of SSRI treatment on serotonin and dopamine transporters in patients with social anxiety disorder
    Open this publication in new window or tab >>Response expectancies shape the effect of SSRI treatment on serotonin and dopamine transporters in patients with social anxiety disorder
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-406310 (URN)
    Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06
    4. Changes in serotonin and dopamine transporter availability after combined treatment with escitalopram and cognitive-behavioral therapy in patients with social anxiety disorder
    Open this publication in new window or tab >>Changes in serotonin and dopamine transporter availability after combined treatment with escitalopram and cognitive-behavioral therapy in patients with social anxiety disorder
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-406311 (URN)
    Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06
  • Bane, Octavia
    et al.
    Icahn Sch Med Mt Sinai, BioMed Engn & Imaging Inst, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USA.
    Mendichovszky, Iosif A.
    Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Dept Radiol, Cambridge, England.
    Milani, Bastien
    Lausanne Univ Hosp, Ctr BioMed Imaging, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland.
    Dekkers, Ilona A.
    Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands.
    Deux, Jean-Francois
    Grp Hosp Henri Mondor, Dept Radiol, Creteil, France.
    Eckerbom, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Grenier, Nicolas
    Univ Bordeaux, CHU Bordeaux, Dept Radiol, Bordeaux, France.
    Hall, Michael E.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Inoue, Tsutomu
    Saitama Med Univ, Fac Med, Dept Nephrol, Saitama, Japan.
    Laustsen, Christoffer
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Aarhus, Denmark.
    Lerman, Lilach O.
    Mayo Clin, Div Nephrol & Hypertens, Dept Internal Med, Rochester, MN USA.
    Liu, Chunlei
    Univ Calif Berkeley, Elect Engn & Comp Sci, Berkeley, CA 94720 USA;Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA.
    Morrell, Glen
    Univ Utah, Dept Radiol & Imaging Sci, Salt Lake City, UT USA.
    Pedersen, Michael
    Aarhus Univ Hosp, Comparat Med Lab, Dept Clin Med, Aarhus, Denmark.
    Pruijm, Menno
    Univ Lausanne, Lausanne, Switzerland;Lausanne Univ Hosp, Nephrol & Hypertens Serv, Lausanne, Switzerland.
    Sadowski, Elizabeth A.
    Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA.
    Seeliger, Erdmann
    Charite Univ Med Berlin, Inst Physiol, Berlin, Germany.
    Sharma, Kanishka
    Univ Leeds, Dept Biomed Imaging Sci, Imaging Biomarkers Grp, Leeds, W Yorkshire, England.
    Thoeny, Harriet
    Univ Fribourg, Hop Cantonal Fribourgois, Dept Radiol, Fribourg, Switzerland.
    Vermathen, Peter
    Univ Spital Bern, Inselspital, Dept BioMed Res, Bern, Switzerland;Univ Spital Bern, Inselspital, Dept Radiol, Bern, Switzerland.
    Wang, Zhen J.
    Univ Calif San Francisco, Med Ctr, Dept Radiol & Biomed Imaging, San Francisco, CA USA.
    Serafin, Zbigniew
    Nicolaus Copernicus Univ, Dept Radiol, Coll Med, Bydgoszcz, Poland.
    Zhang, Jeff L.
    Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02115 USA.
    Francis, Susan T.
    Univ Notthingham, Sir Peter Mansfield Ctr, Notthingham, England.
    Sourbron, Steven
    Univ Leeds, Dept Biomed Imaging Sci, Imaging Biomarkers Grp, Leeds, W Yorkshire, England.
    Pohlmann, Andreas
    Helmholtz Assoc, Max Delbrueck Ctr Mol Med, Berlin Ultrahigh Field Facil, Berlin, Germany.
    Fain, Sean B.
    Univ Wisconsin, Dept Biomed Engn, Madison, WI USA;Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA;Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USA.
    Prasad, Pottumarthi V.
    NorthShore Univ Hlth Syst, Ctr Adv Imaging, Dept Radiol, Evanston, IL USA.
    Consensus-based technical recommendations for clinical translation of renal BOLD MRI2020In: Magnetic Resonance Materials in Physics, Biology and Medicine, ISSN 0968-5243, E-ISSN 1352-8661, Vol. 33, no 1, p. 199-215Article, review/survey (Refereed)
    Abstract [en]

    Harmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based on a consensus report with the aim to move towards standardized protocols that facilitate clinical translation and comparison of data across sites. We used a recently published systematic review paper, which included a detailed summary of renal BOLD MRI technical parameters and areas of investigation in its supplementary material, as the starting point in developing the survey questionnaires for seeking consensus. Survey data were collected via the Delphi consensus process from 24 researchers on renal BOLD MRI exam preparation, data acquisition, data analysis, and interpretation. Consensus was defined as >= 75% unanimity in response. Among 31 survey questions, 14 achieved consensus resolution, 12 showed clear respondent preference (65-74% agreement), and 5 showed equal (50/50%) split in opinion among respondents. Recommendations for subject preparation, data acquisition, processing and reporting are given based on the survey results and review of the literature. These technical recommendations are aimed towards increased inter-site harmonization, a first step towards standardization of renal BOLD MRI protocols across sites. We expect this to be an iterative process updated dynamically based on progress in the field.

  • Carlevaro-Fita, Joana
    et al.
    Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland.
    Lanzos, Andres
    Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland.
    Feuerbach, Lars
    Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany;Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany.
    Hong, Chen
    Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany;Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany.
    Mas-Ponte, David
    Barcelona Inst Sci & Technol, Ctr Gen Regulat CRG, Dr Aiguader 88, E-08003 Barcelona, Spain;Univ Pompeu Fabra UPF, Barcelona, Spain;Inst Hosp Mar Invest Med IMIM, Dr Aiguader 88, E-08003 Barcelona, Spain.
    Pedersen, Jakob Skou
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark;Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Johnson, Rory
    Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland.
    Abascal, Federico
    Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.
    Amin, Samirkumar B.
    Univ Texas MD Anderson Canc Ctr, Dept Gen Med, Houston, TX 77030 USA;Jackson Lab Gen Med, Farmington, CT 06032 USA;Baylor Coll Med, Quantitat & Computat Biosci Grad Program, Houston, TX 77030 USA.
    Bader, Gary D.
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
    Barenboim, Jonathan
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Beroukhim, Rameen
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Bertl, Johanna
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark;Aarhus Univ, Dept Math, DK-8000 Aarhus, Denmark.
    Boroevich, Keith A.
    RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan;RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan.
    Brunak, Soren
    Tech Univ Denmark, DK-2800 Lyngby, Denmark;Univ Copenhagen, DK-2200 Copenhagen, Denmark.
    Campbell, Peter J.
    Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England;Univ Cambridge, Dept Haematol, Cambridge CB2 2XY, England.
    Chakravarty, Dimple
    Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol Res, Div Canc Med, Houston, TX 77030 USA.
    Chan, Calvin Wing Yiu
    German Canc Res Ctr, Div Theoret Bioinformat, DE-69120 Heidelberg, Germany;Heidelberg Univ, Fac Biosci, DE-69120 Heidelberg, Germany.
    Chen, Ken
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Choi, Jung Kyoon
    Korea Adv Inst Sci & Technol, Daejeon 34141, South Korea.
    Deu-Pons, Jordi
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Dhingra, Priyanka
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA.
    Diamanti, Klev
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Fink, J. Lynn
    Barcelona SuperComp Ctr, E-08034 Barcelona, Spain;Univ Queensland, Inst Mol BioSci, Queensland Ctr Med Gen, St Lucia, Qld 4072, Australia.
    Fonseca, Nuno A.
    Univ Porto, Res Ctr Biodivers & Genet Resources, CIBIO InBIO, P-4485601 Vairao, Portugal;European Bioinformat Inst EMBLEBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England.
    Frigola, Joan
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain.
    Gambacorti-Passerini, Carlo
    Univ Milano Bicocca, I-20052 Monza, Italy.
    Garsed, Dale W.
    Peter MacCallum Canc Ctr, Melbourne, Vic 3000, Australia;Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3052, Australia.
    Gerstein, Mark
    Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA;Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA;Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Getz, Gad
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02129 USA;Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA.
    Gonzalez-Perez, Abel
    Inst Hosp Mar Invest Med IMIM, Dr Aiguader 88, E-08003 Barcelona, Spain;Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Guo, Qianyun
    Aarhus Univ, Bioinformat Res Ctr BiRC, DK-8000 Aarhus, Denmark.
    Gut, Ivo G.
    Univ Pompeu Fabra UPF, Barcelona, Spain;Barcelona Inst Sci & Technol BIST, Ctr Gen Regulat CRG, CNAG CRG, E-08028 Barcelona, Spain.
    Haan, David
    Univ Calif, BioMol Engn Dept, Santa Cruz, CA 95064 USA.
    Hamilton, Mark P.
    Stanford Univ, Dept Internal Med, Stanford, CA 94305 USA.
    Haradhvala, Nicholas J.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Harmanci, Arif O.
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Univ Texas Hlth Sci Ctr, Ctr Precis Hlth, Sch BioMed Informat, Houston, TX 77030 USA.
    Helmy, Mohamed
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.
    Herrmann, Carl
    German Canc Res Ctr, Div Theoret Bioinformat, DE-69120 Heidelberg, Germany;Univ Clin, Hlth Data Sci Unit, DE-69120 Heidelberg, Germany;Heidelberg Univ, Inst Pharm & Mol Biotechnol & BioQuant, DE-69120 Heidelberg, Germany.
    Hess, Julian M.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Massachusetts Gen Hosp Ctr Canc Res, Charlestown, MA 02129 USA.
    Hobolth, Asger
    Aarhus Univ, Dept Math, DK-8000 Aarhus, Denmark;Aarhus Univ, Bioinformat Res Ctr BiRC, DK-8000 Aarhus, Denmark.
    Hodzic, Ermin
    Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada.
    Hornshoj, Henrik
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Isaev, Keren
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada;Univ Toronto, Dept Med BioPhys, Toronto, ON M5S 1A8, Canada.
    Izarzugaza, Jose M. G.
    Tech Univ Denmark, DK-2800 Lyngby, Denmark.
    Johnson, Todd A.
    RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan.
    Juul, Malene
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Juul, Randi Istrup
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Kahles, Andre
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA;Swiss Fed Inst Technol, Dept Biol, CH-8093 Zurich, Switzerland;Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland;SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland;Univ Hosp Zurich, CH-8091 Zurich, Switzerland.
    Kahraman, Abdullah
    Swiss Inst Bioinformat, Clin Bioinformat, CH-1202 Geneva, Switzerland;Univ Hosp Zurich, Inst Pathol & Mol Pathol, CH-8091 Zurich, Switzerland;Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland.
    Kellis, Manolis
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;MIT, MIT Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
    Khurana, Ekta
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA;Weill Cornell Med, Englander Inst Precis Med, New York, NY 10065 USA;Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA.
    Kim, Jaegil
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Kim, Jong K.
    Natl Canc Ctr Korea, Res Core Ctr, Goyangsi 410769, South Korea.
    Kim, Youngwook
    Sungkyunkwan Univ Sch Med, Dept Hlth Sci & Technol, Seoul 06351, South Korea;Samsung Genome Inst, Seoul 06351, South Korea.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland.
    Korbel, Jan O.
    European Bioinformat Inst EMBLEBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England;European Mol Biol Lab EMBL, Genome Biol Unit, DE-69117 Heidelberg, Germany.
    Kumar, Sushant
    European Bioinformat Inst EMBLEBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England;Univ Milano Bicocca, I-20052 Monza, Italy.
    Larsson, Erik
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA.
    Lawrence, Michael S.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan;Massachusetts Gen Hosp Ctr Canc Res, Charlestown, MA 02129 USA.
    Lee, Donghoon
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Lehmann, Kjong-Van
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA;Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland;SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland;Univ Hosp Zurich, CH-8091 Zurich, Switzerland;Swiss Fed Inst Technol, Dept Biol, Wolfgang-Pauli-Str 27, CH-8093 Zurich, Switzerland.
    Li, Shantao
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Li, Xiaotong
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Lin, Ziao
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Univ, Cambridge, MA 02138 USA.
    Liu, Eric Minwei
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA;Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.
    Lochovsky, Lucas
    Jackson Lab Gen Med, Farmington, CT 06032 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, New Haven, CT 06520 USA.
    Lou, Shaoke
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Madsen, Tobias
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Marchal, Kathleen
    Univ Ghent, Dept Informat Technol, B-9000 Ghent, Belgium;Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9000 Ghent, Belgium.
    Martincorena, Inigo
    Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.
    Martinez-Fundichely, Alexander
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA;Weill Cornell Med, Englander Inst Precis Med, New York, NY 10065 USA.
    Maruvka, Yosef E.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Massachusetts Gen Hosp, Boston, MA 02114 USA;Massachusetts Gen Hosp Ctr Canc Res, Charlestown, MA 02129 USA.
    McGillivray, Patrick D.
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA.
    Meyerson, William
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Yale Univ, Yale Sch Med, New Haven, CT 06520 USA.
    Muinos, Ferran
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Mularoni, Loris
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Nakagawa, Hidewaki
    RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan.
    Nielsen, Morten Muhlig
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Paczkowska, Marta
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Park, Keunchil
    Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Div Hematol Oncol, Seoul 06351, South Korea;Sungkyunkwan Univ Sch Med, Samsung Adv Inst Hlth Sci & Technol, Seoul 06351, South Korea.
    Park, Kiejung
    Sangmyung Univ, Cheonan Ind Acad Collaborat Fdn, Cheonan 31066, South Korea.
    Pich, Oriol
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Pons, Tirso
    Spanish Natl Canc Res Centre, E-28029 Madrid, Spain.
    Pulido-Tamayo, Sergio
    Univ Ghent, Dept Informat Technol, B-9000 Ghent, Belgium;Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9000 Ghent, Belgium.
    Raphael, Benjamin J.
    Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA.
    Reimand, Juri
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada;Univ Toronto, Dept Med BioPhys, Toronto, ON M5S 1A8, Canada.
    Reyes-Salazar, Iker
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain.
    Reyna, Matthew A.
    Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA.
    Rheinbay, Esther
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Rubin, Mark A.
    Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA;Univ Bern, Univ Hosp Bern, Bern Ctr Precis Med, CH-3008 Bern, Switzerland;Weill Cornell Med, Englander Inst Precis Med, New York, NY 10021 USA;NewYork Presbyterian Hosp, New York, NY 10021 USA;Weill Cornell Med Coll, Pathol & Lab, New York, NY 10021 USA.
    Rubio-Perez, Carlota
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain;Vall Hebron Inst Oncol VHIO, E-08035 Barcelona, Spain.
    Sabarinathan, Radhakrishnan
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain;Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, India.
    Sahinalp, S. Cenk
    Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada;Indiana Univ, Bloomington, IN 47405 USA;Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada.
    Saksena, Gordon
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Salichos, Leonidas
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Sander, Chris
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA;Harvard Med Sch, Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA;Dana Farber Canc Inst, Boston, MA 02215 USA;Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
    Schumacher, Steven E.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
    Shackleton, Mark
    Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3052, Australia;Univ Melbourne, Melbourne, Vic 3000, Australia;Peter MacCallum Canc Inst, Melbourne, Vic 3000, Australia.
    Shapira, Ofer
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Med Sch, Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA.
    Shen, Ciyue
    Harvard Med Sch, Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA;Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
    Shrestha, Raunak
    Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada.
    Shuai, Shimin
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada;Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Sidiropoulos, Nikos
    Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark;Univ Copenhagen, Finsen Lab, DK-2200 Copenhagen, Denmark.
    Sieverling, Lina
    Heidelberg Univ, Fac Biosci, DE-69120 Heidelberg, Germany;Univ Porto, Res Ctr Biodivers & Genet Resources, CIBIO InBIO, P-4485601 Vairao, Portugal.
    Sinnott-Armstrong, Nasa
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Stanford Univ Sch Med, Dept Genet, Stanford, CA 94305 USA.
    Stein, Lincoln D.
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada;Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Stuart, Joshua M.
    Univ Calif, BioMol Engn Dept, Santa Cruz, CA 95064 USA.
    Tamborero, David
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Tiao, Grace
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Tsunoda, Tatsuhiko
    RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan;Japan Sci & Technol Agcy, CREST, Tokyo, Tokyo 1130033, Japan;Tokyo Med & Dent Univ, Med Res Inst, Dept Med Sci Math, Bunkyo Ku, Tokyo 1138510, Japan;Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Lab Med Sci Math,Bunkyo Ku, Tokyo 1130033, Japan.
    Umer, Husen Muhammad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Uuskula-Reimand, Liis
    Tallinn Univ Technol, Dept Gene Technol, EE-12616 Tallinn, Estonia;Hosp Sick Children, SickKids Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.
    Valencia, Alfonso
    Barcelona SuperComp Ctr, E-08034 Barcelona, Spain;Inst Catalana Recerca & Estudis Avancats ICREA, E-08010 Barcelona, Spain.
    Vazquez, Miguel
    Barcelona SuperComp Ctr, E-08034 Barcelona, Spain;Norwegian Univ Sci & Technol, Fac Med & Hlth Sci, Dept Clin & Mol Med, N-7030 Trondheim, Norway.
    Verbeke, Lieven P. C.
    Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9000 Ghent, Belgium;Univ Ghent, Dept Informat Technol, Interuniv Microelectron Centrum IMEC, B-9000 Ghent, Belgium.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wadi, Lina
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Wang, Jiayin
    Xi'an Jiaotong Univ, Sch Comp Sci & Technol, Xian 710048, Peoples R China;Xi'an Jiaotong Univ, Sch Elect & Informat Engn, Xian 710048, Peoples R China;McDonnell Genome Inst Washington Univ, St. Louis, MO 63108 USA.
    Warrell, Jonathan
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Waszak, Sebastian M.
    European Mol Biol Lab EMBL, Genome Biol Unit, DE-69117 Heidelberg, Germany.
    Weischenfeldt, Joachim
    European Mol Biol Lab EMBL, Genome Biol Unit, DE-69117 Heidelberg, Germany;Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark;Univ Copenhagen, Finsen Lab, DK-2200 Copenhagen, Denmark;Charite Univ Med Berlin, Dept Urol, DE-10117 Berlin, Germany.
    Wheeler, David A.
    Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Wu, Guanming
    Oregon Hlth & Sci Univ, Portland, OR 97239 USA.
    Yu, Jun
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China;Second Mil Med Univ, Shanghai 200433, Peoples R China.
    Zhang, Jing
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Zhang, Xuanping
    Xi'an Jiaotong Univ, Sch Comp Sci & Technol, Xian 710048, Peoples R China;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA.
    Zhang, Yan
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Ohio State Univ, Coll Med, Dept BioMed Informat, Columbus, OH 43210 USA;Ohio State Univ Comprehens Canc Ctr OSUCCC James, Columbus, OH 43210 USA.
    Zhao, Zhongming
    Univ Texas Hlth Sci Ctr Houston, Sch BioMed Informat, Houston, TX 77030 USA.
    Zou, Lihua
    Northwestern Univ, Feinberg Sch Med, Dept Biochem & Mol Genet, Chicago, IL 60637 USA.
    von Mering, Christian
    Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;Univ Zurich, Swiss Inst Bioinformat, CH-8057 Zurich, Switzerland.
    Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis2020In: COMMUNICATIONS BIOLOGY, ISSN 2399-3642, Vol. 3, no 1, article id 56Article in journal (Refereed)
    Abstract [en]

    Joana Carlevaro-Fita, Andres Lanzos et al. present the Cancer LncRNA Census (CLC), a manually curated dataset of 122 long noncoding RNAs (lncRNAs) with experimentally-validated functions in cancer based on data from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. CLC lncRNAs have unique gene features, and a number display evidence for cancer-driving functions that are conserved from humans to mice. Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.

  • Public defence: 2020-04-24 13:15 Room A1:111a, Uppsala
    Baião, Guilherme Costa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Genomic and transcriptomic investigation of reproductive incompatibility in Drosophila2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Both nuclear and cytoplasmic elements can contribute to the emergence of reproductive incompatibilities that influence evolution and speciation. In the projects that compose this thesis, we use genomics and transcriptomics to study some of those elements in Drosophila.

    In the first study, we show that Wolbachia, an endosymbiotic bacterium known to cause reproductive alterations in its hosts, influences gene expression in D. paulistorum. Affected genes were associated with biological functions such as metabolism, immunity, reproduction, and chemical communication. Our results indicate that Wolbachia accentuates the differences in expression profiles between semispecies and suggest that the symbiont influences host pre-and postmating isolation.

    In the second paper, we uncover widespread persistent heteroplasmy in D. paulistorum. We reveal that D. paulistorum mitochondria are polyphyletic, with two divergent mitotypes, and that the heteroplasmy likely originated through introgression. One of the mitotypes shows biparental inheritance, non-responsiveness to host energy demands and rapid titer increase in the early embryo. We hypothesize that such selfish traits evolved in response to competition between mitotypes.

    In the third project, we show that differentially expressed genes between D. paulistorum semispecies are associated with a variety of biological processes, especially broad regulatory functions that occur via variability in transcription, translation and ubiquitination of post-translational modification. We reveal that the expression profile of F1 inter-semispecies hybrids is markedly similar to that of the maternal line, and that Wolbachia has a small but potentially significant interaction with genes that are differentially expressed in semispecies and F1 hybrids.

    Finally, we use comparative genomics to study the evolution of closely related Wolbachia strains with known reproductive phenotypes. We confirm previous observations that Wolbachia genomes are very dynamic and that phage-associated regions are particularly variable and likely involved in horizontal transfer of genes linked to reproductive phenotypes. An in-depth screen for genetic elements potentially involved in Wolbachia-induced cytoplasmic incompatibility recovers genes previously known to be involved in the phenotype and novel candidates.

    In conclusion, this thesis contributes to our understanding of genetic factors that affect Drosophila evolution, particularly those leading to reproductive incompatibility in D. paulistorum and associated with Wolbachia.

    List of papers
    1. The effect of Wolbachia on gene expression in Drosophila paulistorum and its implications for symbiont-induced host speciation
    Open this publication in new window or tab >>The effect of Wolbachia on gene expression in Drosophila paulistorum and its implications for symbiont-induced host speciation
    2019 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 20, article id 465Article in journal (Refereed) Published
    Abstract [en]

    Background: The Neotropical fruit fly Drosophila paulistorum (Diptera: Drosophilidae) is a species complex in statu nascendi comprising six reproductively isolated semispecies, each harboring mutualistic Wolbachia strains. Although wild type flies of each semispecies are isolated from the others by both pre- and postmating incompatibilities, mating between semispecies and successful offspring development can be achieved once flies are treated with antibiotics to reduce Wolbachia titer. Here we use RNA-seq to study the impact of Wolbachia on D. paulistorum and investigate the hypothesis that the symbiont may play a role in host speciation. For that goal, we analyze samples of heads and abdomens of both sexes of the Amazonian, Centro American and Orinocan semispecies of D. paulistorum.

    Results: We identify between 175 and 1192 differentially expressed genes associated with a variety of biological processes that respond either globally or according to tissue, sex or condition in the three semispecies. Some of the functions associated with differentially expressed genes are known to be affected by Wolbachia in other species, such as metabolism and immunity, whereas others represent putative novel phenotypes involving muscular functions, pheromone signaling, and visual perception.

    Conclusions: Our results show that Wolbachia affect a large number of biological functions in D. paulistorum, particularly when present in high titer. We suggest that the significant metabolic impact of the infection on the host may cause several of the other putative and observed phenotypes. We also speculate that the observed differential expression of genes associated with chemical communication and reproduction may be associated with the emergence of pre- and postmating barriers between semispecies, which supports a role for Wolbachia in the speciation of D. paulistorum.

    Keywords
    Speciation, symbiosis, Wolbachia, transcriptome, Drosophila paulistorum, host-symbiont interactions
    National Category
    Genetics Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-389597 (URN)10.1186/s12864-019-5816-9 (DOI)000470715200001 ()31174466 (PubMedID)
    Funder
    Swedish Research Council, 2014-4353
    Available from: 2019-07-24 Created: 2019-07-24 Last updated: 2020-03-12Bibliographically approved
    2. Persistence of high-level heteroplasmy through biparental transmission of a selfish mitochondrion in Drosophila paulistorum
    Open this publication in new window or tab >>Persistence of high-level heteroplasmy through biparental transmission of a selfish mitochondrion in Drosophila paulistorum
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Heteroplasmy, or the coexistence of multiple mitotypes in an individual, has during recent years been shown to be more common in animals than previously anticipated. However, cases of stable, high-titer heteroplasmy are still relatively rare, as are systems with consistent paternal mitochondrial inheritance. In this study, we sequenced and assembled the full mitochondrial genomes of 23 Neotropical Drosophila lines belonging to six species of the willistoni group and three of the saltans group and discovered that 40% the 13 sequenced Drosophila paulistorum lines, are persistently heteroplasmic. We further showed that the mitochondria of D. paulistorum are polyphyletic, forming two clades, a and b, and that mitochondria of the a2 clade are exclusively found in heteroplasmic flies. Genomic analysis indicates that a2 is a functional mitochondrion, with no signs of loss of function mutations. Even so, our results demonstrate that a2 displays unusual features, including lack of titer response to energetic demands, higher titer in males than females, and consistent biparental transmission due to rapid replication during early embryo development. Together these features indicate that a2 might be a selfish mitochondrion that persists due to efficient biparental transmission.

    Using the assembled genomes, we reconstructed the evolutionary history of mitochondria in the willistoni subgroup and identified signs of multiple mitochondrial losses, gains and introgressions. The data indicated an a-like mitochondrial ancestor in the willistoni subgroup, with the b mitochondrion likely being acquired through introgression from an unidentified donor. We hypothesize that the selfish characteristics of a2 might have emerged as a response to competition for inheritance with the introgressed b

    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-406755 (URN)
    Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-03-12
    3. Differential gene expression in semispecies and hybrids of Drosophila paulistorum
    Open this publication in new window or tab >>Differential gene expression in semispecies and hybrids of Drosophila paulistorum
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Gene expression divergence is correlated with and can be either a cause or a consequence of species divergence. Studying gene expression differences between closely related species, and their hybrid offspring, can thus give us clues about genes and mechanisms associated with reproductive isolation (RI) between them and allow us to better understand early stages of speciation. In this study, we use RNA-Seq to investigate gene expression divergence between the Amazonian, Centro-American and Orinocan semispecies of Drosophila paulistorum, a species cluster in statu nascendi, and between inter-semispecies hybrids and their parents. We uncover a large number of genes with varying expression between semispecies, with the highest numbers in male abdomens. The differentially expressed genes are associated with a range of biological functions, but especially with broad, regulatory functions, that are governed by transcription, translation, post-translational modifications and induced by signal transduction. We found that the expression pattern of hybrids was much more similar to the maternal line and that very few genes have a different expression than both of their parents. When comparing the differentially expressed genes in semispecies and hybrids to gene affected by Wolbachia in D. paulistorum, we see a small overlap. However, especially in hybrids, some of the overlapping genes appear to be highly relevant. Our study provides insights about expression differences associated with RI in D. paulistorum, and the impact of Wolbachia on the divergence of semispecies and hybrid sterility.

    National Category
    Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-406757 (URN)
    Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-03-12
    4. Comparative genomics of closely related Wolbachia strains infecting Drosophila
    Open this publication in new window or tab >>Comparative genomics of closely related Wolbachia strains infecting Drosophila
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Cytoplasmic incompatibility (CI) is the most common form of reproductive manipulation induced by the vertically inherited endosymbiont Wolbachia. The phenotype causes partial or complete sterility in crosses between infected males and non-infected females, thus benefiting infected females in the population and the spread of the bacteria. Because of these properties, CI-inducing Wolbachia has been implicated as a mean for biological pest control. Although CI has been known for several decades, the first CI-associated genes, cifA and cifB, were only recently discovered. In this study, we sequenced five complete Wolbachia genomes (wSan, wYak, wTei, wAu, wMa,) and performed comparative genomic analyses between these and four previously published complete Wolbachia genomes (wRi, wNo, wHa, wMel), that have all had their CI properties tested in the same genetic host background, Drosophila simulans STC. Using these genomes, we investigate what types of genes differ between closely related Wolbachia strains and compare the sequences from some of the strains in their natural host vs. after transfer to D. simulans STC. We find that phage-associated and hypothetical genes are likely to vary more between genomes and that very few mutations have occurred when strains were transferred to D. simulans. Furthermore, we investigate the evolution of the known CI genes and take advantage of the highly similar genomes of some strains as well as their complex CI properties to identify further genes associated with both mod and resc functions of CI.

    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-406756 (URN)
    Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-03-12
  • Kistenich, Sonja
    et al.
    Univ Oslo, Nat Hist Museum, POB 1172 Blindern, N-0318 Oslo, Norway.
    Ekman, Stefan
    Uppsala University, Music and Museums, Museum of Evolution.
    Bendiksby, Mika
    Univ Oslo, Nat Hist Museum, POB 1172 Blindern, N-0318 Oslo, Norway;Norwegian Univ Sci & Technol, NTNU Univ Museum, Elvegata 17, N-7012 Trondheim, Norway.
    Timdal, Einar
    Univ Oslo, Nat Hist Museum, POB 1172 Blindern, N-0318 Oslo, Norway.
    (2687) Proposal to conserve the name Phyllopsora against Triclinum and Crocynia (Ramalinaceae, lichenized Ascomycota)2019In: Taxon, ISSN 0040-0262, E-ISSN 1996-8175, Vol. 68, no 3, p. 590-592Article in journal (Other academic)
  • De Boniface, Jana
    et al.
    Capio St Goran's Hosp, Dept Surg, Stockholm, Sweden;Karolinska Inst, Dept Mol Med, Surg, Stockholm, Sweden.
    Ahlgren, Johan
    Univ orebro, Dept Oncology, Orebro, Sweden;Reg Onclg Centre, orebro Hlth Care Reg, Uppsala, Sweden.
    Andersson, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Vastmanland Cty Hosp, Dept Surg, Vasteras, Sweden.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Frisell, Jan
    Karolinska Universitety Hosp, Dept Breast,Div Canc,Endocrine Tumours,Sarcoma, Stockholm, Sweden.
    Lundstedt, Dan
    Sahlgrens Univ Hosp, Univ Gothenburg,Inst Clin Sciences, Sahlgrenska Acad,Dept Oncology, Gothenburg, Sweden.
    Olofsson Bagge, Roger
    Univ Gothenburg, Wallenberg Centre Mol, Translat Med, Gothenburg, Sweden;Sahlgrens Univ Hosp, Sahlgrenska Acad Univ Gothenburg, Inst Clin Sciences, Dept Surg, Gothenburg, Sweden.
    Ryden, Lisa
    Lund Univ, Dept Clin Sciences Lund, Div Surg, Lund, Sweden;Skane Univ Hosp, Dept Surg, Gastroenterology, Lund, Sweden.
    Sund, Malin
    Norrland Univ Hosp, Surg Ctr, Umea, Sweden;Umea Univ, Dept Surg, Perioperat Sci, Surg, Umea, Sweden.
    Christiansen, Peer
    Filtenborg Tvedskov, Tove
    Offersen, Birgitte Vrou
    Reimer, Toralf
    Kuehn, Thorsten
    Kontos, Michalis
    Gentilini, Oreste
    Reitsamer, Roland
    The generalisability of randomised clinical trials: an interim external validity analysis of the ongoing SENOMAC trial in sentinel lymph node-positive breast cancer2020In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 180, no 1, p. 167-176Article in journal (Refereed)
    Abstract [en]

    Purpose: None of the key randomised trials on the omission of axillary lymph node dissection (ALND) in sentinel lymph-positive breast cancer have reported external validity, even though results indicate selection bias. Our aim was to assess the external validity of the ongoing randomised SENOMAC trial by comparing characteristics of Swedish SENOMAC trial participants with non-included eligible patients registered in the Swedish National Breast Cancer Register (NKBC).

    Methods: In the ongoing non-inferiority European SENOMAC trial, clinically node-negative cT1-T3 breast cancer patients with up to two sentinel lymph node macrometastases are randomised to undergo completion ALND or not. Both breast-conserving surgery and mastectomy are eligible interventions. Data from NKBC were extracted for the years 2016 and 2017, and patient and tumour characteristics compared with Swedish trial participants from the same years.

    Results: Overall, 306 NKBC cases from non-participating and 847 NKBC cases from participating sites (excluding SENOMAC participants) were compared with 463 SENOMAC trial participants. Patients belonging to the middle age groups (p = 0.015), with smaller tumours (p = 0.013) treated by breast-conserving therapy (50.3 versus 47.1 versus 65.2%, p < 0.001) and less nodal tumour burden (only 1 macrometastasis in 78.8 versus 79.9 versus 87.3%, p = 0.001) were over-represented in the trial population. Time trends indicated, however, that differences may be mitigated over time.

    Conclusions: This interim external validity analysis specifically addresses selection mechanisms during an ongoing trial, potentially increasing generalisability by the time full accrual is reached. Similar validity checks should be an integral part of prospective clinical trials. Trial registration: NCT 02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015

  • Hu, Haiyan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab. Chinese Acad Sci, Inst Geochem, State Key Lab Environm Geochem, Guiyang 550081, Peoples R China.
    Wang, Baolin
    Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, SE-75007 Uppsala, Sweden.
    Bravo, Andrea G.
    CSIC, ICM, Dept Marine Biol & Oceanog, Pg Maritim Barceloneta 37-49, E-08003 Barcelona, Catalunya, Spain.
    Björn, Erik
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden.
    Skyllberg, Ulf
    Swedish Univ Agr Sci, Dept Forest Ecol & Management, SE-90183 Umea, Sweden.
    Amouroux, David
    Univ Pau & Pays Adour, CNRS, UMR5254, Inst Sci Analyt & Physicochim Environm & Mat Mira, F-64000 Pau, France.
    Tessier, Emmanuel
    Univ Pau & Pays Adour, CNRS, UMR5254, Inst Sci Analyt & Physicochim Environm & Mat Mira, F-64000 Pau, France.
    Zopfi, Jakob
    Univ Basel, Dept Environm Sci, Biogeochem, CH-4056 Basel, Switzerland.
    Feng, Xinbin
    Chinese Acad Sci, Inst Geochem, State Key Lab Environm Geochem, Guiyang 550081, Peoples R China.
    Bishop, Kevin
    Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, SE-75007 Uppsala, Sweden.
    Nilsson, Mats B.
    Swedish Univ Agr Sci, Dept Forest Ecol & Management, SE-90183 Umea, Sweden.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, SE-75007 Uppsala, Sweden.
    Shifts in mercury methylation across a peatland chronosequence: From sulfate reduction to methanogenesis and syntrophy2020In: Journal of Hazardous Materials, ISSN 0304-3894, E-ISSN 1873-3336, Vol. 387, article id 121967Article in journal (Refereed)
    Abstract [en]

    Peatlands are globally important ecosystems where inorganic mercury is converted to bioaccumulating and highly toxic methylmercury, resulting in high risks of methylmercury exposure in adjacent aquatic ecosystems. Although biological mercury methylation has been known for decades, there is still a lack of knowledge about the organisms involved in mercury methylation and the drivers controlling their methylating capacity. In order to investigate the metabolisms responsible for mercury methylation and methylmercury degradation as well as the controls of both processes, we studied a chronosequence of boreal peatlands covering fundamentally different biogeochemical conditions. Potential mercury methylation rates decreased with peatland age, being up to 53 times higher in the youngest peatland compared to the oldest. Methylation in young mires was driven by sulfate reduction, while methanogenic and syntrophic metabolisms became more important in older systems. Demethylation rates were also highest in young wetlands, with a gradual shift from biotic to abiotic methylmercury degradation along the chronosequence. Our findings reveal how metabolic shifts drive mercury methylation and its ratio to demethylation as peatlands age.

  • Wångdahl, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, Huddinge, Sweden.
    Jaensson, Maria
    Orebro Univ, Fac Med & Hlth, Sch Hlth Sci, Orebro, Sweden.
    Dahlberg, Karuna
    Orebro Univ, Fac Med & Hlth, Sch Hlth Sci, Orebro, Sweden.
    Nilsson, Ulrica
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, Huddinge, Sweden;Karolinska Univ Hosp, Dept Perioperat Med & Intens Care, Stockholm, Sweden.
    The Swedish Version of the Electronic Health Literacy Scale: Prospective Psychometric Evaluation Study Including Thresholds Levels2020In: JMIR mhealth and uhealth, E-ISSN 2291-5222, Vol. 8, no 2, article id e16316Article in journal (Refereed)
    Abstract [en]

    Background: To enhance the efficacy of information and communication, health care has increasingly turned to digitalization. Electronic health (eHealth) is an important factor that influences the use and receipt of benefits from Web-based health resources. Consequently, the concept of eHealth literacy has emerged, and in 2006 Norman and Skinner developed an 8-item self-report instrument to measure these skills: the eHealth Literacy Scale (eHEALS). However, the eHEALS has not been tested for reliability and validity in the general Swedish population and no threshold values have been established.

    Objective: The aim of this study was to translate and adapt eHEALS into a Swedish version; evaluate convergent validity and psychometric properties; and determine threshold levels for inadequate, problematic, and sufficient eHealth literacy.

    Methods: Prospective psychometric evaluation study included 323 participants equally distributed between sexes with a mean age of 49 years recruited from 12 different arenas.

    Results: There were some difficulties translating the English concept health resources. This resulted in this concept being translated as health information (ie, Halsoinformation in Swedish). The eHEALS total score was 29.3 (SD 6.2), Cronbach alpha .94, Spearman-Brown coefficient .96, and response rate 94.6%. All a priori hypotheses were confirmed, supporting convergent validity. The test-retest reliability indicated an almost perfect agreement, .86 (P<.001). An exploratory factor analysis found one component explaining 64% of the total variance. No floor or ceiling effect was noted. Thresholds levels were set at 8 to 20 = inadequate, 21 to 26 = problematic, and 27 to 40 = sufficient, and there were no significant differences in distribution of the three levels between the Swedish version of eHEALS and the HLS-EU-Q16.

    Conclusions: The Swedish version of eHEALS was assessed as being unidimensional with high internal consistency of the instrument, making the reliability adequate. Adapted threshold levels for inadequate, problematic, and sufficient levels of eHealth literacy seem to be relevant. However, there are some linguistic issues relating to the concept of health resources.

  • Spicer, Christopher D.
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden;Univ York, Dept Chem, Heslington YO10 5DD, England;Univ York, York Biomed Res Inst, Heslington YO10 5DD, England.
    Pujari-Palmer, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Autefage, Helene
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden.
    Insley, Gerard
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Procter, Philip
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
    Stevens, Molly M.
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden;Imperial Coll London, Dept Mat, Dept Bioengn, London SW7 2AZ, England;Imperial Coll London, Inst Biomed Engn, London SW7 2AZ, England.
    Synthesis of Phospho-Amino Acid Analogues as Tissue Adhesive Cement Additives2020In: ACS CENTRAL SCIENCE, ISSN 2374-7943, Vol. 6, no 2, p. 226-231Article in journal (Refereed)
    Abstract [en]

    In this paper we report the synthesis of a library of phospho-amino acid analogues, via a novel single-step allyl-phosphoester protection/Pd-mediated deprotection strategy. These phosphoserine and phosphotyrosine analogues were then applied as additives to create adhesive calcium phosphate cements, allowing us to probe the chemical origins of the increased surface binding strength. We demonstrate the importance of multiple calcium binding motifs in mediating adhesion, as well as highlighting the crucial role played by substrate hydrophobicity and orientation in controlling binding strength.

  • George, Leena
    et al.
    Univ Leicester, Leicester NIHR Biomed Res Ctr, Inst Lung Hlth, Leicester, Leics, England.
    Taylor, Adam R.
    GSK Resp Therapeut Area Unit, Stevenage, Herts, England.
    Esteve-Codina, Anna
    Barcelona Inst Sci & Technol, CNAG CRG Ctr Nacl Anal Genom, Ctr Genom Regulat, Barcelona, Spain.
    Soler Artigas, Maria
    Univ Leicester, Leicester NIHR Biomed Res Ctr, Inst Lung Hlth, Leicester, Leics, England;Barcelona Inst Sci & Technol, CNAG CRG Ctr Nacl Anal Genom, Ctr Genom Regulat, Barcelona, Spain;Univ Autonoma Barcelona, VHIR, Grp Psychiat Mental Hlth & Addict, Psychiat Genet Unit, Barcelona, Spain;Biomed Network Res Ctr Mental Hlth CIBERSAM, Inst Salud Carlos III, Barcelona, Spain.
    Andri Thun, Gian
    Barcelona Inst Sci & Technol, CNAG CRG Ctr Nacl Anal Genom, Ctr Genom Regulat, Barcelona, Spain.
    Bates, Stewart
    GSK Resp Therapeut Area Unit, Stevenage, Herts, England.
    Pavlidis, Stelios
    Imperial Coll London, Airway Dis Sect, Natl Heart & Lung Inst, London, England;Imperial Coll London, Data Sci Inst, London, England.
    Wagers, Scott
    Biosci Consulting, Maasmechelen, Belgium.
    Boland, Anne
    CEA, CNG Ctr Natl Genotypage, Inst Genom, Evry, France.
    Prasse, Antje
    Univ Med Ctr, Dept Pneumol, Freiburg, Germany.
    Boschetto, Piera
    Univ Ferrara, Dept Med Sci, Ferrara, Italy;Ferrara City Hosp, Ferrara, Italy.
    Parr, David G.
    Univ Hosp Coventry & Warwickshire NHS Trust, Dept Resp Med, Coventry, W Midlands, England.
    Nowinski, Adam
    Natl Inst TB & Lung Dis, Dept Resp Med, Warsaw, Poland.
    Barta, Imre
    Natl Koranyi Inst TB & Pulmonol, Dept Pathophysiol, Budapest, Hungary.
    Hohlfeld, Jens
    Fraunhofer Inst Toxicol & Expt Med, Hannover, Germany.
    Greulich, Timm
    Philipps Univ Marburg, Univ Med Ctr Giessen & Marburg, Dept Med Pulm & Crit Care Med, Marburg, Germany;German Ctr Lung Res DZL, Grosshansdorf, Germany.
    van den Berge, Maarten
    Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis, Groningen, Netherlands.
    Hiemstra, Pieter S.
    Leiden Univ, Med Ctr, Dept Pulm Dis, Leiden, Netherlands.
    Timens, Wim
    Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands.
    Hinks, Timothy
    Univ Oxford, Oxford, England.
    Wenzel, Sally
    Univ Pittsburgh, Dept Med, Pittsburgh, PA USA;Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA.
    Siddiqui, Salman
    Univ Leicester, Leicester NIHR Biomed Res Ctr, Inst Lung Hlth, Leicester, Leics, England.
    Richardson, Matthew
    Univ Leicester, Leicester NIHR Biomed Res Ctr, Inst Lung Hlth, Leicester, Leics, England.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Heath, Simon
    Barcelona Inst Sci & Technol, CNAG CRG Ctr Nacl Anal Genom, Ctr Genom Regulat, Barcelona, Spain.
    Gut, Ivo
    Barcelona Inst Sci & Technol, CNAG CRG Ctr Nacl Anal Genom, Ctr Genom Regulat, Barcelona, Spain;Univ Pompeu Fabra, Barcelona, Spain.
    Tobin, Martin D.
    Univ Leicester, Leicester NIHR Biomed Res Ctr, Inst Lung Hlth, Leicester, Leics, England.
    Edwards, Lindsay
    GSK Resp Therapeut Area Unit, Stevenage, Herts, England.
    Riley, John H.
    GSK Resp Therapeut Area Unit, Stevenage, Herts, England.
    Djukanovic, Ratko
    NIHR Southampton Resp Biomed Res Unit & Clin & Ex, Southampton, Hants, England.
    Auffray, Charles
    Univ Lyon, EISBM, CNRS, ENS,UCBL, Lyon 07, France.
    De-Meulder, Bertrand
    Univ Lyon, EISBM, CNRS, ENS,UCBL, Lyon 07, France.
    Erik-Dahlen, Sven
    Karolinska Inst, Stockholm, Sweden.
    Adcock, Ian M.
    Biomed Network Res Ctr Mental Hlth CIBERSAM, Inst Salud Carlos III, Barcelona, Spain.
    Chung, Kian Fan
    Biomed Network Res Ctr Mental Hlth CIBERSAM, Inst Salud Carlos III, Barcelona, Spain.
    Ziegler-Heitbrock, Loems
    Helmholtz Zentrum Muenchen, EvA Study Ctr, Gauting, Germany;Asklepios Klin, Gauting, Germany.
    Sterk, Peter J.
    Univ Amsterdam, Med Ctr, Dept Resp Med, Amsterdam, Netherlands.
    Singh, Dave
    Univ Manchester, Ctr Resp Med & Allergy, Manchester, Lancs, England;Univ Hosp South Manchester NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England.
    Brightling, Christopher E.
    Univ Leicester, Leicester NIHR Biomed Res Ctr, Inst Lung Hlth, Leicester, Leics, England.
    Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma2020In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 75, no 2, p. 370-380Article in journal (Refereed)
    Abstract [en]

    Background: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.

    Methods: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/mu L as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).

    Results: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.

    Conclusion: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

  • Engelbrecht, Eric
    et al.
    Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.
    Levesque, Michel, V
    Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Huddinge, Sweden.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Huddinge, Sweden.
    Nitzsche, Anja
    Univ Paris, Paris Cardiovasc Res Ctr, INSERM U970, Paris, France.
    Niazi, Hira
    Univ Paris, Paris Cardiovasc Res Ctr, INSERM U970, Paris, France.
    Kuo, Andrew
    Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.
    Singh, Sasha A.
    Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Ctr Interdisciplinary Cardiovasc Sci, Boston, MA 02115 USA.
    Aikawa, Masanori
    Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Ctr Interdisciplinary Cardiovasc Sci, Boston, MA 02115 USA.
    Holton, Kristina
    Harvard Med Sch Res Comp, Boston, MA USA.
    Proia, Richard L.
    NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA.
    Kono, Mari
    NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA.
    Pu, William T.
    Harvard Med Sch, Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA;Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA.
    Camerer, Eric
    Univ Paris, Paris Cardiovasc Res Ctr, INSERM U970, Paris, France.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Huddinge, Sweden.
    Hla, Timothy
    Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.
    Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta2020In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e52690Article in journal (Refereed)
    Abstract [en]

    Despite the medical importance of G protein-coupled receptors (GPCRs), in vivo cellular heterogeneity of GPCR signaling and downstream transcriptional responses are not understood. We report the comprehensive characterization of transcriptomes (bulk and single-cell) and chromatin domains regulated by sphingosine 1-phosphate receptor-1 (S1PR1) in adult mouse aortic endothelial cells. First, S1PR1 regulates NF kappa B and nuclear glucocorticoid receptor pathways to suppress inflammation-related mRNAs. Second, S1PR1 signaling in the heterogenous endothelial cell (EC) subtypes occurs at spatially-distinct areas of the aorta. For example, a transcriptomically distinct arterial EC population at vascular branch points (aEC1) exhibits ligand-independent S1PR1/beta-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/beta-arrestin coupling was observed in non-branch point aEC2 cells that exhibit an inflammatory gene expression signature. Moreover, S1P/S1PR1 signaling regulates the expression of lymphangiogenic and inflammation-related transcripts in an adventitial lymphatic EC (LEC) population in a ligand-dependent manner. These insights add resolution to existing concepts of endothelial heterogeneity, GPCR signaling and S1P biology.

  • Mantas, Athanasios
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.
    Petit, Marie-Amelie
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Nanotechnology and Functional Materials.
    Directly Compressed Tablets of Free Acid Ibuprofen with Nanocellulose Featuring Enhanced Dissolution: A Side-by-Side Comparison with Commercial Oral Dosage Forms2020In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 1, article id 71Article in journal (Refereed)
    Abstract [en]

    We have previously reported that heated powder mixtures of ibuprofen (IBU) and high surface area nanocellulose exhibit an enhanced dissolution and solubility of the drug due to IBU amorphization. The goal of the present work was to further elaborate the concept and conduct side-by-side in vitro drug release comparisons with commercial formulations, including film-coated tablets, soft gel liquid capsules, and IBU-lysine conjugate tablets, in biorelevant media. Directly compressed tablets were produced from heated mixtures of 20% w/w IBU and high surface area Cladophora cellulose (CLAD), with 5% w/w sodium croscarmelose (AcDiSol) as superdisintegrant. The side-by side studies in simulated gastric fluid, fasted-state simulated intestinal fluid, and fed-state simulated intestinal fluid corroborate that the IBU-CLAD tablets show more rapid and less variable release in various media compared to three commercial IBU formulations. On the sidelines of the main work, a possibility of the presence of a new meta-crystalline form of IBU in mixture with nanocellulose is discussed.

  • Crockett, Douglas C.
    et al.
    Univ Oxford, Nuffield Div Anaesthet, Oxford, England.
    Tran, Minh C.
    Univ Oxford, Nuffield Div Anaesthet, Oxford, England;Univ Oxford, Dept Engn Sci, Oxford, England.
    Formenti, Federico
    Univ Oxford, Nuffield Div Anaesthet, Oxford, England;Kings Coll London, Ctr Human & Appl Physiol Sci, London, England;Univ Nebraska, Dept Biomech, Omaha, NE 68182 USA.
    Cronin, John N.
    Kings Coll London, Ctr Human & Appl Physiol Sci, London, England.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Phan, Phi A.
    Univ Oxford, Nuffield Div Anaesthet, Oxford, England.
    Farmery, Andrew D.
    Univ Oxford, Nuffield Div Anaesthet, Oxford, England.
    Validating the inspired sinewave technique to measure the volume of the 'baby lung' in a porcine lung-injury model2020In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 124, no 3, p. 345-353Article in journal (Refereed)
    Abstract [en]

    Background: Bedside lung volume measurement could personalise ventilation and reduce driving pressure in patients with acute respiratory distress syndrome (ARDS). We investigated a modified gas-dilution method, the inspired sinewave technique (IST), to measure the effective lung volume (ELV) in pigs with uninjured lungs and in an ARDS model. Methods: Anaesthetised mechanically ventilated pigs were studied before and after surfactant depletion by saline lavage. Changes in PEEP were used to change ELV. Paired measurements of absolute ELV were taken with IST (ELVIST) and compared with gold-standard measures (sulphur hexafluoride wash in/washout [ELVSF6] and computed tomography (CT) [ELVCT]). Measured volumes were used to calculate changes in ELV (Delta ELV) between PEEP levels for each method (Delta ELVIST, Delta ELVSF6, and Delta ELVCT). Results: The coefficient of variation was <5% for repeated ELVIST measurements (n=13 pigs). There was a strong linear relationship between ELVIST and ELVSF6 in uninjured lungs (r(2)=0.97), and with both ELVSF6 and ELVCT in the ARDS model (r(2)=0.87 and 0.92, respectively). ELVIST had a mean bias of -12 to 13% (95% limits=+/- 17 - 25%) compared with ELVSF6 and ELVCT. Delta ELVIST was concordant with Delta ELVSF6 and Delta ELVCT in 98-100% of measurements, and had a mean bias of -73 to -77 ml (95% limits=+/- 128 - 186 ml) compared with Delta ELVSF6 and -1 ml (95% limits +/- 333 ml) compared with Delta ELVCT. Conclusions: IST provides a repeatable measure of absolute ELV and shows minimal bias when tracking PEEP-induced changes in lung volume compared with CT in a saline-lavage model of ARDS.

  • Akula, Srinivas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Paivandy, Aida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fu, Zhirong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, SE-75007 Uppsala, Sweden.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Quantitative In-Depth Analysis of the Mouse Mast Cell Transcriptome Reveals Organ-Specific Mast Cell Heterogeneity2020In: CELLS, E-ISSN 2073-4409, Vol. 9, no 1, article id 211Article in journal (Refereed)
    Abstract [en]

    Mast cells (MCs) are primarily resident hematopoietic tissue cells that are localized at external and internal surfaces of the body where they act in the first line of defense. MCs are found in all studied vertebrates and have also been identified in tunicates, an early chordate. To obtain a detailed insight into the biology of MCs, here we analyzed the transcriptome of MCs from different mouse organs by RNA-seq and PCR-based transcriptomics. We show that MCs at different tissue locations differ substantially in their levels of transcripts coding for the most abundant MC granule proteins, even within the connective tissue type, or mucosal MC niches. We also demonstrate that transcript levels for the major granule proteins, including the various MC-restricted proteases and the heparin core protein, can be several orders of magnitude higher than those coding for various surface receptors and enzymes involved in protease activation, as well as enzymes involved in the synthesis of heparin, histamine, leukotrienes, and prostaglandins. Interestingly, our analyses revealed an almost complete absence in MCs of transcripts coding for cytokines at baseline conditions, indicating that cytokines are primarily produced by activated MCs. Bone marrow-derived MCs (BMMCs) are often used as equivalents of tissue MCs. Here, we show that these cells differ substantially from tissue MCs with regard to their transcriptome. Notably, they showed a transcriptome indicative of relatively immature cells, both with respect to the expression of granule proteases and of various enzymes involved in the processing/synthesis of granule compounds, indicating that care should be taken when extrapolating findings from BMMCs to the in vivo function of tissue-resident MCs. Furthermore, the latter finding indicates that the development of fully mature tissue-resident MCs requires a cytokine milieu beyond what is needed for in vitro differentiation of BMMCs. Altogether, this study provides a comprehensive quantitative view of the transcriptome profile of MCs resident at different tissue locations that builds nicely on previous studies of both the mouse and human transcriptome, and form a solid base for future evolutionary studies of the role of MCs in vertebrate immunity.

  • Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Salihovic, Samira
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical AB, Gothenburg, Sweden.
    Johansson, Lars
    Antaros Medical AB, Gothenburg, Sweden.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical AB, Gothenburg, Sweden.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oscarsson, Jan
    BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    THE PLASMA METABOLOMIC PROFILE IS DIFFERENTLY ASSOCIATED WITH LIVER FAT, VISCERAL ADIPOSE TISSUE AND PANCREATIC FAT: Supplementary Table 1.2020Data set
  • Public defence: 2020-04-24 13:15 Enghoffsalen, Uppsala
    Mogensen, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Inflammation in asthma: relation to symptomatology, exacerbations and lung function2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Asthma is an inflammatory disease in the airways. It is characterized by respiratory symptoms such as wheezing, variable airflow obstruction and impaired lung function development. A better understanding of the underlying inflammation is crucial in order to treat and prevent asthma symptoms and lung function deterioration.

    We have evaluated six inflammatory markers in relation to asthma symptoms, asthma attacks, and lung function measures (fixed airflow obstruction (FAO) and lung function development over time) in five investigations. The markers (elevated levels) were fraction of exhaled NO (FeNO) (elevated ≥25ppb), serum eosinophil cationic protein (S-ECP) (≥20 µg/L), blood eosinophils (B-Eos) (≥300 cells/µL), urinary eosinophil derived neurotoxin (U-EDN) (≥65.95mg/mol creatinine), serum periostin (S-periostin) ( ≥74μg/L), and blood neutrophils (B-Neu) (≥5,100 cells/µL).  The studied populations consisted of mainly adults (except in Paper II) and included asthmatics from the Swedish part of the Global Allergy and Asthma European Network survey (Papers I and III), the American National Health and Nutrition Examination Survey (Papers II and IV), the Uppsala part of the European Community Respiratory Health Survey I-III, the Vlagtwedde and Vlaardingen study, and the Rotterdam study, the latter two from the Netherlands (Paper V). All study populations were population based, and the asthmatics included had mainly mild to moderately severe asthma.

    The main findings are that simultaneously elevated FeNO and S-ECP are associated with more reported asthma symptoms and attacks, and elevated FeNO and B-Eos are associated with lower lung function, suggesting a value in measuring both local (FeNO) and systemic (S-ECP, B-Eos) inflammation in asthma. Eosinophil inflammation (elevated U-EDN and S-ECP) was associated with FAO in asthma, while the other type-2 markers FeNO and S-periostin were not. Elevated B-Eos was further associated to lower lung function measures in a general population, and a faster lung function decline in asthmatics. FeNO was more often elevated in asthmatics, but was difficult to robustly associate to a specific disease characteristic. B-Neu was associated to FAO in participants with current smoking or pronounced smoking history.

    In conclusion, asthma with elevated markers for eosinophil inflammation was associated to worse morbidity and lung function development in comparison with asthmatics without elevated markers for eosinophil inflammation. These results indicate ongoing eosinophil inflammation in asthma as closely associated to disease activity and the absence of eosinophil inflammation to less morbidity.

    List of papers
    1. Simultaneously elevated exhaled nitric oxide and serum-eosinophil cationic protein relate to recent asthma events in asthmatics in a cross-sectional population-based study.
    Open this publication in new window or tab >>Simultaneously elevated exhaled nitric oxide and serum-eosinophil cationic protein relate to recent asthma events in asthmatics in a cross-sectional population-based study.
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    2016 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 12, p. 1540-1548Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: We have reported that increased fraction of exhaled nitric oxide (FeNO), a measure of TH2 -driven airway inflammation, and blood eosinophil count, a marker of systemic eosinophil inflammation, correlated with asthma attacks in a population-based study.

    OBJECTIVE: To investigate the relation between simultaneously elevated FeNO and serum eosinophil cationic protein (S-ECP) levels and asthma events among asthmatics.

    METHODS: Measurements of FeNO (elevated ≥ 25 ppb) and S-ECP (elevated ≥ 20 ng/mL) were performed in 339 adult asthmatics. Asthma events (attacks and symptoms) were self-reported.

    RESULTS: Simultaneously normal S-ECP and FeNO levels were found in 48% of the subjects. Subjects with simultaneously elevated S-ECP and FeNO (13% of the population) had a higher prevalence of asthma attacks in the preceding 3 months than subjects with normal S-ECP and FeNO (51% vs. 25%, P = 0.001). This was not found for subjects with singly elevated S-ECP (P = 0.14) or FeNO (P = 0.34) levels. Elevated S-ECP and FeNO levels were independently associated with asthma attacks in the preceding 3 months after adjusting for potential confounders (OR (95% CI) 4.2 (2.0-8.8).

    CONCLUSIONS: Simultaneously elevated FeNO and S-ECP levels were related to a higher likelihood of asthma attacks in the preceding 3 months. This indicates that there is a value in measuring both FeNO and systemic eosinophilic inflammation in patients with asthma to identify individuals at high risk of exacerbations.

    CLINICAL RELEVANCE: FeNO and S-ECP are markers for inflammation in asthma, but are dependent on different inflammatory pathways and weakly correlated. Simultaneous measurements of both offer better risk characterization of adult asthmatics.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-311297 (URN)10.1111/cea.12792 (DOI)000389203600005 ()27513280 (PubMedID)
    Funder
    Swedish Heart Lung FoundationSwedish Asthma and Allergy Association
    Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2020-03-04
    2. Simultaneously elevated FeNO and blood eosinophils relate to asthma morbidity in asthmatics from NHANES 2007-12
    Open this publication in new window or tab >>Simultaneously elevated FeNO and blood eosinophils relate to asthma morbidity in asthmatics from NHANES 2007-12
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    2018 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 48, no 8, p. 935-943Article in journal (Refereed) Published
    Abstract [en]

    BackgroundFraction of exhaled nitric oxide (FeNO) and blood eosinophil (B-Eos) count are biomarkers for type 2 inflammation. However, they signal different inflammatory pathways. Simultaneously elevated, they are related to more asthma events in a general population and among younger asthmatics. ObjectiveTo investigate if simultaneously elevated FeNO and B-Eos relate to asthma outcomes and lung function among subjects with asthma at a wide age span, and how different cut-offs for the markers affect these relations. MethodFeNO, B-Eos and forced expiratory volume in 1 second (FEV1) were assessed in 1419 subjects with asthma, aged 6-79 years old, from the National Health and Nutrition Examination Survey (NHANES) 2007-12. Elevated levels were defined as FeNO 20 p.p.b. for children <12 years and 25 p.p.b. for subjects 12 years and B-Eos count 300 cells/L. Additional analyses were performed for the cut-offs FeNO >35/30 and >50/35 p.p.b., and for B-Eos 400 and 500 cells/L, as well as for different age subgroups (6-17, 18-44, >44 years old). Asthma events during the past year were self-reported. ResultsSubjects with simultaneously elevated FeNO and B-Eos compared with normal levels of both markers had a higher adjusted odds ratio (aOR (95%CI)) for having FEV1 <80% of predicted (2.15 (1.28-3.59), wheeze disturbing sleep (1.88 (1.27, 2.78)) but did not differ regarding asthma attacks past year. Elevated B-Eos, but not FeNO, was related to higher aOR for asthma attack (1.57 (1.14, 2.18) or emergency room (ER) visit due to asthma (1.88 (1.33, 2.64) when elevated FeNO and elevated B-Eos were studied as independent predictors. ConclusionSimultaneously elevated FeNO and B-Eos related to reduced lung function in asthmatics, wheezing symptoms, but not to a history of asthma attacks. Asthma attacks and ER-visit due to asthma were related to increased B-Eos levels.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2018
    Keywords
    asthma, eosinophils, epidemiology
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-362036 (URN)10.1111/cea.13137 (DOI)000440137000005 ()29575336 (PubMedID)
    Funder
    Swedish Heart Lung Foundation
    Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2020-03-04Bibliographically approved
    3. Fixed airflow obstruction relates to eosinophil activation in asthmatics
    Open this publication in new window or tab >>Fixed airflow obstruction relates to eosinophil activation in asthmatics
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    2019 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, no 2, p. 155-162Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Some asthmatics develop irreversible chronic airflow obstruction, for example, fixed airflow obstruction (fixed-AO). This is probably a consequence of airway remodelling, but neither its relation to inflammation nor which asthma biomarkers can be clinically useful are elucidated. We hypothesized that the presence of type 2 inflammation relates to fixed-AO.

    OBJECTIVES: To evaluate the presence of four markers for type 2 inflammation in fixed airflow obstruction among asthmatics.

    METHODS: This was a cross-sectional study of 403 participants with asthma, aged 17-75 years, from three Swedish centres. Fixed airflow obstruction was defined as forced expiratory volume during the first second (FEV1 ) over forced vital capacity (FVC) being below the lower limit of normal (LLN). The following type 2 inflammation markers were assessed: exhaled nitric oxide (FeNO), serum periostin, serum eosinophil cationic protein (S-ECP), and urinary eosinophil-derived neurotoxin (U-EDN).

    RESULTS: Elevated U-EDN (values in the highest tertile, ≥65.95 mg/mol creatinine) was more common in subjects with fixed-AO vs. subjects without fixed-AO: 55% vs. 29%, P < 0.001. Elevated U-EDN related to increased likelihood of having fixed-AO in both all subjects and never-smoking subjects, with adjusted (adjusted for sex, age group, use of inhaled corticosteroids last week, atopy, early-onset asthma, smoking history, and packyears) odds ratios (aOR) of 2.38 (1.28-4.41) and 2.51 (1.04-6.07), respectively. In a separate analysis, having both elevated S-ECP (>20 μg/L) and U-EDN was related to having the highest likelihood of fixed-AO (aOR (95% CI) 6.06 (2.32-15.75)). Elevated serum periostin or FeNO did not relate to fixed-AO.

    CONCLUSIONS AND CLINICAL RELEVANCE: These findings support that type 2 inflammation, and in particular eosinophil inflammation, is found in asthma with fixed-AO. This could indicate a benefit from eosinophil-directed therapies. Further longitudinal studies are warranted to investigate causality and relation to lung function decline.

    National Category
    Medical and Health Sciences Immunology in the medical area
    Research subject
    Clinical Physiology
    Identifiers
    urn:nbn:se:uu:diva-372784 (URN)10.1111/cea.13302 (DOI)000457469600003 ()30365193 (PubMedID)
    Funder
    Swedish Heart Lung FoundationSwedish Research CouncilVårdal FoundationStockholm County CouncilSwedish Asthma and Allergy AssociationSwedish Foundation for Strategic Research
    Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2020-03-04Bibliographically approved
    4. Inflammatory patterns in fixed airflow obstruction are dependent on the presence of asthma
    Open this publication in new window or tab >>Inflammatory patterns in fixed airflow obstruction are dependent on the presence of asthma
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    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Background: Fixed airflow obstruction (FAO) can complicate asthma. Inflammation is a proposed underlying mechanism. The aim with this cross-sectional study was to evaluate the blood leucocyte pattern and level of exhaled nitric oxide in asthmatics and non-asthmatics with or without FAO.

    Methods: A total of 11,579 individuals aged ≥20 years from the US National Health and Nutrition Examination Survey were included. They were grouped as: controls without asthma and FAO (n=9,935), asthmatics without FAO (n=674), asthmatics with FAO (n=180) and non-asthmatics with FAO (n=790). FAO was defined as post-bronchodilator FEV1/FVC < lower limit of normal. Exhaled nitric oxide ≥ 25ppb, blood eosinophil levels ≥300 cells/μL, and blood neutrophil levels ≥5100 cells/μL were defined as elevated.

    Results: Elevated blood eosinophil levels were more common in all groups compared to the controls, and the group with asthma and fixed airflow obstruction had the highest prevalence of all groups (p<0.01). In a multiple logistic regression model adjusted for potential confounders including smoking, the asthma groups had significantly higher odds ratios for elevated B-Eos levels compared to the control group (odds ratio 1.4, (confidence interval: 1.1-1.7) for the asthma group without fixed airflow obstruction and 2.5 (1.4-4.2) for the asthma group with fixed airflow obstruction). The group with fixed airflow obstruction without asthma had higher odds ratio for elevated blood neutrophil levels compared to the controls: 1.4 (1.1-1.8).

    Conclusion: Fixed airflow obstruction in asthma was associated with elevated blood eosinophil levels, whereas fixed airflow obstruction without asthma was associated with elevated blood neutrophil levels.

    Keywords
    Eosinophil, FeNO, neutrophil, asthma, fixed airflow obstruction
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-406038 (URN)
    Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2020-03-04
    5. Blood eosinophil level and lung function trajectories – cross-sectional and longitudinal studies in European cohorts
    Open this publication in new window or tab >>Blood eosinophil level and lung function trajectories – cross-sectional and longitudinal studies in European cohorts
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Elevated blood eosinophils have been associated with lower lung function and are believed to be associated with an accelerated lung function decline.

    Method: Blood eosinophils were measured in four cohorts:  <45 years old cohort within the Vlagtwedde-Vlaardingen (V&V) study,  the Uppsala cohort of the European Community Respiratory Health Survey (ECRHS-Uppsala ; <45 years),  ≥45 years cohort within the V&V study and  the Rotterdam study (≥45 years). Blood eosinophils at baseline were classified as normal (<300 cells/μL) or elevated (≥300 cells/μL). Lung function was measured at baseline and follow-up with spirometry: forced exhaled volume during the first second (FEV1), vital capacity (VC) and their ratio FEV1/VC. The association between blood eosinophils and lung function was tested cross-sectionally using linear regression and longitudinally using a mixed model, both adjusted for age, sex, height, pack-years smoking and smoking status. Stratified analyses were done for asthma.

    Results: Elevated blood eosinophils associated to lower FEV1 (regression coefficient -149mL (95% Confidence Interval: -191; -107), VC (-124mL (-169; -78)) and FEV1/VC (-1.3% (-1.9; -0.7)) at baseline in the two <45 years cohorts, and to lower FEV1 (-79mL (-116; -41)) and FEV1/VC (-1.8% (-2.6; -1.0)) in the two ≥45 years cohorts. Longitudinally, elevated compared to normal blood eosinophils were associated with an excess decline in FEV1 (-5.7mL/year (-11.1; -0.4), V&V <45 years) and VC (-12mL/year (-23.6; -0.9), ECRHS-Uppsala) only in asthmatics.

    Conclusion: Elevated blood eosinophils are associated with lower lung function in the general population and with an accelerated lung function decline among asthmatics.

    Keywords
    eosinophil, lung function, asthma
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-406040 (URN)
    Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2020-03-04
  • Public defence: 2020-04-24 13:15 Hörsal 2, Uppsala
    Backman, Jenny
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    An Eye for Accounting: Studies investigating judgmental effects of visual cues in accounting communication2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This dissertation investigates judgmental effects of visual cues in accounting communication. The dissertation comprises a comprehensive summary and four empirical studies. My overall objective is to highlight the relevance of the visual to both accounting theory and practice by empirically demonstrating that, in corporate reports, visual elements juxtaposed with accounting information can significantly influence report readers’ evaluative judgments regarding corporate performance. My research aims to bring theoretical work on framing and the power of the visual into the accounting domain, focusing predominantly on the emotive power of visual imagery and color. Using experiments and complementary methods such as interviews and eye-tracking, the empirical studies demonstrate that these supplementary visual elements, despite not conveying any additional facts, can indeed influence report readers’ evaluative judgments regarding various aspects of communicated corporate performance. In line with psychology-based theoretical propositions that frames can promote different interpretations, the combined results suggest that the presentation format of accounting information does matter for evaluative judgments of corporate performance, and that information-redundant but affect-laden visual cues in accounting discourse can systematically affect stakeholder understanding. A central line of argument in this dissertation is that in an increasingly visual society, it is essential to gain a more nuanced understanding of the psychological effects of visual graphics in accounting discourse if we are to advance our understanding of accounting-related judgment and decision making. The potential judgmental effects of visuals in accounting communication has so far received little attention in accounting research or from regulators, and the display of visuals is currently not considered by general guidelines regarding corporate reporting. My overall motivation for this research is to address this incompleteness in extant accounting research and practice.

    List of papers
    1. Imag(in)ing the Benefit of CSR: The Judgmental Effect of Affect-laden Visual Imagery in Social Accounting Reports
    Open this publication in new window or tab >>Imag(in)ing the Benefit of CSR: The Judgmental Effect of Affect-laden Visual Imagery in Social Accounting Reports
    (English)Manuscript (preprint) (Other academic)
    National Category
    Social Sciences
    Identifiers
    urn:nbn:se:uu:diva-406026 (URN)
    Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2020-03-03
    2. The Effect of CEO Facial Portraits in Financial Reporting: A Study of Performance Judgments Using the Annual Report
    Open this publication in new window or tab >>The Effect of CEO Facial Portraits in Financial Reporting: A Study of Performance Judgments Using the Annual Report
    (English)Manuscript (preprint) (Other academic)
    National Category
    Social Sciences Social Sciences
    Identifiers
    urn:nbn:se:uu:diva-406028 (URN)
    Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2020-03-03
    3. The Effect of Color use in Management Reports: A Study of Performance Judgments Using the Balanced Scorecard
    Open this publication in new window or tab >>The Effect of Color use in Management Reports: A Study of Performance Judgments Using the Balanced Scorecard
    (English)Manuscript (preprint) (Other academic)
    National Category
    Social Sciences
    Identifiers
    urn:nbn:se:uu:diva-406029 (URN)
    Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2020-03-03
    4. The Judgmental Effect of Traffic-Light Colors in Balanced Scorecard Reports: An Experimental Study Among Professional Controllers
    Open this publication in new window or tab >>The Judgmental Effect of Traffic-Light Colors in Balanced Scorecard Reports: An Experimental Study Among Professional Controllers
    (English)Manuscript (preprint) (Other academic)
    National Category
    Social Sciences
    Identifiers
    urn:nbn:se:uu:diva-406030 (URN)